comorbidity Early identification of renal impairment due to chronic kidney disease associated with diabetes is key to timely intervention and management Denise Blanchfield
Type 2 and CKD – what’s going on? Approximately 13% of the adult population suffers from chronic kidney disease (CKD) with numbers expected to continue to climb.1 Diabetes is the leading cause of established renal failure in the western world.2 Failure to identify renal impairment of CKD associated with diabetes may lead to a delay in timely management of this problem. This has important healthcare management implications such as increased mortality and morbidity, cost and duration of hospitalisation.3 An effective disease management strategy requires consolidation of all aspects of the disease, such as assessment of renal function to ensure timely and appropriate interventions which can have a significant impact of slowing the progression of CKD together with effective hypertension, lipid, and glycaemic management. 4 Kidney structure The kidney is a complex organ involved in the excretion of the waste products of metabolism. Within the kidney, the nephron is the basic structural and functional unit which eliminates waste products, regulates water concentration, electrolyte and pH balance. Each nephron has three parts: the afferent arteriole which is a small blood vessel which brings unfiltered blood to the glomeruli, which is a capillary tuft which in turn filters the blood; and the efferent arteriole which returns filtered blood to the body (see Figure 1).5 Renal pathology Diabetic nephropathy is a chronic condition which develops over a period of years
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characterised by Figure 1: Excretion of waste products by nephron increasing urinary albumin excretion Afferent Efferent rate and blood arteriole arteriole pressure, which 1. Filtration results in declining 2. Reabsorption Glomerular glomular filtra3. Secretion capillaries tion rate (GFR). The 4. Excretion main pathology Bowman’s of nephropathy capsule occurs within the 1 glomeruli and the 2 nephron support Peritubular capillaries structure: tubular interstitium.6 3 What damages the kidney? 4 Renal vein Estimated glomerular filtration rate (eGFR) can Urinary excretion be interpreted as Excretion = filtration – reabsorption + secretion the percentage of normal kidney function such that an eGFR of 50ml/ filtering unit which separates the blood min/1.73m2 approximates 50% of normal from the urine. Within the capillaries of kidney clearance. Three distinct metabolic the renal glomeruli, plasma proteins bind pathways are attributed to the pathogento the glycated basement membrane esis of long-term diabetic complications resulting in the basement membrane such as nephropathy,6 the primacy of thickening. This thickening is the earliest these has yet to established; detectable change in renal glomeruli and Non-enzymatic glycosylation is the prois associated with diabetic glomerulopacess by which glucose chemically attaches thy as demonstrated by Figure 2.6 Damage to this membrane causes proteins to leak to free amino groups of proteins without from the blood into the urine. the aid of enzymes. This is glucose dependActivation of protein kinase C (PKC) ent, a higher blood glucose level results in Intracellular hyperglycaemia can stimuan increased proportion of non-enzymatic late the de novo synthesis of diacylglycerol glycosylation. (DAG), a messenger resulting in the The glomular capillary wall is the
comorbidity activation of PKC. PKC activation results in the development of pre-angiogenic molecules such as vascular growth factor which leads to increased deposition of extra-cellular matrix and basement membrane material in the glomerular messangium and tubular interstitium. This increased deposition results in the glomular sclerosis or scarring associated with diabetic nephropathy.7 Disturbance in the polypol pathway The lens, kidneys nerves and blood vessels do not require insulin for glucose transport and thus there is an increase in intracellular hyperglycaemia. The increased intracellular glucose is converted by the enzyme aldose reductase to sorbitol (a polyol) and eventually to fructose. This has been associated with increased susceptibility to oxidative stress as intracellular antioxidant reserves are depleted as sorbitol is metabolised.7 How to assess renal function Serum creatinine alone is a poor reflection of glomerular filtration rate (GFR). Calculation of estimated GFR is now recommended using ‘The Modification Diet in Renal Disease’ formula (MDRD) which estimates glomerular filtration rate (GFR) using the following variables: serum creatinine, race, age and sex.8 This classification divides CKD into five stages, defined by evidence of kidney damage and level of renal function as measured by glomerular filtration rate (GFR) (see Table 1).9 Frequency of eGFR measurement should depend on the clinical situation and is illustrated in Table 2.9 Progression Progression of XXX should be defined as a decline in eGFR of more than 5ml/ min/1.73m2 within one year, or more than 10ml/min/1.73m2 within five years. A correction factor for ethnicity to GFR values should be applied for African-Caribbean ethnicity, by multiplying the eGFR by 1.21. A minimum of three GFR estimations should be obtained over a period of not less than 90 days.9 In those with a new finding of reduced eGFR, repeat the eGFR within two weeks to exclude causes of acute deterioration of GFR, for example, acute kidney injury or initiation of an ACE inhibitor/ARB therapy. If there is a fall in eGFR or rise in plasma creatinine post commencement, or increase in the dose of ACE inhibitor/ARB, which is < 25% (eGFR) or < 30% (serum creatinine) of baseline, the test should be repeated in a further one to two weeks. It is not recommended to modify the ACE inhibitor/ARB dose if the change in eGFR is less than 25% or the change in
plasma creatinine is less Figure 2: Normal and diabetic capillary than 30%.10 Proteinuria Normal capillary Diabetic capillary The natural history of nephropathy is characterised by a progressive rise in urine albumin excretion, through macroalbuminuria to clinical proteinuria, accompanied by rising blood pressure and declining GFR.6 Upon diagnosis of type 2 diabetes, urine albumin excretion (UAE) may be raised resulting in microalbuminuria, but returns to normal with improved glycaemic control; however Diagram and electron Diagram and electron in 10-48% microalbumuria microscopic photograph microscopic photograph of a persists.11 When proteinuof a normal glomerular diabetic glomerular capillary. ria develops, if untreated capillary. The basement The basement membrane is the rate of decline of GFR membrane is normal abnormally thick compared is similar to that in type to a normal membrane 1 diabetes at 10-12ml/ proteinuria, use of urine albumin creatimin/1.73m2.12 There is evidence that improved nine ratio (ACR) has greater sensitivity and glucose control delays progression of is the recommended method for people microalbumuria, in the ADVANCE study a with diabetes. difference in HbA1c: 48mmol/mol versus Falsely elevated ACR values can occur 56mmol/mol over a five-year period was which influence the appearance of albuassociated with a relative risk reduction in min in the urine; these include ketosis, the development of proteinuria of 21%.13 hyperglycaemia and haemodynamic In a variety of studies, inhibition of factors such as exercise, dietary protein renin-angiotensin-aldosterone system intake, diuresis, and the presence of a (RAS) has proved beneficial in terms of urinary tract infection and semen.9 ACR and protein creatinine ratio (PCR) has improved clinical outcomes for those been shown to correlate with the 24-hour with renal impairment. In the RENAL albumin or protein excretion rate.16 study, the effects of angiotensin receptor The UK CKD Guidelines have defined blocker (ARB) therapy were compared with proteinuria as a PCR of ≥ 45mg/mmol or placebo in addition to conventional antian ACR ≥ 30mg/mmol but suggest that, hypertensive agents. In the group taking in the absence of concomitant haemaARB therapy, 43.5% reached the primary turia, this should not act as a trigger for outcome: doubling of serum sreatinine, active intervention until the PCR exceeds end-stage renal disease (ESRD) or death 100mg/mmol (ACR > 70mg/mmol) (see compared to 47.1% in the control group.14 Treatment with ARB therapy was associTable 3).10 In those with diabetes, consider clinically ated with a 20% reduction in the primary significant proteinuria to be present when end point: doubling of serum creatinine, ACR is above 30mg/mmol or a urinary proend-stage renal disease (ESRD) or death tein excretion 0.5g/24-hour or more. For compared to a placebo and 23% compared the initial detection of proteinuria, if the to calcium channel blocker therapy (CCB).15 Assessment of proteinuria ACR is 30mg/mmol or more and less than Significant proteinuria is an independ50mg/mmol this should be confirmed by ent risk factor for both progression of CKD a subsequent early morning sample. It is and cardiovascular disease. Monitoring recommended to repeat microalbumuria of urinary proteinuria is both part of the within a three to six-month period. If two routine evaluation of those at risk of CKD. out of three tests are positive, treat as Proteins normally excreted in the urine microalbumuria. If negative, screen on an include albumin, low molecular weight annual basis.9 What about haematuria? immunoglobulin (filtered plasma proIn the assessment for the presence of teins), and secreted tubular proteins.10 Albumin is the principle component of haematuria, use reagent strips rather than glomular disease. To detect and identify urine microscopy. Current best practice
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comorbidity Table 1. CKD stage and glomerular filtration rate CKD stage
eGFR
Description
1
> 90 ml/min/1.73m2
Normal GFR with other evidence of chronic kidney damage
2
60-89 ml/min/1.73m2
Slight decrease in GFR, with other evidence of chronic kidney damage
3A 3B
45-59 ml/min/1.73m2 30-44 ml/min/1.73m2
Moderate decrease in GFR: 30-59ml/min/1.73m2, with or without evidence of kidney damage
4
15-29ml/min/1.73m2
Severe decrease in GFR: 15-29ml/min/1.73m2 with or without evidence of kidney damage
5
< 15ml/min/1.73m2
End-stage kidney disease (ESKD): eGFR < 15ml/min/1.73m2 or on dialysis. Established renal failure
Table 2. Typical eGFR testing frequency Stage
eGFR
1 and 2
≥ 60 + other evidence of kidney disease
12 monthly
Typical testing frequency
3A and 3B
30-59
Six monthly
4
15-29
Three monthly
5
< 15
Six weekly
Table 3. Proteinuria Proteinuria
Microalbuminuria
Macroalbuminuria Sub-nephrotic
24-hour urine Albumin-creatinine Protein-creatinine ratio collection ratio (ACR) (PCR) Detects all protein 30-300mg
> 300mg
2.5-30 male 3.5-30 female
> 30
< 3.5g/24 hours total protein
guidelines recommend evaluating further if there is a result of 1+ or more of blood on urinalysis.10 It is not recommended to use urine microscopy to confirm a positive result. In clinical situations where there is the need to differentiate persistent invisible haematuria in the absence of proteinuria from transient haematuria, regard two out of three positive reagent strip tests as confirmation of persistent invisible haematuria.10 Persistent invisible haematuria, with or without proteinuria, requires prompt investigation to rule out urinary tract malignancy in appropriate age groups.10 Is a renal ultrasound really necessary? It is recommended that a renal ultrasound is offered to those who have CKD and demonstrate the following:16 • Progressive eGFR decline, ie. > 5ml/ min/1.73m2 within one year or >10ml/
16
PCR > 45mg/mmol+ haematuria, refer to nephrology services PCR >100mg/mmol, refer to nephrology services
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min/1.73m2 within five years) • Visible or persistent invisible haematuria • Symptoms of urinary tract obstruction • A family history of polycystic kidney disease and are aged over 20 • Stage 4 or 5 CKD • Require a renal biopsy as per nephrologist. Anaemia and CKD: what is the link? A normocytic/normochromic anaemia is a common feature in those with CKD, and erythropoietin deficiency is the primary cause. Erythropoietin is a glycoprotein hormone, 90% of which is produced by the kidneys and 10% by the liver. It is produced in response to hypoxia and production is controlled by negative feedback and inhibited when hypoxia/haemoglobin/red blood cell (RBC) production is corrected.17 The principal action of erythropoietin is to stimulate the proliferation, survival and differentiation of red cells known
as erythrocytes. Reduced erythropoietin production from a diseased kidney results in a progressive decline in red blood cell production and subsequent drop in haemoglobin.7 Basal erythropoietin hormone, iron, vitamin B12 and folic acid are required to maintain normal healthy RBC production. In order to maintain the haem component of the red blood cell it is necessary to have available iron from: • Ferritin, which is stored iron, found in all tissues in particular liver, bone marrow and spleen reticuloendothelial (RE) stores. Serum ferritin concentrations become elevated during episodes of inflammation and may hinder the ability to diagnose the iron deficiency anaemia of renal disease17 • Transferrin, the iron transport protein. The transferrin saturation rate (TSAT) is the amount of immediate available iron in the blood for the bone marrow and RBC production. A persistently low TSAT less than 20% is associated with iron deficient erythropoiesis.17 In the anaemia of CKD, it is recommended that a haemoglobin level between 10 and 12g/dl is maintained for adults. When Hb levels fall below 9.5g/dl it may be necessary to commence an erythropoietin stimulating agent (ESA). However, if the TSAT (transferrin saturation) level is lower than 20%, the ESA will fail to be effective as adequate TSAT level is necessary for ESA function. A lower TSAT level may be treated by oral or intravenous iron therapy.16 Targets of care The targets of care for those with diabetes and CKD are as follows: • Blood pressure: systolic blood pressure < 130mmHg and diastolic blood pressure < 80mmHg is recommended for those with CKD/diabetes/ACR > 70mg/mmol/ PCR >100 mg/mmol16 • Lipid management: Total cholesterol < 4; triglyceride < 1.7mmol/l; LDL < 1.8mmol/l; and HDL cholesterol 1.0mmol/l in men 1.3mmol/l in women18 • HbA1c < 53mmol/mol (7%) has been shown to reduce microvascular complications associated with diabetes.19 In the anaemia of CKD and diabetes, it is recommended that a haemoglobin level between 10 and 12g/dl for adults and a TSAT > 20% is maintained.16 Denise Blanchfield is an advanced nurse practitioner in diabetes and renal impairment at St Luke’s General Hospital, Kilkenny References on request 1. Coresh J, Selvin E, Stevens LA, et al .Prevalence of chronic kidney disease in the United States. Journal of