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Kidney Disease Suzanne Watnick, MD Tonja Dirkx, MD

Kidney disease can be discovered incidentally during a routine medical evaluation or with evidence of kidney dysfunction, such as hypertension, edema, nausea, or hematuria. The initial approach in both situations should be to assess the cause and severity of renal abnormalities.

In all cases this evaluation includes (1) an estimation of disease duration, (2) a careful urinalysis, and (3) an assessment of the glomerular filtration rate (GFR). The history and physical examinations, though equally important, are variable among renal syndromes—thus, specific symptoms and signs are discussed under each disease entity. cc

Assessment of Kidney Disease

``Disease Duration Kidney disease may be acute or chronic. Acute kidney injury, also known as acute renal failure, is worsening of kidney function over hours to days, resulting in the retention of nitrogenous wastes (such as urea nitrogen) and creatinine in the blood. Retention of these substances is called azotemia. Chronic kidney disease (CKD) results from an abnormal loss of kidney function over months to years. Differentiating between the two is important for diagnosis, treatment, and outcome. Oliguria is unusual in CKD. Anemia (from low kidney erythropoietin production) is rare in the initial period of acute kidney disease.

Small kidneys are most consistent with CKD, whereas normal to large-size kidneys can be seen with both chronic and acute disease.

``Urinalysis A urinalysis can provide information similar to a renal biopsy in a way that is cost-effective and, of course, noninvasive. The urine is collected in midstream or, if that is not feasible, by bladder catheterization. The urine should be examined within 1 hour after collection to avoid destruction of formed elements. Urinalysis includes a dipstick examination followed by microscopic assessment if the dipstick has positive findings. The dipstick examination measures urinary pH, protein, hemoglobin, glucose,

ketones, bilirubin, nitrites, and leukocyte esterase. Urinary specific gravity is often reported, too. Microscopy searches for all formed elements—crystals, cells, casts, and infecting organisms.

Various findings on the urinalysis are indicative of certain patterns of kidney disease. A bland (normal) urinary sediment is common, especially in CKD and acute disorders that are not intrinsic to the kidney, such as limited effective blood flow to the kidney or obstruction of outflow of urine. Casts are composed of Tamm-Horsfall urinary mucoprotein in the shape of the nephron segment where they were formed. Heavy proteinuria and lipiduria are consistent with the nephrotic syndrome. The presence of hematuria with dysmorphic red blood cells, red blood cell casts, and proteinuria is indicative of glomerulonephritis.

Dysmorphic red blood cells are misshapen during abnormal passage from the capillary through the glomerular basement membrane (GBM) into the urinary space of Bowman capsule. Pigmented granular casts and renal tubular epithelial cells alone or in casts suggest acute tubular necrosis. White blood cells, including neutrophils and eosinophils, white blood cell casts (Table 22–1), red blood cells, and small amounts of protein can be found in interstitial nephritis and pyelonephritis; Wright and Hansel stains can detect eosinophiluria. Pyuria alone can indicate a urinary tract infection. Hematuria and proteinuria are discussed more thoroughly below.

A. Proteinuria Proteinuria is defined as excessive protein excretion in the urine, generally > 150–160 mg/24 h in adults. Significant proteinuria is a sign of an underlying kidney abnormality, usually glomerular in origin when > 1 g/d to < 2 g/d. Less than 1 g/d can be due to multiple causes along the nephron segment, as listed below. Proteinuria can be accompanied by other clinical abnormalities—elevated blood urea nitrogen (BUN) and serum creatinine levels, abnormal urinary sediment, or evidence of systemic illness (eg, fever, rash, vasculitis).

There are several reasons for development of proteinuria: (1) Functional proteinuria is a benign process stemming from stressors such as acute illness, exercise, and

Kidney Disease

Table 22–1. Significance of specific urinary casts.

Type

Significance

Hyaline casts

Concentrated urine, febrile disease, after strenuous exercise, in the course of diuretic therapy (not indicative of renal disease)

Red cell casts

Glomerulonephritis

White cell casts

Pyelonephritis, interstitial nephritis (indicative of infection or inflammation)

Renal tubular cell casts

Acute tubular necrosis, interstitial nephritis

Coarse, granular casts

Nonspecific; can represent acute tubular necrosis

Broad, waxy casts

Chronic kidney disease (indicative of stasis in enlarged collecting tubules)

“orthostatic proteinuria.” The latter condition, generally found in people under age 30 years, usually results in urinary protein excretion of < 1 g/d. The orthostatic nature of the proteinuria is confirmed by measuring an 8-hour overnight supine urinary protein excretion, which should be < 50 mg. (2) Overload proteinuria can result from overproduction of circulating, filterable plasma proteins (monoclonal gammopathies), such as Bence Jones proteins associated with multiple myeloma. Urinary protein electrophoresis will exhibit a discrete protein peak. Other examples of overload proteinuria include myoglobinuria in rhabdomyolysis and hemoglobinuria in hemolysis. (3) Glomerular proteinuria results from effacement of epithelial cell foot processes and altered glomerular permeability with an increased filtration fraction of normal plasma proteins. Glomerular diseases exhibit some degree of proteinuria. The urinary protein electrophoresis will have a pattern exhibiting a large albumin spike indicative of increased permeability of albumin across a damaged GBM. (4) Tubular proteinuria occurs as a result of faulty reabsorption of normally filtered proteins in the proximal tubule, such as β2-microglobulin and immunoglobulin light chains. Causes include acute tubular necrosis, toxic injury (lead, aminoglycosides), drug-induced interstitial nephritis, and hereditary metabolic disorders (Wilson disease and Fanconi syndrome).

Evaluation of proteinuria by urinary dipstick primarily detects albumin, while overlooking positively charged light chains of immunoglobulins. These proteins can be detected by the addition of sulfosalicylic acid to the urine specimen.

Precipitation without dipstick detection of albumin indicates the presence of paraproteins.

The next step is an estimation of proteinuria from a 24-hour urine collection. A finding of > 150–160 mg/24 h is abnormal, and > 3.5 g/24 h is consistent with nephroticrange proteinuria. The simplest method is to collect a random urine sample. The ratio of urinary protein concentration to urinary creatinine concentration ([Uprotein]/ [Ucreatinine]) correlates with 24-hour urine protein collection (< 0.2 is normal and corresponds to excretion of < 200

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mg/24 h). The benefit of a urine protein-to-creatinine ratio is the ease of collection and the lack of error from overcollection or undercollection of urine. If a patient has proteinuria with or without loss of kidney function, kidney biopsy may be indicated, particularly if the kidney disease is acute in onset. The clinical consequences of proteinuria are discussed in the section Nephrotic Spectrum Glomerular Diseases below.

B. Hematuria Hematuria is significant if there are more than three red cells per high-power field on at least two occasions. It is usually detected incidentally by the urine dipstick examination or clinically following an episode of macroscopic hematuria.

The diagnosis must be confirmed via microscopic examination, as false-positive dipstick tests can be caused by myoglobin, oxidizing agents, beets and rhubarb, hydrochloric acid, and bacteria. Transient hematuria is common, but in patients younger than 40 years, it is less often of clinical significance due to lower concern for malignancy.

Hematuria may be due to renal or extrarenal causes.

Extrarenal causes are addressed in Chapters 23 and 39; most worrisome are urologic malignancies. Renal causes account for approximately 10% of cases and are best considered anatomically as glomerular or nonglomerular. The most common extraglomerular sources include cysts, calculi, interstitial nephritis, and renal neoplasia. Glomerular causes include immunoglobulin A (IgA) nephropathy, thin GBM disease, membranoproliferative glomerulonephritis (MPGN), other hereditary glomerular diseases (eg, Alport syndrome), and systemic nephritic syndromes.

Currently, the United States Health Preventive Services Task Force does not recommend screening for hematuria.

See Chapter 23 for evaluation of hematuria.

``Estimation of GFR The GFR provides a useful index of kidney function at the level of the glomerulus. Patients with kidney disease can have a decreased GFR from any process that causes loss of nephron (and thus glomerular) mass. However, they can also have a normal or increased GFR, either from hyperfiltration at the glomerulus or disease at a different segment of the nephron, interstitium, or vascular supply. The GFR measures the amount of plasma ultrafiltered across the glomerular capillaries and correlates with the ability of the kidneys to filter fluids and various substances. Daily GFR in normal individuals is variable, with a range of 150–250 L/24 h or 100–120 mL/min/1.73 m2 of body surface area. GFR can be measured indirectly by determining the renal clearance of plasma substances that are not bound to plasma proteins, are freely filterable across the glomerulus, and are neither secreted nor reabsorbed along the renal tubules. The formula used to determine the renal clearance of a substance is C=

U × V P

where C is the clearance, U and P are the urine and plasma concentrations of the substance (mg/dL), and V˙ is the urine

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flow rate (mL/min). In clinical practice, the clearance rate of endogenous creatinine, the creatinine clearance, is one way of estimating GFR. Creatinine is a product of muscle metabolism produced at a relatively constant rate and cleared by renal excretion. It is freely filterable by the glomerulus and not reabsorbed by the renal tubules. With stable kidney function, creatinine production and excretion are equal; thus, plasma creatinine concentrations remain constant. However, it is not a perfect indicator of GFR for the following reasons: (1) A small amount is normally eliminated by tubular secretion, and the fraction secreted progressively increases as GFR declines (overestimating GFR); (2) with severe kidney failure, gut microorganisms degrade creatinine; (3) an individual’s meat intake and muscle mass affect baseline plasma creatinine levels; (4) commonly used drugs such as aspirin, cimetidine, probenecid, and trimethoprim reduce tubular secretion of creatinine, increasing the plasma creatinine concentration and falsely indicating kidney dysfunction; and (5) the accuracy of the measurement necessitates a stable plasma creatinine concentration over a 24-hour period, so that during the development of and recovery from acute kidney injury, when the serum creatinine is changing, the creatinine clearance is of questionable value (Table 22–2). Of note, the creatinine clearance is the traditional estimation equation used for consideration of drug dosing in patients with kidney disease.

One way to measure creatinine clearance is to collect a timed urine sample and determine the plasma creatinine level midway through the collection. An incomplete or prolonged urine collection is a common source of error. One way of estimating the completeness of the collection is to calculate a 24-hour creatinine excretion; the amount should be constant: Ucr × V˙ = 15–20 mg/kg for healthy young women U × V˙ = 20–25 mg/kg for healthy young men cr

The creatinine clearance (Ccr) is approximately 100 mL/ min/1.73 m2 in healthy young women and 120 mL/ min/1.73 m2 in healthy young men. The Ccr declines by an

Table 22–2. Conditions affecting serum creatinine independently of glomerular filtration rate.

Condition

Mechanism

Conditions elevating creatinine Ketoacidosis, cephalothin, cefoxitin, flucytosine

Noncreatinine chromogen

Other drugs: aspirin, cimetidine, probenecid, trimethoprim

Inhibition of tubular creatinine secretion

Conditions decreasing creatinine Advanced age

Physiologic decrease in muscle mass

Cachexia

Pathologic decrease in muscle mass

Liver disease

Decreased hepatic creatine synthesis and cachexia

average of 0.8 mL/min/yr after age 40 years as part of the aging process, but 35% of subjects in one study had no decline in kidney function over 10 years.

Ccr can be estimated from the formula of Cockcroft and Gault, which incorporates age, sex, and weight to estimate Ccr from plasma creatinine levels without any urinary measurements: Ccr =

(140 − Age) × Weight (kg) Pcr × 72

For women, the creatinine clearance is multiplied by 0.85 because muscle mass is less. This formula overestimates GFR in patients who are obese or edematous and is most accurate when normalized for body surface area of 1.73 m2.

BUN is another index used in assessing kidney function.

It is synthesized mainly in the liver and is the end product of protein catabolism. Urea is freely filtered by the glomerulus, and about 30–70% is reabsorbed in the renal tubules.

Unlike creatinine clearance, which overestimates GFR, urea clearance underestimates GFR. Urea reabsorption may be decreased in volume replete patients, whereas volume depletion causes increased urea reabsorption, in conjunction with increased sodium reabsorption, from the kidney, increasing BUN. A normal BUN:creatinine ratio is 10:1, although this can vary between individuals. With volume depletion, the ratio can increase to 20:1 or higher. Other causes of increased BUN include increased catabolism (gastrointestinal [GI] bleeding, cell lysis, and corticosteroid usage), increased dietary protein, and decreased renal perfusion (congestive heart failure, renal artery stenosis) (Table 22–3). Reduced BUN is seen in liver disease and in the syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

As patients approach end-stage renal disease (ESRD), a more accurate measure of GFR than creatinine clearance is the average of the creatinine and urea clearances. The creatinine clearance overestimates GFR, as mentioned above, while the urea clearance underestimates GFR. Therefore, an average of the two more accurately approximates the true GFR. The four-variable estimated GFR is a complex equation, including serum creatinine, age, weight, and race, that is often reported alongside serum creatinine measurements Table 22–3. Conditions affecting BUN independently of GFR. Increased BUN Reduced effective circulating blood volume (prerenal azotemia) Catabolic states (gastrointestinal bleeding, corticosteroid use) High-protein diets Tetracycline Decreased BUN Liver disease Malnutrition Sickle cell anemia SIADH BUN, blood urea nitrogen; GFR, glomerular filtration rate; SIADH, syndrome of inappropriate antidiuretic hormone.

Kidney Disease and more accurate than creatinine or urea clearance. This was derived from data collected for the Modification of Diet and Renal Disease (MDRD) study and has been validated in several other populations. Many laboratories will report a value for the estimated GFR in addition to a serum creatinine. Several web-based calculators will calculate this; one location is www.nephron.com.

Other useful, well-validated estimators of GFR include the CKD-EPI formula. This is more accurate and precise than the MDRD equation at higher levels of true GFR, possibly decreasing false-positive results. This formula may perform better in elderly populations; however, this estimation equation did not include large numbers of nonwhite patients.

Cystatin C is another endogenous marker of GFR, filtered freely at the glomerulus and produced at a relatively constant rate, irrespective of muscle mass. It is reabsorbed and partially metabolized in the renal tubular epithelial cells. Studies show less variability with age, gender, or race for cystatin C versus serum creatinine.

Renal Biopsy Indications for percutaneous needle biopsy include (1) unexplained acute kidney injury or CKD; (2) acute nephritic syndromes; (3) unexplained proteinuria and hematuria; (4) previously identified and treated lesions to plan future therapy; (5) systemic diseases associated with kidney dysfunction, such as systemic lupus erythematosus, Goodpasture syndrome, and granulomatosis with polyangiitis (formerly Wegener granulomatosis), to confirm the extent of renal involvement and to guide management; (6) suspected transplant rejection, to differentiate it from other causes of acute kidney injury; and (7) to guide treatment. If a patient is unwilling to accept therapy based on biopsy findings, the risk of biopsy may outweigh its benefit. Relative contraindications include a solitary or ectopic kidney (exception: transplant allografts), horseshoe kidney, ESRD, congenital anomalies, and multiple cysts. Absolute contraindications include an uncorrected bleeding disorder, severe uncontrolled hypertension, renal infection, renal neoplasm, hydronephrosis, or an uncooperative patient.

Prior to biopsy, patients should not use medications that prolong clotting times and should have well-controlled blood pressure. Blood work should include a hemoglobin, platelet count, prothrombin time, and partial thromboplastin time. After biopsy, hematuria occurs in nearly all patients.

Less than 10% will have macroscopic hematuria. Patients should remain supine for 4–6 hours postbiopsy. A patient with a 6-hour postbiopsy hematocrit > 3% lower than baseline should be closely monitored.

Percutaneous kidney biopsies are generally safe.

Approximately 1% of patients will experience significant bleeding requiring blood transfusions. More than half of patients will have at least a small hematoma. Risk of major bleeding persists up to 72 hours after the biopsy.

Any type of anticoagulation therapy should be held for 5–7 days postbiopsy if possible. The risks of nephrectomy and mortality are about 0.06–0.08%. When a percutaneous needle biopsy is technically not feasible and

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renal tissue is deemed clinically essential, a closed renal biopsy via interventional radiologic techniques or open renal biopsy under general anesthesia can be done.

Bairy M et al. Safety of outpatient kidney biopsy: one center’s experience with 178 native kidney biopsies. Am J Kidney Dis. 2008 Sep;52(3):631–2. [PMID: 18725027] Campbell KH et al. Kidney disease in the elderly: update on recent literature. Curr Opin Nephrol Hypertens. 2008 May;17(3):298–303. [PMID: 18408482] Nguyen MT et al. Misapplications of commonly used kidney equations: renal physiology in practice. Clin J Am Soc Nephrol. 2009 Mar;4(3):528–34. [PMID: 19261813] Patel JV et al. Hematuria: etiology and evaluation for the primary care physician. Can J Urol. 2008 Aug;15(Suppl 1):54–61.

[PMID: 18700066] Stevens LA et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis. 2010 Sep;56(3):486–95. [PMID: 20557989]

cc

Acute KIDNEY INJURY (ACUTE Renal Failure)

``

E ssent i a l s of d i a gnos i s

Sudden increase in BUN or serum creatinine.

Oliguria can be associated. `` Symptoms and signs depend on cause. `` ``

``General Considerations Acute kidney injury, also known as acute renal failure, is defined as a sudden decrease in kidney function, resulting in an inability to maintain acid-base, fluid and electrolyte balance and to excrete nitrogenous wastes. Serum creatinine is a convenient marker. A clinically applicable definition of acute kidney injury has been developed. The RIFLE criteria describe three progressive levels of acute kidney injury (risk, injury, and failure) based on the elevation in serum creatinine or decline in urinary output with two outcome measures (loss and ESRD). Risk, injury, and failure are defined, respectively, as a 1.5-fold increase in serum creatinine, a twofold or threefold increase in serum creatinine, or a decline in urinary output to 0.5 mL/kg/h over 6, 12, or 24 hours. These definitions were created by an international consensus panel and correlate with prognosis. The AKIN criteria are also predictive of outcomes, and closely follow the RIFLE criteria, with the addition of a change in serum creatinine of ≥ 0.3 mg/day qualifying as a risk for injury. In the absence of functioning kidneys, serum creatinine concentration will typically increase by 1–1.5 mg/dL daily, although with certain conditions, such as rhabdomyolysis, serum creatinine can increase more rapidly. On average, 5% of hospital admissions and 30% of intensive care unit (ICU) admissions carry a diagnosis of acute kidney injury, and it will develop in 25% of hospitalized patients. Patients with

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acute kidney injury of any type are at higher risk for allcause mortality according to recent prospective cohorts, whether or not there is substantial renal recovery.

``Clinical Findings A. Symptoms and Signs The uremic milieu of acute kidney injury can cause nonspecific symptoms. When present, symptoms are often due to uremia or its underlying cause. Uremia can cause nausea, vomiting, malaise, and altered sensorium. Hypertension can occur, and fluid homeostasis is often altered. Hypovolemia can cause states of low blood flow to the kidneys, sometimes termed “prerenal” states, whereas hypervolemia can result from intrinsic or “postrenal” disease. Pericardial effusions can occur with uremia, and a pericardial friction rub can be present. Effusions may result in cardiac tamponade. Arrhythmias occur, especially with hyperkalemia. The lung examination may show rales in the presence of hypervolemia. Acute kidney failure can cause nonspecific diffuse abdominal pain and ileus as well as platelet dysfunction; thus, bleeding and clotting disorders are more common in these patients.

The neurologic examination reveals encephalopathic changes with asterixis and confusion; seizures may ensue.

B. Laboratory Findings Elevated BUN and serum creatinine levels are present, though these elevations do not distinguish acute kidney disease from CKD. Hyperkalemia can occur from impaired renal potassium excretion. With hyperkalemia, the ECG can reveal peaked T waves, PR prolongation, and QRS widening. A long QT segment can occur with hypocalcemia. Anion gap and non-gap metabolic acidosis (due to decreased organic and nonorganic acid clearance) is often noted. Hyperphosphatemia occurs when phosphorus

cannot be secreted by damaged tubules either with or without increased cell catabolism. Metastatic calcium phosphate deposition may be observed when the product of calcium and phosphorus is elevated (eg, exceeding 55-65 mg2/dL2). Anemia can occur as a result of decreased erythropoietin production over weeks, and associated platelet dysfunction is typical.

``Classification & Etiology Acute kidney injury can be divided into three categories: prerenal causes (renal hypoperfusion leading to lower GFR), intrinsic renal disease, and postrenal causes (obstructive uropathy). Identifying the cause is the first step toward treating the patient (Table 22–4).

A. Prerenal Causes Prerenal causes are the most common reason for acute kidney insults and injury, accounting for 40–80% of cases, depending on the population studied. Prerenal azotemia is due to renal hypoperfusion, which is an appropriate physiologic change. If it can be immediately reversed with restoration of renal blood flow, renal parenchymal damage often does not occur. If hypoperfusion persists, ischemia can result, causing intrinsic kidney injury.

Decreased renal perfusion can occur in several ways, such as a decrease in intravascular volume, a change in vascular resistance, or low cardiac output. Causes of volume depletion include hemorrhage, GI losses, dehydration, excessive diuresis, extravascular space sequestration, pancreatitis, burns, trauma, and peritonitis.

Changes in vascular resistance can occur systemically with sepsis, anaphylaxis, anesthesia, and afterload-reducing drugs. Blockers of the renin-angiotensin-aldosterone system, such as angiotensin-converting enzyme (ACE) inhibitors, prevent efferent renal arteriolar constriction out of

Table 22–4. Classification and differential diagnosis of acute kidney injury.

Intrinsic Renal Disease Prerenal Azotemia

Postrenal Azotemia

Acute Tubular Necrosis (Oliguric or Polyuric)

Acute Glomerulonephritis

Acute Interstitial Nephritis

Etiology

Poor renal perfusion

Obstruction of the urinary tract

Ischemia, nephrotoxins

Immune complexmediated, pauciimmune, anti-GBM related

Allergic reaction; drug reaction; infection, collagen vascular disease

Serum BUN:Cr ratio

> 20:1

> 20:1

< 20:1

> 20:1

< 20:1

Urinary indices UNa (mEq/L)

< 20

Variable

> 20

< 20

Variable

Fena (%)

<1

Variable

> 1 (when oliguric)

<1

< 1; > 1

Urine osmolality (mosm/kg)

> 500

< 400

250–300

Variable

Variable

Urinary sediment

Benign or hyaline casts

Normal or red cells, white cells, or crystals

Granular (muddy brown) casts, renal tubular casts

Red cells, dysmorphic red cells and red cell casts

White cells, white cell casts, with or without eosinophils

BUN:Cr, blood urea nitrogen:creatinine ratio; Fena, fractional excretion of sodium; UNa, urinary concentration of sodium.

Kidney Disease proportion to the afferent arteriolar constriction; thus, GFR will decrease with these medications. Nonsteroidal antiinflammatory drugs (NSAIDs) prevent afferent arteriolar vasodilation by inhibiting prostaglandin-mediated signals. Thus, in cirrhosis and congestive heart failure, when prostaglandins are recruited to increase renal blood flow, NSAIDs will have particularly deleterious effects.

Epinephrine, norepinephrine, high-dose dopamine, anesthetic agents, and cyclosporine also can cause renal vasoconstriction. Renal artery stenosis causes increased resistance and decreased renal perfusion.

Low cardiac output is a state of low effective renal arterial blood flow. This occurs in states of cardiogenic shock, congestive heart failure, pulmonary embolism, and pericardial tamponade. Arrhythmias and valvular disorders can also reduce cardiac output. In the ICU setting, positive pressure ventilation will decrease venous return, also decreasing cardiac output.

When GFR falls acutely, it is important to determine whether acute kidney injury is due to prerenal or intrinsic renal causes. The history and physical examination are important, and urinalysis can be helpful. The BUN:creatinine ratio will typically exceed 20:1 due to increased urea reabsorption. In an oliguric patient, another useful index is the fractional excretion of sodium (Fena). With decreased GFR, the kidney will reabsorb salt and water avidly if there is no intrinsic tubular dysfunction. Thus, patients with prerenal causes should have a low fractional excretion percent of sodium (< 1%). Oliguric patients with intrinsic kidney dysfunction typically have a high fractional excretion of sodium (> 1–2%). The Fena is calculated as follows: Fena = clearance of Na+/GFR = clearance of Na+/Ccr: F ENA =

UrineNA × SerumNA × 100 Urinecr × Serumcr

Renal sodium handling is more accurately assessed by the Fena in oliguric states than in nonoliguric states because the Fena could be relatively low in nonoliguric acute tubular necrosis if sodium intake and excretion are relatively low.

(Oliguria is defined as urinary output < 400–500 mL/d, or < 20 mL/h.) Diuretics can cause increased sodium excretion.

Thus, if the Fena is high within 12–24 hours after diuretic administration, the cause of acute kidney injury may not be accurately predicted. Acute kidney injury due to glomerulonephritis can have a low Fena because sodium reabsorption and tubular function may not be compromised.

Treatment of prerenal insults depends entirely on the causes, but maintenance of euvolemia, attention to serum potassium, and avoidance of nephrotoxic drugs are benchmarks of therapy. This involves careful assessment of volume status, cardiac function, diet, and drug usage.

B. Postrenal Causes Postrenal causes are the least common reason for acute kidney injury, accounting for approximately 5–10% of cases, but important to detect because of their reversibility. Postrenal azotemia occurs when urinary flow from both kidneys, or a single functioning kidney, is obstructed. Occasionally,

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postrenal uropathies can occur when a single kidney is obstructed if the contralateral kidney cannot adjust for the loss in function, (eg, in a patient with advanced CKD).

Obstruction leads to elevated intraluminal pressure, causing kidney parenchymal damage, with marked effects on renal blood flow and tubular function, and a decrease in GFR. Postrenal causes include urethral obstruction, bladder dysfunction or obstruction, and obstruction of both ureters or renal pelvises. In men, benign prostatic hyperplasia is the most common cause. Patients taking anticholinergic drugs are particularly at risk. Obstruction can also be caused by bladder, prostate, and cervical cancers; retroperitoneal fibrosis and other processes; and neurogenic bladder. Less common causes are blood clots, bilateral ureteral stones, urethral stones or stricture, and bilateral papillary necrosis.

Patients may be anuric or polyuric and may complain of lower abdominal pain. Polyuria can occur in the setting of partial obstructions with resultant tubular dysfunction and an inability to appropriately reabsorb salt and water loads. Obstruction can be constant or intermittent and partial or complete. On examination, the patient may have an enlarged prostate, distended bladder, or mass detected on pelvic examination.

Laboratory examination may initially reveal high urine osmolality, low urine sodium, high BUN:creatinine ratio, and low Fena (as tubular function may not be compromised initially). These indices are similar to a prerenal picture because extensive intrinsic renal damage has not occurred.

After several days, the urine sodium increases as the kidneys fail and are unable to concentrate the urine—thus, isosthenuria is present. The urine sediment is generally benign.

Patients with acute kidney injury and suspected postrenal insults should undergo bladder catheterization and ultrasonography to assess for hydroureter and hydronephrosis.

After reversal of the underlying process, these patients often undergo a postobstructive saliuresis and diuresis, and care should be taken to avoid volume depletion. Rarely, obstruction is not diagnosed by ultrasonography. For example, patients with retroperitoneal fibrosis from tumor or radiation may not show dilation of the urinary tract. If suspicion does exist, a CT scan or MRI can establish the diagnosis.

Prompt treatment of obstruction within days by catheters, stents, or other surgical procedures can result in partial or complete reversal of the acute process.

C. Intrinsic Acute Kidney Injury Intrinsic renal disorders account for up to 50% of all cases of acute kidney injury. Intrinsic dysfunction is considered after prerenal and postrenal causes have been excluded.

The sites of injury are the tubules, interstitium, vasculature, and glomeruli.

``When to Refer • If a patient has signs of acute kidney injury that have not reversed over 1–2 weeks, but no signs of acute uremia, the patient can usually be referred to a nephrologist rather than admitted.

• If a patient has signs of persistent urinary tract obstruction, the patient should be referred to a urologist.

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``When to Admit The patient should be admitted if there is sudden loss of kidney function resulting in abnormalities that cannot be handled expeditiously in an outpatient setting (eg, hyperkalemia, volume overload, uremia) or other requirements for acute intervention, such as emergent urologic intervention or dialysis.

Jun M et al. Intensities of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2010 Jun;5(6):956–63. [PMID: 20395356] Kinsey GR et al. Pathogenesis of acute kidney injury: foundation for clinical practice. Am J Kidney Dis. 2011 Aug;58(2): 291–301. [PMID: 21530035] Lafrance JP et al. Acute kidney injury associates with increased long-term mortality. J Am Soc Nephrol. 2010 Feb;21(2):345–52.

[PMID: 20019168] Stevens LM et al. JAMA patient page. Kidney failure. JAMA. 2009 Feb 11;301(6):686. [PMID: 19211477]

Acute Tubular Necrosis

``

E ssent i a l s of d i a gnos i s

Acute kidney injury.

Ischemic or toxic insult. `` Urine sediment with pigmented granular casts and renal tubular epithelial cells is pathognomonic but not essential. `` ``

``General Considerations Acute kidney injury due to tubular damage is termed “acute tubular necrosis” and accounts for approximately 85% of intrinsic acute kidney injury. The two major causes of acute tubular necrosis are ischemia and nephrotoxin exposure. Ischemia causes tubular damage from states of prolonged low kidney perfusion, often termed a “prerenal” state, with resultant tubular necrosis and apoptosis.

Ischemic acute kidney injury is characterized not only by inadequate GFR but also by renal blood flow inadequate to maintain parenchymal cellular formation. This occurs in the setting of prolonged hypotension or hypoxemia, such as volume depletion, shock, and sepsis. Major surgical procedures can involve prolonged periods of hypoperfusion, which are exacerbated by vasodilating anesthetic agents.

Aside from the serum creatinine, other urinary and serum biomarkers, including neutrophil gelatinase-associated lipocalin and cystatin C, are being investigated in order to diagnose and treat acute kidney injury earlier in its course, with the potential for better outcomes.

Exogenous nephrotoxins more commonly cause damage than endogenous nephrotoxins.

A. Exogenous Nephrotoxins Aminoglycosides cause some degree of acute tubular necrosis in up to 25% of hospitalized patients receiving

therapeutic levels of the drugs. Nonoliguric kidney injury typically starts to occur after 5–10 days of exposure.

Predisposing factors include underlying kidney damage, volume depletion, and advanced age. Aminoglycosides can remain in renal tissues for up to a month, so kidney function may not recover for some time after stopping the medication. Monitoring of peak and trough levels is important, but trough levels are more helpful in predicting renal toxicity. Gentamicin is as nephrotoxic as tobramycin; streptomycin is the least nephrotoxic of the aminoglycosides, likely due to the number of cationic amino side chains present on each molecule.

Amphotericin B is typically nephrotoxic after a dose of 2–3 g. This causes a type I renal tubular acidosis with severe vasoconstriction and distal tubular damage, which can lead to hypokalemia and nephrogenic diabetes insipidus.

Vancomycin, intravenous acyclovir, and several cephalosporins have been known to cause acute tubular necrosis.

Radiographic contrast media may be directly nephrotoxic. Contrast nephropathy is the third leading cause of new acute kidney injury in hospitalized patients. It probably results from the synergistic combination of direct renal tubular epithelial cell toxicity and renal medullary ischemia. Predisposing factors include advanced age, preexisting kidney disease (serum creatinine > 2 mg/dL), volume depletion, diabetic nephropathy, congestive heart failure, multiple myeloma, repeated doses of contrast, and recent exposure to other nephrotoxic agents, including NSAIDs and ACE inhibitors. The combination of preexisting diabetes mellitus and kidney dysfunction poses the greatest risk (15–50%) for contrast nephropathy. Lower volumes of contrast with lower osmolality are recommended in highrisk patients. Toxicity usually occurs within 24–48 hours after the radiocontrast study. Nonionic contrast media may be less toxic, but this has not been well proven.

Prevention should be the goal when using these agents.

The mainstay of therapy is a liter of intravenous 0.9% saline over 10–12 hours both before and after the contrast administration—cautiously in patients with preexisting cardiac dysfunction. Neither mannitol nor furosemide offers benefit over 0.9% (normal) saline administration. In fact, furosemide may lead to increased rates of renal dysfunction in this setting. In some but not all studies, N-acetylcysteine given before and after contrast decreases the incidence of dye-induced nephrotoxicity. Acetylcysteine is a thiol-containing antioxidant with little toxicity whose mechanism of action is unclear. It is rarely given unless a patient has a preexisting risk factor. With little harm and possible benefit, administering acetylcysteine 600 mg orally every 12 hours twice, before and after a dye load, for patients at risk for acute kidney injury, is a reasonable strategy. Intravenous N-acetylcysteine, 1200 mg prior to an emergent procedure, has shown benefit compared with placebo and may be a good option if a patient needs contrast dye urgently. One large prospective randomized controlled trial showed no benefit of N-acetylcysteine in over 2300 patients randomized to either 1200 mg orally twice versus placebo prior to and after angiographic procedures.

The primary endpoint was a 25% increase in serum creatinine within 48–96 hours after the procedure. Some

Kidney Disease investigators have shown a benefit using sodium bicarbonate (154 mEq/L, intravenously at 3 mL/kg/h for 1 hour before the procedure, then 1 mL/kg/h for 6 hours after the procedure) over a more conventional regimen of normal saline as the isotonic volume expander. However, others have shown sodium bicarbonate was not superior to sodium chloride when using similar administration regimens. Other nephrotoxic agents should be avoided during the day before and after dye administration.

Cyclosporine toxicity is usually dose dependent. It causes distal tubular dysfunction (a type 4 renal tubular acidosis) from severe vasoconstriction. Regular blood level monitoring is important to prevent both acute and chronic nephrotoxicity. With patients who are taking cyclosporine for renal transplant rejection, kidney biopsy is often necessary to distinguish transplant rejection from cyclosporine toxicity. Renal function usually improves after reducing the dose or stopping the drug.

Other exogenous nephrotoxins include antineoplastics, such as cisplatin and organic solvents, and heavy metals such as mercury, cadmium, and arsenic.

B. Endogenous Nephrotoxins Endogenous nephrotoxins include heme-containing products, uric acid, and paraproteins. Myoglobinuria as a consequence of rhabdomyolysis leads to acute tubular necrosis.

Necrotic muscle releases large amounts of myoglobin, which is freely filtered across the glomerulus. The myoglobin is reabsorbed by the renal tubules, and direct damage can occur. Distal tubular obstruction from pigmented casts and intrarenal vasoconstriction can also cause damage. This type of kidney injury occurs in the setting of crush injury, or muscle necrosis from prolonged unconsciousness, seizures, cocaine, and alcohol abuse.

Dehydration and acidosis predispose to the development of myoglobinuric acute kidney injury. Patients may complain of muscular pain and often have signs of muscle injury. Rhabdomyolysis of clinical importance commonly occurs with a serum creatine kinase (CK) > 20,000–50,000 international units/L. One study showed that 58% of patients with acute kidney injury from rhabdomyolysis had CK levels > 16,000 international units/L. Only 11% of patients without kidney injury had CK values > 16,000 international units/L. The globin moiety of myoglobin will cause the urine dipstick to read falsely positive for hemoglobin: the urine appears dark brown, but no red cells are present. With lysis of muscle cells, patients also become hyperkalemic, hyperphosphatemic, and hyperuricemic.

Hypocalcemia may ensue due to phosphorus and calcium precipitation. The mainstay of treatment is volume repletion. Other adjunctive treatments include mannitol for free radical clearance and diuresis as well as alkalinization of the urine. These modalities have not been proved to change outcomes in human trials. Hypocalcemia should not be treated unless the patient is symptomatic. As the patient recovers, calcium can move back from tissues to plasma, so early exogenous calcium administration is not recommended unless the patient has symptoms or the level becomes exceedingly low in an unconscious patient because

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such repletion could result in hypercalcemia later in the course of the illness.

Hemoglobin can cause a similar form of acute tubular necrosis. Massive intravascular hemolysis is seen in transfusion reactions and in certain hemolytic anemias. Reversal of the underlying disorder and hydration are the mainstays of treatment.

Hyperuricemia can occur in the setting of rapid cell turnover and lysis. Chemotherapy for germ cell neoplasms and leukemia and lymphoma are the primary causes. Acute kidney injury occurs with intratubular deposition of uric acid crystals; serum uric acid levels are often > 15–20 mg/dL and urine uric acid levels > 600 mg/24 h. A urine uric acid to urine creatinine ratio > 1.0 indicates risk of acute kidney injury.

Bence Jones protein seen in conjunction with multiple myeloma can cause direct tubular toxicity and tubular obstruction. Other renal complications from multiple myeloma include hypercalcemia and renal tubular dysfunction, including proximal renal tubular acidosis (see Multiple Myeloma, below).

``Clinical Findings A. Symptoms and Signs See Acute Kidney Injury.

B. Laboratory Findings Hyperkalemia and hyperphosphatemia are commonly encountered. BUN:creatinine ratio is usually < 20:1 because tubular function is not intact, per the mechanisms described in the general section on acute kidney injury (Table 22–4).

Urinalysis may show evidence of acute tubular damage.

The urine may be brown. Urinary output can be either oliguric or nonoliguric, with oliguria portending a worse prognosis. Urine sodium concentration is typically elevated, but the Fena is more indicative of tubular function, as discussed above. On microscopic examination, an active sediment may show pigmented granular casts or “muddy brown” casts. Renal tubular epithelial cells and epithelial cell casts can be present (see Table 22–1).

``Treatment Treatment is aimed at hastening recovery and avoiding complications. Preventive measures should be taken to avoid volume overload and hyperkalemia. Loop diuretics have been used in large doses (eg, furosemide in doses ranging from 20 mg to 160 mg orally or intravenously twice daily, or as a continuous infusion) to affect adequate diuresis and may help convert oliguric to nonoliguric renal failure. Such a conversion has never been shown to affect outcomes such as mortality, though. One retrospective study has shown potentially worse outcomes in patients who receive doses of furosemide, including nonrecovery of renal function and an increased risk of death.

A prospective randomized controlled trial has shown no difference between the administration of large doses of diuretics versus placebo on either recovery from acute kidney injury or death. Widespread use of diuretics in

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critically ill patients with acute kidney injury should thus be discouraged. Disabling side effects of supranormal dosing include hearing loss and cerebellar dysfunction. This is mainly due to peak furosemide levels; this risk can be minimized by the use of a furosemide drip. A starting dose of 0.1–0.3 mg/kg/h is appropriate, increasing to a maximum of 0.5–1 mg/kg/h. A bolus of 1–1.5 mg/kg should be administered at the beginning of each dose escalation.

Intravenous thiazide diuretics can be used to augment urinary output; chlorothiazide, 250–500 mg intravenously every 8–12 hours, is a reasonable choice. Another good choice to augment diuresis is metolazone at doses of 2.5–5 mg given orally once to twice daily, 30 minutes prior to loop diuretics. It is less expensive than intravenous chlorothiazide and has reasonable bioavailability. Short-term effects of loop diuretics include activation of the renin–angiotensin system. One prospective randomized trial showed the longterm benefits of plasma ultrafiltration over the use of intravenous diuretics in patients with decompensated heart failure. This intervention can be considered in ICU patients with acute kidney injury in need of volume removal who are nonresponsive to diuretics. Nutritional support should maintain adequate intake while preventing excessive catabolism. Dietary protein restriction of 0.6 g/kg/d helps prevent metabolic acidosis. Hypocalcemia and hyperphosphatemia can be improved with diet and phosphatebinding agents, such as aluminum hydroxide (500 mg orally with meals) over the short term, and calcium carbonate (500–1500 mg orally three times daily), calcium acetate (667 mg, two or three tablets, orally before meals), sevelamer carbonate (800–1600 mg orally three times daily), and lanthanum carbonate (1000 mg orally with meals) over longer periods. Hypocalcemia should not be treated in patients with rhabdomyolysis unless they are symptomatic. Hypermagnesemia can occur because of reduced magnesium excretion by the renal tubules, so magnesium-containing antacids and laxatives should be avoided in these patients. Dosages of all medications must be adjusted according to the estimated degree of renal impairment for drugs eliminated by the kidney.

Indications for dialysis in acute kidney injury from acute tubular necrosis or other intrinsic disorders include lifethreatening electrolyte disturbances (such as hyperkalemia), volume overload unresponsive to diuresis, worsening acidosis, and uremic complications (eg, encephalopathy, pericarditis, and seizures). In gravely ill patients, less severe but worsening abnormalities may also be indications for dialytic support. Two prospective randomized control trials, each with more than 1100 patients, showed that an intensive dialysis dose was not superior to a more conventional dose.

``Course & Prognosis The clinical course of acute tubular necrosis is often divided into three phases: initial injury, maintenance, and recovery. The maintenance phase is expressed as either oliguric (urinary output < 500 mL/d) or nonoliguric.

Nonoliguric acute tubular necrosis has a better outcome.

Conversion from oliguric to nonoliguric states may be attempted but has not been shown to change the prognosis.

Drugs such as dopamine and diuretics are sometimes used

for this purpose but have not been shown to improve outcomes. In numerous studies, dopamine use in this setting has no benefit. Average duration of the maintenance phase is 1–3 weeks but may be several months. Cellular repair and removal of tubular debris occur during this period.

The recovery phase can be heralded by diuresis. GFR begins to rise; BUN and serum creatinine fall.

The mortality rate associated with acute kidney injury is 20–50% in hospitalized settings, and up to 70% with additional comorbid illnesses. Increased mortality is associated with advanced age, severe underlying disease, and multisystem organ failure. Leading causes of death are infections, fluid and electrolyte disturbances, and worsening of underlying disease. Mortality rates may be starting to improve slightly according to two retrospective cohort studies conducted within the last 10 years.

``When to Refer • A patient with acute tubular necrosis should be referred to a nephrologist when the etiology is unclear or renal function continues to worsen despite intervention.

• Also, referral is appropriate if fluid, electrolyte, and acidbase abnormalities are recalcitrant to interventions.

• Studies have shown that nephrology referral improves outcome in acute kidney injury.

``When to Admit Admission is appropriate when a patient has symptoms or signs of acute kidney injury that require immediate intervention, such as intravenous fluids, dialytic therapy, or that requires a team approach that cannot be coordinated as an outpatient.

Interstitial Nephritis

``

E ssent i a l s of d i a gnos i s

Fever.

Transient maculopapular rash. `` Acute or chronic kidney injury. `` Pyuria (including eosinophiluria), white blood cell casts, and hematuria. `` ``

``General Considerations Acute interstitial nephritis accounts for 10–15% of cases of intrinsic renal failure. An interstitial inflammatory response with edema and possible tubular cell damage is the typical pathologic finding. Cell-mediated immune reactions prevail over humoral responses. T lymphocytes can cause direct cytotoxicity or release lymphokines that recruit monocytes and inflammatory cells.

Although drugs account for over 70% of cases, acute interstitial nephritis also occurs in infectious diseases, immunologic disorders, or as an idiopathic condition. The most common drugs are penicillins and cephalosporins,

Kidney Disease sulfonamides and sulfonamide-containing diuretics, NSAIDs, rifampin, phenytoin, and allopurinol. Proton pump inhibitors have also been recognized as a cause of acute interstitial nephritis. Infectious causes include streptococcal infections, leptospirosis, cytomegalovirus, histoplasmosis, and Rocky Mountain spotted fever.

Immunologic entities are more commonly associated with glomerulonephritis, but systemic lupus erythematosus, Sjögren syndrome, sarcoidosis, and cryoglobulinemia can cause interstitial nephritis.

``Clinical Findings Clinical features can include fever (> 80%), rash (25–50%), arthralgias, and peripheral blood eosinophilia (80%). The classic triad of fever, rash, and arthralgias is present in only 10–15% of cases. The urine often contains red cells (95%), white cells, and white cell casts. Proteinuria can be a feature, particularly in NSAID-induced interstitial nephritis, but is usually modest (< 2 g/24 h). Eosinophiluria is neither very sensitive nor specific and can be detected by Wright or Hansel stain.

``Treatment & Prognosis Acute interstitial nephritis often carries a good prognosis.

Recovery occurs over weeks to months, but urgent dialytic therapy may be necessary in up to one-third of all referred patients before resolution. Patients rarely progress to ESRD. Those with prolonged courses of oliguric failure and advanced age have a worse prognosis. Treatment consists of supportive measures and removal of the inciting agent. If kidney injury persists after these steps, a short course of corticosteroids can be given, although the data to support use of corticosteroids are not substantial. Short-term, high-dose methylprednisolone (0.5–1 g/d intravenously for 1–4 days) or prednisone (60 mg/d orally for 1–2 weeks) followed by a prednisone taper can be used in these more severe cases of drug-induced interstitial nephritis.

Glomerulonephritis

``

E ssent i a l s of d i a gnos i s

Hematuria, dysmorphic red cells, red cell casts, and mild proteinuria. `` Dependent edema and hypertension. `` Acute renal insufficiency. ``

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Categorization of acute glomerulonephritis can be done by serologic analysis. Markers include anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCAs), and other immune markers of disease.

Immune complex deposition usually occurs when moderate antigen excess over antibody production occurs.

Complexes formed with marked antigen excess tend to remain in the circulation. Antibody excess with large antigen–antibody aggregates usually results in phagocytosis and clearance of the precipitates by the mononuclear phagocytic system in the liver and spleen. Causes include IgA nephropathy (Berger disease), peri-infectious or postinfectious glomerulonephritis, endocarditis, lupus nephritis, cryoglobulinemic glomerulonephritis (often associated with hepatitis C virus), and MPGN. Anti-GBM–associated acute glomerulonephritis is either confined to the kidney or associated with pulmonary hemorrhage. The latter is termed “Goodpasture syndrome.” Injury is related to autoantibodies aimed against type IV collagen in the GBM rather than to immune complex deposition.

Pauci-immune acute glomerulonephritis is a form of small-vessel vasculitis associated with ANCAs, causing primary and secondary kidney diseases that do not have direct immune complex deposition or antibody binding. Tissue injury is believed to be due to cell-mediated immune processes. An example is granulomatosis with polyangiitis, a systemic necrotizing vasculitis of small arteries and veins associated with intravascular and extravascular granuloma formation. In addition to glomerulonephritis, these patients can have upper airway, pulmonary, and skin manifestations of disease. Cytoplasmic ANCA (c-ANCA) is a common pattern. Microscopic polyangiitis is another pauci-immune vasculitis causing acute glomerulonephritis. Perinuclear staining (p-ANCA) is the common pattern. ANCA-associated and anti-GBM-associated acute glomerulonephritis can evolve to crescentic glomerulonephritis and often have poor outcomes unless treatment is started early. Both are described more fully below.

Other vascular causes of acute glomerulonephritis include hypertensive emergencies and the thrombotic microangiopathies such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura (see Chapter 14).

``Clinical Findings A. Symptoms and Signs Patients with acute glomerulonephritis are often hypertensive and edematous, and have an abnormal urinary sediment. The edema is found first in body parts with low tissue tension, such as the periorbital and scrotal regions.

``General Considerations

B. Laboratory Findings

Acute glomerulonephritis is a relatively uncommon cause of acute kidney injury, accounting for about 5% of cases.

Pathologically, inflammatory glomerular lesions are seen.

These include mesangioproliferative, focal and diffuse proliferative, and crescentic lesions. The larger the percentage of glomeruli involved and the more severe the lesion, the more likely it is that the patient will have a poor clinical outcome.

Serum creatinine can rise over days to months, depending on the rapidity of the underlying process. The BUN:creatinine ratio is not a reliable marker of kidney function and is more reflective of the underlying volume status of the patient.

Dipstick and microscopic evaluation will reveal evidence of hematuria, moderate proteinuria (usually < 3 g/d), and cellular elements such as red cells, red cell casts, and white cells.

Red cell casts are specific for glomerulonephritis, and a

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detailed search is warranted. Either spot urinary proteincreatinine ratios or 24-hour urine collections can quantify protein excretion; the latter can quantify creatinine clearance when renal function is stable. However, in cases of rapidly changing serum creatinine values, the urinary creatinine clearance is an unreliable marker of GFR. The Fena is usually low unless the renal tubulo-interstitial space is affected, and renal dysfunction is marked (see Table 22–4).

Further tests include complement levels (C3, C4, CH50), ASO titer, anti-GBM antibody levels, ANCAs, antinuclear antibody titers, cryoglobulins, hepatitis serologies, blood cultures, renal ultrasound, and occasionally renal biopsy.

``Treatment Depending on the nature and severity of disease, treatment can consist of high-dose corticosteroids and cytotoxic agents such as cyclophosphamide. Plasma exchange can be used in Goodpasture disease and pauci-immune glomerulonephritis as a temporizing measure until chemotherapy can take effect. Treatment and prognosis for specific diseases are discussed more fully below.

Cruz DN et al. Clinical review: RIFLE and AKIN—time for reappraisal. Crit Care. 2009;13(3):211. [PMID: 19638179] Hoste EA et al. Epidemiology of acute kidney injury. Contrib Nephrol. 2010;165:1–8. [PMID: 20427949] Lafrance JP et al. Acute kidney injury associates with increased long-term mortality. J Am Soc Nephrol. 2010 Feb;21(2):345–52. [PMID: 20019168] Navaneethan SD et al. Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Am J Kidney Dis. 2009 Apr;53(4):617–27.

[PMID: 19027212] Perazella MA et al. Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin J Am Soc Nephrol. 2008 Nov;3(6):1615–9.

[PMID: 18784207] Vaidya VS et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2008 Dec;1(3):200–8. [PMID: 19212447]

Cardiorenal Syndrome

``

E ssent i a l s of d i a gnos i s

Cardiac dysfunction: signs or symptoms of heart failure, ischemic injury or arrhythmias. `` Kidney disease: acute or chronic, depending on type of cardiorenal syndrome. ``

``General Considerations Cardiorenal syndrome is a pathophysiologic disorder of the heart and kidneys wherein the acute or chronic deterioration of one organ results in the acute or chronic deterioration of the other. This syndrome has been classified into five types.

Type 1 consists of acute kidney injury stemming from acute cardiac disease. Type 2 is CKD due to chronic cardiac disease. Type 3 is acute cardiac disease as a result of acute

kidney injury. Type 4 is chronic cardiac decompensation from CKD. Type 5 consists of heart and kidney dysfunction due to other acute or chronic systemic disorders (such as sepsis). Identifying and defining this common syndrome may assist in the future with treatments to improve its morbidity and mortality. cc

``

chronic kidney disease

E ssent i a l s of d i a gnos i s

Decline in the GFR over months to years Persistent proteinuria or abnormal renal morphology. `` Symptoms and signs of uremia when nearing end-stage disease. `` Hypertension in most cases. `` ``

Bilateral small kidneys on ultrasound in advanced disease.

``

``General Considerations CKD affects more than 20 million Americans, or one in nine adults. Most are unaware of the condition because they remain asymptomatic until the disease has significantly progressed. The National Kidney Foundation’s staging system helps clinicians formulate practice plans (Table 22–5). Over 70% of cases of late-stage CKD (stage 5 CKD and ESRD) in the United States are due to diabetes mellitus or hypertension. Glomerulonephritis, cystic diseases, and other urologic diseases account for another 12%, and 15% of patients have other or unknown causes (Table 22–6). Recently, genetic polymorphisms of the APOL-1 gene has been shown to be associated with an increased risk of the development of CKD in African Americans.

CKD is rarely reversible and usually leads to a progressive decline in kidney function even after the inciting event has been removed. Destruction of nephrons (inciting event) leads to compensatory hypertrophy of the remaining nephrons, which must increase their individual GFRs to supranormal in order to maintain overall homeostasis. One consequence of this compensatory hyperfiltration is that the serum creatinine may remain relatively normal even in the face of significant loss of renal mass; therefore, it is a relatively insensitive marker for renal damage and scarring. In addition, compensatory hyperfiltration leads to overwork injury in the remaining nephrons, which in turn causes progressive glomerular sclerosis and interstitial fibrosis. Angiotensin receptor blockers (ARBs) and ACE inhibitors can help reduce hyperfiltration injury and are particularly helpful in slowing the progression of proteinuric CKD. Fortunately, an individual’s decreased renal mass as a result of kidney donation is not associated with the development of CKD later in life.

CKD is an independent risk factor for cardiovascular disease; proteinuric CKD confers an even higher risk of cardiovascular mortality.

Kidney Disease

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Table 22–5. Stages of chronic kidney disease: A clinical action plan.1,2 Stage 1

Description Kidney damage with normal or ↑­ GFR

GFR (mL/min/1.73 m2)

Action3

≥ 90

Diagnosis and treatment. Treatment of comorbid conditions. Slowing of progression. Cardiovascular disease risk reduction.

2

Kidney damage with mildly ↓ GFR

60–89

Estimating progression.

3

Moderately ↓ GFR

30–59

Evaluating and treating complications.

4

Severely ↓ GFR

15–29

Preparation for kidney replacement therapy.

5

End-stage renal disease (ESRD)

< 15 (or dialysis)

Replacement (if uremia is present).

1

From National Kidney Foundation, KDOQI, Chronic Kidney Disease Guidelines.

Chronic kidney disease is defined as either kidney damage or GFR < 60 mL/min/1.73 m2 for 3 or more months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.

3 Includes actions from preceding stages.

GFR, glomerular filtration rate.

2

``Clinical Findings A. Symptoms and Signs Table 22–6. Major causes of chronic kidney disease.

Glomerular diseases Primary glomerular diseases Focal and segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy Membranous nephropathy Alport syndrome (hereditary nephritis) Secondary glomerular diseases Diabetic nephropathy Amyloidosis Postinfectious glomerulonephritis HIV-associated nephropathy Collagen-vascular diseases (eg, SLE) HCV-associated membranoproliferative glomerulonephritis

In the early stages, CKD is asymptomatic. Symptoms develop slowly with the progressive decline in GFR, are nonspecific, and do not manifest until kidney disease is far advanced (GFR < 10–15 mL/min/1.73 m2). At this point, the build-up of metabolic waste products, or uremic toxins, can result in the uremic syndrome (Table 22–7). General

Table 22–7. Symptoms and signs of uremia.

Organ System

Symptoms

General

Fatigue, weakness

Sallow-appearing, chronically ill

Skin

Pruritus, easy bruisability

Pallor, ecchymoses, excoriations, edema, xerosis

ENT

Metallic taste in mouth, epistaxis

Urinous breath

Tubulointerstitial nephritis Drug hypersensitivity Heavy metals Analgesic nephropathy Reflux/chronic pyelonephritis Sickle cell nephropathy Idiopathic Cystic diseases Polycystic kidney disease Medullary cystic disease Obstructive nephropathies Prostatic disease Nephrolithiasis Retroperitoneal fibrosis/tumor Congenital Vascular diseases Hypertensive nephrosclerosis Renal artery stenosis HCV, hepatitis C virus; SLE, systemic lupus erythematosus.

Signs

Eye

Pale conjunctiva

Pulmonary

Shortness of breath

Rales, pleural effusion

Cardiovascular

Dyspnea on exertion, retrosternal pain on inspiration (pericarditis)

Hypertension, cardiomegaly, friction rub

Gastrointestinal

Anorexia, nausea, vomiting, hiccups

Genitourinary

Nocturia, erectile dysfunction

Neuromuscular

Restless legs, numbness and cramps in legs

Neurologic

Generalized irritability and inability to concentrate, decreased libido

Isosthenuria

Stupor, asterixis, myoclonus, peripheral neuropathy

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Chapter 22 B. Laboratory Findings The diagnosis of CKD is made by documenting elevations of the serum creatinine over at least 3 months. Persistent proteinuria or abnormalities on renal imaging (eg, polycystic kidneys) are also diagnostic of CKD, even when estimated GFR is normal. It is helpful to plot the inverse of serum creatinine (1/SCr) versus time or estimated GFR (if reported by the laboratory) versus time. If three or more prior measurements are available, the time to ESRD can thus be estimated (Figure 22–1). If the slope of the line acutely declines, new and potentially reversible renal insults should be excluded as outlined above. Anemia, hyperphosphatemia, hypocalcemia, hyperkalemia, and metabolic acidosis can occur with both acute kidney disease and CKD. The urinalysis shows isosthenuria if tubular concentrating and diluting ability are impaired. The urinary sediment can show broad waxy casts as a result of dilated, hypertrophic nephrons. Proteinuria may be present. If so, it should be quantified as described above. Quantification of urinary protein is important for several reasons. First, it helps narrow the differential diagnosis of the etiology of the CKD (Table 22–6); for example, glomerular diseases tend to present with protein excretion of > 1 g/d. Second, the presence of proteinuria is associated with more rapid progression of CKD and cardiovascular mortality.

1

•

1.0 0.9

0.7 1/Scr

symptoms of uremia may include fatigue, weakness, and malaise. GI symptoms, such as anorexia, nausea, vomiting, and a metallic taste in the mouth, are common. Neurologic problems may include irritability, difficulty in concentrating, insomnia, subtle memory defects, restless legs, paresthesias, and twitching. Pruritus is common and difficult to treat. Alterations in sexual function, including decreased libido, and menstrual irregularities are common. Chest pain is rare but can occur with pericarditis. Drug toxicity can develop as renal clearance worsens; in particular, hypoglycemia may become problematic, and even lifethreatening, in diabetics since insulin is eliminated by the kidneys.

The most common physical finding in CKD is hypertension. It is often present in early stages of CKD and may worsen with CKD progression. The uremic patient (CKD stage 5) appears chronically ill. The skin may be sallow, with easy bruisability. Rarely seen in the current era is uremic frost, a cutaneous reflection of ESRD. Uremic fetor is the characteristic fishy odor of the breath.

Cardiopulmonary signs may include rales, cardiomegaly, jugular venous distention, edema, and a pericardial friction rub (rarely). Mental status can vary from decreased concentration to confusion, stupor, and coma. Myoclonus and asterixis may be signs of uremia.

Symptoms and signs of uremia warrant immediate hospital admission and nephrology consultation for initiation of dialysis. The uremic syndrome resolves or lessens significantly with dialytic therapy.

In any patient with kidney disease, it is important to identify and correct all possibly reversible insults or exacerbating factors (Table 22–8). Urinary tract infections, obstruction, extracellular fluid volume depletion, hypotension, nephrotoxins (such as NSAIDs), severe or emergent hypertension, and congestive heart failure should be excluded. Any of the above can worsen underlying CKD.

2

0.5

•

Table 22–8. Reversible causes of kidney injury.

Reversible Factors

Diagnostic Clues

Infection

Urine culture and sensitivity tests

Obstruction

Bladder catheterization, then renal ultrasound

Extracellular fluid volume depletion or significant hypotension relative to baseline

Blood pressure and pulse, including orthostatic pulse

Hypokalemia, hypercalcemia, and hyperuricemia (usually > 15 mg/dL)

Serum electrolytes, calcium, phosphate, uric acid

Nephrotoxic agents

Drug history

Severe/urgent hypertension

Blood pressure, chest radiograph

Congestive heart failure

Physical examination, chest radiograph

0.3

•3 0.1 1

2

3

4 5 6 Time (years)

7

8

9

10

1

Value of serum creatinine level = 1.0 mg/dL Value of serum creatinine level = 2.0 mg/dL 3 Value of serum creatinine level = 5.0 mg/dL 2

s Figure 22–1. Decline in kidney function (expressed as the reciprocal of serum creatinine as shown here, or as estimated glomerular filtration rate [eGFR]) plotted against time to end-stage renal disease (ESRD). The solid line indicates the linear decline in kidney function over time. The dotted line indicates the approximate time to ESRD.

Kidney Disease C. Imaging The finding of small echogenic kidneys bilaterally (< 9–10 cm) by ultrasonography supports a diagnosis of CKD, although normal or even large kidneys can be seen with adult polycystic kidney disease, diabetic nephropathy, HIV-associated nephropathy, multiple myeloma, amyloidosis, and obstructive uropathy.

``Complications The complications of CKD tend to occur at relatively predictable stages of disease as noted in Figure 22–2.

A. Cardiovascular Complications Patients with CKD experience greater morbidity and mortality from cardiovascular disease in comparison to the general population. Death from cardiovascular causes accounts for 45% of all deaths of patients receiving dialysis.

Eighty to 90 percent of patients with CKD die, primarily of cardiovascular disease, before reaching need for dialysis.

The precise biologic mechanisms for this enhanced mortality are unclear but may have to do with the uremic milieu including abnormal phosphorus and calcium homeostasis, increased burden of oxidative stress, increased vascular reactivity, increased left ventricular hypertrophy, and underlying coexistent comorbidities such as hypertension and diabetes mellitus.

1. Hypertension— Hypertension is the most common complication of CKD. As kidney disease progresses, hypertension due to salt and water retention usually develops.

Hyperreninemic states and exogenous erythropoietin administration can also exacerbate hypertension.

As with other patient populations, control of hypertension should focus on both nonpharmacologic therapy (eg, diet, exercise, weight loss, treatment of obstructive sleep apnea) and pharmacologic therapy. CKD results in disturbed sodium homeostasis such that the ability of the

5

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kidney to adjust to variations in sodium and water intake becomes limited as GFR declines. The clinician should recommend institution of a diet with mildly decreased salt intake (3 g/d), and salt intake should be reduced to 2 g/d if hypertension persists or signs of CHF develop. Diuretics are nearly always needed to help control hypertension.

However, volume contraction as a result of very low sodium intake or over-diuresis in the presence of impaired sodium homeostasis can result in further impairment of the GFR. In addition to diuretics, initial drug therapy should include ACE inhibitors or ARBs as recommended by national guidelines (if serum potassium permits). When an ACE inhibitor or an ARB is initiated or uptitrated, patients should have serum creatinine and potassium checked within 5–14 days. Hyperkalemia or a rise in serum creatinine > 30% from baseline mandates reduction or cessation of the drug. Second-line antihypertensive agents include calcium channel-blocking agents and β-blocking agents. Because of the difficulty in controlling hypertension in CKD, additional agents from other classes are often needed. Current guidelines suggest a blood pressure goal of 130/80 mm Hg for patients with CKD; a goal of 125/75 mm Hg is recommended for patients with proteinuria. It should be noted that treatment of blood pressure significantly below these goals is not supported by current data and may be dangerous in some populations, such as the elderly.

Ongoing randomized controlled trials are looking at the benefit of systolic blood pressure goals of < 120 mm Hg versus < 140 mm Hg regarding outcomes such as ESRD and cardiac death in high-risk populations.

2. Coronary artery disease—Patients with CKD are at higher risk for death from cardiovascular disease than the general population. Traditional modifiable risk factors for cardiovascular disease, such as hypertension, tobacco use, and hyperlipidemia, should be aggressively treated in patients with CKD. Uremic vascular calcification involving disordered phosphorus homeostasis and other mediators may also be a cardiovascular risk factor in these patients.

3

2

HTN ↑ PTH Anemia ↑ Phosphorus Acidosis, hyperkalemia Uremic syndrome

0

20 40 60 80 Glomerular filtration rate (mL/min)

100

s Figure 22–2. Complications of chronic kidney disease (CKD) by stage and glomerular filtration rate (GFR).

Complications arising from CKD tend to occur at the stages depicted, although there is considerable variability noted in clinical practice. HTN, hypertension; PTH, parathyroid hormone. (Adapted, with permission, from William Bennett, MD.)

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3. Congestive heart failure—The complications of CKD result in increased cardiac workload via underlying hypertensive disease, volume overload, and anemia. Patients with CKD may also have accelerated rates of atherosclerosis, and vascular calcification resulting in vessel stiffness. All of these factors contribute to left ventricular hypertrophy and diastolic dysfunction, which are present in most patients starting dialysis. Over time, systolic dysfunction may also develop. Water and salt restriction is usually necessary.

Diuretics are of value if they can affect an increased urine volume, although thiazides are ineffective by themselves when the GFR is < 20–30 mL/min/1.73 m2. Loop diuretics are commonly used, potentially in combination with thiazide diuretics, and higher doses are required as renal function declines. Digoxin is excreted by the kidney, and its toxicity is exacerbated in the presence of electrolyte disturbances which are common in CKD. The proven efficacy of ACE inhibitors in congestive heart failure holds true for patients with CKD. Despite the risks of hyperkalemia and worsening renal function, ACE inhibitors and ARBs can be used for patients with a serum creatinine > 3 mg/dL with close supervision and laboratory test monitoring.

4. Pericarditis—Pericarditis may develop in uremic patients but is rare. Symptoms include chest pain and fever. Pulsus paradoxus can be present; a friction rub may be auscultated, but the lack of a rub does not rule out a significant pericardial effusion. The chest radiograph can show an enlarged cardiac silhouette, and the ECG, generalized ST and T wave changes, characteristically a progression from diffuse ST elevation followed by a return to baseline and then T wave inversion. If pericardial effusion occurs, the ECG often shows nonspecific T wave changes and low QRS voltage; electrical alternans is a pathognomonic finding. Cardiac tamponade can occur; patients with tamponade have signs of poor cardiac output, with jugular venous distention and lungs clear to auscultation. Uremic pericarditis is a mandatory indication for hospitalization and initiation of hemodialysis.

B. Disorders of Mineral Metabolism The metabolic bone disease of CKD refers to the complex disturbances of calcium and phosphorus metabolism, parathyroid hormone (PTH), active vitamin D, and possibly fibroblast growth factor-23 (FGF-23) homeostasis (see Chapter 21 and Figure 22–3). A typical pattern seen as early as CKD stage 3 is hyperphosphatemia, hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism as a result of the first three abnormalities. Traditionally, the emphasis on treating these disturbances centered around concern for the consequential bone disease and increased fracture risk noted in CKD patients. Now it is recognized that such disturbances also lead to vascular calcification and may be partly responsible for the accelerated cardiovascular disease and excess mortality seen in the CKD population.

Epidemiologic studies in humans show an association between elevated phosphorus levels and increased risk of cardiovascular mortality in early CKD through ESRD. As yet, there are no intervention trials suggesting the best course of treatment in these patients; control of mineral and PTH levels per current guidelines is discussed below.

↓GFR

↓25(OH) Vitamin D

↑Phosphorus

↓1,25(OH) Vitamin D

↓Calcium

↑PTH

s Figure 22–3. Mineral abnormalities of chronic kidney disease (CKD). Decline in glomerular filtration rate (GFR) and loss of renal mass lead directly to increased serum phosphorus and hypovitaminosis D. Both of these abnormalities result in hypocalcemia and hyperparathyroidism. Many CKD patients also have nutritional 25(OH) vitamin D deficiency. PTH, parathyroid hormone.

Bone disease, or renal osteodystrophy, in advanced CKD is common and there are several types of lesions.

Renal osteodystrophy can only be diagnosed by bone biopsy, which is rarely done. The most common bone disease, osteitis fibrosa cystica, is a result of secondary hyperparathyroidism and the osteoclast-stimulating effects of PTH. This is a high-turnover disease with osteoclastic bone resorption and subperiosteal lesions. Metastatic calcifications, such as tumoral calcinosis, can occur.

Radiographically, lesions are most prominent in the phalanges and lateral ends of the clavicles. Adynamic bone disease, or low-bone turnover, is becoming more common and results from relatively low PTH levels or activity; it may result iatrogenically from suppression of PTH or via spontaneously low PTH production. Osteomalacia, or lack of bone mineralization, is another lesion associated with CKD. In the past, osteomalacia was associated with aluminum toxicity—either as a result of chronic ingestion of prescribed aluminum-containing phosphorus binders or from high levels of aluminum in untreated dialysate.

Currently, osteomalacia is more likely to result from hypovitaminosis D; there is also theoretical risk of osteomalacia associated with use of bisphosphonates in advanced CKD. All of the above entities can cause bony pain, proximal muscle weakness, and higher risk for fractures. Treatment involves correction of calcium, phosphorus, and 25-OH vitamin D levels toward normal values, along with treatment of hyperparathyroidism. Understanding the interplay between these abnormalities can help target therapy (Figure 22–3). Declining GFR leads to phosphorus retention. This results in hypocalcemia as phosphorus complexes with calcium, deposits in soft tissues, and stimulates PTH. Loss of renal mass, and low 25-OH vitamin D levels often seen in CKD patients results in low 1,25(OH) vitamin D production by the kidney. Because 1,25(OH) vitamin D is a suppressor of PTH production, hypovitaminosis D also leads to secondary hyperparathyroidism.

The first step in treatment of metabolic bone disease is control of hyperphosphatemia (defined as a serum phosphorus of ≤ 4.5 mg/dL in pre-ESRD CKD, or ≤ 5.5 mg/dL in ESRD patients). This involves dietary phosphorus

Kidney Disease restriction initially, followed by the administration of oral phosphorus binders if targets are not achieved (see below).

Dietary phosphorus restriction to 1000 mg/d can be challenging as many phosphorus sources are also rich in protein; care must be taken to avoid protein malnutrition. Oral phosphorus binders, such as calcium carbonate (650 mg/ tablet) or calcium acetate (667 mg/capsule), block absorption of dietary phosphorus in the gut and are given three or four times daily at the beginning of meals. These should be titrated to a serum phosphorus of < 4.6 mg/dL in stage 3–4 of CKD (GFR of 15–59 mL/min) and < 4.6–5.5 mg/dL in ESRD patients. National guidelines recommend maximal elemental calcium doses of 1500 mg/d (eg, nine tablets of calcium acetate); doses should be decreased if serum calcium rises above 10 mg/dL. Phosphorus-binding agents that do not contain calcium are sevelamer and lanthanum.

Sevelamer, 800 mg orally, and lanthanum carbonate, 1000 mg orally, are given at the beginning of meals. Aluminum hydroxide is a highly effective phosphorus binder but can cause osteomalacia and neurologic complications when used long-term. While it can be used in the acute setting for serum phosphorus > 7 mg/dL or for short periods (eg, 3 weeks) in CKD patients, long-term use should be avoided.

Once serum phosphorus levels are controlled, active vitamin D (1,25[OH] vitamin D, or calcitriol) or active vitamin D analogs are recommended to treat secondary hyperparathyroidism in stage 3–5 CKD. Serum 25-OH vitamin D levels should be measured and brought to normal (see Chapter 26) prior to considering administration of active vitamin D. Active vitamin D (calcitriol) increases serum calcium and phosphorus levels; both need to be monitored closely during calcitriol therapy, and its dose should be decreased if hypercalcemia or hyperphosphatemia occurs. Typical calcitriol dosing is 0.25 or 0.5 mcg orally daily or every other day initially. Cinacalcet is a calcimimetic agent that targets the calcium-sensing receptor on the chief cells of the parathyroid gland and suppresses PTH production. Cinacalcet, 30–90 mg orally once a day, can be used if elevated serum phosphorus or calcium levels prohibit the use of vitamin D analogs; cinacalcet can cause hypocalcemia. Optimal PTH levels in CKD are not known, but because skeletal resistance to PTH develops with uremia, relatively high levels are targeted in advanced CKD to avoid adynamic bone disease. Expert guidelines generally suggest goal PTH levels near or just above the upper limit of normal for moderate CKD, and at least twofold and up to ninefold the upper limit of normal for ESRD.

C. Hematologic Complications 1. Anemia—The anemia of CKD is primarily due to decreased erythropoietin production, which often becomes clinically significant during stage 3 CKD. Many patients are iron deficient as well due to impaired GI iron absorption.

Erythropoiesis-stimulating agents (eg, recombinant erythropoietin [epoetin] and darbepoetin) are FDAapproved in CKD for a goal hemoglobin (Hgb) of 10–11 g/dL if no other treatable causes for anemia are present. One study in patients with CKD showed no benefit of starting erythropoietin-like agents before Hgb values were < 9 g/dL. The dose needed can vary; the starting dose of epoetin is

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50 units/kg (3000–4000 units/dose) once or twice a week.

Darbepoetin is started at 0.45 mcg/kg and can be administered every 2–4 weeks. These agents can be given intravenously (eg, to the hemodialysis patient) or subcutaneously (eg, to the predialysis or dialysis patient); subcutaneous dosing of erythropoietin is roughly 30% more effective than intravenous dosing. Erythropoiesis-stimulating agents should be titrated to a Hgb of 10–11 g/dL for optimal safety; studies show that targeting a higher Hgb increases risk of stroke and possibly other cardiovascular events.

When titrating doses, Hgb levels should rise no more than 1 g/dL every 3–4 weeks. Hypertension is a complication of erythropoietin or darbepoetin therapy in about 20% of patients. The dosage may require adjustment, or antihypertensive drugs may need to be given.

Iron stores must be adequate to ensure response to erythropoiesis-stimulating agents. Patients with CKD tend to have progressively increasing level of hepcidin, a molecule that blocks GI iron absorption and mobilization of iron from body stores. Therefore, traditional measures of iron stores are measured in CKD patients but are considered abnormal at a higher reference level. In CKD, a serum ferritin < 100–200 ng/mL or iron saturation < 20% is suggestive of iron deficiency. Iron stores should be repleted with oral or parenteral iron prior to the initiation of erythropoietic agents. Iron therapy should be withheld if the serum ferritin is > 500–800 ng/mL, even if the iron saturation is < 20%. Oral therapy with ferrous sulfate, gluconate, or fumarate (the latter two tend to be better tolerated), 325 mg once to three times daily, is the initial therapy for patients who are not yet receiving dialysis. For those that do not respond due to poor GI absorption or lack of tolerance, intravenous iron may be necessary.

The preliminary investigation of anemia in any CKD patient should also include assessment of thyroid function tests, serum vitamin B12, and red blood cell folate stores, and fecal occult blood testing prior to initiating erythropoiesisstimulating agent therapy.

2. Coagulopathy—The coagulopathy of CKD is mainly caused by platelet dysfunction. Platelet counts may be mildly decreased, and the bleeding time is prolonged due to abnormal adhesiveness and aggregation. Clinically, patients can have petechiae, purpura, and an increased tendency for bleeding during surgery.

Treatment is required only in patients who are symptomatic. Raising the Hgb to 9–10 g/dL in anemic patients can reduce bleeding time via increased blood viscosity.

Desmopressin (25 mcg intravenously every 8–12 hours for two doses) is a short-lived but effective treatment for platelet dysfunction and it is often used in preparation for surgery. Conjugated estrogens, 2.5–5 mg orally for 5–7 days, may have an effect for several weeks but is very seldom used. Dialysis improves the bleeding time but does not normalize it. Cryoprecipitate (10–15 bags) is rarely used and lasts < 24 hours.

D. Hyperkalemia Potassium balance generally remains intact in CKD until stages 4–5. However, hyperkalemia may occur at earlier stages

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when certain conditions are present, such as type 4 renal tubular acidosis (seen in patients with diabetes mellitus), high potassium diets, or medications that decrease renal potassium secretion (amiloride, triamterene, spironolactone, eplerenone, NSAIDs, ACE inhibitors, ARBs) or block cellular potassium uptake (β-blockers). Other causes include acidemic states, and any type of cellular destruction causing release of intracellular contents (which are high in potassium), such as hemolysis and rhabdomyolysis.

Treatment of acute hyperkalemia is discussed in Chapter 21 (see Table 21–6). Cardiac monitoring is indicated for any ECG changes seen with hyperkalemia or a serum potassium level > 6.0–6.5 mEq/L. The ion exchange resin sodium polystyrene sulfonate exchanges sodium for potassium and results in GI potassium excretion and is often used to treat acute hyperkalemia in addition to β-agonists, insulin plus glucose, and calcium gluconate as indicated.

Chronic hyperkalemia is best treated with dietary potassium restriction (2 g/d) and minimization or elimination of any medications that may impair renal potassium excretion, as noted above. Loop diuretics may also be administered for their kaliuretic effect as long as the patient is not volume-depleted.

E. Acid–Base Disorders Damaged kidneys are unable to excrete the 1 mEq/kg/d of acid generated by metabolism of dietary animal proteins in the typical Western diet. The resultant metabolic acidosis is primarily due to loss of renal mass; distal tubular defects may contribute to or worsen the acidosis. Although patients with CKD are in positive hydrogen ion balance, the arterial blood pH is maintained at 7.33–7.37 and serum bicarbonate concentration rarely falls below 15 mEq/L. The excess hydrogen ions are buffered by the large calcium carbonate and calcium phosphate stores in bone. This results in leaching of calcium and phosphorus from the bone and contributes to the metabolic bone disease described above. To help mitigate damage to bone and encourage normal growth, the serum bicarbonate level should be maintained at > 21 mEq/L. The most commonly used alkali salt is sodium bicarbonate. Administration should begin with 20–30 mEq/d divided into two doses per day and titrated as needed.

Citrate salts increase the absorption of dietary aluminum and should be avoided in CKD patients.

F. Neurologic Complications Uremic encephalopathy, resulting from the aggregation of uremic toxins, does not occur until GFR falls below 5–10 mL/min/1.73 m2. Symptoms begin with difficulty in concentrating and can progress to lethargy, confusion, and coma. Physical findings may include nystagmus, weakness, asterixis, and hyperreflexia. These symptoms and signs improve after initiation of dialysis.

Neuropathy is found in 65% of CKD stage 5 and ESRD patients but can also be seen in patients with CKD stage 4.

Peripheral neuropathies manifest themselves as sensorimotor polyneuropathies (stocking-glove distribution) and isolated or multiple isolated mononeuropathies; other

CKD-associated neuropathies result in erectile dysfunction and autonomic dysfunction. Patients may have restless leg syndrome, loss of deep tendon reflexes, and distal pain.

The earlier initiation of dialysis may prevent peripheral neuropathies, although the response to dialysis is variable.

G. Endocrine Disorders In advanced CKD, circulating insulin levels are higher because of decreased renal insulin clearance, and, in diabetics, there is risk of developing dangerous hypoglycemia if this phenomenon is not anticipated. Doses of oral hypoglycemics and insulin may need reduction. Metformin is associated with risk of lactic acidosis when estimated GFR is < 60 mL/min/1.73 m2 and should be discontinued at this point.

Decreased libido and erectile dysfunction are common in advanced CKD. Men have decreased testosterone levels; women are often anovulatory. Women with serum creatinine < 1.4 mg/dL are not at increased risk for poor outcomes in pregnancy; however, those with serum creatinine > 1.4 mg/dL may experience faster progression of CKD with pregnancy. Fetal survival is not compromised, however, unless CKD is advanced. Despite a high degree of infertility in patients with ESRD, pregnancy can occur in this setting—particularly in women who are well dialyzed and well nourished. However, fetal mortality approaches 50%, and babies who survive are often premature. In female patients with ESRD, renal transplantation with a well-functioning allograft affords the best chances for a successful pregnancy.

``Treatment A. Slowing Progression Treatment of the underlying cause of CKD is vital. Control of diabetes should be aggressive in early CKD; risk of hypoglycemia increases in advanced CKD as described above, and glycemic targets may need to be relaxed to avoid this dangerous complication. Blood pressure control is vital to slow progression of all forms of CKD; agents that block the renin-angiotensin-aldosterone system are particularly important in proteinuric disease (see section on hypertension). Several small studies suggest a possible benefit of oral alkali therapy in slowing CKD progression when acidemia is present (see above); there is also theoretic value in lowering uric acid levels in those with concomitant hyperuricemia, but clinical data are lacking at this time.

Management of traditional cardiovascular risk factors should also be emphasized.

B. Dietary Management Every patient with CKD should be evaluated by a renal nutritionist. Specific recommendations should be made concerning protein, salt, water, potassium, and phosphorus intake to help manage CKD progression and complications.

1. Protein restriction—Experimental models have shown that protein restriction slows the progression to ESRD;

Kidney Disease however, this has not been consistently proved in clinical trials. The questionable benefits of protein restriction in slowing the rate of decline of GFR must be weighed against the risk of cachexia upon the initiation of dialysis; low serum albumin at the start of dialysis is one of the strongest predictors of mortality in this population.

2. Salt and water restriction—In advanced CKD, the kidney is unable to adapt to large changes in sodium intake. Intake > 3–4 g/d can lead to edema, hypertension, and congestive heart failure, whereas intake of < 1 g/d can lead to volume depletion and hypotension. For the nondialysis patient approaching ESRD, 2 g/d of sodium is an initial recommendation. A daily intake of 2 L of fluid maintains water balance.

3. Potassium restriction—Restriction is needed once the GFR has fallen below 10–20 mL/min/1.73 m2, or earlier if the patient is hyperkalemic. Patients should receive detailed lists concerning potassium content of foods and should limit their intake to < 50–60 mEq/d (2 g); this is about half of normal intake.

4. Phosphorus restriction—The phosphorus level should be kept in the ‘normal’ range (<4.5 mg/dL) predialysis, and between 3.5 and 5.5 mg/dL when on dialysis, with a dietary restriction of 800–1000 mg/d. Foods rich in phosphorus such as cola beverages, eggs, dairy products, nuts, beans, and meat should be limited, although care must be taken to avoid protein malnutrition. Below a GFR of 20–30 mL/ min/1.73 m2, dietary restriction is rarely sufficient to reach target levels, and phosphorus binders are usually required.

The treatment of hyperphosphatemia is discussed above in the section on disorders of mineral metabolism.

C. Medication Management Many drugs are excreted by the kidney; dosages should be adjusted for GFR. Insulin doses may need to be adjusted as noted above. Magnesium-containing medications, such as laxatives or antacids, should be avoided as should phosphorus-containing medicines, particularly cathartics.

Morphine metabolites are active and can accrue in advanced CKD; this problem is not encountered with other opioid agents. Drugs with potential nephrotoxicity (NSAIDs, intravenous contrast, as well as others noted in the Acute Kidney Injury section) should be avoided.

D. Treatment of End-Stage Renal Disease When GFR declines to 5–10 mL/min/1.73 m2 (with or without overt uremic symptoms), renal replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation) is required to sustain life. Select patients with limited life expectancy because of very advanced age or comorbid conditions may choose not to pursue dialysis therapy.

Patient education is very important in understanding which mode of therapy is most suitable; timely preparation for treatment is also key. Referral to a nephrologist for consideration of ESRD treatment should take place in late stage 3 CKD, or when the GFR is declining rapidly.

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1. Dialysis—Dialysis initiation should be considered when GFR is 10 mL/min/1.73 m2. Recent studies suggest that the well-selected patient without overt uremic symptoms may wait to initiate dialysis until GFR is closer to 7 mL/ min/1.73 m2. Other indications for dialysis, which may occur when GFR is 10–15 mL/min/1.73 m2 include (1) uremic symptoms, (2) fluid overload unresponsive to diuresis, (3) refractory hyperkalemia, and (4) severe metabolic acidosis (pH < 7.20). Preparation for dialysis requires a team approach. Dietitians and social workers should be involved as well as primary care clinicians and nephrologists. The patient and family need early counseling regarding the risks and benefits of therapy. For very elderly patients, or those with multiple debilitating or life-limiting comorbidities, dialysis therapy may not meaningfully prolong life, and the option of not starting dialysis with the development of ESRD should be discussed with the patient and family. Conversely, for patients who are otherwise relatively healthy, evaluation for possible kidney transplantation should be considered prior to initiation of dialysis.

A. Hemodialysis—Hemodialysis requires a constant flow of blood along one side of a semipermeable membrane with a cleansing solution, or dialysate, along the other. Diffusion and convection allow the dialysate to remove unwanted substances from the blood while adding back needed components. Vascular access for hemodialysis can be accomplished by an arteriovenous fistula (the preferred method) or prosthetic graft; creation of dialysis access should be considered well before dialysis initiation. An indwelling catheter is used when there is no useable vascular access; because catheters confer a high risk of bloodstream infection, they should be considered a temporary measure.

Native fistulas typically last longer than prosthetic grafts but require a longer time (6–8 weeks or more after surgical construction) for maturation. Infection, thrombosis, and aneurysm formation are complications seen more often in grafts than fistulas. Staphylococcus species are the most common cause of soft-tissue infections and bacteremia.

Dialysis at a hemodialysis center occurs three times a week. Sessions last 3–5 hours depending on patient size, type of dialyzer used, and other factors. Other hemodialysis schedules can be considered depending on available resources and patient preferences. Results from nocturnal dialysis trials have not been uniform but have shown improvements over thrice weekly dialysis for blood pressure control, mineral metabolism, and quality of life.

Home hemodialysis is often performed more frequently (3–6 days per week for shorter sessions) and requires a trained helper, and large equipment. The availability of these quotidian modalities (nocturnal and frequent home hemodialysis) is becoming more widespread; results of trials comparing these to conventional in-center dialysis have not thus far shown significant mortality differences.

B. Peritoneal dialysis—With peritoneal dialysis, the peritoneal membrane is the “dialyzer.” Dialysate is instilled into the peritoneal cavity through an indwelling catheter; water and solutes move across the capillary bed that lies between the visceral and parietal layers of the membrane

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into the dialysate during a “dwell.” After equilibration, the dialysate is drained, and fresh dialysate is instilled—this is an “exchange.”

There are three kinds of peritoneal dialysis: continuous ambulatory peritoneal dialysis (CAPD), in which the patient exchanges the dialysate four to six times a day manually; continuous cyclic peritoneal dialysis (CCPD), which utilizes a cycler machine to automatically perform exchanges at night; and nocturnal intermittent peritoneal dialysis (NIPD), where patients use a cycler machine at night without any fluid in the peritoneum during the day. As with hemodialysis, peritoneal dialysis prescriptions are guided by adequacy measurements (ie, dialytic clearance of urea).

Peritoneal dialysis permits significant patient autonomy. Its continuous nature minimizes the symptomatic volume and electrolyte shifts observed in hemodialysis patients, and poorly dialyzable compounds (such as phosphates) are better cleared, which permits less dietary restriction. However, peritoneal dialysate removes large amounts of albumin, and nutritional status must be closely watched.

The most common complication of peritoneal dialysis is peritonitis. Rates are improving (< 0.5 episodes per patient-year). Peritonitis may present with nausea and vomiting, abdominal pain, diarrhea or constipation, and fever. The dialysate is usually cloudy; and a diagnostic peritoneal fluid cell count is > 100 white blood cells/mcL of which over 50% are polymorphonuclear neutrophils.

Staphylococcus aureus is the most common infecting organism, but streptococci and gram-negative species are also common.

2. Kidney transplantation—Up to 50% of all patients with ESRD are otherwise healthy enough to be suitable for transplantation. Older age is becoming less of a barrier, as long as reasonable life expectancy is anticipated. Two-thirds of kidney allografts come from deceased donors, with the remainder from living related or unrelated donors. There are over 90,000 patients on the active waiting list for a deceased donor transplant in the United States; the average wait is 2–6 years, depending on geographic location and recipient blood type.

The 1- and 3-year kidney graft survival rates are approximately 96% and 91%, respectively, for living donor transplants and 91% and 81%, respectively, for deceased donor transplants. Factors that determine outcome include antigenic disparity (ABO blood groups and major histocompatibility or HLA) between donor and recipient, the type of immunologic response mounted by the host, and the immunosuppressive regimen used to prevent graft rejection. Nonimmunologic factors that affect the risk of chronic rejection include age and race of recipient; donor age; length of time on dialysis; and coexisting hyperlipidemia, hypertension, or cytomegalovirus infection.

Immunosuppressive regimens to prevent allograft rejection generally include a combination of a corticosteroid, an antimetabolite (azathioprine or mycophenolate mofetil), and a calcineurin inhibitor (tacrolimus or cyclosporine) or mTor inhibitor (sirolimus). Maintenance doses are lower than doses given at the time of transplant, with the aim of preventing recurrent rejection and chronic allograft

nephropathy, prolonging graft survival, and minimizing potentially serious medication side effects. Aside from medication use, the life of a transplant recipient can return to nearly normal, although these patients are at higher risk for certain cancers and infections.

3. Medical management of ESRD—As noted above, some patients are not candidates for transplantation and may not benefit from dialysis. Recent studies suggest that very elderly persons who do not die soon after dialysis initiation rapidly lose functional status in the first year of treatment. The decision to initiate dialysis in patients with limited life expectancy should be weighed against possible deleterious changes in quality of life. For patients with ESRD who elect not to undergo dialysis, death occurs within days to weeks. In general, uremia develops and patients lose consciousness prior to death. Arrhythmias can occur as a result of electrolyte imbalance. Volume overload and dyspnea can be managed by volume restriction and opioids as described in Chapter 5. Involvement of a palliative care team is essential.

``Prognosis in ESRD Compared with kidney transplant recipients and agematched controls, mortality is higher for patients undergoing dialysis. There is likely little difference in survival for well-matched peritoneal versus hemodialysis patients.

Survival rates on dialysis depend on the underlying disease process. Five-year Kaplan-Meier survival rates vary from 36% for patients with diabetes to 53% for patients with glomerulonephritis. Overall 5-year survival is currently estimated at 42%. Patients undergoing dialysis have an average life-expectancy of 3–5 years, but survival for as long as 25 years may be achieved depending on comorbidities.

The most common cause of death is cardiac disease (50%).

Other causes include infection (12%), cerebrovascular disease (15%), and malignancy (6%). Diabetes, advanced age, a low serum albumin, lower socioeconomic status, and inadequate dialysis are all significant predictors of mortality; high fibroblast growth factor (FGF)-23 levels have emerged as a novel marker for mortality in ESRD.

``When to Refer • A patient with stage 3–5 CKD should be referred to a nephrologist for management in conjunction with the primary care provider.

• A patient with other forms of CKD such as those with significant proteinuria (>1 g/d) or polycystic kidney disease should be referred to a nephrologist at earlier stages.

``When to Admit • Admission should be considered for patients with decompensation of problems related to CKD, such as worsening of acid-base status, electrolyte abnormalities, and volume status that cannot be appropriately treated in the outpatient setting.

• Admission is appropriate when a patient needs to start dialysis and is not stable for outpatient initiation.

Kidney Disease

Abboud H et al. Clinical practice. Stage IV chronic kidney disease.

N Engl J Med. 2010 Jan 7;362(1):56–65. [PMID: 20054047] Chrysant SG et al. Current status of aggressive blood glucose and blood pressure control in diabetic hypertensive subjects. Am J Cardiol. 2011 Jun 15;107(12):1856–61. [PMID: 21481823] FHN Trial Group; Chertow GM et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010 Dec 9;362(24):2287–300. [PMID: 21091062] Galliford J et al. Modern renal transplantation: present challenges and future prospects. Postgrad Med J. 2009 Feb;85(1000): 91–101. [PMID: 19329704] Himmelfarb J et al. Hemodialysis. N Engl J Med. 2010 Nov 4;363(19):1833–45. [PMID: 21047227] James MT et al. Early recognition and prevention of chronic kidney disease. Lancet. 2010;375(9722):1296–309. [PMID: 20382326] Kuritzky L et al. Identification and management of albuminuria in the primary care setting. J Clin Hypertens. 2011 Jun; 13(6):438–49. [PMID: 21649844] Matzke GR et al. Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).

Kidney Int. Dec;80(11):1122–37. [PMID: 21918498] Power A et al. Management of the dialysis patient for the hospital physician. Postgrad Med J. 2009 Jul;85(1005):376–381. [PMID: 19581248]

Renal Artery Stenosis

``

E ssent i a l s of d i a gnos i s

Produced by atherosclerotic occlusive disease (80–90% of patients) or fibromuscular dysplasia (10–15%). `` Hypertension. `` Acute kidney injury in patients starting ACE inhibitor therapy. ``

``General Considerations Atherosclerotic ischemic renal disease accounts for nearly all cases of renal artery stenosis. Fibromuscular dysplasia is a rare cause of renal artery stenosis. Approximately 5% of Americans with hypertension suffer from renal artery stenosis. It occurs most commonly in those over 45 years of age with a history of atherosclerotic disease. Other risk factors include CKD, diabetes mellitus, tobacco use, and hypertension.

``Clinical Findings A. Symptoms and Signs Patients with atherosclerotic ischemic renal disease may have refractory hypertension, new-onset hypertension (in an older patient), pulmonary edema with poorly controlled blood pressure, and acute kidney injury upon starting an ACE inhibitor. In addition to hypertension, physical examination may reveal an audible abdominal bruit on the affected side. Fibromuscular dysplasia primarily affects young women. Unexplained hypertension in a woman younger than 40 years is reason to screen for this disorder.

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B. Laboratory Findings Laboratory values can show elevated BUN and serum creatinine levels in the setting of significant renal ischemia.

C. Imaging Abdominal ultrasound can reveal asymmetric kidney size when one renal artery is affected out of proportion to the other.

Three prevailing methods used for screening are Doppler ultrasonography, CT angiography, and magnetic resonance angiography (MRA). Doppler ultrasonography is highly sensitive and specific (> 90% with an experienced ultrasonographer) and relatively inexpensive. However, this method is extremely operator and patient dependent.

Measurements of blood flow must be made at the aorta and along each third of the renal artery in order to assess the disease. This test is a poor choice for patients who are obese, unable to lie supine, or have interfering bowel gas patterns.

CT angiography consists of intravenous digital subtraction angiography with arteriography and is a noninvasive procedure. The procedure uses a spiral (helical) CT scan with intravenous contrast injection. The sensitivities from various studies range from 77% to 98%, with less varying specificities in a range of 90–94%.

MRA is an excellent but expensive way to screen for renal artery stenosis, particularly in those with atherosclerotic disease. Sensitivity is 77–100%, although one study with particular flaws showed a sensitivity of only 62%. Specificity ranges from 71% to 96%. Turbulent blood flow can cause false-positive results. The imaging agent for MRA (gadolinium) has been associated with nephrogenic systemic fibrosis, which occurs primarily in patients with a GFR of < 15 mL/ min/1.73 m2, and rarely in patients with a GFR of 15–30 mL/ min/1.73 m2. It has also been seen in those with acute kidney injury and kidney transplants.

Renal angiography is the gold standard for diagnosis.

CO2 subtraction angiography can be used in place of dye when the risk of dye nephropathy exists—eg, in diabetic patients with kidney injury. Lesions are most commonly found in the proximal third or ostial region of the renal artery. The risk of atheroembolic phenomena after angiography ranges from 5% to 10%. Fibromuscular dysplasia has a characteristic “beads-on-a-string” appearance on angiography.

``Treatment Treatment of atherosclerotic ischemic renal disease is controversial. Options include medical management, angioplasty with or without stenting, and surgical bypass. A 2009 study has shown that intervention is no better than optimal medical management in typical patients in whom renal artery stenosis was diagnosed via gold-standard mechanisms. Angioplasty might reduce the number of antihypertensive medications but does not significantly change the progression of kidney dysfunction in comparison to patients medically managed. Stenting produces significantly better angioplastic results. However, blood pressure is equally improved, and serum creatinines are similar at

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6 months of observation compared with both angioplasty and stents. Angioplasty is equally as effective as, and safer than, surgical revision. Treatment of fibromuscular dysplasia with percutaneous transluminal angioplasty is often curative.

ASTRAL Investigators; Wheatley K et al. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009 Nov 12;361(20):1953–62. [PMID: 19907042] Balk E et al. Effectiveness of management strategies for renal artery stenosis: a systematic review. Ann Intern Med. 2006 Dec 19;145(12):901–12. [PMID: 17062633] Hildreth CJ et al. JAMA patient page. Renal artery stenosis.

JAMA. 2008 Nov 5;300(17):2084. [PMID: 18984899] Textor SC et al. Renovascular hypertension and ischemic nephropathy. Am J Hypertens. 2010 Nov;23(11):1159–69. [PMID: 20864945]

cc

Glomerular Diseases

Abnormalities of glomerular function can be caused by damage to the major components of the glomerulus: the epithelium (podocytes), basement membrane, capillary endothelium, or mesangium. The damage may be caused by overwork injury, such as in CKD; by an inflammatory process, such as systemic lupus erythematosus; by a podocyte

protein mutation, such as in hereditary focal and segmental glomerulosclerosis; or a deposition disease, such as diabetes or amyloidosis. A specific histologic pattern of glomerular injury results from this damage and can be seen on renal biopsy.

``Classification Clinically, a glomerular disease can be classified as being in one of two spectra—either in the nephritic spectrum or the nephrotic spectrum (Figure 22–4). In the “least severe” end of the nephritic spectrum, the findings of glomerular hematuria (ie, dysmorphic red blood cells) are characteristic. The nephritic syndrome, comprising glomerular hematuria, subnephrotic proteinuria (<3 g/d), edema, and elevated creatinine, falls in the mid-portion of the spectrum. The rapidly progressive glomerulonephridities are at the “most severe” and clinically urgent end of the nephritic spectrum.

The nephrotic spectrum comprises diseases that present with primarily proteinuria of at least 0.5–1 g/d and a bland urine sediment (no cells or cellular casts). The more severe end of the nephrotic spectrum comprises the nephrotic syndrome, which is characterized by the constellation of nephrotic-range proteinuria of > 3 g/d, hypoalbuminuria, edema, and hyperlipidema. Differentiating between a clinical presentation within the nephritic spectrum versus the

Nephritic spectrum

Nephrotic Spectrum

Asymptomatic glomerular hematuria

Nephritic syndrome

Rapidly progressive glomerulonephritis

Asymptomatic proteinuria

Microscopic or macroscopic hematuria with or without proteinuria (<1 g/d)

Acute kidney injury with proteinuria of 1-3 g/d, hematuria, RBC casts, edema, and hypertension

Acute kidney injury with proteinuria of 1-3 g/d, hematuria, RBC casts, and systemic symptoms

Proteinuria of 300 mg/d - 10 g/d, and bland urine

Nephrotic syndrome

Proteinuria of > 3 g/d plus

Chronic Glomerular Disease

hypoalbuminemia, edema, hyperlipidemia, and possible oval fat bodies in urine

Chronic kidney disease with or without hematuria, proteinuria, hypertension, late-stage glomerulonephritis, burned-out disease

s Figure 22–4. Glomerular diseases present within one of the clinical spectra shown, the exact presentation is determined by the severity of the underlying disease and the pattern of injury. Nephritic diseases are characterized by the presence of an active urine sediment with glomerular hematuria and often with proteinuria. Nephrotic spectrum diseases are proteinuric with bland urine sediments (no cells or cellular casts). All glomerular diseases may progress to a chronic, scarred state. (Adapted, with permission, from Megan Troxell, MD, PhD.)

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Table 22–9. Classification and findings in glomerulonephritis: Nephritic spectrum presentations.

Typical presentation

Association/notes

Serology

Postinfectious glomerulonephritis

Children: abrupt onset of nephritic syndrome and acute kidney injury but can present anywhere in nephritic spectrum

Streptococci, other bacterial infections (eg, staphylococci, endocarditis, shunt infections)

Rising ASO titers, low complement levels

IgA nephropathy (Berger disease) and HenochSchönlein purpura, systemic IgA vasculitis

Classically: gross hematuria with upper respiratory tract infection; can present anywhere in nephritic spectrum; Henoch-Schönlein purpura with vasculitic rash and gastrointestinal hemorrhage

Abnormal IgA glycosylation in both primary (familial predisposition) and secondary disease (associated with cirrhosis, HIV, celiac disease) Henoch-Schönlein purpura in children after an inciting infection

No serologic tests helpful; complement levels are normal

Pauci-immune (granulomatosis with polyangiitis, ChurgStrauss, polyarteritis, idiopathic crescentic glomerulonephritis)

Classically as crescentic or RPGN, but can present anywhere in nephritic spectrum; may have respiratory tract/sinus symptoms in granulomatosis with polyangiitis

See Figure 22-5

ANCAs: MPO or PR3 titers high; complement levels normal

Anti-glomerular basement membrane glomerulonephritis; Goodpasture syndrome

Classically as crescentic or RPGN, but can present anywhere in nephritic spectrum; with pulmonary hemorrhage in Goodpasture syndrome

May develop as a result of respiratory irritant exposure (chemicals or tobacco use)

Anti-GBM antibody titers high; complement levels normal

Cryoglobulin-associated glomerulonephritis

Often acute nephritic syndrome; often with systemic vasculitis including rash and arthritis

Most commonly associated with chronic hepatitis C; may occur with other chronic infections or some connective tissue diseases

Cryoglobulins positive; rheumatoid factor may be elevated; complement levels low

Idiopathic MPGN

Classically presents with acute nephritic syndrome, but can see nephrotic syndrome features in addition

Most patients are < 30 years old Type I most common Type II (dense deposit disease) associated with C3 nephritic factor

Low complement levels

Hepatitis C infection

Anywhere in nephritic spectrum

Can cause MPGN pattern of injury or cryoglobulinemic glomerulonephritis; membranous nephropathy pattern of injury uncommon

Low complement levels; positive hepatitis C serology; rheumatoid factor may be elevated

Systemic lupus erythematosus

Anywhere in nephritic spectrum, depending on pattern/severity of injury

Treatment depends on clinical course and International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification on biopsy

High ANA and anti-doublestranded DNA titers; low complement levels

ANA, antinuclear; ANCAs: antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; MPGN, membranoproliferative glomerulonephritis; RPGN, rapidly progressive glomerulonephritis.

nephrotic spectrum is important because it helps narrow the differential diagnosis of the underlying glomerular disease (Tables 22–9 and 22–10).

Glomerular diseases can also be classified according to whether they cause only renal abnormalities (primary renal disease) or whether the renal abnormalities result from a systemic disease (secondary renal disease).

Further evaluation prior to renal biopsy may include serologic testing for systemic diseases that can result in glomerular damage (Figure 22–5).

Beck LH Jr et al. Glomerular and tubulointerstitial diseases.

Prim Care. 2008 Jun;35(2):265–96. [PMID: 18486716] Chiang CK et al. Glomerular diseases: genetic causes and future therapeutics. Nat Rev Nephrol. 2010 Sep;6(9):539–54. [PMID: 20644582] El Nahas M. Cardio-Kidney-Damage: a unifying concept. Kidney Int. 2010 Jul;78(1):14–8. [PMID: 20445499] McGrogan A et al. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011 Feb;26(2):414–30. [PMID: 21068142]

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Table 22–10. Classification and findings in glomerulonephritis: Nephrotic spectrum presentations.

Disease

Typical presentation

Association/notes

Minimal change disease (nil disease; lipoid nephrosis)

Child with sudden onset of full nephrotic syndrome

Children: associated with allergy or viral infection Adults: associated with Hodgkin disease, NSAIDs

Membranous nephropathy

Anywhere in nephrotic spectrum, but nephrotic syndrome not uncommon; particular predisposition to hypercoagulable state

Primary (idiopathic) may be associated with antibodies to PLA2R Associated with non-Hodgkin lymphoma, carcinoma (gastrointestinal, renal, bronchogenic, thyroid), gold therapy, penicillamine, SLE, chronic hepatitis B or C infection

Focal and segmental glomerulosclerosis

Anywhere in nephrotic spectrum; children with congenital disease have nephrotic syndrome

Children: congenital disease with podocyte gene mutation, or in spectrum of disease with minimal change disease Adults: Associated with heroin abuse, HIV infection, reflux nephropathy, obesity, pamidronate, podocyte protein mutations

Amyloidosis

Anywhere in nephrotic spectrum

AL: plasma cell dyscrasia with Ig light chain over-production and deposition; check SPEP and UPEP AA: serum amyloid protein A over-production and deposition in response to chronic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease, chronic infection)

Diabetic nephropathy

High GFR (hyperfiltration) → microalbuminuria → frank proteinuria → decline in GFR

Diabetes diagnosis precedes diagnosis of nephropathy by years

HIV-associated nephropathy

Heavy proteinuria, often nephrotic syndrome, progresses to ESRD relatively quickly

Usually seen in antiviral treatment-naïve patients (rare in HAART era), predilection for those of African descent

Membranoproliferative glomerulonephropathy

Can present with nephrotic syndrome, but usually with nephritic features as well (glomerular hematuria)

See Table 22-9

ESRD, end-stage renal disease; GFR, glomerular filtration rate; HAART, highly active antiretroviral therapy; NSAIDs, nonsteroidal antiinflammatory drugs; PLA2R, phospholipase A2 receptor; SLE, systemic lupus erythematosus; SPEP/UPEP: serum and urine protein electrophoresis.

Nephritic SPectrum Glomerular diseases

``

E ssent i a l s of d i a gnos i s

Glomerular hematuria (dysmorphic red blood cells), possibly red blood cell urinary casts. `` Less than nephrotic range proteinuria (0.3–3 g/d). `` Hypertension is common. `` Entity classified into one of three groups: asymptomatic glomerular hematuria, acute nephritic syndrome, or rapidly progressive glomerulonephritis. `` Edema, if present, in dependent (eg, periorbital or scrotal) areas. ``

``General Considerations Glomerulonephritis is a term given to those diseases that present in the nephritic spectrum and usually signifies an

inflammatory process causing renal dysfunction. It can be acute, developing over days to weeks, with or without resolution, or may be more chronic and indolent with progressive scarring. As noted above, diseases that cause a nephritic spectrum presentation may present with glomerular hematuria with some proteinuria, with nephritic syndrome, or with rapidly progressive glomerulonephritis (Figure 22–4). The presentation depends on the severity of the underlying inflammation and the pattern of injury caused by the disease process.

``Clinical Findings A. Symptoms and Signs If the nephritic syndrome is present, edema is first seen in regions of low tissue pressure such as the periorbital and scrotal areas. Hypertension in the nephritic syndrome is due to sodium retention resulting from acute decrease in GFR. Heavy glomerular bleeding from inflammation may result in gross hematuria (smoky or cola-colored urine).

Glomerulonephritis (GN) Serologic analysis Anti-glomerular basement membrane (GBM) antibodies

+

+

Immune complex disease markers

+

No extrarenal disease

Systemic necrotizing vasculitis

Respiratory necrotizing granulomas

Asthma and eosinophilia

No lung hemorrhage

Lung hemorrhage

Antinuclear antibodies

Antipathogen antibodies

ANCAassociated crescentic GN

Microscopic polyangiitis

Granulomatosis with polyangiitis

ChurgStrauss syndrome

Anti-GBM GN

Goodpasture syndrome

Lupus GN

IgA Cryoglobulinemic Postinfectious nephropathy GN or periinfectious GN

Anti-GBM GN

Cryoglobulins C3 nephritic factor MPGN

Immune complex GN

s Figure 22–5. Serologic analysis of patients with glomerulonephritis. MPGN, membranoproliferative glomerulonephritis. (Reproduced, with permission, from Greenberg A et al. Primer on Kidney Diseases. Academic Press, 1994 and Jennette JC, Falk RJ. Diagnosis and management of glomerulonephritis and vasculitis presenting as acute renal failure. Med Clin North Am. 1990;74(4):893–908. © Elsevier.)

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IgA

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Antineutrophil cytoplasmic antibodies (ANCA)

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B. Laboratory Findings 1. Serologic testing—Serologic tests, including complement levels, antinuclear antibodies, cryoglobulins, hepatitis serologies, ANCAs, anti-GBM antibodies, and antistreptolysin O (ASO) titers (Figure 22–5), are done based on the history and physical examination to narrow the differential diagnosis of the nephritic spectrum disorder.

2. Urinalysis—The urinalysis shows protein and red blood cells. On microscopy, these cells are misshapen from traversing a damaged capillary membrane—so-called dysmorphic red blood cells. Red blood cell casts are seen with heavy glomerular bleeding and tubular stasis. When quantified, proteinuria is usually subnephrotic (<3 g/d).

3. Biopsy—Renal biopsy should be considered if there are no contraindications (eg, bleeding disorders, thrombocytopenia, uncontrolled hypertension). Light microscopy delineates the pattern of injury; underlying disease process can be further categorized according to the immunofluorescence pattern and appearance on electron microscopy.

``Treatment General measures for all include aggressive treatment of hypertension and fluid overload if present. Dialysis may be needed as discussed in the acute kidney injury section. The inflammatory glomerular injury may require corticosteroids or cytotoxic agents, or both. (See specific diseases discussed below.)

``When to Refer Any patient in whom a glomerulonephritis is suspected should be referred to a nephrologist.

``When to Admit Any suspicion of acute nephritic syndrome or rapidly progressive glomerulonephritis warrants consideration of immediate hospitalization.

Postinfectious Glomerulonephritis

``

E ssent i a l s of d i a gnos i s

Proteinuria.

Glomerular hematuria. `` Symptoms 1–3 weeks after infection (often pharyngitis or impetigo). ``

(especially with S aureus), bacterial pneumonias, deepseated abscesses, gram-negative infections, infective endocarditis, and shunt infections. Viral, fungal, and parasitic causes of postinfectious glomerulonephritis pattern of glomerular injury include hepatitis B or C, HIV, cytomegalovirus infection, infectious mononucleosis, coccidioidomycosis, malaria, mycobacteria, syphilis, and toxoplasmosis.

``Clinical Findings A. Symptoms and Signs Disease presentation can vary widely across the nephritic spectrum from asymptomatic glomerular hematuria (especially in epidemic cases) to nephritic syndrome with hypertension, oliguria, edema, and perhaps cola-colored urine.

B. Laboratory Findings Serum complement levels are low; in postinfectious glomerulonephritis due to group A streptococcal infection, antistreptolysin O (ASO) titers can be high unless the immune response has been blunted with previous antibiotic treatment. Glomerular hematuria and subnephrotic proteinuria are present; severe cases may demonstrate elevated serum creatinine and red cell casts in the urine. Renal biopsy shows a diffuse proliferative pattern of injury on light microscopy. Immunofluorescence shows IgG and C3 in a granular pattern in the mesangium and along the capillary basement membrane. Electron microscopy shows large, dense subepithelial deposits or “humps.”

``Treatment The underlying infection should be identified and treated appropriately, but otherwise, treatment for postinfectious glomerulonephritis is supportive. Antihypertensives, salt restriction, and diuretics should be used if needed.

Corticosteroids have not been shown to improve outcome.

Prognosis depends on the severity of the glomerular injury and age of the patient. Children are more likely to fully recover; adults are more prone to the development of severe disease (rapidly progressive glomerulonephritis with crescent formation) and CKD. Kanjanabuch T et al. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol. 2009 May; 5(5):259–69. [PMID: 19384327]

``

IgA Nephropathy

``General Considerations Postinfectious glomerulonephritis is most often due to infection with nephritogenic group A β-hemolytic streptococci. It can occur sporadically or in clusters and during epidemics. It commonly appears after pharyngitis or impetigo with onset 1–3 weeks after infection (average 7–10 days).

Other infections have been associated with postinfectious glomerulonephritis including bacteremic states

``

E ssent i a l s of d i a gnos i s

Proteinuria: minimal to nephrotic range.

Glomerular hematuria: microscopic is common; macroscopic (gross) after infection. `` Positive IgA staining on renal biopsy. `` ``

Kidney Disease

``General Considerations IgA nephropathy (Berger disease) is a primary renal disease of IgA deposition in the glomerular mesangium. The inciting cause is unknown but is likely due to abnormal glycosylation of IgA subclass 1 molecules. IgA nephropathy can be a primary (renal-limited) disease, or it can be secondary to hepatic cirrhosis, celiac disease, and infections such as HIV and cytomegalovirus. Susceptibility to IgA nephropathy seems to be inheritable.

IgA nephropathy is the most common primary glomerular disease worldwide, particularly in Asia. It is most commonly seen in children and young adults, with males affected two to three times more commonly than females.

``Clinical Findings An episode of gross hematuria is the most common presenting symptom. Frequently, this is associated with an upper respiratory infection (50%), GI symptoms (10%), or a flu-like illness (15%). The urine becomes red or colacolored 1–2 days after illness onset. In contrast to postinfectious glomerulonephritis, this feature has been called “synpharyngitic hematuria” since there is no significant latent period. IgA nephropathy can present as any of the nephritic syndromes from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis.

Rarely, it can present as a nephrotic syndrome.

There are no serologic tests that aid in the diagnosis of IgA nephropathy; serum IgA subclass 1 testing may be a possibility in the future. Serum complements are normal.

The typical pattern of injury seen on renal biopsy is a focal glomerulonephritis with mesangial proliferation; immunofluorescence demonstrates diffuse mesangial IgA and C3 deposits.

``Treatment The disease course of primary IgA nephrology varies widely among patients; treatment approach needs to be tailored to risk for progression. Patients with low risk for progression (no hypertension, normal GFR, minimal proteinuria) can be monitored annually. Patients at medium to high risk (proteinuria > 0.5 g/d, decreased GFR, or hypertension, or any combination of these three conditions) should be given an initial course of conservative treatment, including ACE inhibitor or ARB therapy and blood pressure control to 130/80 mm Hg. For those in this risk category who have nephrotic syndrome or a rapid decline in GFR, or those in whom proteinuria is not suppressed to < 1 g/d but have relatively preserved GFR (stage 3 CKD or less), immunosuppressive therapy should be considered. In patients with proteinuria of 1.0–3.5 g/d and GFR > 70 mL/min/1.73 m2, corticosteroid therapy has proven beneficial. One such regimen (methylprednisolone, 1 g/d intravenously for 3 days during months 1, 3, and 5, plus prednisone in a dosage of 0.5 mg/kg orally every other day for 6 months) showed a 2% doubling of creatinine after 6 years in the treatment group versus a 21% doubling of creatinine in the control group. For patients with a GFR < 70 mL/min/1.73 m2 and a predicted progression to ESRD in < 5 years, some experts have suggested a trial of low-dose cyclophosphamide followed by maintenance azathioprine. Kidney transplantation is an

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excellent option for patients with ESRD, but recurrent disease has been documented in 30% of patients 5–10 years posttransplant. Fortunately, recurrent disease rarely leads to failure of the allograft.

``Prognosis Approximately one-third of patients experience spontaneous clinical remission. Progression to ESRD occurs in 20–30% of patients. The remaining patients show chronic microscopic hematuria and a stable serum creatinine. The most unfavorable prognostic indicator is proteinuria > 1 g/d; other unfavorable prognostic indicators include hypertension, persistent microscopic hematuria and proteinuria, glomerulosclerosis or glomerular crescents on biopsy, and abnormal GFR on presentation.

Floege J et al. Current therapy for IgA nephropathy. J Am Soc Nephrol. 2011 Oct;22(10):1785–94. [PMID: 21903997] Suzuki H et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011 Oct;22(10):1795–803. [PMID: 21949093]

Henoch-Schönlein Purpura Henoch-Schönlein purpura is a small-vessel leukocytoclastic vasculitis associated with IgA subclass 1 deposition in vessel walls. It is most common in children and is often associated with an inciting infection, such as group A streptococcus or other exposure. There is a male predominance.

It classically presents with palpable purpura in the lower extremities and buttock area; arthralgias; and abdominal symptoms, such as nausea, colic, and melena. A decrease in GFR is common with a nephritic presentation. The renal lesions are considered by most experts to be identical to those found in IgA nephropathy. Most patients with microscopic hematuria and minimal proteinuria recover fully over several weeks. Progressive CKD and possibly ESRD are more likely to develop in those with the nephrotic syndrome and the presence of both nephritic and nephrotic syndrome poses the worst renal prognosis. Histologic classification of the lesions in children may also provide prognostic information. To date, although several treatment regimens of various immunosuppressive agents have been clinically tested, none have been definitively proven to alter the course of severe Henoch-Schönlein purpura nephritis. Rituximab treatment and plasma exchange have been successful for severe disease according to several case reports, but clinical trials are lacking.

Further details about Henoch-Schönlein purpura are provided in Chapter 20.

Davin JC. Henoch-Schonlein purpura nephritis: pathophysiology, treatment, and future strategy. Clin J Am Soc Nephrol.

2011 Mar;6(3):679–89. [PMID: 21393485] Pillebout E et al; CESAR study group. Addition of cyclophosphamide to steroids provides no benefit compared with steroids alone in treating adult patients with severe Henoch Schönlein purpura. Kidney Int. 2010 Sep;78(5):495–502.

[PMID: 20505654] Saulsbury FT. Henoch-Schönlein purpura. Curr Opin Rheumatol.

2010 Sep;22(5):598–602. [PMID: 20473173] Xia Y et al. Clinical outcomes in children with Henoch-Schönlein purpura nephritis grade IIIa or IIIb. Pediatr Nephrol. 2011 Jul;26(7):1083–8. [PMID: 21387156]

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Pauci-Immune Glomerulonephritis (ANCA-Associated) Pauci-immune necrotizing glomerulonephritis is caused by the following systemic ANCA-associated small-vessel vasculitides: granulomatosis with polyangiitis, microscopic polyangiitis, and Churg-Strauss disease (see Chapter 20).

ANCA-associated glomerulonephritis can also present as a primary renal lesion without systemic involvement; this is termed “idiopathic crescentic glomerulonephritis.” The precise pathogenesis of these entities is unknown; it is likely that ANCAs are responsible for neutrophil activation and consequent vascular damage. Immunofluorescence of renal biopsy specimens do not reveal any evidence of immunoglobulin or complement deposition, hence the term“pauci-immune.” Renal involvement classically presents as a rapidly progressive glomerulonephritis.

``Clinical Findings A. Symptoms and Signs Symptoms of a systemic inflammatory disease, including fever, malaise, and weight loss may be present and usually precede initial presentation by several months. In addition to hematuria and proteinuria from glomerular inflammation, some patients exhibit purpura from dermal capillary involvement and mononeuritis multiplex from nerve arteriolar involvement. Ninety percent of patients with granulomatosis with polyangiitis have upper (especially sinus) or lower respiratory tract symptoms with nodular lesions that can cavitate and bleed. Hemoptysis is a concerning sign and usually warrants hospitalization.

B. Laboratory Findings

``Prognosis Without treatment, prognosis is extremely poor. However, with aggressive treatment, complete remission can be achieved in about 75% of patients. Prognosis depends on the extent of renal involvement before treatment is started.

ANCA titers should be monitored to follow treatment efficacy; rising titers herald relapse. Patients receiving cyclophosphamide should receive prophylaxis for Pneumocystis jiroveci, such as trimethoprim-sulfamethoxazole doublestrength orally 3 days per week.

Hiemstra TF et al; European Vasculitis Study Group (EUVAS).

Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010 Dec 1;304(21):2381–8. [PMID: 21060104] Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis. 2011 Mar;70(Suppl 1):i59–63. [PMID: 21339221] Rutgers A et al. Pauci-immune necrotizing glomerulonephritis.

Rheum Dis Clin North Am. 2010 Aug;36(3):559–72. [PMID: 20688250] Walsh M et al. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis. 2011 Apr;57(4):566–74. [PMID: 21194817]

Anti-glomerular Basement Membrane Glomerulonephritis & Goodpasture Syndrome Goodpasture syndrome is defined by the clinical constellation of glomerulonephritis and pulmonary hemorrhage; injury to both is mediated by antibodies to epitopes in the GBM (Figure 22–5). Up to one-third of patients with anti-GBM glomerulonephritis have no evidence of concomitant lung injury. Anti-GBM-associated glomerulonephritis accounts for 10–20% of patients with rapidly progressive acute glomerulonephritis. The incidence peaks in the second and third decades of life during which time males are predominantly affected and lung involvement is more common, and again in the sixth and seventh decades with less gender predominance. Lung involvement has been associated with pulmonary infection, tobacco use, and hydrocarbon solvent exposure; HLA-DR2 and -B7 antigens may predispose as well.

Serologically, ANCA subtype analysis is done. A c-ANCA is specific for antiproteinase-3 antibodies (PR3-ANCA), while a p-ANCA is specific for antimyeloperoxidase antibodies (MPO-ANCA). Most patients with granulomatosis with polyangiitis are c-ANCA positive; the remainder can have a p-ANCA pattern or rarely do not demonstrate ANCA serologically. Microscopic angiitis has either a p-ANCA or c-ANCA pattern about 80% of the time. As noted above, the small vessels and glomeruli lack immune deposits on immunofluorescence. Necrotizing lesions and crescents are the pattern of injury associated with this rapidly progressive glomerulonephritis.

``Clinical Findings

``Treatment

A. Symptoms and Signs

Treatment should be instituted early. Induction therapy of high-dose corticosteroids (methylprednisolone, 1–2 g/d intravenously for 3 days, followed by prednisone, 1 mg/kg orally for 1 month, with a slow taper over the next 6 months) and cytotoxic agents (cyclophosphamide, 0.5–1 g/m2 intravenously per month or 1.5–2 mg/kg orally for 3–6 months) is followed by long-term azathioprine or mycophenolate mofetil. Plasma exchange has been shown to be beneficial in conjunction with induction therapy; however, a recent meta-analysis calls into question the strength of this benefit. Rituximab has recently been shown to be noninferior to cyclophosphamide for induction.

The onset of disease is preceded by an upper respiratory tract infection in 20–60% of cases; hemoptysis, dyspnea, and possible respiratory failure may ensue. Other findings are consistent with a rapidly progressive acute glomerulonephritis, although some cases may present with much milder forms of the nephritic spectrum of disease (eg, glomerular hematuria and proteinuria with minimal renal dysfunction).

B. Laboratory Findings Laboratory evaluation can show iron deficiency anemia if pulmonary hemorrhage has been prolonged. Serum

Kidney Disease complement levels are normal. Sputum may contain hemosiderin-laden macrophages. Chest radiographs can show shifting pulmonary infiltrates due to pulmonary hemorrhage. The diffusion capacity of carbon monoxide is markedly increased. Diagnosis is confirmed by finding circulating anti-GBM antibodies, which are positive in over 90% of patients. About 15% of patients also have elevated ANCA titers; these patients should be treated with plasma exchange as for anti-GBM disease. Renal biopsy typically shows crescent formation on light microscopy, with linear IgG staining along the GBM on immunofluorescence.

``Treatment The treatment of choice is a combination of plasma exchange therapy to remove circulating antibodies, and administration of immunosuppressive drugs to prevent formation of new antibodies and control the inflammatory response. Corticosteroids are typically given initially in pulse doses of methylprednisolone, 1–2 g/d for 3 days, then prednisone orally 1 mg/kg/d. Cyclophosphamide is administered intravenously at a dose of 0.5–1 g/m2 per month or orally at a dosage of 2–3 mg/kg/d. Daily plasma exchange is performed for up to 2 weeks. A poorer prognosis exists in patients with oliguria and a serum creatinine > 6–7 mg/dL, or requiring dialysis upon presentation. Anti-GBM antibody titers should decrease as the clinical course improves.

Cui Z et al. Advances in human antiglomerular basement membrane disease. Nat Rev Nephrol. 2011 Jul 19;7(12):697–705.

[PMID: 21769105]

Cryoglobulin-Associated Glomerulonephritis Essential (mixed) cryoglobulinemia is a disorder associated with cold-precipitable immunoglobulins (cryoglobulins). Glomerular disease results from the precipitation of cryoglobulins in glomerular capillaries (Figure 22–5).

The cause is typically hepatitis C infection, but other infections (such as hepatitis B) or other occult or clinically apparent viral, bacterial, and fungal infections can be causative; it is also associated with some connective tissue diseases.

Patients exhibit purpuric and necrotizing skin lesions in dependent areas, arthralgias, fever, and hepatosplenomegaly.

Serum complement levels are depressed. Rheumatoid factor is often elevated when cryoglobulins are present. Renal biopsy may show several different patterns of injury; there may be crescent formation, glomerular capillary thrombi, or MPGN (see below). Treatment consists of aggressively targeting the causative infection. Pulse corticosteroids, plasma exchange, and cytotoxic agents have been used when risk of exacerbating the underlying infection is resolved. Interferon-α (IFN-α) has been shown to benefit patients with hepatitis C–related cryoglobulinemia; in patients who do not respond to such treatment or for whom antiviral treatment is not indicated, there is some suggestion that rituximab may improve renal outcomes.

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Colucci G et al. Cryoglobulinemic membranoproliferative glomerulonephritis: beyond conventional therapy. Clin Nephrol.

2011 Apr;75(4):374–9. [PMID: 21426893]

Idiopathic Membranoproliferative Glomerulonephritis MPGN in its primary form is an idiopathic renal disease that usually presents with nephritic features ranging from asymptomatic glomerular hematuria and proteinuria, to episodes of gross hematuria, to the acute nephritic syndrome. MPGN may also present with the nephrotic syndrome. Most patients are under 30 years of age, and a recent history of upper respiratory tract infection is present in nearly half. At least two major subgroups are recognized: type I and type II. Both are characterized by hypocomplementemia; in type I MPGN, the classic complement pathway is activated, leading to low or normal C3 with low C4, whereas in type II disease, the alternative complement pathway is activated and C3 is low while C4 is normal. Prognosis is worse in type II disease.

Renal biopsy in type I MPGN demonstrates a thickened GBM due to immune complex deposition and abnormal mesangial cell proliferation between the GBM and the endothelial cells. This gives a characteristic “splitting” or “tram-track” appearance to the capillary wall.

Immunofluorescence shows IgG, IgM, and granular deposits of C3, C1q, and C4. Subendothelial deposits are seen on electron microscopy.

Type II MPGN (dense deposit disease) is less common than type I and is associated with C3 nephritic factor, a circulating IgG antibody. Light microscopy is similar to type I. Electron microscopy shows a characteristic ribbon-like deposit of homogeneous material that replaces part of the GBM. Treatment of idiopathic MPGN is controversial. After ruling out secondary or systemic causes, treatment of children with nephrotic syndrome consists of corticosteroids at 40 mg/m2 every other day for a prolonged duration.

Uncontrolled studies suggest that there may be some role for other immunosuppressive regimens, including cyclophosphamide, cyclosporine, and mycophenolate mofetil.

ACE inhibitors and ARBs should be used to treat hypertension and proteinuria. Adults are less likely to respond to corticosteroid treatment. In the past, 50% of patients progressed to ESRD in 10 years; this rate may now be slightly lower with the introduction of more aggressive therapy.

Less favorable prognostic findings include type II MPGN, early renal insufficiency, hypertension, and persistent nephrotic syndrome. Both types of MPGN will recur after renal transplantation; however, type II recurs more commonly.

Plasma exchange has been used with mixed results to treat post-transplant recurrence of MPGN. Alchi B et al. Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010 Aug;25(8):1409–18. [PMID: 19908070] Yuan M et al. Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis. Clin Nephrol. 2010 May; 73(5):354–9. [PMID: 20420795]

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Hepatitis C Virus Infection Renal disease in the setting of hepatitis C viral infection was not well-recognized until 1993. Now it accounts for approximately 8% of patients with ESRD. The three patterns of renal injury associated with hepatitis C are secondary MPGN, cryoglobulinemic glomerulonephritis, and membranous nephropathy. A type I MPGN (see section above) is the most common lesion found on kidney biopsy. These patients typically have hematuria and proteinuria, hypertension, and anemia. Occasionally, they also exhibit features of the nephrotic syndrome. Many patients have elevated serum transaminases and an elevated rheumatoid factor.

Hypocomplementemia is very common, with C4 typically more reduced than C3. Cryoglobulinemic disease is discussed above. Membranous glomerulopathy is the least common of the three and presents with a typical nephrotic picture; neither cryoglobulins nor rheumatoid factor is present.

``Treatment In patients with hepatitis C virus–associated MPGN not receiving treatment for liver disease, the question arises whether to initiate therapy for kidney disease. The main indications for therapy are poor renal function, nephrotic syndrome, new or worsening hypertension, fibrosis or tubulointerstitial disease on biopsy, and progressive disease. IFN-α may result in suppression of viremia and improvement in hepatic function. Renal function rarely improves unless viral suppression occurs; however, renal function often worsens when therapy is abated. Ribavirin is relatively contraindicated in kidney disease because of the dose-related hemolysis that occurs with renal dysfunction. Despite this, some case series have shown benefit with combined IFN-α and ribavirin in closely monitored settings.

Perico N et al. Hepatitis C infection and chronic renal diseases. Clin J Am Soc Nephrol. 2009 Jan;4(1):207–20. [PMID: 19129320]

Systemic Lupus Erythematosus Systemic lupus erythematosus is an autoimmune disease in which renal involvement is common. In various series, renal involvement ranges from 35% to 90% (see Chapter 20), with the higher estimates encompassing subclinical disease.

Lupus nephritis may present as any entity in the spectrum of clinical glomerular disease, although most presentations are as glomerulonephritis. Nonglomerular syndromes include tubulointerstitial nephritis and vasculitis. All patients with systemic lupus erythematosus should have routine urinalyses to monitor for the appearance of hematuria or proteinuria. If urinary abnormalities are detected, renal biopsy is often performed. The 2003 International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification of renal glomerular lesions is class I, minimal mesangial nephritis; class II, mesangial proliferative nephritis; class III, focal (< 50% of glomeruli affected with capillary involvement) proliferative nephritis;

class IV, diffuse (> 50% of glomeruli affected with capillary involvement) proliferative nephritis; class V, membranous nephropathy; and class VI, advanced sclerosis without residual disease activity. Classes III and IV, the most severe forms of lupus nephritis, are further classified as active or chronic, and global or segmental, which confers additional prognostic value.

``Treatment Individuals with class I and class II lesions require no treatment. Transformation of these types to a more active lesion may occur and is usually accompanied by an increase in lupus serologic activity and evidence of deteriorating renal function (eg, rising serum creatinine, increasing proteinuria). Repeat biopsy to confirm the transformation in these patients is recommended. Patients with extensive class III lesions and all class IV lesions should receive aggressive immunosuppressive therapy. The features signifying the poorest prognosis in patients with class III or IV lesions include elevated serum creatinine, lower complement levels, male sex, presence of antiphospholipid antibodies, nephrotic-range proteinuria, black race, and poor response to therapy. Indications for treatment of class V lesions are unclear; however, if superimposed proliferative lesions exist, aggressive therapy should be instituted.

Treatment of proliferative lupus nephritis consists of induction therapy, followed by maintenance treatment. All induction therapy includes corticosteroids (eg, methylprednisolone 1 g intravenously daily for 3 days followed by prednisone, 1 mg/kg orally daily with subsequent taper over 4–6 weeks) in combination with either cyclophosphamide or mycophenolate mofetil. Current data suggest that blacks and Hispanics respond more favorably to mycophenolate mofetil rather than cyclophosphamide; in addition, mycophenolate mofetil has a more favorable side-effect profile than does cyclophosphamide. Cyclophosphamide induction regimens vary but usually involve monthly intravenous pulse doses (500–750 mg/m2) for 4–8 months.

Induction is followed by daily oral mycophenolate mofetil or azathioprine maintenance therapy. A recent trial showed that mycophenolate mofetil was superior to azathioprine maintenance and caused few adverse effects.

Mycophenolate mofetil induction is typically given at 2–3 g/d, then tapered to 1–2 g/d for maintenance.

Tacrolimus or cyclosporine may also be considered, but the relapse rate is high upon discontinuation of these agents.

Rituximab has also been used for induction therapy, but clinical trial data are lacking. Remission rates with induction vary from 80% for partial remission to 50–60% for full remission; it may take more than 6 months to see these effects. Relapse is common and rates of disease flare are higher in those who do not experience complete remission; similarly, progression to ESRD is more common in those who relapse more frequently, or in whom no remission has been achieved.

The normalization of various laboratory tests (doublestranded DNA antibodies, serum C3, C4, CH50 levels) can be useful in monitoring treatment. Urinary protein levels and sediment activity are also helpful markers. Patients with systemic lupus erythematosus who undergo dialysis have a

Kidney Disease favorable prospect for long-term survival; interestingly, systemic lupus symptoms may become quiescent with the development of ESRD. Patients with systemic lupus erythematosus undergoing kidney transplants have recurrent renal disease in 8% of cases.

Dooley MA et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17; 365(20):1886–95. [PMID: 22087680] Ortega LM et al. Lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus. 2010 Apr; 19(5):557–74. [PMID: 20089610] Tesar V et al. Treatment of proliferative lupus nephritis: a slowly changing landscape. Nat Rev Nephrol. 2011 Feb;7(2):96–109.

[PMID: 21173789]

Nephrotic SPECTRUM Glomerular diseases

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Bland urine sediment (few if any cells or cellular casts). `` Full-blown nephrotic syndrome consists of the following: ● -Urine protein excretion > 3 g per 24 hours. ● -Hypoalbuminemia (albumin < 3 g/dL). ● -Peripheral edema. ● -Hyperlipidemia. ● -Oval fat bodies in the urine. ``

``General Considerations In adults, about one-third of patients with nephrotic syndrome have a systemic disease such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus. With the current epidemic of type 2 diabetes mellitus, the proportion with diabetes is slowly increasing. The remainder have proteinuria due to primary renal disease. The most common causes are minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and MPGN (see above). Any of these disease processes can present on the less severe end of the spectrum with a bland urinalysis and proteinuria, or with the full-blown nephrotic syndrome. Serum creatinine may or may not be abnormal at the time of presentation, depending on the severity, acuity and chronicity of the disease.

``Clinical Findings A. Symptoms and Signs Peripheral edema is a hallmark of the nephrotic syndrome, occurring when the serum albumin concentration is < 3 g/dL (30 g/L). Edema is most likely due to sodium retention and, at albumin levels < 2 g/dL (20 g/L), arterial underfilling from low plasma oncotic pressure. Initially, this presents in

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the dependent areas of the body subject to gravity, such as the lower extremities; however, such edema can become generalized, including notable periorbital edema. Patients can experience dyspnea due to pulmonary edema, pleural effusions, and diaphragmatic compromise with ascites.

Complaints of abdominal fullness may also be present in patients with ascites.

Patients with the nephrotic syndrome may also have an increase incidence of infection owing to loss of immunoglobulins and certain complement moieties in the urine; similarly, there can be increased risk of venous thrombosis secondary to loss of anticoagulant factors.

B. Laboratory Findings 1. Urinalysis—Proteinuria occurs as a result of effacement of podocytes (foot processes) and an alteration of the negative charge of the GBM. The screening test for proteinuria is the urinary dipstick analysis; however, this test indicates albumin only. The addition of sulfosalicylic acid to the urine sediment allows abnormal paraproteins to be detected. A spot urine protein to urine creatinine ratio gives a reasonable approximation of grams of protein excreted per day.

Microscopically, the urinary sediment has relatively few cellular elements or casts. However, if marked hyperlipidemia is present, the urine can have oval fat bodies resulting from lipid deposits in sloughed renal tubular epithelial cells. They appear as “grape clusters” under light microscopy and “Maltese crosses” under polarized light.

2. Blood chemistries—The nephrotic syndrome results in hypoalbuminemia (< 3 g/dL [30 g/L]) and hypoproteinemia (< 6 g/dL [60 g/L]). Hyperlipidemia occurs in over 50% of patients with early nephrotic syndrome, and becomes more frequent and worsens in degree as the severity of the nephritic syndrome increases. A fall in oncotic pressure triggers increased hepatic production of lipids (cholesterol and apolipoprotein B). There is also decreased clearance of very low-density lipoproteins, causing hypertriglyceridemia. Patients may also have an elevated erythrocyte sedimentation rate as a result of alterations in some plasma components such as increased levels of fibrinogen.

Patients may become deficient in vitamin D, zinc, and copper from loss of binding proteins in the urine.

Laboratory testing to determine the underlying cause may include complement levels, serum and urine protein electrophoresis, antinuclear antibodies, and serologic tests for hepatitis.

3. Renal biopsy—Renal biopsy is often performed in adults with new-onset idiopathic nephrotic syndrome if a primary renal disease that may require drug therapy (eg, corticosteroids, cytotoxic agents) is suspected. Chronically and significantly elevated creatinine levels may indicate irreversible kidney disease mitigating the usefulness of kidney biopsy. In the setting of long-standing diabetes mellitus type 1 or 2, proteinuric renal disease is rarely biopsied unless atypical features (such as significant glomerular hematuria or cellular casts) are also present, or if there is other reason to suspect a second renal lesion.

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``Treatment A. Protein Loss The daily total dietary protein intake should replace the daily urinary protein losses so as to avoid negative nitrogen balance. Protein malnutrition often occurs with urinary protein losses > 10 g/d. In the past, protein restriction was suggested for patients with kidney disease. The largest human trial to date (the MDRD Study) did not show a significant benefit, but two meta-analyses in 1999 and 2001 have shown a mild renal benefit. For this reason, the KDOQI recommends protein restriction to 0.6–0.8 g/kg/d in patients with a GFR < 25 mL/min/1.73 m2 prior to starting dialysis. However, great care must be taken to avoid malnutrition in these patients.

In both diabetic and nondiabetic patients, therapy that is aimed at reducing proteinuria may also reduce progression of renal disease. ACE inhibitors and ARBs lower urine protein excretion by lowering efferent arteriolar resistance, thereby reducing glomerular capillary pressure; they also have antifibrotic effects. ACE inhibitors and ARBs can be used in patients with reduced GFR as long as significant hyperkalemia (potassium > 5.2–5.5 mEq/L) does not occur and serum creatinine rises < 30%; these patients should be monitored closely to avoid acute kidney injury and hyperkalemia. The combination of an ACE inhibitor and ARB versus ARB alone for slowing the progression of diabetic nephropathy is being tested in a multicenter, prospective randomized study.

B. Edema Dietary salt restriction is essential for managing edema; most patients also require diuretic therapy. Commonly used diuretics include thiazide and loop diuretics (both are highly protein bound). With hypoalbuminemia and decreased GFR, diuretic delivery to the kidney is reduced, and patients often require larger doses. A combination of loop and thiazide diuretics can potentiate the diuretic effect. This may be needed for patients with refractory fluid retention.

C. Hyperlipidemia Hypercholesterolemia and hypertriglyceridemia occur as noted above. Dietary modification and exercise should be advocated; however, effective lipid-lowering usually also requires pharmacologic treatment (see Chapter 28). Statins are hepatically cleared, so dosage is not altered for CKD. Rhabdomyolysis, however, is more common in patients with CKD who take gemfibrozil in combination with statins; combining fenofibrate or niacin with a statin poses less risk of rhabdomyolysis.

D. Hypercoagulable State Patients with serum albumin < 2 g/dL can become hypercoagulable. Nephrotic patients have urinary losses of antithrombin, protein C, and protein S and increased platelet activation. Patients are prone to renal vein thrombosis and other venous thromboemboli, particularly with membranous glomerulopathy. Anticoagulation therapy is

warranted for at least 3–6 months in patients with evidence of thrombosis in any location. Patients with renal vein thrombosis or recurrent thromboemboli require indefinite anticoagulation.

``When to Refer Any patient noted to have nephrotic syndrome should be referred immediately to a nephrologist for aggressive volume and blood pressure management, assessment for renal biopsy, and treatment of the underlying disease.

Proteinuria of > 1 g/d without the nephrotic syndrome also merits nephrology referral, though with less urgency.

``When to Admit Patients with edema refractory to outpatient therapy or rapidly worsening kidney function that may require inpatient interventions should be admitted.

Haider DG et al. Kidney biopsy in patients with diabetes mellitus. Clin Nephrol. 2011 Sep;76(3):180–5. [PMID: 21888854] Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009 Nov 15;80(10):1129–34.

[PMID: 19904897]

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Nephrotic SPECTRUM Disease In Primary Renal Disorders

Minimal Change Disease

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Nephrotic range proteinuria.

Kidney biopsy shows no changes on light microscopy. `` Characteristic foot-process effacement on electron microscopy. `` ``

``General Considerations Minimal change disease is the most common cause of proteinuric renal disease in children, accounting for about 80% of cases. It often remits upon treatment with a course of corticosteroids. Indeed, children with nephrotic syndrome are often treated for minimal change disease empirically without a biopsy diagnosis. Biopsy should be considered for children with nephrotic syndrome who exhibit unusual features (such as signs of other systemic illness), who are steroid-resistant (see below), or who relapse frequently upon withdrawal of corticosteroid therapy. Minimal change disease is less common in adults, accounting for 20–25% of cases of primary nephrotic syndrome in those over age 40 years. This entity can be idiopathic but also occurs following viral upper respiratory infections (especially in children), in association with tumors such as Hodgkin disease, with drugs (lithium), and with hypersensitivity reactions (especially to NSAIDs and bee stings).

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``Clinical Findings

``General Considerations

A. Symptoms and Signs

Membranous nephropathy is the most common cause of primary nephrotic syndrome in adults, usually presenting in the fifth and sixth decades. It is an immune-mediated disease characterized by immune complex deposition in the subepithelial portion of glomerular capillary walls.

The antigen in the primary form of the disease appears to be a phospholipase A2 receptor (PLA2R) on the podocyte in 70–80% of patients. Secondary disease is associated with underlying carcinomas; infections, such as hepatitis B, endocarditis, and syphilis; autoimmune disease, such as systemic lupus erythematosus, mixed connective tissue disease, and thyroiditis; and certain drugs, such as penicillamine and captopril. The course of disease is variable, with about 50% of patients progressing to ESRD over 3–10 years. Poorer outcome is associated with concomitant tubulointerstitial fibrosis, male sex, elevated serum creatinine, hypertension, and heavy proteinuria (> 10 g/d).

Patients often exhibit the manifestations of full-blown nephrotic syndrome. They are more susceptible to infection, especially with gram-positive organisms, have a tendency toward thromboembolic events, develop severe hyperlipidemia, and experience protein malnutrition.

Minimal change disease can rarely cause acute kidney injury due to tubular changes and interstitial edema.

B. Histologic Findings Glomeruli show no changes on light microscopy or immunofluorescence. On electron microscopy, there is a characteristic effacement of podocyte foot processes. A subgroup of patients also shows mesangial cell proliferation; such patients have more hematuria and hypertension and poor response to standard corticosteroid treatment.

``Treatment Treatment is with prednisone, 60 mg/m2/d orally. Adults often require longer courses of therapy than children. It can take up to 16 weeks to achieve a response to corticosteroids. Treatment should be continued for several weeks after complete remission of proteinuria. A significant number of patients will relapse and require further corticosteroid treatment. Steroid-resistant nephrotic syndrome is defined as persistent proteinuria after a 4-week course of prednisone. Patients with frequent relapses or corticosteroid resistance may need cyclophosphamide or cyclosporine to induce subsequent remissions; tacrolimus or rituximab may also be considered, although controlled trials are lacking. Progression to ESRD is rare. Complications most often arise from prolonged corticosteroid use.

Palmer SC et al. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001537. [PMID: 18253993] Roberti I et al. Long-term outcome of children with steroidresistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol. 2010 Jun;25(6):1117–24. [PMID: 20217433] van Husen M et al. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011 Jun;26(6):881–92. [PMID: 21229269]

Membranous Nephropathy

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Nephrotic range proteinuria.

Associated with coagulopathy, eg, renal vein thrombosis, if nephrotic syndrome present. `` ”Spike and dome” pattern on kidney biopsy from subepithelial deposits. `` Secondary causes notably include hepatitis B virus and carcinomas. `` ``

``Clinical Findings A. Symptoms and Signs Patients with membranous nephropathy and nephrotic syndrome have a higher risk of hypercoagulable state than those with nephrosis from other etiologies; there is a particular predisposition to renal vein thrombosis in these patients. There may be symptoms or signs of an underlying infection or neoplasm (especially lung, stomach, breast, and colon cancers) in secondary membranous nephropathy.

B. Laboratory Findings See above for laboratory findings in the nephrotic syndrome.

Serum evaluation for circulating PLA2R antibodies to assess for idiopathic membranous nephropathy may be available in the future. By light microscopy, capillary wall thickness is increased without inflammatory changes or cellular proliferation; when stained with silver methenamine, a “spike and dome” pattern may be observed owing to projections of excess GBM between the subepithelial deposits.

Immunofluorescence shows IgG and C3 uniformly along capillary loops. Electron microscopy shows a discontinuous pattern of dense deposits along the subepithelial surface of the basement membrane.

``Treatment Treatment is controversial. After underlying causes are excluded, treatment depends on the risk of renal disease progression. One algorithm is based on the degree of proteinuria. In patients with proteinuria < 3.5 g/d, the risk of progression is low. These individuals should be closely monitored with a low-salt diet, strict blood pressure control, and an ACE inhibitor or ARB for reduction of proteinuria. Patients with proteinuria of 3.5–8 g/d but normal renal function are at moderate risk. They should follow the above suggestions and can elect immunosuppressive regimens with corticosteroids and chlorambucil or cyclophosphamide for 6 months, although only 65% of these patients experience partial or complete remission within 3–4 years.

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Cyclosporine is a second choice. The highest-risk patients— those with > 8 g/d of proteinuria and possible renal dysfunction—might receive corticosteroids with a cytotoxic agent as first-line immunosuppressant therapy, though the choice of cyclosporine is also reasonable.

Mycophenolate mofetil and rituximab are becoming more widely accepted as possible first-line agents of treatment or for patients who relapse or do not tolerate other immunosuppressive agents. Patients with primary membranous nephropathy are excellent candidates for transplant.

Cravedi P et al. Efficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study. Am J Nephrol. 2011;33(5):461–8.

[PMID: 21508634] Hofstra JM et al. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2011 Jun;6(6):1286–91.

[PMID: 21474589] Hofstra JM et al. Management of patients with membranous nephropathy. Nephrol Dial Transplant. 2012 Jan; 27(1)6–9.

[PMID: 21737514]

Focal Segmental GlomeruloSclerosis This lesion can present as idiopathic disease or secondary to such conditions as heroin use, morbid obesity, chronic urinary reflux, and HIV infection. Idiopathic disease may be related to heritable abnormalities of any of several podocyte proteins. Clinically, patients with nephrotic spectrum findings may have overt nephrotic syndrome.

Decreased kidney function is present in 25–50% at time of diagnosis. Patients with focal segmental glomerulosclerosis and nephrotic syndrome typically progress to ESRD in 6–8 years.

Diagnosis requires renal biopsy. Light microscopy shows sclerosis of portions (or segments) of some, but not all glomeruli (thus, focal and not diffuse disease). IgM and C3 are seen in the sclerotic lesions on immunofluorescence, although it is presumed that these immune components are simply trapped in the sclerotic glomeruli and are not participating in the pathogenesis of the disease.

Electron microscopy shows fusion of epithelial foot processes as seen in minimal change disease.

Treatment for primary focal segmental glomerulosclerosis is controversial, although supportive care for nephrotic patients is indicated (diuretics for edema, ACE inhibitors or ARBs to target proteinuria and hypertension, statins or niacin for hyperlipidemia). High-dose oral prednisone (1–1.5 mg/kg/d) for 2–3 months followed by a slow taper can induce remission within 5–9 months in over half of patients. Other cytotoxic drug therapy can be considered for steroid-resistant patients, including calcineurin inhibitors and mycophenolate mofetil. For those patients with primary focal segmental glomerulosclerosis who progress to ESRD and undergo renal transplantation, relapse rate and graft loss is relatively high; plasma exchange therapy just prior to transplant and with early signs of relapse appear to be beneficial in lowering risk of these outcomes.

Gbadegesin R et al. Pathogenesis and therapy of focal segmental glomerulosclerosis: an update. Pediatr Nephrol. 2011 Jul; 26(7):1001–15. [PMID: 21110043] Meyrier A. Focal and segmental glomerulosclerosis: multiple pathways are involved. Semin Nephrol. 2011 Jul;31(4):326–32.

[PMID: 21839365] Ulinski T. Recurrence of focal segmental glomerulosclerosis after kidney transplantation: strategies and outcome. Curr Opin Organ Transplant. 2010 Oct;15(5):628–32. [PMID: 20733489]

cc Nephrotic

SPECTRUM Disease From Systemic Disorders

Amyloidosis Amyloidosis is caused by extracellular deposition of the fibrous protein amyloid in one or more sites in the body.

The amyloid fibrils are composed of proteins that have formed characteristic β-pleated sheets. Primary renal amyloidosis (AL amyloidosis) may occur in the absence of systemic disease or associated with multiple myeloma; indeed, both are plasma cell dyscrasias, which overproduce immunoglobulin light chain (the amyloid protein). Serum and urine protein electrophoresis can be helpful in delineating the light chain present in such cases. Secondary amyloidosis (AA amyloidosis) is due to a chronic inflammatory disease, such as rheumatoid arthritis, inflammatory bowel disease, or chronic infection. In these cases, acute phase reactant serum amyloid A is synthesized in the liver and deposited in the tissues. Amyloid-affected kidneys can be enlarged as a result of this deposition disease.

Pathologically, glomeruli are filled with amorphous deposits that stain positive with Congo red and show green birefringence.

Treatment options are few. Remissions can occur in secondary amyloidosis if the inciting agent is removed.

Primary amyloidosis of the kidney progresses to ESRD in an average of 2–3 years. Five-year overall survival is < 20%, with death occurring from ESRD and heart disease. The use of alkylating agents and corticosteroids—eg, melphalan and prednisone—can reduce proteinuria and improve renal function in a small percentage of patients. Significant reduction in free light chain burden (> 90%) has been shown to correlate with improved renal outcomes. Melphalan and stem cell transplantation are associated with high toxicity (45% mortality) but induce remission in 80% of the remaining patients. Renal transplant is an option in patients with secondary amyloid.

Pinney JH et al. Outcome in renal AL amyloidosis after chemotherapy. J Clin Oncol. 2011 Feb 20;29(6):674–81. [PMID: 21220614] Qu Z et al. Clinical and pathological features of renal amyloidosis: an analysis of 32 patients in a single Chinese centre.

Nephrology (Carlton). 2010 Feb;15(1):102–7. [PMID: 20377777]

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Diabetic Nephropathy

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Prior evidence of diabetes mellitus, typically over 10 years. `` Albuminuria (microscopic or macroscopic) precedes decline in GFR. `` Signs of diabetic nephropathy on renal biopsy, if done. `` Other end-organ damage, such as retinopathy, is common. ``

``General Considerations Diabetic nephropathy is the most common cause of ESRD in the United States (about 4000 cases a year). Type 1 diabetes mellitus carries a 30–40% risk of nephropathy after 20 years, whereas type 2 has a 15–20% risk after 20 years. ESRD is much more likely to develop in persons with type 1 diabetes mellitus, in part due to fewer comorbidities and deaths before ESRD ensues. With the current epidemic of obesity and type 2 diabetes mellitus, rates of diabetic nephropathy are projected to continue to increase. Patients at higher risk include males, African Americans, and Native Americans.

``Clinical Findings The first stage of diabetic nephropathy is hyperfiltration, with an increase in GFR, followed by the development of microalbuminuria (30–300 mg/d). As the nephropathy progresses, (macro)albuminuria (> 300 mg/d, or enough to be detected on regular dipstick) is seen, and the GFR returns to normal and then goes on to decrease. Yearly screening for the development of microalbuminuria is recommended for all diabetic patients. In patients prone to nephropathy, microalbuminuria develops within 10–15 years after onset of diabetes and progresses over the next 3–7 years to overt proteinuria (> 300 mg of albuminuria per day).

The most common lesion in diabetic nephropathy is diffuse glomerulosclerosis, but nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) is pathognomonic. The kidneys in these patients are usually enlarged as a result of cellular hypertrophy and proliferation.

Patients with diabetes are prone to other renal disease.

These include papillary necrosis, chronic interstitial nephritis, and type 4 (hyporeninemic hypoaldosteronemic) renal tubular acidosis. Patients are more susceptible to acute kidney injury from many insults, including intravenous contrast material and concomitant use of renin-angiotensin blockers (eg, ACE inhibitors) and NSAIDs. In diabetic patients with consequent comorbidities, there is a poor prognosis once dialysis is begun.

``Treatment With the onset of microalbuminuria, aggressive treatment is necessary. Strict glycemic control and treatment of

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hypertension have been proven to slow progression of disease; current guidelines support a goal blood pressure of 130/80 mm Hg in most patients, and possibly 120/75 mm Hg in overtly proteinuric patients. In particular, ACE inhibitors and ARBs lower the rate of progression to clinical proteinuria and slow progression to ESRD by reducing intraglomerular pressure as well as by treating hypertension; they may also have antifibrotic effects. Even in the subset of patients with markedly diminished GFR, these agents seem to provide renal benefit if patients can avoid hyperkalemia and as long as GFR does not decline more than 30% with the initiation of this therapy. Some experts have advocated for combination ACE inhibitor and ARB therapy as a way to maximally target proteinuria; however, the ONTARGET trial suggested great caution in using combination therapy because of the development of hyperkalemia and worsening kidney function in the group given both telmisartan and ramipril. de Boer IH et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011 Jun 22; 305(24):2532–9. [PMID: 21693741] Rossing P et al. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl. 2011 Mar;(120):S28–32.

[PMID: 21358699] Ruggenenti P et al. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010 Jun;6(6): 319–30. [PMID: 20440277] Seaquist ER et al. Approach to the patient with type 2 diabetes and progressive kidney disease. J Clin Endocrinol Metab. 2010 Jul;95(7):3103–10. [PMID: 20610606] Ting RZ et al. Treatment and landmark clinical trials for renoprotection. Contrib Nephrol. 2011;170:184–95. [PMID: 21659771]

HIV-Associated Nephropathy HIV-associated nephropathy can present as the nephrotic syndrome in patients with HIV infection. Decline in GFR can progress rapidly. Most patients are black, possibly because of a genetic predisposition. Often, patients have low CD4 counts and have advanced HIV disease, but HIV-associated nephropathy can also be the initial presentation of disease.

Light microscopy shows focal segmental glomerulosclerosis as described above. Lesions are often of the collapsing variety, and renal biopsy specimens also exhibit severe tubulointerstitial damage.

Small, uncontrolled studies have shown that highly active antiretroviral therapy (HAART) for a prolonged course can slow progression of disease. Despite this minimal evidence, HAART has been recommended for use in these patients given the therapy’s other beneficial effects and reasonable toxicity profile. Either ACE inhibitors or ARBs can be used to control blood pressure and slow disease progression.

Corticosteroid treatment has been used with variable success at a dosage of 1 mg/kg/d, along with cyclosporine.

Atta MG. Diagnosis and natural history of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010 Jan;17(1):52–8.

[PMID: 20005489] Kalayjian RC. The treatment of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010 Jan;17(1):59–71. [PMID: 20005490]

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Tubulointerstitial Diseases

Tubulointerstitial disease may be acute or chronic. Acute disease is most commonly associated with medications, infectious agents, and systemic rheumatologic disorders.

Interstitial edema, infiltration with polymorphonuclear neutrophils, and tubular cell necrosis can be seen. (See Acute Kidney Injury, above, and Table 22–11.) Chronic disease is associated with insults from an acute factor or progressive insults without any obvious acute cause. Interstitial fibrosis and tubular atrophy are present, with a mononuclear cell predominance. The chronic disorders are described below.

Chronic Tubulointerstitial Diseases

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Kidney size is small and contracted.

Decreased urinary concentrating ability. `` Hyperchloremic metabolic acidosis. `` Reduced GFR. `` ``

Table 22–11. Causes of acute tubulointerstitial nephritis (abbreviated list).

Drug reactions Antibiotics β-Lactam antibiotics: methicillin, penicillin, ampicillin, cephalosporins Ciprofloxacin Erythromycin Sulfonamides Tetracycline Vancomycin Trimethoprim-sulfamethoxazole Ethambutol Rifampin Nonsteroidal anti-inflammatory drugs Diuretics Thiazides Furosemide Miscellaneous Allopurinol Cimetidine Phenytoin Systemic infections Bacteria Streptococcus Corynebacterium diphtheriae Legionella Viruses Epstein-Barr Others Mycoplasma Rickettsia rickettsii Leptospira icterohaemorrhagiae Toxoplasma Idiopathic Tubulointerstitial nephritis-uveitis (TIN–U)

``General Considerations The primary causes of chronic tubulointerstitial disease are discussed below. Other causes include multiple myeloma and gout, which are discussed in the section on multisystem disease with variable kidney involvement.

A. Obstructive Uropathy The most common cause of chronic tubulointerstitial disease is prolonged obstruction of the urinary tract. In partial obstruction, patients can exhibit polyuria (possibly due to vasopressin insensitivity and poor ability to concentrate the urine) or oliguria (due to decreased GFR). Azotemia and hypertension (due to increased renin-angiotensin production) are usually present. The major causes are prostatic disease in men; ureteral calculus in a single functioning kidney; bilateral ureteral calculi; carcinoma of the cervix, colon, or bladder; and retroperitoneal tumors or fibrosis.

Abdominal, rectal, and genitourinary examinations are helpful. Urinalysis can show hematuria, pyuria, and bacteriuria but is often benign. Abdominal ultrasound may detect mass lesions, hydroureter, and hydronephrosis. CT scanning and MRI provide more detailed information.

B. Vesicoureteral Reflux Reflux nephropathy is primarily a disorder of childhood and occurs when urine passes retrograde from the bladder to the kidneys during voiding. It is the second most common cause of chronic tubulointerstitial disease. It occurs as a result of an incompetent vesicoureteral sphincter.

Urine can extravasate into the interstitium; an inflammatory response develops, and fibrosis occurs. The inflammatory response is due to either bacteria or normal urinary components.

Patients are typically diagnosed as young children with a history of recurrent urinary tract infections. This entity can be detected before birth via screening fetal ultrasonography. After birth, a voiding cystourethrogram can be done.

Less commonly, this entity is not diagnosed until adolescence or young adulthood when patients present with hypertension and substantial proteinuria, unusual in most tubular diseases. At this point, renal ultrasound or IVP can show renal scarring and hydronephrosis. IVP is relatively contraindicated in patients with kidney dysfunction who are at higher risk for contrast nephropathy. On renal biopsy, focal glomerulosclerosis can be seen in those with kidney damage. Although most damage occurs before age 5 years, progressive renal deterioration to ESRD continues as a result of the early insults.

C. Analgesics Analgesic nephropathy is most commonly seen in patients who ingest large quantities of analgesic combinations. The drugs of concern are phenacetin, paracetamol, aspirin, and NSAIDs, with acetaminophen a possible but less certain culprit. Ingestion of at least 1 g/d for 3 years of these

Kidney Disease analgesics is considered necessary for kidney dysfunction to develop. This disorder occurs most frequently in individuals who are using analgesics for chronic headaches, muscular pains, and arthritis. Most patients grossly underestimate their analgesic use.

Tubulointerstitial inflammation and papillary necrosis are seen on pathologic examination. Papillary tip and inner medullary concentrations of some analgesics are tenfold higher than in the renal cortex. Phenacetin—once a common cause of this disorder and now rarely available—is metabolized in the papillae by the prostaglandin hydroperoxidase pathway to reactive intermediates that bind covalently to interstitial cell macromolecules, causing necrosis. Aspirin and other NSAIDs can cause damage by their metabolism to active intermediates which can result in cell necrosis. These drugs also decrease medullary blood flow (via inhibition of prostaglandin synthesis) and decrease glutathione levels, which are necessary for detoxification.

Patients can exhibit hematuria, mild proteinuria, polyuria (from tubular damage), anemia (from GI bleeding or erythropoietin deficiency), and sterile pyuria. As a result of papillary necrosis, sloughed papillae can be found in the urine. An IVP may be helpful for detecting these—contrast will fill the area of the sloughed papillae, leaving a “ring shadow” sign at the papillary tip. However, IVP is rarely used in patients with significant kidney dysfunction, given the need for dye and associated acute kidney injury.

D. Heavy Metals Environmental exposure to heavy metals—such as lead and cadmium—is seen infrequently now in the United States. Chronic lead exposure can lead to tubulointerstitial disease. Individuals at risk are those with occupational exposure (eg, welders who work with lead-based paint) and drinkers of alcohol distilled in automobile radiators (“moonshine” whiskey users). Lead is filtered by the glomerulus and is transported across the proximal convoluted tubules, where it accumulates and causes cell damage.

Fibrosed arterioles and cortical scarring also lead to damaged kidneys. Proximal tubular damage leads to decreased secretion of uric acid, resulting in hyperuricemia and saturnine gout. Patients commonly are hypertensive.

Diagnosis is most reliably performed with a calcium disodium edetate (EDTA) chelation test. Urinary excretion of > 600 mg of lead in 24 hours following 1 g of EDTA indicates excessive lead exposure.

Occupational exposure to cadmium also causes proximal tubular dysfunction. Hypercalciuria and nephrolithiasis can be seen. Other heavy metals that can cause tubulointerstitial disease include mercury and bismuth.

``Clinical Findings A. Symptoms and Signs Polyuria is common because tubular damage leads to inability to concentrate the urine. Volume depletion can also occur as a result of a salt-wasting defect in some individuals.

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B. Laboratory Findings Patients can become hyperkalemic both because the GFR is lower and the distal tubules become aldosterone resistant. A hyperchloremic renal tubular acidosis is characteristic from a component of type 4 or type 1 renal tubular acidosis. Less commonly, a proximal renal tubular acidosis is seen due to direct proximal tubular damage. The cause of the renal tubular acidosis is threefold: (1) reduced ammonia production, (2) inability to acidify the distal tubules, and (3) proximal tubular bicarbonate wasting. The urinalysis is nonspecific, as opposed to that seen in acute interstitial nephritis. Proteinuria is typically < 2 g/d (owing to inability of the proximal tubule to reabsorb freely filterable proteins); a few cells may be seen; and broad waxy casts are often present.

``Treatment Treatment depends first on identifying the disorder responsible for kidney dysfunction. The degree of interstitial fibrosis that has developed can help predict recovery of renal function. Once there is evidence for loss of parenchyma (small shrunken kidneys or interstitial fibrosis on biopsy), little can prevent the progression toward ESRD. Treatment is then directed at medical management. Tubular dysfunction may require potassium and phosphorus restriction and sodium, calcium, or bicarbonate supplements.

If hydronephrosis is present, relief of obstruction should be accomplished promptly. Prolonged obstruction leads to further tubular damage—particularly in the distal nephron— which may be irreversible despite relief of obstruction. Neither surgical correction of reflux nor medical therapy with antibiotics can prevent deterioration toward ESRD once renal scarring has occurred.

Patients in whom lead nephropathy is suspected should continue chelation therapy with EDTA if there is no evidence of irreversible renal damage (eg, renal scarring or small kidneys). Continued exposure should be avoided.

Treatment of analgesic nephropathy requires withdrawal of all analgesics. Stabilization or improvement of renal function may occur if significant interstitial fibrosis is not present. Hydration during exposure to analgesics may also have some beneficial effects.

``When to Refer • Patients with stage 3–5 CKD should be referred to a nephrologist when tubulointerstitial diseases are suspected. Other select cases of stage 1–2 CKD should also be referred.

• Patients with urologic abnormalities should be referred to a urologist.

Gooch K et al. NSAID use and progression of chronic kidney disease. Am J Med. 2007 Mar;120(3):280.e1–7. [PMID: 17349452] cc

Cystic Diseases of the Kidney

Renal cysts are epithelium-lined cavities filled with fluid or semisolid material. They develop primarily from renal

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Table 22–12. Clinical features of renal cystic disease.

Simple Renal Cysts

Acquired Renal Cysts

Autosomal Dominant Polycystic Kidney Disease

Medullary Sponge Kidney

Medullary Cystic Kidney

Prevalence

Common

Dialysis patients

1:1000

1:5000

Rare

Inheritance

None

None

Autosomal dominant

None

Autosomal dominant

Age at onset

...

...

20–40

40–60

Adulthood

Kidney size

Normal

Small

Large

Normal

Small

Cyst location

Cortex and medulla

Cortex and medulla

Cortex and medulla

Collecting ducts

Corticomedullary junction

Hematuria

Occasional

Occasional

Common

Rare

Rare

Hypertension

None

Variable

Common

None

None

Associated complications

None

Adenocarcinoma in cysts

Urinary tract infections, renal calculi, cerebral aneurysms 10–15%, hepatic cysts 40–60%

Renal calculi, urinary tract infections

Polyuria, salt wasting

Kidney failure

Never

Always

Frequently

Never

Always

tubular elements. One or more simple cysts are found in 50% of individuals over the age of 50 years. They are rarely symptomatic and have little clinical significance. In contrast, generalized cystic diseases are associated with cysts scattered throughout the cortex and medulla of both kidneys and can progress to ESRD (Table 22–12).

Terada N et al. Risk factors for renal cysts. BJU Int. 2004 Jun;93(9): 1300–2. [PMID: 15180627]

Autosomal Dominant Polycystic Kidney Disease

Simple or Solitary Cysts ``

Simple cysts account for 65–70% of all renal masses. They are generally found at the outer cortex and contain fluid that is consistent with an ultrafiltrate of plasma. Most are found incidentally on ultrasonographic examination. Simple cysts are typically asymptomatic but can become infected.

The main concern with simple cysts is to differentiate them from malignancy, abscess, or polycystic kidney disease. Renal cystic disease can develop in dialysis patients.

These cysts have a potential for progression to malignancy. Ultrasound and CT scanning are the recommended procedures for evaluating these masses. Simple cysts must meet three sonographic criteria to be considered benign: (1) echo free, (2) sharply demarcated mass with smooth walls, and (3) an enhanced back wall (indicating good transmission through the cyst). Complex cysts can have thick walls, calcifications, solid components, and mixed echogenicity. On CT scan, the simple cyst should have a smooth thin wall that is sharply demarcated. It should not enhance with contrast media. A renal cell carcinoma will enhance but typically is of lower density than the rest of the parenchyma. Arteriography can also be used to evaluate a mass preoperatively. A renal cell carcinoma is hypervascular in 80%, hypovascular in 15%, and avascular in 5% of cases.

If a cyst meets the criteria for being benign, periodic reevaluation is the standard of care. If the lesion is not consistent with a simple cyst, follow-up with a urologic consultant and possible surgical exploration is recommended.

E ssent i a l s of d i a gnos i s

Multiple cysts in bilateral kidneys; total number depends on age. `` Large, palpable kidneys on examination. `` Combination of hypertension and abdominal mass suggestive of disease. `` Family history is compelling but not necessary. `` Chromosomal abnormalities present in some patients. ``

``General Considerations This disorder is among the most common hereditary diseases in the United States, affecting 500,000 individuals, or 1 in 800 live births. Fifty percent of patients will have ESRD by age 60 years. The disease has variable penetrance but accounts for 10% of dialysis patients in the United States. At least two genes account for this disorder: ADPKD1 on the short arm of chromosome 16 (85–90% of patients) and ADPKD2 on chromosome 4 (10–15%). Patients with the PKD2 mutation have slower progression of disease and longer life expectancy than those with PKD1. Other sporadic cases without these mutations have also been recognized.

``Clinical Findings Abdominal or flank pain and microscopic or gross hematuria are present in most patients. A history of urinary tract

Kidney Disease infections and nephrolithiasis is common. A family history is positive in 75% of cases, and > 50% of patients have hypertension (see below) that may antedate the clinical manifestations of the disease. Patients have large kidneys that may be palpable on abdominal examination. The combination of hypertension and an abdominal mass should suggest the disease. Forty to 50 percent have concurrent hepatic cysts.

Pancreatic and splenic cysts occur also. Hemoglobin and hematocrit tend to be maintained as a result of erythropoietin production by the cysts. The urinalysis may show hematuria and mild proteinuria. In patients with PKD1, ultrasonography confirms the diagnosis—two or more cysts in patients under age 30 years (sensitivity of 88.5%), two or more cysts in each kidney in patients age 30–59 years (sensitivity of 100%), and four or more cysts in each kidney in patients age 60 years or older are diagnostic for autosomal dominant polycystic kidney disease. If sonographic results are unclear, CT scan is recommended and highly sensitive.

``Complications & Treatment A. Pain Abdominal or flank pain is caused by infection, bleeding into cysts, and nephrolithiasis. Bed rest and analgesics are recommended. Cyst decompression can help with chronic pain.

B. Hematuria Gross hematuria is most commonly due to rupture of a cyst into the renal pelvis, but it can also be caused by a kidney stone or urinary tract infection. Hematuria typically resolves within 7 days with bed rest and hydration. Recurrent bleeding should suggest the possibility of underlying renal cell carcinoma, particularly in men over age 50 years.

C. Renal Infection An infected renal cyst should be suspected in patients who have flank pain, fever, and leukocytosis. Blood cultures may be positive, and urinalysis may be normal because the cyst does not communicate directly with the urinary tract. CT scans can be helpful because an infected cyst may have an increased wall thickness. Bacterial cyst infections are difficult to treat. Antibiotics with cystic penetration should be used, eg, fluoroquinolones or trimethoprim-sulfamethoxazole and chloramphenicol. Treatment may require 2 weeks of parenteral therapy followed by long-term oral therapy.

D. Nephrolithiasis Up to 20% of patients have kidney stones, primarily calcium oxalate. Hydration (2–3 L/d) is recommended.

E. Hypertension Fifty percent of patients have hypertension at time of presentation, and it will develop in most patients during the course of the disease. Cyst-induced ischemia appears to cause activation of the renin–angiotensin system, and cyst decompression can lower blood pressure temporarily. Hypertension should be treated aggressively, as this may prolong the time to ESRD. (Diuretics should be used cautiously since the effect on renal cyst formation is unknown.)

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F. Cerebral Aneurysms About 10–15% of these patients have arterial aneurysms in the circle of Willis. Screening arteriography is not recommended unless the patient has a family history of aneurysms or is undergoing elective surgery with a high risk of developing moderate to severe hypertension.

G. Other Complications Vascular problems include mitral valve prolapse in up to 25% of patients, aortic aneurysms, and aortic valve abnormalities. Colonic diverticula are more common in patients with polycystic kidneys.

``Prognosis Significant research is ongoing regarding therapy.

Vasopressin receptor antagonists have been successful in animal models but have not yet been shown to be helpful in slowing down progression of disease in humans. These agents lower renal epithelial cell intracellular cyclic AMP (cAMP) levels, and in vitro evidence suggests that intracellular cAMP plays a significant role in cystogenesis in polycystic kidney disease. Other agents, octreotide and sirolimus, have shown a decreased rate of cyst growth but no decrease in the rate of decline in kidney function.

Avoidance of caffeine may prevent cyst formation due to effects on G-coupled proteins. Treatment of hypertension and a low-protein diet may slow the progression of disease, although this is not well proven.

Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008 Oct 2;359(14):1477–85.

[PMID: 18832246] Schrier RW. Randomized intervention studies in human polycystic kidney and liver disease. J Am Soc Nephrol. 2010 Jun;21(6):891–3. [PMID: 20431043] Torres VE et al. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis. 2011 May;57(5):692–9. [PMID: 21333426] Watnick T et al. mTOR inhibitors in polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):879–81. [PMID: 20581393]

Medullary Sponge Kidney This disease is a relatively common and benign disorder that is present at birth and not usually diagnosed until the fourth or fifth decade. It is caused by autosomal dominant mutations in the MCKD1 or MCKD2 genes on chromosomes 1 and 16, respectively. Kidneys have a marked irregular enlargement of the medullary and interpapillary collecting ducts. This is associated with medullary cysts that are diffuse, giving a “Swiss cheese” appearance in these regions.

``Clinical Findings Medullary sponge kidney presents with gross or microscopic hematuria, recurrent urinary tract infections, or nephrolithiasis. Common abnormalities are a decreased urinary concentrating ability and nephrocalcinosis; less common is incomplete type I distal renal tubular acidosis. The diagnosis can be made by CT, which shows cystic dilatation of the

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distal collecting tubules, a striated appearance in this area, and calcifications in the renal collecting system.

``Treatment There is no known therapy. Adequate fluid intake (2 L/d) helps prevent stone formation. If hypercalciuria is present, thiazide diuretics are recommended because they decrease calcium excretion. Alkali therapy is recommended if renal tubular acidosis is present.

``Prognosis Renal function is well maintained unless there are complications from recurrent urinary tract infections and nephrolithiasis. cc Multisystem

Diseases with Variable Kidney Involvement1

Multiple Myeloma Multiple myeloma is a malignancy of plasma cells (see Chapter 13). Renal involvement occurs in about 25% of all patients. “Myeloma kidney” is the presence of light chain immunoglobulins (Bence Jones protein) in the urine causing renal toxicity. Bence Jones protein causes direct renal tubular toxicity and results in tubular obstruction by precipitating in the tubules. The earliest tubular damage results in Fanconi syndrome (a type II proximal renal tubular acidosis). The proteinuria seen with multiple myeloma is primarily due to light chains that are not detected on urine dipstick, which mainly detects albumin. Hypercalcemia and hyperuricemia are frequently seen. Glomerular amyloidosis can develop in patients with multiple myeloma; in these patients, dipstick protein determinations are positive due to glomerular epithelial cell foot process effacement and albumin “spilling” into Bowman capsule with resultant albuminuria. Other conditions resulting in renal dysfunction include plasma cell infiltration of the renal parenchyma and a hyperviscosity syndrome compromising renal blood flow.

Therapy for acute kidney injury attributed to multiple myeloma includes correction of hypercalcemia, volume repletion, and chemotherapy for the underlying malignancy. Plasmapheresis had been considered appropriate to decrease the burden of existing monoclonal proteins while awaiting chemotherapeutic regimens to take effect. However, in the largest randomized prospective trial to date, plasmapheresis did not provide any renal benefit to these patients.

Pheresis therapy still remains controversial.

Clark WF et al. Plasma exchange for myeloma kidney: cast(s) away? Kidney Int. 2008 Jun;73(11):1211–3. [PMID: 18480853] Roussou M et al. Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents.

Leuk Res. 2010 Oct;34(10):1395–7. [PMID: 20510452] 1

Other diseases with variable involvement described elsewhere in this chapter include systemic lupus erythematosus, diabetes mellitus, and the vasculitides such as granulomatosis with polyangiitis and Goodpasture disease.

Sickle Cell Disease Renal dysfunction associated with sickle cell disease is most commonly due to sickling of red blood cells in the renal medulla because of low oxygen tension and hypertonicity.

Congestion and stasis lead to hemorrhage, interstitial inflammation, and papillary infarcts. Clinically, hematuria is common. Damage to renal capillaries also leads to diminished concentrating ability. Isosthenuria (urine osmolality equal to that of serum) is routine, and patients can easily become dehydrated. Papillary necrosis occurs as well. These abnormalities are commonly encountered in sickle cell trait. Sickle cell glomerulopathy is less common but will inexorably progress to ESRD. Its primary clinical manifestation is proteinuria. Optimal treatment requires adequate hydration and control of the sickle cell disease.

Davenport A et al. Sickle cell kidney. J Nephrol. 2008 Mar–Apr; 21(2):253–5. [PMID: 18446721] Maigne G et al. Glomerular lesions in patients with sickle cell disease. Medicine (Baltimore). 2010 Jan;89(1):18–27. [PMID: 20075701]

Tuberculosis The classic renal manifestation of tuberculosis is the presence of microscopic pyuria with a sterile urine culture—or “sterile pyuria.” More often, other bacteria are also present.

Microscopic hematuria is often present with pyuria. Urine cultures are the gold standard for diagnosis. Three to six first morning midstream specimens should be performed to improve sensitivity. Papillary necrosis and cavitation of the renal parenchyma occur less frequently, as do ureteral strictures and calcifications. Adequate drug therapy can result in resolution of renal involvement.

Chapagain A et al. Presentation, diagnosis, and treatment outcome of tuberculous-mediated tubulointerstitial nephritis.

Kidney Int. 2011 Mar;79(6):671–7. [PMID: 21160461] Figueiredo AA et al. Epidemiology of urogenital tuberculosis worldwide. Int J Urol. 2008 Sep;15(9):827–32. [PMID: 18637157]

Gout & the Kidney The kidney is the primary organ for excretion of uric acid.

Patients with proximal tubular dysfunction have decreased excretion of uric acid and are more prone to gouty attacks.

Depending on the pH and uric acid concentration, deposition can occur in the tubules, the interstitium, or the urinary tract. The more alkaline pH of the interstitium causes urate salt deposition, whereas the acidic environment of the tubules and urinary tract causes uric acid crystal deposition at high concentrations.

Three disorders are commonly seen: (1) uric acid nephrolithiasis, (2) acute uric acid nephropathy, and (3) chronic urate nephropathy. Kidney dysfunction with uric acid nephrolithiasis stems from obstructive nephropathy. Acute uric acid nephropathy presents similarly to acute tubulointerstitial nephritis with direct toxicity

Kidney Disease from uric acid crystals. Chronic urate nephropathy is caused by deposition of urate crystals in the alkaline medium of the interstitium; this can lead to fibrosis and atrophy. Epidemiologically, hyperuricemia and gout have been associated with worsening cardiovascular outcomes.

Treatment between gouty attacks involves avoidance of food and drugs causing hyperuricemia, aggressive hydration, and pharmacotherapy aimed at reducing serum uric acid levels. These disorders are seen in both “overproducers” and “underexcretors” of uric acid. The latter situation may seem counterintuitive; however, these patients have hyperacidic urine, which explains the deposition of relatively insoluble uric acid crystals. For those with uric acid nephrolithiasis, fluid intake should exceed 3 L/d, and use of a urinary alkalinizing agent can be considered.

Edwards NL. The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med. 2008 Jul;75(Suppl 5): S13–6. [PMID: 18822470] Goicoechea M et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010 Aug;5(8):1388–93. [PMID: 20538833]

Nephrogenic Systemic Fibrosis Nephrogenic systemic fibrosis is a multisystem disorder seen only in patients with CKD (primarily with a GFR < 15 mL/min/1.73 m2, but rarely with a GFR of 15–29 mL/ min/1.73 m2), acute kidney injury, and after kidney transplantation. Histopathologically, there is an increase in dermal

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spindle cells positive for CD34 and procollagen I. Collagen bundles with mucin and elastic fibers are also noted.

Nephrogenic systemic fibrosis was first recognized in hemodialysis patients in 1997 and has been strongly linked to use of contrast agents containing gadolinium. Incidence is projected to be 1–4% in the highest risk (ESRD) population that has received gadolinium, and lower in patients with less severe kidney dysfunction. The FDA has issued a warning regarding avoidance of exposure to this agent for patients with GFR < 30 mL/min/1.73 m2.

``Clinical Findings Nephrogenic systemic fibrosis affects several organ systems, including the skin, muscles, lungs, and cardiovascular system. The most common manifestation is a debilitating fibrosing skin disorder that can range from skin-colored to erythematous papules, which coalesce to brawny patches.

The skin can be thick and woody in areas and is painful out-of-proportion to findings on examination.

``Treatment Several case reports and series have described benefit for patients after treatment with corticosteroids, photopheresis, plasmapheresis, and sodium thiosulfate. The true effectiveness of these interventions is still unclear. Alternative or no imaging agents should be used for patients requiring MR with contrast at risk for nephrogenic systemic fibrosis.

Agarwal R et al. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis.

Nephrol Dial Transplant. 2009 Mar;24(3):856–63. [PMID: 18952698]