Memorias Curso de Actualización en Nefrología by sanangelstudio

AMMVEPE 1968 - 2015

MEMORIAS DE LAS PONENCIAS EN EL CURSO DE ACTUALIZACIÓN EN NEFROLOGÍA MÉXICO, D. F. , DICIEMBRE 2, 3 y 4 DE 2015

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

PONENCIAS DEL CURSO DE ACTUALIZACIÓN EN NEFROLOGÍA AMMVEPE

Diciembre 2, 3 y 4 de 2015

PONENTE INTERNACIONAL DAVID F. SENIOR

ANATOMY AND PHYSIOLOGY OF THE URINARY TRACT AZOTEMIA AND ACUTE KIDNEY INJURY CHRONIC KIDNEY DISEASE

DISORDERS OF MICTURITION

FELINE URETHRAL OBSTRUCTION HYPERTENSION

NON-OBSTRUCTIVE FELINE LOWER URINARY TRACT DISEASE PROSTATIC DISEASE PROTEINURIA

TESTS OF URINARY FUNCTION URINALYSIS

URINARY TRACT IMAGING

URINARY TRACT INFECTION UROLITHIASIS

EVENTO PATROCINADO POR

11/21/2015

Distribution of Body Water ANATOMY AND PHYSIOLOGY OF THE URINARY TRACT

David F. Senior Professor Emeritus Louisiana State University dfsenior37@cox.net

Composition of Body Water

VESICOURETERAL JUNCTION

11/21/2015

VESICOURETERAL JUNCTION

RENAL VASCULATURE

PREVENTS REFLUX

Increased intravesicular pressure

RENAL CORTEX AND MEDULLA

RENAL VASCULATURE

11/21/2015

RENAL HEMODYNAMICS

Autoregulation

From Valtin, Renal Physiology

GT BALANCE

From Valtin, Renal Physiology

FILTRATION FRACTION

GLOMERULUS EFFERENT ARTERIOLE

AFFERENT ARTERIOLE

70 % HIGH OSMOLALITY

30 % PROTEIN-FREE

FILTRATION FRACTION = GFR/RPF

RENAL HEMODYNAMICS

Renal Arteriolar Resistance

Nitric Oxide

AII TBA2

PGE2 PGI2

11/21/2015

Afferent Arteriolar Resistance NORMAL

CRF

Efferent Arteriolar Resistance NORMAL

Nitric Oxide?

AII

ACE-INHIBITOR INCREASED PGC

DECREASED PGC

AFFERENT ARTERIOLAR VASODILATION

EFFERENT ARTERIOLAR VASODILATION

Efferent Arteriolar Resistance NORMAL

TBA3

HIGH N3:N6 PUFA DIET

PGE3 PGI3

Filtration Reabsorption Secretion Excretion

DECREASED PGC

EFFERENT ARTERIOLAR VASODILATION

GLOMERULAR FILTRATION Glomerular Tuft

GLOMERULAR FILTRATION

Image Courtesy Dr. Jill Verlander-Reid

Images Courtesy Dr. Jill Verlander-Reid

11/21/2015

GLOMERULAR FILTRATION

Image Courtesy Dr. Jill Verlander-Reid

GLOMERULAR FILTRATION

Endothelial Pores Basement Membrane Filtration slits

Podocytes Foot Processes Filtration Slits

Image Courtesy Dr. Jill Verlander-Reid

Images Courtesy Dr. Jill Verlander-Reid

GLOMERULAR FILTRATION

Endothelial Pores Basement Membrane Filtration slits Mesangium

Images Courtesy Dr. Jill Verlander-Reid

Image Courtesy Dr. Jill Verlander-Reid

11/21/2015

GLOMERULAR FILTRATION

Endothelial Pores Basement Membrane Filtration Slits

RENAL HANDLING OF PLASMA PROTEINS Protein

M.W.

S-E Radius

Filtrate/ Plasma

Inulin Insulin Lysozyme Myoglobin PTH Gr. Hormone Amylase Albumin Gamma Glob. Ferritin

5300 6000 14,600 16,900 9,000 20,000 48,000 69,000 160,000 480,000

1.4 1.6 1.9 1.9 2.1 2.1 2.9 3.6 5.5 6.1

1.0 0.9 0.75 0.75 0.65 0.6-0.7 0.02 0.02 0.00 0.02

Images Courtesy Dr. Jill Verlander-Reid

GLOMERULAR FILTRATION

TUBULAR REABSORPTION

Bowmanâ&#x20AC;&#x2122;s Space Proximal tubule Brush Border

Trans-glomerular Starling forces

Image Courtesy Dr. Jill Verlander-Reid

From Valtin, Renal Physiology

TUBULAR REABSORPTION

From Valtin, Renal Physiology

11/21/2015

From Valtin, Renal Physiology

TUBULAR REABSORPTION Proximal Tubule Brush Border Lat. Intercell. Spaces Mitochondria

Image Courtesy Dr. Jill Verlander-Reid

Sodium Reabsorption (% of Filtered Load)

TUBULAR REABSORPTION

TUBULAR REABSORPTION 5%

67%

25% 3%

From Valtin, Renal Physiology

TUBULAR REABSORPTION

Thick Ascending Limb

RENAL UREA HANDLING ADH present

Impermeable to urea

Permeable to urea

From Valtin, Renal Physiology

11/21/2015

EFFECT OF URINE VOLUME ON UREA EXCRETION

CONCENTRATED URINE Units: Osmolality (mOsm/kg H2O)

ADH Present

TFurea ↑

ADH Absent INNER MEDULLARY COLLECTING DUCT

TFurea ↓

From Valtin, Renal Physiology

DILUTE URINE Units: Osmolality (mOsm/kg H2O)

URINE CONCENTRATION AND DILUTION

From Valtin, Renal Physiology

ADH and Microtubule Formation

From Valtin, Renal Physiology

TUBULAR REABSORPTION

Carrier-Mediated Transport

From Valtin, Renal Physiology

11/21/2015

TUBULAR REABSORPTION Glucose Tolerance Curve

The Magnitude of Renal Function Daily Renal Turnover in a 20 kg Dog Water (L/Day) Na (mM/day) Cl (mM/day) HCO3 (mM/day)

Filtered

Excreted

FE (%) Total in ECF

110 16,500 12,430 2,000

0.8 70 100 1

0.7 0.4 0.8 0.05

4L 600 mM 400 mM 80 mM

The Magnification Effect

From Valtin, Renal Physiology

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

DEFINITIONS

AZOTEMIA AND ACUTE KIDNEY INJURY

AZOTEMIA Pre-renal Primary renal Post-renal Acute Kidney Injury Chronic Kidney Disease

David F. Senior dfsenior37@cox.net

Uremia

PRERENAL AZOTEMIA

AZOTEMIA

PRERENAL

RENAL

POSTRENAL

HYPOTENSION HEMORRHAGE REDUCED ECF VOLUME PHYSIOLOGICAL RESPONSE

ACUTE

GLOMERULAR

1. INCREASE FLUID INTAKE THIRST 2. DECREASE FLUID LOSS OLIGURIA

CHRONIC

INTERSTITIAL OBSTRUCTION

PRERENAL AZOTEMIA

OLIGURIA REDUCED GFR MAXIMALLY CONCENTRATED URINE

RUPTURE

PRERENAL AZOTEMIA

REDUCED GFR • • • •

NORMAL

DEHYDRATION (Hem./Shock) URINE SG: HIGH PCV & T.S.: HIGH MILD AZOTEMIA CREATININE: Up to 3 mg/dl* BUN: Up to 60 mg/dl*

• FENa <<< 1 % • FLUID REPLACMENT CORRECTS AZOTEMIA

AFFERENT ARTERIOLAR VASOCONSTRITION DECREASED PGC

* Addisonians can be a lot higher FENa = % of filtered Na that is excreted

11/21/2015

PRERENAL AZOTEMIA TREATMENT

Return to normal homeostasis Replace lost volume and composition

RAPID REVERSAL OF BODY FLUID DEFICITS PREVENT RENAL PARENCHYMAL DAMAGE

FLUID THERAPY Composition: what to give? Volume: how much? Rate: how fast?

COLLECT LAB SAMPLES BEFORE TREATMENT!!

Minimum data base Body weight PCV and total solids Urine S.G. BUN Glucose

Advanced data base Creatinine Electrolytes Na, K, Cl, HCO3 Ca, P Blood gases ECG

Hypovolemia

hemorrhage balanced loss pure water loss

Balanced electrolyte loss vomiting diarrhea

11/21/2015

Available Fluids Whole blood Plasma expanders Similar to ECF Half strength ECF Pure water (D5W)

Similar to extracellular fluid 0.9% saline (normal saline) Lactated Ringer’s solution Normosol-R

ECF 0.9% saline L-Ringer’s Normosol-R

Na+ content (mEq/l) 138-152 154 130 140

Pure water 5% dextrose in water

ECF 5% dex in water

Plasma expanders Hetastarch 6% in 0.9% saline Dextran 70 6% w/v in 0.9% saline Plasma

One half of extracellular fluid 2.5%dextrose in 0.45% saline 2.5% dextrose in half strength lactated Ringer’s solution Normosol-M

Na+ content (mEq/l) ECF 138-152 2.5%dex in 0.45% NaCl 77 2.5% dex in HS LR 65 Normosol-M 40

Replacement (What was lost?) Plasma expander (Colloids) Full strength solution Half strength solution Water (D5W)

Na+ content (mEq/l) 138-152 0

11/21/2015

Balanced losses vomiting, diarrhea, burns

Full strength solution (replacement)

FLUID THERAPY Composition: what to give? Volume: how much? Rate: how fast?

Pure water loss water dep., dementia

Half strength solution D5W (water)

Replacement Daily volume % dehydration x body weight (kg) x 0.8

PRERENAL AZOTEMIA

Crystalloids Dog: 50 ml/kg/hr Cat: 40 ml/kg/hr

• Mild azotemia induced by reduced renal perfusion • Renal response of sodium and water conservation is physiologically appropriate • Severe prerenal azotemia can lead to renal parenchymal damage • Rapid correction of fluid deficits is indicated • Prerenal azotemia is immediately reversible • Azotemia can be both prerenal and renal; only the prerenal component is immediately correctible.

11/21/2015

PRIMARY RENAL AZOTEMIA

AZOTEMIA

PRERENAL

RENAL

ACUTE

POSTRENAL

ACUTE KIDNEY INJURY RAPIDLY PROGRESSING REVERSIBLE?

CHRONIC KIDNEY DISEASE

CHRONIC

SLOWLY PROGRESSING IRREVERSIBLE GLOMERULAR

INTERSTITIAL OBSTRUCTION

RUPTURE

REDUCED RENAL RESERVE RENAL INSUFFICIENCY UREMIA

AZOTEMIA

Acute Kidney Injury

PRERENAL

Rapidly Progressing Loss of Renal Function

David F. Senior dfsenior37@cox.net

RENAL

ACUTE

GLOMERULAR

POSTRENAL

CHRONIC

INTERSTITIAL OBSTRUCTION

Etiology of AKI PRERENAL Hypovolemia Hemorrhage Hypovolemic shock Hypoadrenocorticism Hypotension Prolonged deep anesthesia Endotoxic shock Vascular obstruction Arterial thrombosis Venous thrombosis Hemolytic-uremic syndrome Disseminated intravascular coagulation

RUPTURE

Etiology AKI PRERENAL

Hypovolemia

11/21/2015

Etiology of AKI

RENAL

RENAL Infections Leptospirosis Pyelonephritis Borreliosis Leishmaniasis Babesiosis Septicemia Vasculitis Heat stroke Hemolytic-uremic syndrome Other Hypercalcemia Hemoglobinuria Multiple organ failure

Etiology of AKI

THERAPEUTIC AGENTS Antimicrobials Aminoglycosides Amphotericin B Penicillins Cephalosporins Acyclovir Chemotherapy drugs Cisplatin Carboplatin Doxorubicin Azathioprine

Other Drugs NSAIDS ACE inhibitors Acetaminophen Cyclosporin Thiacetarsemide Diuretics

Etiology of AKI RENAL

TOXINS Ethylene glycol Raisin/grape ingestion Lily plants Jerky treats Heavy metals (all) Lead (most common) Rodendicides Vitamin D analogues

Etiology of AKI

POST-RENAL URINE STASIS Bilateral ureteral obstruction Urethral obstruction

Etiology of AKI

POST-RENAL URINE STASIS Bilateral ureteral obstruction Urethral obstruction RUPTURE (??) Ureters Bladder Urethra

• There are many potential causes of AKI • Etiology can be pre-renal, renal or post-renal • Several factors can combine to induce AKI • Iatrogenic AKI is common and can be prevented • Most common causes include: hypovolemia/hemorrhage ethylene glycol aminoglycosides heat stroke

11/21/2015

PATHOPHYSIOLOGY OF AKI

Reduced Kf

•ALTERED REABSORPTION OF Na+ •ACTIVATES THE RAS •INDUCES RENAL VASOCONSTRICTION

PATHOPHYSIOLOGY OF AKI

REDUCED RBF

PATHOPHYSIOLOGY OF AKI

TUBULAR OBSTRUCTION

Effect of Angiotensin on the Renal Vascular Bed

PATHOPHYSIOLOGY OF AKI

BACKLEAK

11/21/2015

Pathophysiology of AKI

OLIGURIA MOST CAUSES

POLYURIA AMINOGLYCOSIDES

POLYURIA FLUID OVERLOAD EXCRETION OF ACCUMULATED SOLUTES IMPAIRED WATER REABSORPTION

Pathophysiology of AKI Reduced GFR and oliguria in AKI are caused by: Reduced glomerular Kf Reduced RBF (ultimately all have reduced RBF) Can be induced by renal vascular event RAS induces reduced RBF in all cases Tubular obstruction Tubular backleak

Clinical Signs of AKI Depression Anorexia Vomiting Polydipsia Oliguria? Polyuria?

Oliguria may be followed by polyuria during the recovery phase Some forms of AKI develop polyuria first.

11/21/2015

Clinical Pathology of AKI

Clinical Signs of AKI

Typical Values in a Dog with AKI

Dehydration Body condition Oral necrosis (rare) Hypothermia? Renal enlargement Renal pain

CBC PCV:

42 %

Not anemic

Chemistry Panel Creatinine: 6.4 mg/dl BUN: 150 mg/dl K+: 6.5 mM/l PO4: 9.2 mg/dl Glucose: 135 mg/dl TCO2: 12 mM/l A.G.: 35 mM/l

Azotemia (rapidly rising) Hyperkalemia Hyperphosphatemia Hyperglycemia (mild) Metabolic acidosis Wide anion gap

Imaging in AKI

Clinical Pathology of AKI

Radiographs Renal size Ultrasound Renal size Echogenicity

Urine: S.G.: Isosthenuria Proteinuria Hematuria Glucosuria

Dog with Ethylene Glycol Intoxication

Urine Sediment: “Active” Crystals

DIAGNOSIS OF AKI

AZOTEMIA

PRERENAL USG: Isosthenuric Fluids don’t correct

ACUTE

RENAL

ACUTE

POSTRENAL Bladder not distended No peritoneal fluid

CHRONIC

Acute Kidney Insufficiency history - risk factors sudden onset normal body condition normal hair coat rapidly rising azotemia normal hematocrit hyperkalemia oliguria or polyuria active urine sediment carbamylated hemoglobin low normal or enlarged kidneys biopsy – acute damage

CHRONIC Chronic Kidney Disease history – often unrevealing prolonged course weight loss poor hair coat stable azotemia anemic normokalemia (hypokalemia in cats) polyuria inactive urine sediment carbamylated hemoglobin high small kidneys (many exceptions) biopsy – chronic disease

11/21/2015

DIAGNOSIS OF AKI

IRIS Staging of AKI

ACUTE KIDNEY INSUFFICIENCY IS A SYNDROME

Grade 1:

Non-Azotemic AKI:

SCr: < 1.6 mg/dl < 140µmol/l

a. Documented AKI: Historical, clinical, laboratory, or imaging evidence of acute kidney injury, clinical oliguria/anuria, volume responsiveness*… and/or b. Progressive non-azotemic increase in SCr: 0.3 mg/dl (26.4 µmol/l) in 48 hrs

IDENTIFY AND TREAT THE PRIMARY CAUSE

c. Measured oliguria (<1 ml/kg/hr) or anuria over 6 hrs *Volume responsive is an increase in urine production to >1 ml/kg/hr over 6 hours; and/or decrease in serum creatinine to baseline over 48 hours)

IRIS Staging of AKI

Grade 2:

Mild AKI

SCr: 1.7-2.5 mg/dl 141-220 µmol/l

a. Documented AKI and static or progressive azotemia

SCr: 2.6-5.0 mg/dl 221-439 µmol/l

Moderate to Severe AKI

b. Progressive azotemic increase in SCr : 0.3 mg/dl (26.4 µmol/l) in 48 hrs or volume responsiveness*

Grade 4:

a. Documented AKI and increasing severities of azotemia and functional renal failure

c. Measured oliguria (<1 ml/kg/hr) or anuria over 6 hrs

Grade 5

Grade 3:

SCr: 5.1-10 mg/dl 440-880 µmol/l

SCr: > 10 mg/dl > 880 µmol/l

*Volume responsive is an increase in urine production to >1 ml/kg/hr over 6 hours; and/or decrease in serum creatinine to baseline over 48 hours)

MANAGEMENT OF AKI

ELIMINATE THE PRIMARY CAUSE CORRECT ALL PRE-RENAL FACTORS FLUIDS DIURETICS ANTIEMETICS DIALYSIS

Management of AKI

FLUIDS

FULL STRENGTH 0.9% Saline Normosol R Lactated Ringer’s

(Na: 154) (Na: 140) (Na: 130)

HALF STRENGTH 2.5% Dextrose in O.45 % Saline Normosol M 2.5% Dextrose in 1/2 Str. L. R.

(Na: 77) (Na: 40) (Na: 65.5)

SODIUM FREE 5% Dextrose in Water

11/21/2015

Management of AKI

FLUIDS

Management of AKI

FLUIDS

Electrolyte/Acid-base Correction REHYDRATION

Hyperkalemia (> 8 mM/l, or abnormal ECG)

First Day: Vol. of fluid (ml) = % dehydration x B.W. (kg) x 1,000 x 0.8 Shock: 50 ml/kg/hr Don’t exceed 90 ml/kg/hr Use balanced electrolyte solution (full strength) Consider hematologic, colloidal, electrolyte and acid-base status Monitor: CVP, respiration rate

Management of AKI

FLUIDS

10% Ca gluconate: 0.5-1.0 ml/kg IV over 10-15 minutes NaHCO3 1-2 mM/kg IV over 20 minutes Insulin/glucose IV Metabolic acidosis (HCO3 < 16 mM/l) Acidemia (pH < 7.2) Replacement HCO3 (mM) = BW (kg) x 0.3 x HCO3 deficit HCO3 deficit = target HCO3 - patient HCO3 50% in 30 min, 50% over next 2-4 hours

Management of AKI

FLUIDS

INTAKE

OUTPUT

Fluid Administration in the Oliguric Patient

URINE

Measure body weight daily Daily fluid volume = insensible losses + extraordinary losses (10-15 ml/kg/day) (vomit, diarrhea, fever)

IV FLUID ADMINISTRATION

BODY FLUID

Use half-strength solutions or 5% dextrose in water

Management of AKI

FLUIDS

FECES ? VOMITING, ETC ? INSENSIBLE LOSSES (10-15 ml/kg/day)

Management of AKI

DIURETICS Afferent arteriole dilation

Identify and eliminate the primary cause of AKI Correct pre-renal factors with fluids Rapid rehydration (full strength solutions) Don’t overhydrate Correct electrolyte and acid-base imbalances Special maintenance of oliguric patients Monitor body weight Monitor urine production Use half-strength solutions

OSMOTIC DIURETIC THROUGHOUT THE NEPHRON MANNITOL (20-25%) 0.25-1.0 g/kg IV (slow push over 3-5 minutes) Repeat if no effect in 60 minutes If diuresis established (1 ml/kg/hr) CRI at 1-2 mg/kg/min IV OR 0.25-0.5 g/kg IV q4-6h (continue for 24-48 hours)

11/21/2015

Management of AKI

DIURETICS

Management of AKI

DIURETICS

FUROSEMIDE (Lasix®)

Afferent arteriole dilation Secreted in Proximal CT Acts on tal-Loop of Henle Diuresis in distal tubule

Management of AKI

DIURETICS

Management of AKI

Calcium Channel Blockers

FUROSEMIDE (Lasix®) To induce diuresis: 2-6 mg/kg IV Repeat at 2-12 mg/kg IV if no effect in 30 minutes To maintain diuresis: 0.5-2.0 mg/kg IV q6-8h or CRI at 0.1-1.0 mg/kg/hr Monitor fluids carefully to prevent hypovolemia

DILTIAZEM AA vasodilation Inhibit mesangial contractility Inhibit renin release Induce natriuresis “Cytoprotective”

Management of AKI

DOPAMINE AGONISTS

FENOLDOPAM Dopamine-A1 receptor agonist Vasodilation renal vessels Renoprotective in human patients with AKI Beneficial effect not noted in dogs and cats with AKI dosed at 0.8 µg/kg/min (dog) and 0.5 µg/kg/min (cat) 1 More studies needed in veterinary species

Dose: 0.1-0.5 mg/kg slow IV push followed by CRI at 1-5 µg/kg/min

DIURETICS

Mannitol Increases RBF Freely filtered Osmotic diuresis throughout the nephron Avoid in hyperosmolar conditions (EG poisoning) Furosemide Increases RBF Secreted proximally (impaired in AKI) Osmotic diuresis in distal nephron May prevent damage to tal Loop of Henle Diltiazem Increases RBF DIURETICS DO NOT CURE AKI

Neilson LK et al., J Vet Emerg Crit Care, 25: 396-404, 2015

11/21/2015

Management of AKI

ANTIEMETICS

Management of AKI

POLYURIA

Maropitant 1 mg/kg SQ q24h Cimetidine 5-10 mg/kg IV, IM or PO q8h Ranitidine 0.5-1.0 mg/kg IV or PO q8-12h Omeprazole 0.5-1.0 mg/kg PO q24h Metoclopramide 0.2-0.4 mg/kg PO or SQ q8h

Monitor: Body Weight Electrolytes Appetite Urine Output

Best Fluids: Half-Strength Supplement Potassium As Required

AVOID DEHYDRATION!!

Chlorpromazine (?) 3.3 mg/kg PO q6-24h

Leptospirosis

Diagnosis: Suspicion!! Seasonal - Fall Environment: Standing water Azotemia with Fever! Azotemia and Incr. Liver Enzymes

Leptospirosis

Diagnosis: Further Evidence Neutrophilia with left shift Microscopic Agglutination Test (MAT) Acute and convalescent (7-10 days apart) Blood/Urine culture (slow) PCR

Leptospirosis

Definitive Treatment:

Biosafety â&#x20AC;&#x201C; Zoonosis!!

Doxycycline 5mg/kg PO or IV q12h 2 weeks

Gloves and gowns (eye protection?) Wash hands Care with urine and blood Disinfect cages and runs 5% bleach Owner education re. urine exposure

If vomiting: Ampicillin: 20 mg/kg IV q6h Then doxycycline once GI signs subside

11/21/2015

Ethylene Glycol Intoxication

Minimal Lethal Dose Dog: 4.4-6.6 ml/kg BW Cat: 1.4 ml/kg BW Usually 95-97% E.G.

Ethylene Glycol Intoxication

Clinical Signs alcohol dehydrogenase

Early (First 12 hours): Depression, ataxia, weakness, tachypnea vomiting, dehydration, polyuria, polydipsia 18-36 hours: Oliguric AKI signs

Ethylene Glycol Intoxication

Diagnosis

Early (First 12 hours):

Elevated PCV, T.S. Severe metabolic acidosis Calcium oxalate monohydrate crystals

REACTTM Ethylene glycol test kit

(Osmolar gap)

plasma or serum 60 second result PRN Pharmacal

11/21/2015

Ethylene Glycol Intoxication

Treatment (Dog & Cat)

Treatment

Early (First hour): 1. Gastric lavage 2. Induced Emesis (Dog only) hydogen peroxide (3%) 2.2 ml/kg (up to 45 ml max.) apomorphine 0.03 mg/kg IV xylazine 1.1 mg/kg IM or SC

Early (First 12 hours):

Ethylene Glycol Intoxication

Treatment Early (First 12 hours): Dialysis: CRRT IRRT

Ethylene Glycol Intoxication

Treatment (Dog) Early (First 12 hours): Ethanol (7%) 8.6 mg/kg IV bolus then 100-200 mg/kg/hour CRI or Ethanol (20%) 5.5 ml/kg q4h x 5 then q6h x 4

Ethylene Glycol Intoxication

Treatment (Dog) Early (First 12 hours):

Fomepizole 1. 20 mg/kg (slow IV over 15-30 minutes), 2. 15mg/kg (slow IV) at 12 and 24 hours, 3. 5mg/kg is given at 36 hours

Ethylene Glycol Intoxication

Treatment (Cat) Early (First 12 hours): Ethanol (20%) 5.0 ml/kg q6h x 5 then q8h x 4 (Fomepizole not an option)

11/21/2015

Ethylene Glycol Intoxication

AKI Prognosis

Treatment (General)

Infection ATN (hypoxia/shock) NSAIDS

Early (First 12 hours): Dehydration Metabolic acidosis AKI phase Avoid osmotic agents (e.g., mannitol)

Peritoneal Dialysis

POOR!!

Ethylene glycol

Indications for Dialysis • Uncontrolled azotemia • Fluid overload • Drug elimination toxins • Electrolyte/acid-base extremes hyperkalemia!

Peritoneal Dialysis

HEMODIALYSIS INTERMITTENT (IRRT)

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HEMODIALYSIS CONTINUOUS (CRRT)

Fewer complications More time consuming

MANAGEMENT OF AKI

BUY TIME - SOME WILL REVERSE DONâ&#x20AC;&#x2122;T KILL THE PATIENT!! ELIMINATE THE PRIMARY CAUSE CORRECT ALL PRE-RENAL FACTORS FLUIDS DIURETICS ANTIEMETICS DIALYSIS

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

AZOTEMIA

CHRONIC KIDNEY DISEASE

PRERENAL

Slowly Progressing Loss of Renal Function David F. Senior dfsenior37@cox.net

RENAL

ACUTE

GLOMERULAR

POSTRENAL

CHRONIC

INTERSTITIAL OBSTRUCTION

Etiology of CKD Congenital renal dysplasia and aplasia Inherited conditions IgA nephropathy (dogs) Fanconi Syndrome Polycystic kidney disease Irreversible acute kidney injury

Etiology of CKD Chronic outflow obstruction Trigonal tumor with ureteral obstruction Renoliths (particularly if infected) Neoplasia Lymphosarcoma Feline infectious peritonitis Hypercalcemia Borreliosis

RUPTURE

Etiology of CKD Glomerular disease Glomerulonephritis Amyloidosis Tubulo-interstitial disease Pyelonephritis Idiopathic

11/21/2015

Etiology of CKD

Can lose > 60% of GFR before owner recognition of problem First presented for care late in progression Initial insult often not clear

• A wide variety of causes • Develops at all ages • Often first detected when advanced • Primary cause often not clear • Most commonly idiopathic • Can be multifactorial

Clinical Signs of CKD

History

Reduced appetite and anorexia Weight loss Diarrhea Melena Lethargy, weakness, depression, drowsiness, dementia Tremors, myoclonus Seizures Halitosis Vomiting Poor exercise tolerance Polydipsia, polyuria Nocturia Blindness Poor hair coat, shedding

CKD and the UREMIC SYNDROME A complex combination of events due to: 1. Accumulation of toxic metabolites 2. Physiological responses to maintain ECF 3. Reduced renal endocrine production

Clinical Signs of CKD

Physical Findings

Poor body condition Dry hair coat Stomatitis Oral ulceration Periodontal disease Pale mucous membranes Uremic breath odor Altered kidney shape, size, texture Small Enlarged Lumpy, irregular Firm Scleral injection, conjunctival injection

Pathogenesis of CKD

Susceptibility to Stress in CKD If GFR is 10% of normal Dietary changes require 10x the tubular adjustment required of a healthy animal to achieve external balance

11/21/2015

Pathogenesis of CKD

Renal Secondary Hyperparathyroidism

GT BALANCE Filtered Load of PO4 = GFR x PPO4

Reduced GFR GFR x PPO4 = Dietary P unchanged PPO4 =





Ca2+ + PO43-  Ca salts Bone Soft tissues

Pathogenesis of CKD

Renal Secondary Hyperparathyroidism

PO4 Reabsorption

EARLY

ADVANCED

Pathogenesis of CKD

Renal Secondary Hyperparathyroidism

Pphosphorus stays normal until GFR down to 20% of normal (advanced renal disease) PTH gets progressively higher

15%

85%

PTH Blocks PO4 Reabsorption 15%

85%

Pathogenesis of CKD

Renal Secondary Hyperparathyroidism

 RENAL MASS  GFR

 -HYDROXYLASE

 TUBULAR H+ SECRETION

 PO43-CALCITRIOL

HYPOCALCEMIA

H+ RETENTION

BONE BUFFERING

 INTESTINAL Ca2+ ABSORPTION

 PTH

BONE DEMINERALIZATION

11/21/2015

Pathogenesis of CKD

Renal Secondary Hyperparathyroidism

Pathogenesis of CKD

Toxic Effects of Hyperparathyroidism Carbohydrate intolerance Platelet dysfunction Impaired cardiac and skeletal muscle function Weakness Lethargy Anemia Inhibition of erythropoiesis Increased red cell fragility Reduced nerve conduction velocity Mental dullness Inappetance Immunodeficiency Nephrocalcinosis

RENAL MINERALIZATION IN CATS WITH CKD FED A PHOSPHORUS REPLETE DIET

Pathogenesis of Hyperparathyroidism in CKD

• Retention of phosphorus as GFR falls

• No dietary phosphate restriction • Ca2+ and PO43- in equilibrium with mineralized forms • PTH rises and tubular PO43- reabsorption is inhibited • Eventually plasma PO43- rises • Hyperphosphatemia inhibits -hydroxylase • Reduced calcitriol leads to further increased PTH • PTH causes bone demineralization • PTH is a wide ranging uremic toxin Ross LA, et al. Am J Vet Res 1982;43:1023-6

HYPERGASTRINEMIA IN CKD

11/21/2015

HYPERGASTRINEMIA IN CATS WITH CKD

MEAN RANGE

CONTROL < 18 pg/ml

Oral Ulceration in CKD

CKD 45 pg/ml <18-1,333

PROPORTION WITH HYERGASTRINEMIA MILD CKD: MODERATE SEVERE

3/9 6/11 9/10

33% 55% 90%

Goldstein RE et al J Am Vet Med Assoc 1998;213:826-8

Pathogenesis of GI signs in CKD

• Vomiting, Anorexia • Chemoreceptor trigger zone • Hypergastrinemia • Increased gastric acid • Histamine release • Urea induced H+ back diffusion • Ammonia effects

Polyuria and Polydipsia in CKD Reduced Medullary Hypertonicity

• Oral ulceration •High salivary ammonia

Anemia in CKD

Anemia in CKD  RENAL MASS  GFR

 -HYDROXYLASE

 TUBULAR H+ SECRETION

 PO43-CALCITRIOL

HYPOCALCEMIA

H+ RETENTION

BONE BUFFERING

 INTESTINAL Ca2+ ABSORPTION

 PTH

BONE DEMINERALIZATION

11/21/2015

Anemia in CKD

• Many potential causes • GI blood loss • Impaired erythropoiesis • Reduced RBC life span • Increased 2,3 DPG • Most important: lack of erythropoietin

Acid-Base Disturbances in CKD

Organic Acid + HCO3  Organic Anion + CO2 + H2O

Normal Adaptive Reclamation of Consumed Bicarbonate Buffer

Metabolic Acidosis Wide Anion Gap

Acid-Base Disturbances in CKD

Loss of Tubular NH3 Generation Capacity in CKD Condition

mM of Urinary H+ per day

Consequences of Metabolic Acidosis in CKD

Health H+ combined with NH3 H+ as T.A.

10-30 10-50

Diabetic acidosis H+ combined with NH3 H+ as T.A.

Anorexia Vomiting Lethargy Weight loss

300-500 75-250

Osteoporosis

Chronic kidney disease H+ combined with NH3 H+ as T.A.

0.5-15 2-20

Arrhythmia Protein Catabolism

11/21/2015

Hypertension in CKD

Consequences of Hypertension in CKD Ophthalmic Retinal detachment Retinal hemorrhage Blindness Neurological Vascular events Progression of CKD

Hypokalemia in Cats with CKD

Anorexia Myopathy Weakness Elevated creatine phosphokinase Progression of renal disease

Progression of CKD

Hyperfiltration may play a role in progression of CKD in dogs and cats

Progression of CKD

Causes of hyperfiltration in CKD High protein feeding* High N6:N3 PUFA ratio diet Protein filtration with reabsorption

Normal NORMAL PGC

*Only in advanced renal disease

(Remaining Nephrons) High protein intake (mediated by arginine/NO)

CKD INCREASED PGC

11/21/2015

Progression of CKD

Causes of hyperfiltration in CKD

Progression of CKD

High protein feeding* High N6:N3 PUFA ratio diet Protein filtration with reabsorption

Causes of hyperfiltration in CKD High protein feeding* High N6:N3 PUFA ratio diet Protein filtration with reabsorption

*Only in advanced renal disease

CKD High N-6:N:3 PUFA diet TBA2

PGE2 PGI2

INCREASED PGC

Mild Proteinuria

Progression of CKD

Normal phosphate intake induces progression of CKD in dogs and cats

Progression of CKD

• High phosphorus diet • Increased PGC • High protein feeding* • High N6:N3 PUFA ratio diet • Protein filtration with reabsorption *Only in advanced renal disease

Hypertension in CKD

11/21/2015

Hypertension in CKD

Diagnosis of CKD

• Hypertension common in CKD • Usually mild • Occasionally severe • Blindness • Neurological signs • Progression of CKD

AZOTEMIA

PRERENAL

RENAL

ACUTE

GLOMERULAR

POSTRENAL

CHRONIC

INTERSTITIAL OBSTRUCTION

Diagnosis of CKD – EARLY RECOGNITION

RUPTURE

Diagnosis of CKD – EARLY RECOGNITION

Tests of function: Tests of function: Serum creatinine/BUN Non-renal factor confusion Creatinine (muscle mass) BUN (dietary protein/urine volume)

Microalbuminuria May provoke an investigation

SDMA More specific Perhaps earlier Dx on routine screen

Diagnosis of CKD – EARLY RECOGNITION

Tests of function: Clearance studies Too expensive/tedious to perform as routine screening tests Glomerular Filtration Rate by Iohexol clearance Please supply the following information: Animal wt __________ lb or __________ kg Exact volume administered __________ mL Concentration of Iohexol administered (from label) _____ mg/mL

Time of administered dose: ________ to nearest minute 2 hour post sample time: ________ to nearest minute 3 hour post sample time: ________ to nearest minute 4 hour post sample time: ________ to nearest minute

Diagnosis of CKD – Differentiation from AKI Acute kidney injury history - risk factors sudden onset normal body condition normal hair coat normal hematocrit hyperkalemia oliguria or polyuria active urine sediment carbamylated hemoglobin low normal or enlarged kidneys biopsy – acute damage

Chronic kidney disease history – often unrevealing prolonged course weight loss poor hair coat anemic normokalemia (hypo in cats) polyuria inactive urine sediment carbamylated hemoglobin high small kidneys (exceptions) biopsy – chronic disease

11/21/2015

IRIS Staging of CKD in Dogs and Cats

Staging of CKD Stage

Plasma creatinine

Comments

μmol/l mg/dl SDMA μg/dl Dogs Cats

For Management and Prognosis

•Azotemia • Proteinuria • Hypertension

1 2

<125 <140 At risk of CKD <1.4 <1.6 ≥ 14 ≥ 14 <125 <140 Non-azotemic <1.4 <1.6 125 - 179 140 - 249 Mild renal azotemia 1.4 - 2.0 1.6 - 2.8 ≥ 25 ≥ 25 180 - 439 250 - 439 Mod. renal azotemia 2.1 - 5.0 2.9 – 5.0 ≥ 45 ≥ 45 >440 >440 Severe renal azotemia >5.0 >5.0

IRIS Sub-staging by Blood Pressure

IRIS Sub-staging by Proteinuria

Systolic BP mm Hg <150

UPC value Dogs

Cats

<0.2

0.2 to 0.5 >0.5

<95

Substage 150 – 159

Non-proteinuric (NP)

0.2 to 0.4 Borderline proteinuric (BP) >0.4

Diastolic Adaptation when breedBP specific reference range mm Hg is available

95 - 99

160 – 179 100 - 119 ≥ 180

≥ 120

Proteinuric (P)

Staging of CKD

For Management and Prognosis

•Azotemia • Proteinuria • Hypertension e.g., Pre-treatment: Stage 2, P2, H - Borderline Post-treatment: Stage 2, P1 (T), H - Normotension

Arterial Pressure Substage

<10 mm Hg above

Normotension

reference range

Minimal Risk

10 – 20 mm Hg above Borderline hypertension reference range

Low Risk

20 – 40 mm Hg above

Hypertension

reference range

Moderate Risk

≥ 40 mm Hg above

Severe hypertension

reference range

High Risk

Management of CKD

Control Clinical Signs Reduce stress Azotemia Polydipsia, polyuria and nocturia Anorexia and gastroenteritis Anemia Prevention of progression Hyperparathyroidism and hyperphosphatemia Proteinuria Hypertension Metabolic acidosis Hypokalemia

11/21/2015

Susceptibility to Stress in CKD

Management of CKD

Azotemia Signs develop BUN > 80 mg/dl

If GFR is 10% of normal

With low protein diet: Aim for BUN < 60 mg/dl

Dietary changes require 10x the tubular adjustment required of a healthy animal to achieve external balance

Minimum daily protein: Dog: 5.1 g/100 kcal Cat: 6.5 g/100 kcal Commercial rations: Many choices Can rotate - palatability

Make dietary adjustments GRADUALLY

Polyuria and Polydipsia in CKD

Obligatory Water Loss Usually mild Due to: Reduced medullary hypertonicity Increased tubular flow/nephron Inability to concentrate urine Can dehydrate rapidly if reduced water intake

CKD Diets: Control PU/PD ADVANCING RENAL DISEASE

Management of CKD

Anorexia and Gastroenteritis

Management of CKD

Anorexia and Gastroenteritis

Appetite Stimulation in CKD Feeding Tips • Start new foods early in CKD • Introduce new foods at home • Transfer to new foods gradually

Mirtazapine (Remeron®) • tricyclic antidepressant • antiemetic properties • main side-effect: sedation • effective in cats * (dogs ??)

• Frequent small feedings • Feed soft food • Warm the food to body temperature

Dose: 1.88 mg/cat/day (1/4 of 7.5 mg tablet) q2d in advanced CKD (higher doses cause sedation; no more effective) *Quimby JM et al, Vet J., 97(3):651-5, 2013

11/21/2015

Management of CKD

Anorexia and Gastroenteritis

Management of CKD

Anorexia and Gastroenteritis

Anabolic Steroids

H2 histamine Receptor Antagonists

Nandrolone decanoate Dog and Cat: 2-5 mg/kg IM or SC q21d

Ranitidine 1-2 mg/kg po q12-24h (reduce dose by 50-75% in advanced CKD)

Stanozolol (WinstrolV®) Small Dog: 1-2 mg PO q12h Large Dog: 2-4 mg PO q12h Cat: Avoid - hepatotoxic

Famotidine 0.5-1 mg/kg po q12-24h (reduce dose by 10-25% in CKD) Proton Pump Inhibitor Omeprazole Dog and Cat: 0.5-1.0 mg/kg PO sid

Management of CKD

Anorexia and Gastroenteritis

Vomiting in CKD Dogs: • Ondansetron • Maropitant • Metoclopramide Cats: • Ondansetron • Maropitant McLeland SM, J Vet Intern Med, 2014 May-Jun;28(3):827-37

Management of CKD

Anorexia and Gastroenteritis

Vomiting Ondansetron (Zofran®) • 5-HT3 receptor antagonist • Both central and peripheral action? Dose: •Dog: 0.5-1.0 mg/kg PO q12h •Cat: 0.1-1.0 mg/kg PO q6-12h

Management of CKD

Anorexia and Gastroenteritis

Vomiting Maropitant (Cerenia®) • NK-1 receptor antagonist • Acts at the emetic center • Hepatic excretion Dose: Dog: 2 mg/kg PO sid for 5 days max. Cat: 1 mg/kg PO sid (SC injections painful!)

11/21/2015

Management of CKD

Anorexia and Gastroenteritis

Vomiting Metoclopramide (Reglan®) • dopamine antagonist • suppresses chemoreceptor trigger-zone • increases lower esophageal sphincter tone • increases gastric motility • renal excretion • not as effective in cats

Management of CKD

Anorexia and Gastroenteritis

Feeding Tubes E-Tube G-Tube Effective in dogs and cats Regular SQ Fluids Cats: 120 ml LR sq sid or prn

Dose: Dog: 0.2-0.5 mg/kg PO, SC or IM q6-8h (reduce dose 50% in advanced CKD)

Management of CKD

Anemia

HYPERPHOSPHATEMIA

GI BLOOD LOSS

Management of CKD

Anemia

Management of CKD

Anemia

HYPERPTH

 2,3 DPG PLATELET DEFECT

 O2 DELIVERY TO TISSUES

 RBC GLUTATHIONE

 ERYTHROPOIETIN TOXIC INHIBITION

 RBC LIFESPAN

 ERYTHROPOIESIS

 PCV

Management of CKD

Anemia

Epoietin alfa or • rHuEPO • 60% develop antibodies • 30% develop anemia

Darbepoietin alfa (Aranesp®) • Biosynthetic erythropoietic • Less immunogenic? • Once weekly dosing • Very expensive!

Dose: 100 u/kg SC 3x weekly (reduce to half dose and 2x weekly at target PCV)

Dose: 1 µg/kg SC q7d (reduce to 1 µg/kg SC q14-21d at target PCV)

(Epogen®

Procrit®)

• Target PCV: dog 25%, cat 20% • Target PCV: dog 25%, cat 20%

11/21/2015

Management of CKD

Anemia

Management of CKD

Iron Supplement while on Erythropoietic Agents Iron dextran injectable Dose: Dog: 50-300 mg/dog IM q30-60d Cat: 50 mg/cat IM q30-60d For the duration of Epo Rx

Hyperparathyroidism/hyperphosphatemia

Management of CKD

Hyperparathyroidism/hyperphosphatemia

 RENAL MASS  GFR

 -HYDROXYLASE

 TUBULAR H+ SECRETION

 PO43-CALCITRIOL

HYPOCALCEMIA

DIETARY REDUCTION OF PHOSPHORUS IN 15/16 NEPHRECTOMY DOGS

AFTER 3 YEARS

1.5% P n = 12

0.44% P n = 12

 GFR  GFR (%/MONTH) SURVIVAL

10 11.1 +/- 6.3 33%

2.6 +/- 1.1 75%

H+ RETENTION

BONE BUFFERING

 INTESTINAL Ca2+ ABSORPTION

 PTH

Brown SA et al J Am Soc Nephrol 1991;1:1169-79

BONE DEMINERALIZATION

Management of CKD

Hyperparathyroidism/hyperphosphatemia

CURRENT RECOMMENDATIONS • DIETARY

PHOSPHATE RESTRICTION 0.25-0.3% d.m.b. (0.07 g/100kcal M.E.)

Management of CKD

Hyperparathyroidism/hyperphosphatemia

ORAL PHOSPHATE BINDERS ALUMINUM HYDROXIDE GEL •

POWDER FORM - TASTELESS

Dose: 30-100 mg/kg/day (divided)

• +/- ORAL PHOSPHATE BINDERS

CALCIUM CARBONATE Dose: 90-150 mg/kg/day (divided)

Goal: Reduce Serum phosphate to < 5.5 mg/dl Reduce Ca x P to < 70

Start low and work up – to effect Can combine to lessen side effects of each

11/21/2015

Management of CKD

Hyperparathyroidism/hyperphosphatemia

Management of CKD

 RENAL MASS

CURRENT RECOMMENDATIONS Dietary P restriction/P binders

 GFR

 -HYDROXYLASE

Goal: IRIS Stage 1 2 3 4

Serum phosphate N.A. 2.8-4.6 mg/dl < 5 mg/dl < 6 mg/dl

 TUBULAR H+ SECRETION

 PO43-CALCITRIOL

HYPOCALCEMIA

H+ RETENTION

BONE BUFFERING

 INTESTINAL Ca2+ ABSORPTION

 PTH

• Reduce Ca x P to < 70 BONE DEMINERALIZATION

Hyperparathyroidism/hyperphosphatemia

Management of CKD

Fibroblast Growth Factor -23 (FGF-23) • Decreases renal tubular phosphate reabsorption • Inhibits PTH release • More studies needed

Effect of calcitriol in dogs with spontaneous CKD

pg/ml

CALCITRIOL 3 ng/kg P.O. SID

Management of CKD

Hyperparathyroidism/hyperphosphatemia

NOT CURRENTLY RECOMMENDED

Proteinuria in CKD

DAYS

Increased PGC in CKD (Arginine/NO)

Normal NORMAL PGC

• +/- ORAL CALCITRIOL 1.5-3.5 ng/kg p.o. sid (Remaining Nephrons) Goal: Reduce PTH to normal levels

CKD INCREASED PGC

Mild Proteinuria

11/21/2015

Proteinuria in CKD

Protein reabsorption Metabolism Toxic substances Interstitial disease

• Increased PGC causes proteinuria • High protein diets make it worse • Arginine/nitric oxide Proteinuria may induce interstitial disease • Microalbuminuria • Allows early detection of CKD?

Management of CKD

Proteinuria in CKD

Document Proteinuria: UPC elevation: (Repeat test/3 day combination)

Prevention of Progression Hyperfiltration

High N3:N6 PUFA diet Ace-inhibitors (Remaining Nephrons)

Criteria for Therapeutic Intervention Dog Cat UPC > 0.5 > 0.4

AII

CKD INCREASED PGC

Treatment • ACE-Inhibitors • Ca Channel Blockers • Angiotensin Receptor Blockers

AII

Enalapril DECREASED PGC

• Dietary N6:N3 PUFA ratio 5:1

Management of CKD

Prevention of Progression Hyperfiltration

High N3:N6 PUFA diet Ace-inhibitors

Prevention of Progression Hyperfiltration

Effect of benazapril on the progression of induced CKD in cats

N=32 cats (4 groups of 8) 6.5 months

(Remaining Nephrons) CKD INCREASED PGC

High N-3:N:6 PUFA diet

Management of CKD

Placebo TBA3

(no effect)

DECREASED PGC

PGE3 PGI3

Systolic BP GFR IGCP

Benazapril (0.25-2 mg/kg) lower higher lower

11/21/2015

Management of CKD

Hypertension

Treatment Criteria sBP > 160 mm Hg (dog) sBP > 150 mm Hg (cats) Ocular abnormalities Neurologic signs Progressive CKD

Management of CKD

Hypertension

Enalapril Dog: 0.5 mg/kg PO q12-24h Cat: 0.25-0.5 mg/kg PO q12-24h Benazapril: Dog: 0.25-0.5 mg/kg PO q12-24h Cat: 0.5-1.0 mg/kg PO q12-24h Amlodipine Dog: 0.1-0.5 mg/kg PO sid Cat: 0.625-1.25 mg/day PO sid Goal: Dog: sBP < 160 mm Hg Cat: sBP < 150 mm Hg

Management of CKD

Metabolic acidosis

Current Recommendations Potassium citrate Potassium gluconate

Management of CKD

Hypokalemia

Current Recommendations: Potassium gluconate: 2-4 mmol/day PO Goal: Serum Potassium > 4.5 mM/l

Goal: Serum HCO3 > 17mM/l

Management of CKD

Azotemia

Hyperphosphatemia and hyperparathyroidism

Dietary protein restriction

Low P diet and oral P binders

Goal: BUN less than 18 nmol/L (60-80 mg/dl) Goal: Feed: low protein diets (commercial, home cooked) minimum protein minimum energy Monitor:

5.1 g/100 kcal (dog), 6.5 g/100 kcal (cat) 70-110 kcal/kg/day

BUN, HCO3, albumin

Stage 1 2 3 4

Serum P (mg/dl) 2.4-4.6 2.4-4.6 <5 <6

Feed: low P diet Rx: Al(OH)3 pwd. Al2(CO3)3 caps. Ca CO3

30-100 mg/kg PO daily divided Same 90-150 mg/kg PO daily divided

Monitor: Serum P, Ca

11/21/2015

Management of CKD

Proteinuria and hypertension Reduce IGCP with diet, ACE-inhib. and Dog Goal: UPC < 0.5 SBP (mm Hg) < 160

CCCB Cat < 0.4 < 150

Feed: Low sodium diet Rx: Dog: Enalapril: 0.5 mg/kg PO q12-24h Benazapril: 0.25-0.5 mg/kg PO q12-24h Amlodipine: 0.1-0.5 mg/kg PO sid Cat:

Metabolic acidosis Add oral bicarbonate precursors to diet Goal: Serum HCO3 > 17 mmol/L Rx:

Potassium citrate 75 mg/kg PO q8-12h

Monitor:

Serum TCO2

Amlodipine: 0.625-1.25 mg/day PO sid Benazepril: 0.5-1.0 mg/kg PO q12-24h

Monitor: UPC, BP

Management of CKD

Vomiting and Anorexia DOG

Vomiting and Anorexia CAT

Suppress vomiting center, block gastric acid prod.

Suppress vomiting center

Rx: App. Stim:

Omeprazole

Anti-emetic: Ondansetron Maropitant Metoclopramide Monitor:

0.5-1.0 mg/kg PO sid 0.5-1.0 mg/kg PO q12h 2 mg/kg PO sid (5 days max.) 0.2-0.5 mg/kg PO, SC, IM q6h

Vomiting, food intake, BW

Management of CKD

Mirtazepam 1.88 mg/cat/day (q2d in adv. CKD)

Anti-emetic: Ondansetron 0.1-1.0 mg/kg PO q6-12h Maropitant 1 mg/kg PO sid (5 days max.)

Monitor:

Vomiting, food intake, BW

Management of CKD

Anemia Correct anemia

Dose Adjustment in CKD Goal: PCV greater than 25 (20 in cats) Non-toxic drugs Rx: Erythropoietics: Darbepoietin alfa:

1Âľg/kg SC q7d* (reduce to q14-21d at target PCV) Epoetin alfa 100 u/kg SC 3x/wk* (reduce to 50 u/kg 2x/wk at target PCV) *to effect Iron dextran 100-300 mg/day (dog) 50-100 mg/day (cat) Monitor:

Drugs excreted by the kidney 25-75% reduction in CKD Nephrotoxic drugs

PCV

11/21/2015

Management of CKD Stages 1 and 2. Prevention of Progression Dietary adjustment: Low protein Low phosphorus Low (5:1) N6:N3 PUFA ratio ACE-inhibitors/Calcium channel blockers Recheck every 3 months Stages 3 and 4. Institute Major Strategies as Needed Additional protein restriction Oral phosphate binders Anti-emetics Erythropoietics Antihypertensives Potassium alkalinizers Recheck monthly

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Neurophysiology of the Lower Urinary Tract

1. Filling phase

DISORDERS OF MICTURITION

2. Emptying phase

David F. Senior dfsenior37@cox.net

Full bladder

Signal about Bladder content

Neurophysiology of the Lower Urinary Tract

L1-L3

S1-S3

PONS HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

P2X3 channel Sensory nerve ending

Stretched epithelium

BLADDER

ATP

URETHRA

From: Nature 2000;407, 951

Neurophysiology of the Lower Urinary Tract

L1-L3

S1-S3

PONS HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

BLADDER URETHRA

11/21/2015

Neurophysiology of the Lower Urinary Tract

L1-L3

S1-S3

PONS HYPOGASTRIC N.

PUDENDAL N.

PELVIC N.

BLADDER URETHRA

Neurophysiology of the Lower Urinary Tract

L1-L3

S1-S3

PONS HYPOGASTRIC N.

PUDENDAL N.

PELVIC N.

BLADDER URETHRA

Distribution of autonomic receptors in the urinary bladder Filling Phase

Emptying Phase

Cerebral Cortex Youth Dementia Tumor

Neurogenic Disorders of Micturition

L1-L3

S1-S3

PONS HYPOGASTRIC N. PELVIC N.

Beta Adrenergic Alpha Adrenergic

PUDENDAL N.

Cholinergic BLADDER URETHRA

11/21/2015

Peripheral nerve lesions Pelvic nerve Pudendal nerve Hypogastric nerve

Neurogenic Disorders of Micturition

L1-L3

Spinal disease Disc disease Trauma FEM Tumor

Neurogenic Disorders of Micturition

S1-S3 L1-L3

S1-S3

PONS PONS HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

BLADDER URETHRA

Non-neurogenic Disorders of Micturition Tail Avulsion

Non-neurogenic Disorders of Micturition Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

Non-neurogenic Disorders of Micturition Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

11/21/2015

Non-neurogenic Disorders of Micturition

Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

Non-neurogenic Disorders of Micturition

Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

Pelvic bladder vs. Short urethra?

Non-neurogenic Disorders of Micturition

Congenital Anomalies Ectopic ureter Patent urachus Hypoplastic bladder Atonic bladder

Congenital Anomalies - Cats Manx

11/21/2015

Non-neurogenic Disorders of Micturition

Neurophysiology of the Lower Urinary Tract

Inappropriate Urination - Cats Behavioral L1-L3

S1-S3

PONS HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

BLADDER URETHRA

Non-neurogenic Disorders of Micturition Overflow Incontinence - Cats Urethral obstruction

Non-neurogenic Disorders of Micturition Inflammation Urinary tract infection Urolithiasis Tumor

11/21/2015

Stress incontinence Urge incontinence Submissive urination

History for incontinence First occurrence? When? Urgency? Voluntary control? Associated problems?

Data base for incontinence Urinalysis Urethral patency Contrast radiography Cystoscopy Urodynamic evaluation

11/21/2015

Data base for incontinence

Urinalysis Urethral patency Contrast radiography Cystoscopy Urodynamic evaluation

Data base for incontinence

Urinalysis Urethral patency Contrast radiography Cystoscopy Urodynamic evaluation

Cystometrogram of a Dog

Cystometrogram

PRESSURE GUAGE

FLUID INFUSION

Pressure (mm Hg)

FLUIDS

100 90 80 70 60 50 40 30 20 10 0

Maximum Vesicular Contraction 75 mm Hg

Detrusor Threshold 390 ml

100

200

300

400

500

Bladder Volume (ml)

11/21/2015

Urethral pressure profile FLUIDS PRESSURE GUAGE

CATHETER PULLER

Urethral pressure profile of a female dog 60 50 40

Maximum Urethral Closure Pressure

44 mm Hg

Functional Sphincter Length

7.9 cm 0 1

Intravesicular Pressure

Zero Pressure (Vulva)

Medical manipulation of the lower urinary tract Filling Phase

Emptying Phase

Beta Adrenergic Alpha Adrenergic

Cholinergic

11/21/2015

Detrusor contraction

Bethanechol chloride (Urecholine) D: 1-15 mg PO tid C: 1.25-2.5 mg PO tid

Filling Phase

Emptying Phase

Beta Adrenergic

Detrusor contraction

Filling Phase

S1-S3

PELVIC N.

Propantheline (Probanthine) D: 15-30 mg PO tid C: 7.5 mg PO q2d

Filling Phase

PONS HYPOGASTRIC N.

Cholinergic

Alpha Adrenergic

Detrusor relaxation

Neurophysiology of the Lower Urinary Tract

L1-L3

Emptying Phase

Beta Adrenergic

Cholinergic

Alpha Adrenergic

Propranolol (Inderal) D: 0.25-0.5 mg PO tid

Emptying Phase

PUDENDAL N.

BLADDER URETHRA Beta Adrenergic

Cholinergic

Alpha Adrenergic

Detrusor relaxation

Urethral relaxation

Oxybutinin (Ditropan) D: 5 mg PO bid or tid

Filling Phase Filling Phase

Diazepam (Valium) D: 0.2 mg.kg PO tid C: 2.5 mg PO sid

Emptying Phase

Phenoxybenzamine D: 5-15 mg PO tid C: 2.5-5 mg PO sid

Beta Adrenergic Beta Adrenergic Alpha Adrenergic

Alpha Adrenergic Cholinergic

11/21/2015

Urethral relaxation

Urethral contraction Baclofen (Lioresal) D: 5-10 mg PO tid

L1-L3

Ephedrine D: 5-15 mg PO sid C: 2-5 mg PO sid

Filling Phase

S1-S3

Phenylpropanolamine D: 1-1.5 mg/kg PO tid

PONS HYPOGASTRIC N. PELVIC N.

PUDENDAL N.

Beta Adrenergic Alpha Adrenergic BLADDER URETHRA

Hormone responsive incontinence

OHE and incidence of incontinence

Males and females Breed predisposition Doberman Pinscher (U.S.) Boxer (Europe) Abnormal urethra

n = 412

Percent

ALL DOGS < 20 KG >20 KG BOXER GERMAN SHEPHERD DACHSHUND

20.1 9.3 30.9 65 10.6 11.1

Arnold S et al. Schweiz Arch Tierheilk 131:259-263, 1989

Hormone responsive incontinence

OHE and treatment of incontinence

EPINEPHRINE

Complete control Partial control No response

ESTROGEN

(n = 38)

(n = 17)

73.7% 23.7% 2.6%

64.7% 11.8% 23.5%

Female:

Diethylstilbestrol D: 1 mg PO sid 5 days Then 1 mg PO q3-7d to effect Conjugated estrogen (Premarin) D: 0.6 mg PO sid 5 days Then 0.6 mg PO q3-5d to effect

Arnold S et al. Schweiz Arch Tierheilk 131:259-263, 1989

11/21/2015

Hormone responsive incontinence Female: Estrogens Diethylstibestrol Conjugated estrogen (Premarin) Îą-Adrenergic agents Phenylpropanolamine Ephedrine

Synergistic!!

Male Dog Incontinence Urethral Sphincter Mechanism Incontinence Bladder small Urination normal Detrusor/Urethral Dyssynergia Distended bladder Frequent urge to urinate Strain to urinate then narrow stream Attempt urination then drip after

Male Dog Incontinence Detrusor/Urethral Dyssynergia Reduce urethral tone: baclofen: 1-2 mg/kg PO q8h prazosin: 0.5 mg/kg PO q12h phenoxybenzamine: 0.25 mg/kg PO q6-8h diazepam: 2-10 mg/dog PO q8h dantrolene: 1-5 mg/kg PO q8-12h Anxiolytic acepromazine: 0.55-1.5 mg/kg PO q6-12h Prevent over-distention Frequent opportunity Owner catheterization

Medical manipulation of the lower urinary tract Filling Phase

Emptying Phase

Beta Adrenergic Alpha Adrenergic

Cholinergic

Male Dog Incontinence

Urethral Sphincter Mechanism Incontinence Hormone responsive? Testosterone cypionate D: 2.2 mg/kg IM q30d Phenylpropanolamine D: 1.5 mg/kg PO tid

Submucosal bulking agents Teflon paste Collagen 50% effective 70% with Meds.

11/21/2015

Teflon paste Granulomas Extrusion

Artificial Urethral Sphincter

Ectopic ureter

UPP to predict postoperative incontinence in ureteral ectopia

MUP (cm H2O)

Continent

Incontinent

38.3 +/- 7.7

20.2 +/- 10.8

MUCP (cm H2O) 29.8 +/- 8.5

11.8 +/- 9.6

FPL (cm)

3.4 +/- 2.4

MUCP:

6.5 +/- 2.1

Urethral deformity in ectopic ureter

Continent > 19 cm H2O Incontinent < 19 cm H2O

Lane I et al. J Am Vet Med Assoc 206:1348-1357, 1995

11/21/2015

Urethral deformity in ectopic ureter

Aquatic Urodynamics

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Etiology

FELINE URETHRAL OBSTRUCTION

David F. Senior dfsenior37@cox.net

Urethral Obstruction

LOOSE CRYSTALLINE MATERIAL

11/21/2015

CRYSTALLINE URETHRAL PLUG

Frequency of Occurrence for Causes Associated With Urethral Obstruction in Male Cats Characteristic

Urethral plugs Idiopathic Uroliths Strictures

Kruger 1991

Barsanti 1996

59% 29% 12% 0%

42% 42% 5% 11%

Gerber 2008

18% 53% 29% 0%

Kruger JM, Osborne CA, Goyal SM, et al: Clinical evaluation of cats with lower urinary tract disease. J Am Vet Med Assoc 199:211-216, 1991; Barsanti JA, Brown J, Marks A, et al: Relationship of lower urinary tract signs to seropositivity for feline immunodeficiency virus in cats. J Vet Intern Med 10:34-38, 1996; Gerber B, Eichenberger S, Reusch CE: Guarded long-term prognosis in male cats with urethral obstruction. J Feline Med Surg 10:16-23, 2008.

Etiology

11/21/2015

Etiology

Pathogenesis

Urethral obstruction with crystals less common now Still a problem Plugs contain mucus and crystals

Urine Concentration Usual S.G. = 1.055-1.065 (1800-2400 mOsm/kg H2O Crystalluria common

Loose arrangement of crystals Caused by: Mucus stickiness? Increased crystalluria? Combination? Viruses? Urethral spasm

Metabolic Changes in Serum Azotemia

Median

Range

Creatinine (mg/dl) (29%) BUN (mg/dl) (33%)

1.5 25

0.8-7.7 8-257

High P (mg/dl) (25%) Low Ca2+ (mMol/L) (34%)

5.0 1.1

2.8-20 0.57-1.6

< 1.0

Low pH (75%) High K+ (mM/L) (41%)

7.29

7.02-7.45 3.4-10.5

< 7.2 >8

Postrenal Azotemia Rapidly rising azotemia Hyperkalemia Hyperphosphatemia Metabolic acidosis

Pathogenesis

Danger Level

Pathogenesis

Causes of Collapse and Hypotension Hyperkalemia: Venous dilation Bradycardia: Decreased cardiac output Acidemia: Decreased vascular sensitivity to catecholamines Hypocalcemia: Decreased myocardial contractility; vasodilation Acute uremia: Myocardial depression; decreased cardiac output Hypothermia: Reduced BP; reduced cardiac contractility & output

Post obstructive diuresis Accumulation of retained solutes Overhydration Impaired tubular concentrating mechanism

11/21/2015

Pathogenesis

Diagnosis

Cats form very concentrated urine leading to crystalluria Poorly understood matrix disturbances/urethritis Urethral spasm Urethral obstruction causes post-renal azotemia

History Hiding Anorexia Vomiting Dysuria Pollakiuria Hematuria “Accidents”

Physical Exam Depressed/comatose Inflamed penis Urethral plugs? Distended bladder** Painful bladder

ECG No P-wave Wide QRS Tented T-wave VPC’s

Hyperkalemia/hypocalcemia become life-threatening After relief of obstruction cats develop post-obstructive diuresis

Imaging Evaluation

Clinical Signs: Predicting Severity of Metabolic Changes In sick to moribund cats with Urethral Obstruction

Hypothermia: Bradycardia:

< 96°F (35.5°C) < 120 bpm

98-100% accurate predictor of Severe Hyperkalemia (K+ > 8.0 mMole/L)

DIAGNOSIS: ECG Evaluation

Imaging Evaluation Radiographs - Mandatory Calculi Free Fluid Contrast Radiographs Recurrent UO Stricture/Rupture After catheterization Ultrasonography Bladder thickness Small calculi Abdominal fluid

11/21/2015

Diagnosis of Urethral Obstruction

MANAGEMENT

Typical history and enlarged painful bladder is apparent Assess of the severity of metabolic disturbances Hypothermia/bradycardia (<35.5°C; < 120 bpm) ECG, Lead II Serum electrolytes: K+, Ca2+ , HCO3Imaging

Hyperkalemia/Abnormal ECG IV Fluids: 0.9% NaCl/Normosol R (100 ml/hr 4 hrs) Hyperkalemia/Hypocalcemia Calcium gluconate (50-100 mg/kg IV 2-3 min) (monitor ECG) Dextrose 10% (0.5 g/kg IV slow push) Sodium bicarbonate (1 mM/kg IV slow push)

Analgesia/Anesthesia/Sedation Acepromazine Ketamine Diazepam Midazolam

0.02-0.05 mg/kg IV 2-4 mg/kg IV 0.1-0.2 mg/kg IV 0.1-0.2 mg/kg IV

Hydromorphone Fentanyl

0.02-0.05 mg/kg IV 2-4 µg/kg IV

Propofol Buprenorphine

2-4 mg/kg IV 10 µg/kg IM

Anesthetic/Sedative Agents Ketamine: 2-4 mg/kg Diazepam: 0.1-0.2 mg/kg 0.25 ml ketamine (100 mg/ml) plus 0.25 ml diazepam (5 mg/ml) Administer 0.25 ml IV first and the other 0.25 ml as needed* *Plus Inhalation for better relaxation

11/21/2015

Management

Anesthetic/Sedative Agents

Urethral Patency and Catheter Management

Good sedation/anesthesia is essential to minimize trauma

Ketamine: 2-4 mg/kg Acepromazine: 0.02-0.05 mg/kg 0.1 ml ketamine (100mg/ml) plus 0.01 ml acepromazine (10 mg/ml)* *Plus Inhalation for better relaxation

Urethral Patency and Catheter Management

Management Urethral Urethralpatency Patency and Catheter Management

Good sedation/anesthesia is essential to minimize trauma

11/21/2015

Management

Post-Obstructive Diuresis Provide IV fluids to avoid dehydration BW, P.E., PCV & TS. Match urine output Monitor serum electrolytes Gradual reduction in rate of administration When?

If the cat is depressed and cardiotoxic, address the electrolyte abnormalities first Cystocentesis provides rapid bladder decompression Rapid correction of hyperkalemia is needed Catheterization should be atraumatic, if possible Manage post-obstructive diuresis

Clinical signs of obstruction are those of lower urinary tract inflammation Bladder distention is easily palpated Hypothermia and bradycardia indicate hyperkalemia ECG can confirm hyperkalemic cardiotoxicity Sequence of treatment depends on severity

Urethral Spasm Promote urethral relaxation • Prazocin: 0.25-0.5 mg/cat BID-TID • Phenoxybenzamine: 1.25-7.5 mg/cat PO SID-BID • Diazepam: 1.25-2.5 mg/cat PO BID-TID

11/21/2015

Bladder Atony Prevent bladder overfilling Promote bladder contraction • Bethanechol chloride: 1.25-7.5 mg/cat PO TID • Propranolol: 0.25-0.5 mg/kg PO TID

Urethral Rupture/Tear

Urethral Rupture/Tear Indwelling urethral catheter • Retrograde • Antegrade Cystostomy tube Healing time: 5-14 days Recheck with contrast urethrogram

URETHRAL STRICTURE Perineal Urethrostomy Severe urethral trauma Stricture

11/21/2015

Management IV fluids (pure water loss)

Immediately:

2.5 % Dex in 0.45 % NaCl Add 2-6 mM/kg HCO3 1. Intravenous fluids* 2. Decompressive cystocentesis* 20-30 ml 3. Lead II ECG* Hyperkalemia/abnormal ECG 4. Abdominal radiographs Bicarbonate Calcium gluconate Insulin/dextrose

Definitive:

5. Establish urethral patency Catheter/ Flush * These steps can be bypassed in bright/alert patients

URETHRAL SPASM

Imaging Evaluation Radiographs - Mandatory Calculi Free Fluid Contrast Radiographs Recurrent UO Stricture/Rupture After catheterization Ultrasonography Bladder thickness Small calculi Abdominal fluid

Management

Smooth muscle relaxation (ď Ą-blocker) Phenoxybenzamine 2.5-7.5 mg/cat PO q12-24h Skeletal muscle relaxation Diazepam 2.5 mg PO q12h Dantrolene 0.5-2 mg/kg PO q12h(?) Anti-inflammatory Corticosteroids (?)

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Etiology of Hypertension

• White Coat Effect

HYPERTENSION

David F. Senior

• Secondary Dog

Cat

CKD AKI Hyperadrenocortism Diabetes mellitus

CKD Diabetes mellitus Hyperthyroidism

dfsenior37@cox.net

• Idiopathic

Measurement of BP

Direct Indirect

White Coat Effect Major barrier to accuracy • Environment • Consistency Device Cuff size and position Skilled technician • Average of 3-7 measurements (discard 1st)

Measurement of BP

Doppler Ultrasonography Oscillometry Conventional High Definition

Normal Blood Pressure Values (mm Hg)

Blood Pressure Parameters Systolic Diastolic MAP Doppler Yes ? ? (in cats) (highly operator dependent; least expensive) Oscillometric Convent. Yes (slow acquisition time)

Yes

High Def. Yes Yes Yes (rapid acquisition; most accurate; most expensive)

Systolic/Diastolic (MAP) Dog

145/90 (105)

Cat

135/80 (100)

Extreme variability!!!

11/21/2015

Hypertension – Target Organ Damage

Kidney Progressive loss GFR/proteinuria Eyes Retinal detachment/blindness Retinal hemorrhage/edema Hyphema Brain Encephalopathy/Stroke Heart Left ventricular hypertrophy

Hypertension – Clinical Presentation

Clinically silent – MOST!! Blindness Hyphema Episodic neurological signs Epistaxis Weakness Poor exercise tolerance.

Image by David Williams

Hypertension in CKD

11/21/2015

Hypertension in CKD

Diagnosis of Hypertension

• Hypertension common in CKD • Usually mild • Occasionally severe • Blindness • Neurological signs • Progression of CKD

• Elevated BP Values – Repeatable!!! • Concurrent predisposing disease • Target organ damage Kidney, Eye, Brain, Heart

Treatment of Hypertension – When? IRIS Sub-staging by Blood Pressure

BP Value (mm Hg) < 150/95

Risk of Target Organ Damage Minimal

150-159/95-99 160-179/100-119

Mild Moderate

≥ 180/120

Management of CKD

Severe

Systolic BP mm Hg <150 150 – 159

Diastolic Adaptation when breedBP specific reference range mm Hg is available <95 95 - 99

160 – 179 100 - 119 ≥ 180

≥ 120

Arterial Pressure Substage

<10 mm Hg above

Normotension

reference range

Minimal Risk

10 – 20 mm Hg above Borderline hypertension reference range

Low Risk

20 – 40 mm Hg above

Hypertension

reference range

Moderate Risk

≥ 40 mm Hg above

Severe hypertension

reference range

High Risk

Hypertension

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

NON-OBSTRUCTIVE FLUTD

Etiology

NON-OBSTRUCTIVE FELINE LOWER URINARY TRACT DISEASE

David F. Senior dfsenior37@cox.net

ETIOLOGY OF NON-OBSTRUCTIVE FLUTD

Identifiable Etiologies Urolithiasis Anatomical Defects Behavioral Neoplasia UTI Foreign Bodies

(14%) (11%) (?) (9%) (2%) (1%) (Rare)

NON-OBSTRUCTIVE FLUTD

Clinical Signs

History Urgency Dysuria Pollakiuria Hematuria Periuria “Accidents”

ETIOLOGY OF NON-OBSTRUCTIVE FLUTD Urolithiasis Behavioral Anatomical Defects (?) UTI Tumor (Rare) Idiopathic?? Abnormal Stress Response? Infectious agent? Food allergy? Toxic urinary metabolites? Defective GAG layer?

NON-OBSTRUCTIVE FLUTD

Diagnosis

Uroliths (15%)

Physical Examination Bladder wall Thickened Sensitive Crepitus (?)

Can be difficult to palpate Solitary - No crepitus May need contrast radiographs U/S is good

11/21/2015

NON-OBSTRUCTIVE FLUTD

Anatomical Defects (11%)?

Diagnosis

Diverticulum Not clear about role Resolve spontaneously

Behavioral Issues (9%)

11/21/2015

No Escape?

Behavioral Causes

Litter Box issues

STRESS!!!

Location Unsafe place Hygiene

11/21/2015

NON-OBSTRUCTIVE FLUTD

Diagnosis

Foreign bodies (Rare) Catheter

UTI Rare Common in old cats

NON-OBSTRUCTIVE FLUTD

Diagnosis

Foreign bodies (Rare) Grass awn

Non-obstructive FLUTD causes signs of lower urinary tract inflammation The bladder is thickened and sore on palpation Uroliths are the most common identifiable cause Uroliths can be hard to palpate Can be detected on contrast radiographs and U/S Urolith material should be collected for analysis Most are calcium oxalate and struvite

The role of diverticula is not clear Behavioral considerations are important UTI is rare but more common in old cats UTI Suspected? The urine should be cultured The isolates are the same as in the dog

Idiopathic Feline Lower Urinary Tract Disease

? Feline Idiopathic Cystitis (FIC) Feline Interstitial Cystitis (FIC) Feline Urologic Syndrome (FUS)

11/21/2015

FELINE IDIOPATHIC CYSTITIS

Clinical Signs

Diagnosis

Urgency Dysuria Pollakiuria Hematuria Periuria “Accidents”

Cystoscopy

Bladder wall Thickened Sensitive

UROEPITHELIUM

so4 -+ so4 -+ so4 -+ so4 -+ so4 -+ so4 -+ so4 -+ so4 -+ URINE so4 -+ so4 -+ so4 -+ so4 -+ so4 -+ so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 - + so4 +

11/21/2015

VISCERAL PAIN SYNDROME ENHANCED CENTRAL “PERCEPTION”

ENHANCED PERIPHERAL SENSITIVITY

Plasticity

VISCERAL PAIN SYNDROME

Disturbances in the HPA axis

CONTINUED CENTRAL “PERCEPTION”

PERIPHERAL DISEASE RESOLVED NORMAL STIMULUS

DIAGNOSIS OF NON-OBSTRUCTIVE FLUTD

A Diagnosis of Exclusion History Recurrent episodes of signs Physical Examination Thickened bladder wall Urinalysis Erythrocytes, leucocytes (few), epithelial cells Urine Culture Negative

DIAGNOSIS OF NON-OBSTRUCTIVE FLUTD

A Diagnosis of Exclusion Radiographs Normal Ultrasound Thickened bladder wall Cystoscopy Submucosal petechial hemorrhages (glomerulations) Biopsy Erythrocytes, edema, fibrosis, mast cells(?)

11/21/2015

NON-OBSTRUCTIVE FLUTD Diagnosis Cystoscopy

Submucosal Edema, Vasodilation and Red Cell Diapedesis of the Bladder Wall in a Cat with IC

Management of FIC

A dilemma!!

Clinical Features Human Nocturia/Frequency YES Urgency YES Pain YES Stress induced YES Sterile urine YES Glomerulations YES Mast cell infiltration YES Symptoms/Signs Constant

Therapeutic Trends Feline YES YES YES YES YES YES YES Intermittent

1990s antispasmodics acidifiers 1970s Na+ chloride 1980s antibiotics K+ chloride antibiotics antispasmodics diuretics antispasmodics acidifiers corticosteroids 1950s acidifiers Na+ chloride DMSO antibiotics Na+ chloride LRS amitriptyline antispasmodics LRS topical phenol hydrodistention acidifiers 1936 copper coils topical Lugol’s alpha interferon vit A antiseptics FHV1/FCV Curcal® GAGs acidifiers testosterone vaccine 1916 megesterol moist acid diets hylauronidase vit A, D acid Mg diets alkali debridment nothing debridment  fat diet nothing lithium low ash diet tomatoes Mg, phos diet milk

2000s antibiotics analgesics antispasmodics amitriptyline LRS hydrodistention leukotriene antgn corticosteroids alpha interferon megesterol maropitant hydroxyzine GAGs diuretics arginine NSAIDS moist food enrichment omega-3 FA nothing

esvimicpres

11/21/2015

Management of FIC

STRESS REDUCTION!!

Management of FIC

Environmental Enrichment • Litters – One per cat + 1; clean daily

• • • •

Environmental Enrichment

Environmental Enrichment • Litters

• Litters – One per cat; clean daily

• • • •

Scratch posts Perches Toys Water fountains

Environmental Enrichment • Litters – One per cat; clean daily

• • • •

Scratch posts Perches Toys Water fountains

– One per cat; clean daily

• • • •

Scratch posts Perches Toys Water fountains

Management of FIC

Environmental Enrichment • Litters – One per cat + 1; clean daily

• • • •

Scratch posts Perches Toys Water fountains

11/21/2015

CANNED FOOD IN FIC

Dietary Anitioxidants and N-3 PFA IN FIC

54 CATS WITH SPONTANEOUS FIC FED EITHER CANNED OR DRY FOOD FORMULATION OF AN ACIDIFIED DIET (AS IDENTICAL AS POSSIBLE)

NUMBER OF CATS RECURRENCE

CANNED

DRY

18 2 (11 %)*

28 11 (39 %)*

* P < 0.05 Markwell PJ et al J Am Vet Med Assoc 1999;214:361-5

Management of FIC

HIGH

LOW

CLINICAL SIGNS

4/11 (36%)*

9/16 (64%)*

RECURRENCE (per 1,000 cat days)

1.28 (89% lower) * P < 0.05

11.15

Kruger JMProceedings: 2013 Annual ACVIM Forum, Seattle WA, 2013, p.504.

AMITRIPTYLINE IN FIC

Increase Water Intake in FIC 1. Feed twice daily 2. Add water to the food 3. Adjust water container or depth 4. Add wet foods to the diet

Modes of action of amitriptyline 1. Blocks nociception 2. Inhibits histamine release 3. Blocks H-1 receptors 5. Anticholinergic 6. Stabilizes mast cells

5. Offer bottled or distilled water 6. Try a pet fountain 7. Leave water in the sink, bathtub or shower Slow drip so always fresh 8. Flavor water: low salt meat or fish broth 9. Administer “light” salt (KCl) capsules tid

5-10 mg p.o. sid

Pentosan polysulfate in FIC

AMITRIPTYLINE IN FIC

Elmiron®, ALZA Pharmaceuticals

15 CATS WITH SPONTANEOUS FIC AMITRIPTYLINE 10 mg P.O. SID

NO SIGNS HEMATURIA PROTEINURIA CYSTOSCOPY

25 CATS WITH SPONTANEOUS FIC FED EITHER HIGH ANTIOXIDANT AND HIGH N-3 PUFA DIET OR CONTROL DIET FOR 12 MONTHS

6 MTHS

12 MTHS

73 % IMPROVED IMPROVED ABNORMAL

69 % IMPROVED IMPROVED ABNORMAL

Side effects: somnolence, weight gain, reduced grooming, cystic calculi

Chew DJ et al J Am Vet Med Assoc 1998;213:1282-6

8 mg/kg po bid Expensive: $70/month

Bladder Wall GAG layer Fixed H2O Urine

11/21/2015

DMSO in FIC

Hydrodistention in FIC 80 cm H2O for 10 minutes

Modes of Action

Intravesicular 10-20 ml 10 % DMSO

Depletion of sensory neuropeptides Enhanced GAG production Degeneration of sensory nerve endings

Analgesic Anti-inflammatory Antibacterial* Antifungal* Antiviral*

Limited data No controls

80 cm

bladder

* weak effect catheter

2003-2013* Antiinflammatory/Analgesic Prednisolone Methylprednisolone Dexamethasone Piroxicam Meloxicam Ketoprophen Carprofen Tolfedine Tepoxalin DMSO Butorphanol Buprenorphine Oxymorphone Fentanyl Tramadol

Antimicrobics Chloramphenicol Doxycycline Enrofloxacin Amoxicillin

GAGs Pentosan polysulfate Glucosamine Chondroitin sulfate Hyaluronate

Environmental Enrichment Litter box management Facial pheromone

Antidepressant/Anxiolytic Amitriptyline Nortriptyline Imipramine Clomipramine Fluoxetine Paroxetine Diazepam Oxazepam Alprazolam Buspirone Enrichment

Dietary Canned food Acidifying Hypoallergenic Water Omega-3 FA Antioxidants Alpha-casozepine L-tryptophan

Other

Other Treatments in FIC Antispasmodics Propantheline Oxybutynin Aminopentamide Atropine Acepromazine Prazosin Phenoxybenzamine Dantrolene Flavoxate

Fluids Furosemide Megestrol acetate Zafirlukast Montelukast Hydroxyzine Cyproheptadine Trimeprazine Cromolyn Arginine Hydrodistention Mucosal scraping Maropitant

Antispasmodics

Propantheline (Probanthine®) 7.5 mg po q72h

Anti-inflammatories

Prednisolone 1 mg/kg po bid

Antihistamines

Hydroxyzine (Atarax®) 5-10 mg po bid

Alt Med Acupuncture Colloidal silver Herbs (10) Laser therapy

All are unproven in controlled studies

*Compiled from the Veterinary Information Network http://www.vin.com

Many treatments have been tried in FIC 1. Stress reduction seems to be important 2. High antioxidant and high N-3 PUFA diets helpful 3. Canned food/Enhanced water intake may be helpful 4. Tricyclic antidepressant: Amitriptyline The intermittent nature of the syndrome makes anecdotal evaluation of efficacy difficult and very few treatments have undergone controlled trials

11/21/2015

Prostatic Disease David F. Senior dfenior37@cox.net

Proportion of affected male dogs in the population

Per cent

9 8 7 6 5 4 3 2 1 0

Prostatic Disease in Dogs • Benign prostatic hyperplasia • Prostatic Cysts • Bacterial Prostatitis

% Affected

– Acute – Chronic – Abscess

• Neoplasia • Paraprostatic cysts

1 to 2 to 4 to 7 to 10 > 15 2 4 7 10 to 15 Age Group

Frequency of Diagnosis 177 dogs Number of Times Observed Prostatic enlargement Bacterial Prostatitis Prostatic Cysts Neoplasia Benign Hyperplasia Paraprostatic Cysts Mycotic Prostatitis

90 33 27 13 11 2 1

Clinical Features of Prostatic Disease

Per Cent

50.8 18.6 15.3 7.3 6.2 1.1 0.6

CLINICAL SIGNS

REMARKS

Hematuria Urethral Discharge Straining to defecate Fever Anorexia Vomiting Hind Limb Weakness

All prostatic diseases All prostatic diseases All prostatic diseases Abscess and acute bacterial prostatitis Abscess and acute bacterial prostatitis Abscess and acute bacterial prostatitis Neoplasia and acute bacterial prostatitis

Krawiec DR JAVMA, 1992; 200:1119-1122

11/21/2015

Palpable Features of Prostatic Disease in the Dog

Painful Enlarg. Symm. Firm Bacterial Prostatitis Acute Chronic Abscess

+ + +

+ +/+

Benign Hyperplasia

Prostatic Cysts

Neoplasia

Mobile

+ + -

+ + +

+/-

Prostatic Wash

Methods of Collection • • • •

Greater than 80 % Rule

Wash Ejaculate Aspiration Biopsy

Cytology of the Prostate

Diagnostic Efficacy of Collection Methods

MASSAGE BRUSH EJACULATION ASPIRATION NEEDLE BIOPSY WEDGE BIOPSY

Cell Harvest

Accuracy of Cell Collection

Accuracy of Bacterial Culture

+ ++

++ +++ +++

+ ++ ++ ++ +++ +++

11/21/2015

Cytology of the Prostate

Diseases of the Prostate • Benign Prostatic Hyperplasia (BPH) – Common in older intact males – Most common prostatic disease – Associated with high plasma 17β-estradiol – Treatment • Castration • Hormonal treatments (see later)

11/21/2015

Diseases of the Prostate • Prostatic Cysts – Common in old dogs as an incidental finding – Can be caused by estrogen treatment • When doses are too high!

Diseases of the Prostate • Bacterial Prostatitis – Can be acute or chronic – Can be source of recurrent UTI

Isolates from Bacterial Prostatitis E. Coli Mycoplasma spp. Staphylococcus intermedius Streptococcus spp. Proteus mirabilis Klebsiella pneumoniae Micrococcus spp Acinetobacter spp. Enterobacter cloacae Ling GV, JAVMA 1983; 183:201-206

11/21/2015

Effect of pKa on Prostatic Penetration Antimicrobial pKa = 8.4 Interstitium pH 7.4

(1) B

Prostatic Acinus

Interstitium pH 7.4

pH 6.4

B (1)

(10) HB+

Antimicrobial pKa = 5.4

HB (100)

Weak Base

HA (1) -

A (100)

Prostatic Acinus pH 6.4

HA (1) -

A (10)

Treatment of Bacterial Prostatitis • Select antimicrobials based on C/S – Prostatic penetration • Fluoroquinolones, trimethoprim, chloramphenicol (not β-lactam antimicrobials!!)

• Extended treatment (30 days) • Concurrent castration or Rx for BPH

Weak Acid

Diseases of the Prostate • Prostatic Abscess – Can result from poorly treated UTI • Wrong drug • Wrong duration

11/21/2015

Treatment of Prostatic Abscess • Treatment for septic shock • Surgical drainage • Appropriate antimocrobials • Many die despite good treatment • Many have post-operative side-effects

Long-term Postoperative Complications of 57 Dogs with Prostatic Abscessation

Complication Urinary Incontinence Mild Severe UTI (> 3 episodes) (< 3 episodes) Recurrence of Abscess Paraprostatic Cyst Urethrocutaneous fistula Fistula 2° to Marsupialization

Number

% of 57 Dogs

15 11

26.3 19.6

11 6 11 2 1 1

19.6 10.5 19.3 3.6 1.8 1.8

Mullen HS, JAAHA 1990; 26:369-379

Diseases of the Prostate • Prostatic Carcinoma – Relatively rare – Incidence in castrated vs. intact dogs – Almost the only prostatic disease seen in castrated dogs

Intact All Prostatic Diseases Neutered Neoplasia!!

11/21/2015

Prostatic Specific Antigen • • • •

Prostatic tissue size Non-specific Monitor changes Monitor recurrence

Treatment of Prostatic Carcinoma • Radiation, chemotherapy – Limited effectiveness – Palliative only

• Control pain!

Diseases of the Prostate • Paraprostatic Cysts – Can be very large – Can be abdominal or pelvic (or both) – Can become infected • Very serious!!

11/21/2015

Treatment of Paraprostatic Cysts • Drainage – Tend to recur

• Surgical excision – Can be a difficult procedure

Hormonal Treatment of Prostatic Disease

MEGESTROL ACETATE Mode of Action Negative feedback pituitary Increased metabolism of androgens Binds the cytoplasmic DHT receptor Side Effects Diabetes mellitus

11/21/2015

ESTROGENS • Mode of Action – Negative feedback on pituitary • Side Effects – Squamous metaplasia – Retention cysts – Bone marrow aplasia • Dose Premarin – 0.6 mg PO sid 5 days then 0.6 mg PO q3-5d to effect

GNRH AGONISTS LEUPROLIDE • Mode of Action – Down regulates the pituitary receptors

• Side Effects – Impotence (humans)

• Very expensive!

11/21/2015

KETOCONAZOLE • Mode of Action – Inhibits androgen synthesis

• Side Effects – Only a transient effect

5 α-Reductase Inhibitors FINASTERIDE (FOSFESTROL?) • Mode of Action – Blocks DHT production in the testicles

• Side Effects – None known

• Dose – 0.1-0.5 mg/kg po sid

ANDROGEN RECEPTOR BLOCKERS

FLUTAMIDE • Mode of Action – Inhibits binding to the DHT receptor

• Side Effects – Rebound increase in testosterone

11/21/2015

Prostatic Disease in Dogs • Benign prostatic hyperplasia • Prostatic Cysts • Bacterial Prostatitis – Acute – Chronic – Abscess

• Neoplasia • Paraprostatic cysts

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Physiological Basis of Proteinuria

PROTEINURIA David F. Senior dfsenior37@cox.net

GLOMERULAR FILTRATION

RENAL VASCULATURE

Image Courtesy Dr. Jill Verlander-Reid

GLOMERULAR FILTRATION Podocytes Foot Processes Filtration Slits

Images Courtesy Dr. Jill Verlander-Reid

Image Courtesy Dr. Jill Verlander-Reid

11/21/2015

GLOMERULAR FILTRATION

STRUCTURAL BARRIERS TO FILTRATION Endothelial cells

Endothelial Pores Basement Membrane Filtration slits Mesangium

Lamina rara interna Lamina densa Lamina rara externa

Slit Diaphragms Image Courtesy Dr. Jill Verlander-Reid

Image Courtesy Dr. Jill Verlander-Reid

STRUCTURAL BARRIERS TO FILTRATION

Basement Membrane Type IV collagen network laminin heparan sulfate proteoglycans entactin Slit Diaphragm nephrin

RENAL HANDLING OF PLASMA PROTEINS Protein

M.W.

S-E Radius

Filtrate/ Plasma

Inulin Insulin Lysozyme Myoglobin PTH Gr. Hormone Amylase Albumin Gamma Glob. Ferritin

5300 6000 14,600 16,900 9,000 20,000 48,000 69,000 160,000 480,000

1.4 1.6 1.9 1.9 2.1 2.1 2.9 3.6 5.5 6.1

1.0 0.9 0.75 0.75 0.65 0.6-0.7 0.02 0.02 0.00 0.02

Image Courtesy Dr. Jill Verlander-Reid

Glomerular selectivity for albumin

Albumin 3-4 g/dl

Albumin Filtration and Excretion

100 L/day (3,500g/day)

Albumin 0.6 mg/dl

< 300 mg/day

11/21/2015

The Fate of Filtered Albumin 100 L/day (0.6 mg/dl)

PROTEINURIA GLOMERULAR

Most Reabsorbed (at Tm) TUBULAR Tamm-Horsfall Protein Impaired reabsorption

The Fate of Filtered Albumin 100 L/day (0.6 mg/dl)

GLOMERULONEPHROPATHY ETIOLOGY NORMAL

Most Reabsorbed (at Tm) GLOMERULAR CAPILLARY MEMBRANE DYSFUNCTION

Renal Tubular Injury Induced by Reabsorbed Protein

PROTEINURIA Pre-Renal Abnormally high filtered protein in plasma

Renal Glomerular Functional Pathological Tubular (Impaired reabsorption)

Post-Renal Lower UT inflammation Genital source

11/21/2015

Tests for Proteinuria

Standard U/A dipstick test

Sulfosalicylic acid Turbidimetric test

Limit of Sensitivity: >30 mg/dl False positives: Alkaline urine Concentrated urine

Tests for Proteinuria MICROALBUMINURIA TEST

Limit of Sensitivity: 1-30 mg/dl

Tests for Proteinuria 24 hr Protein Excretion  UPr/Cr

UPr/Cr Ualbumin/Cr

Tests for Proteinuria 24 hr Protein Excretion  UPr/Cr

PROTEINURIA

POST-RENAL

INFLAMMATION/HEMORRHAGE

UPr/Cr confirmation 1. Average of 3 collections on successive days 2. Single calculation from pooled sample from 3 days (equal volume from each)

11/21/2015

GLOMERULONEPHROPATHY

PROTEINURIA

CLINICAL SIGNS

UPr/Cr > 2 is thought to confirm glomerular disease

2Y FS MIN. POODLE

Note: Tubular proteinuria can be significant

WEIGHT LOSS EDEMA

Size estimation with SDS* to confirm Glomerular: â&#x2030;¥ 69 kDa Tubular: < 68 kDa * Sodium dodecyl sulfate

GLOMERULONEPHROPATHY

2Y FS MIN. POODLE

GLOMERULONEPHROPATHY

2Y FS MIN. POODLE

SERUM CHEMISTRY CBC PCV WBC NEUT LYMPH MONO EOS

GLOMERULONEPHROPATHY

URINALYSIS Specific Gravity > 1.035 pH 7.0 Protein 4+

UPr/Cr x 3

36 12,600 9,070 2,646 630 252

2Y FS MIN. POODLE

Creatinine BUN Calcium Phosphorus Chloride TCO2 Albumin Globulin

1.6 mg/dl 32 mg/dl 8.2 mg/dl 5.4 mg/dl 117 mM/l 21 mM/l 1 g/dl 2.2 g/dl

GLOMERULONEPHROPATHY

(141) (5.3) (2.0) (1.74)

(10) (22)

2Y FS MIN. POODLE

Urine Sediment

Sediment: casts

11/21/2015

GLOMERULONEPHROPATHY

ETIOLOGY

MILD ANTIGEN EXCESS

INFECTIOUS GLOMERULONEPHRITIS

AMYLOIDOSIS

BACTERIAL ENDOCARDITIS BRUCELLOSIS DIROFILARIASIS EHRLICHIOSIS

NEOPLASTIC PRIMARY

SECONDARY INFLAMMATORY PANCREATITIS SLE

REACTIVE

Ig RELATED

PROSTATITIS

FAMILIAL

OTHER HYPERADRENOCORTICISM IDIOPATHIC

GLOMERULONEPHROPATHY

ETIOLOGY

AMYLOIDOSIS

MEDIATORS OF INFLAMMATION PLATELETS THROMBOXANE NEUTROPHILS LEUKOTRIENES MESANGIAL CELLS AND LEUKOCYTES CYTOKINES GROWTH FACTORS MANY CELLS PLATELET ACTIVATING FACTOR

GLOMERULONEPHROPATHY ETIOLOGY

AMYLOIDOSIS

GLOMERULONEPHROPATHY ETIOLOGY

AMYLOIDOSIS

11/21/2015

GLOMERULONEPHROPATHY

2Y FS MIN. POODLE

ADDITIONAL TESTS Coombâ&#x20AC;&#x2122;s ANA Heartworm Thoracic Rads Abdominal Rads U/Sound

GLOMERULONEPHROPATHY

RENAL BIOPSY

NORM NORM

2Y FS MIN. POODLE

NEPHROTIC SYNDROME

Hypertension Coagulopathy

2Y FS MIN. POODLE

NEG NEG NEG NORM

RENAL BIOPSY

Peripheral Edema Ascites Proteinuria Hypoalbuminemia Hypercholesterolemia Hyperfibrinogenemia

GLOMERULONEPHROPATHY

2Y FS MIN. POODLE

RENAL BIOPSY

GLOMERULONEPHROPATHY

GLOMERULONEPHRITIS AMYLOIDOSIS NEPHROTIC SYNDROME

NEPHROTIC SYNDROME GN

11/21/2015

GLOMERULONEPHROPATHY

DIAGNOSIS

#1 MARKER: PROTEINURIA

URINE PROTEIN/CREATININE RATIO* (mg/dl:mg/dl)

PROTEINURIA/HYPOALBUMINEMIA <1 >2

CONFIRMATION

NORMAL GLOMERULAR DISEASE

URINE PROTEIN/CREATININE RATIO *In the absence of marked hematuria or pyuria

GLOMERULONEPHROPATHY

DIAGNOSIS

GLOMERULONEPHROPATHY

BIOPSY (?)

DIAGNOSIS BLOOD PRESSURE MEASUREMENT • A HIGH PROPORTION OF DOGS WITH GN ARE HYPERTENSIVE

THROMBOEMBOLIC TENDENCY • THROMBOELASTOGRAPHY BEST

GLOMERULONEPHROPATHY

DIAGNOSIS

Management

• • • •

Confirm proteinuria Glomerular origin Search/Rx primary causes of inflammation Biopsy?

TREAT PRIMARY DISEASE (if any) REDUCE PROTEINURIA • Dietary protein restriction • ACE-Inhibitors • Dietary N6:N3 PUFA, 5:1

11/21/2015

GLOMERULONEPHROPATHY

Protein Restriction Reduces Proteinuria

Management

High Protein

TREAT ADDITIONAL FACTORS • Thrombotic tendency • Hypertension • Edema

INCREASED PGC

Low Protein DECREASED PGC

IMMUNOSUPPRESSION?

Effect of Low –Protein Diet on UPC in Dogs with X-Linked Hereditary Nephropathy N = 12; 42 day acclimation

Effect of dietary protein restriction on proteinuria in dogs Rx Enalapril and aspirin; n = 5

Dietary protein g/100 kcal

5 4 UPC 3

Maint MPD LPD

2 1 0

Burkholder et al J Vet Intern Med 2004; 18: 165-175

Dietary protein restriction in GN (dog)

Moderate protein restriction best

7.31 4.71 3.77

SAlb g/dl

UPC

2.8 2.9 2.9

3.84 4.25 4.63

3/5 dogs > 20% reduction in UPC with MPD or LPD Hopwood-Courville et al. J Vet Intern Med 2003; 17: 404-405

GLOMERULONEPHROPATHY

TREATMENT

ACE-Inhibitors

Dietary protein (g/100kcal)

Maintenance Recommended Very low

7.3 5.1* 3.8

AII

EFFECT OF AII INCREASED PGC

• Maintain BCS 4/9 Takes 1 month to see full effect on UPr/Cr

PGE2 PGI2

AII EFFECT SUPPRESSED

ACE-INHIBITOR

PGE2 PGI2

DECREASED PGC

11/21/2015

Enalapril Treatment of GN in Dogs

ΔUPC ΔSBP (mm Hg) ΔSCr. (mg.dl)

Enalapril (mean +/- SD)

Placebo (mean +/- SD)

- 4.2 +/- 1.4 -12.8 +/- 27.3 0.33 +/- 1.68

1.9 +/- 0.9 p < .001 5.9 +/- 21.5 p < .05 1.12 +/- 1.28 p = .16

Grauer G et al. J Vet Intern Med 2000; 14: 526-533

Angiotensin II receptor antagonist (dog)

Telmisartan (Semintra®):

ACE-Inhibitors to Reduce Proteinuria in GN Benazepril (Lotensin®): Dog: 0.25-0.5 mg/kg PO q12-24h Cat: 0.5-1.0 mg/kg PO sid

Monitor: SCr (SDMA?) BP and electrolytes at 5-7 days

Enalapril: (Enacard®) Dog: 0.25-1.0 mg/kg PO q12-24h Cat: 0.25-0.5 mg/kg PO q12-24h Dose adjustment: If SCr > 2.5-3 mg/dl start with lowest dose

EFFECT OF N-6 AND N-3 PUFA DIET ON IGCP

TBA2

High N-6 PUFA

PGE2 PGI2

INCREASED PGC

Dog: 0.43 mg/kg PO q12-24h (1 dog with ACE-Inhibitor resistance)

TBA3

High N-3 PUFA

NO EFFECT

PGE3 PGI3

DECREASED PGC JVIM, 2014; 28:1871-1874

Effect of 5:1 N6:N3 PUFA Diet on GFR in dogs with induced CRF (20 months) 20

N6:N3 PUFA ratio Normal diet: Adjusted diet

10 0 Mean Δ GFR (%)

Dietary N6:N3 PUFA ratio in Proteinuria

20:1 5:1

-10 -20

Suggested Supplementation of Fish Oil

-30 -40 -50 Fish Oil

Saff Oil

Beef Tall

Eicosapentaenoic acid (EPA): 40 mg/kg/day Docosahexaenoic acid (DHA): 25 mg/kg/day

Brown S et al Proc. ACVIM, 1996 (abstract)

11/21/2015

GLOMERULONEPHROPATHY

COAGULOPATHY

TREATMENT- Hypertension Dog: Benazepril: 0.25-0.5 mg/kg PO q12-24h Enalapril: 0.25-1.0 mg/kg PO q12-24h Cat: Amlodipine: 0.625-1.5 mg/cat sid

GLOMERULONEPHROPATHY

COAGULOPATHY

GLOMERULONEPHROPATHY

TREATMENT- Coagulopathy When:

albumin < 2 g/dl fibrinogen > 500 mg/dl fibroelastography

Aspirin: Dog: 0.5-1.0 mg/kg PO sid Cat: 5 mg/cat PO q3d

GLOMERULONEPHROPATHY

TREATMENT- Edema Diuretics* furosemide 1 mg/kg PO q6-12h

* Be careful!!

GLOMERULONEPHROPATHY

TREATMENT- Immunosuppression Peracute and/or Rapidly Progressing GN Prednisolone: 2.2 mg/kg PO sid Mycophenolate: 10 mg/kg PO q12h (CellceptÂ®) Long-term Rx of Chronic GN Mycophenolate: 10 mg/kg PO q12h* * Reassess patient at 8-12 weeks: Discontinue/Continue/Adjust

11/21/2015

GLOMERULONEPHROPATHY

Relation of Survival Time to Urine Protein Excretion in Cats AZOTEMIC

TREATMENT- Monitoring

UPC

Criteria for success

Median Survival (days)

< 0.43

> 0.43

766

282 p < 0.001 Syme H, Elliott J. J Vet Intern Med 2003; 17:405

UPC:

< 0.5 or â&#x2030;¥ 50% reduction from baseline

Salbumin:

> 2.4 g/dl (at least 2.0 g/dl)

SCr:

< 1.4 mg/dl (at least stable)

NON-AZOTEMIC UPC UAC

0.3 (0.26-0.37) 50 (21-95)

0.11 (0.06-0.21) p < 0.05 17 (7-33)

Outcome (days)

Died 357 (280-730)

Survived 507 (112-801) p < 0.05 Syme H, Elliott J. J Vet Intern Med 2004; 18:417

MICROALBUMINURIA

Limit of Sensitivity: 1-30 mg/dl Early indicator of renal disease Many non-renal factors can induce microalbuminuria Elevated microalbuminuria indicates the need for further diagnostics Look for chronic inflammatory conditions that tend to persist

PROTEINURIA Trigger Points (Investigate/Control): UPC Dog:

> 0.5

Cat:

> 0.4

11/21/2015

Glomerular Filtration Rate The Gold Standard

TESTS OF URINARY FUNCTION

David F. Senior dfsenior37@cox.net

Glomerular Filtration Rate For Substances 1. Freely filtered 2. Not reabsorbed 3. Not secreted 4. Not metabolized

Glomerular Filtration Rate Amount filtered = Amount Excreted GFR x Px

= Ux x V

Amount filtered = Amount Excreted x = creatinine or inulin

Glomerular Filtration Rate

Serum Creatinine as a Measure of GFR

Amount filtered = Amount Excreted

GFR x Px = Ux x V and GFR = (Ux x V)/Px

MUSCLE MASS

OUT

ECF

GFR X PCr Creatinine = 1 mg/dl

x = creatinine or inulin

11/21/2015

IN MUSCLE MASS

OUT GFR X PCr

ECF

2 mg/dl

Serum Creatinine as a Measure of GFR

IN MUSCLE MASS

MUSCLE MASS

Creatinine = 1 mg/dl

Assuming constant muscle mass: IF GFR HALVES, PCr =

OUT GFR X PCr

ECF

Creatinine = 1 mg/dl

Assuming constant GFR: IF MUSCLE MASS HALVES, PCr =

0.5 mg/dl

Serum Creatinine as a Measure of GFR

OUT GFR X PCr

ECF

Uremia

Weight loss

If GFR is reduced to 1/16 of normal, PCr =

16 mg/dl

Creatinine = 1 mg/dl

IF GFR HALVES AND MUSCLE MASS HALVES, PCr =

1 mg/dl

Serum Creatinine as a Measure of GFR

Serum Creatinine as a Measure of GFR 1. PCr is a good indicator of GFR 2. Muscle wasted animals in CRF can have almost normal serum creatinine 3. Day-to day changes in PCr are accurate reflections of changes in renal function

If Muscle Mass is reduced to 25% of normal, PCr =

4 mg/dl

BUN as a Measure of GFR

IN Dietary Protein Protein Catabolism GI Bleeding

= ECF

OUT GFR x Purea

Urine Volume

BUN = 10-20 mg/dl

11/21/2015

RENAL UREA HANDLING

EFFECT OF URINE VOLUME ON UREA EXCRETION

ADH present

Impermeable to urea

ADH Present

TFurea ↑

ADH Absent INNER MEDULLARY COLLECTING DUCT

TFurea ↓

Permeable to urea

From Valtin, Renal Physiology

RENAL UREA HANDLING

BUN as a Measure of GFR

1. BUN is a good indicator of GFR in carnivores 2. Non-glomerular factors can alter BUN Dietary protein intake Urine volume GI bleeding

From Valtin, Renal Physiology

BUN and PCr: Poor Indicators of Early Loss of Renal Function

SYMMETRICAL DIMETHYL ARGININE (SDMA) Production: Proteolytic breakdown product after intranuclear methylation of L-arginine by protein-arginine methyltranferases Excretion: 90% renally; Criteria: • Strong negative correlation with GFR • Used as a biomarker for early CKD in humans • Appears to rise before sCr in early CKD in dogs and cats • Early studies promise to provide an early indicator of CKD Soon available commercially IRIS staging criteria not yet established

11/21/2015

SYMMETRICAL DIMETHYL ARGININE (SDMA)

Data from a single cat progressing into CKD

SDMA Values in Normal and Naturally Occurring CKD (Âµg/dL)*

Cat1 Dog2

Normal 9.9 (7.3-12.4) < 14

CKD >14 >14

* Analysis with Liquid Chromatography-Mass Spectometry 1. Hall JA, et al, JVIM 28:1676, 2014 2. Yerramilli M, et al, JVIM 28:1084-1085 (abstr)

From: Hall JA, et al, JVIM 28:1676, 2014

SDMA as a Measure of GFR 1. SDMA may indicate reduced GFR earlier than SCr in dogs and cats

CLEARANCE METHODS TO ESTIMATE GFR

GFR = (Ucr x V)/PCr

2. Independent of muscle mass and diet 3. Soon to be available commercially

4. Criteria need to established

CLEARANCE METHODS TO ESTIMATE GFR 99mTc

DTPA

NORMAL

ADVANCED CRF

MEASUREMENT OF GFR Clearance methods are accurate but they are impractical in most clinical settings Serum creatinine and BUN are relatively imprecise because they are affected by non-renal factors but they serve as the best readily available clinical indicators of renal function Serum creatinine and BUN are inaccurate in early loss of renal function SDMA may provide early evidence of reduced GFR

11/21/2015

RECIPROCAL OF SERUM CREATININE: 1/Scr

GFR = (UCr x V)/PCr If (UCr x V) is constant Then GFRï&#x201A;µ 1/SCr Problems: Not very accurate Muscle mass does not remain constant (long term)

RECIPROCAL OF SERUM CREATININE: 1/Scr

RECIPROCAL OF SERUM CREATININE: 1/Scr 0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0

Dog 1 Dog 2 Dog 3

1 Mth 2 Mth 3 Mth 4 Mth 5 Mth 6 Mth

PROTEINURIA Pre-Renal Abnormally high filtered protein in plasma

Renal A method of monitoring progression of renal disease Not very accurate because of changes in muscle mass and hydration status Not used in most clinical settings

Glomerular Functional Pathological Tubular (Impaired reabsorption)

Post-Renal Lower UT inflammation Genital source

Tests for Proteinuria

Standard U/A dipstick test

Sulfosalicylic acid Turbidimetric test

Limit of Sensitivity: >30 mg/dl False positives: Alkaline urine Concentrated urine

11/21/2015

Tests for Proteinuria

MICROALBUMINURIA TEST

24 hr Protein Excretion ï&#x201A;µ UPr/Cr

Limit of Sensitivity: 1-30 mg/dl

UPr/Cr Ualbumin/Cr

PROTEINURIA

POST-RENAL

PROTEINURIA

INFLAMMATION/HEMORRHAGE

An important indicator of renal function Indicates integrity of the glomerular sieve UPr/Cr is proportional to 24-hour protein excretion UPr/Cr is only accurate once other major sources of urine protein have been eliminated: e.g., UTI, hematuria

URINE SPECIFIC GRAVITY IN RENAL FAILURE

URINE SPECIFIC GRAVITY A RANGE OF NORMAL

MINIMUM USUAL

MAXIMUM

DOG: S.G. mOsm/kgH2O

1.001 50

1.035-1.045 1,300-1,800

1.065 2,400

CAT: S.G. mOsm/kgH2O

1.001 50

1.045-1.065 2,000-2,400

1.085 3,000

ADVANCING RENAL DISEASE

11/21/2015

WATER DEPRIVATION TEST

EVALUATION OF TUBULAR FUNCTION

FRACTIONAL EXCRETION OF ELECTROLYTES RENAL GLUCOSURIA AMINOACIDURIA RENAL TUBULAR ACIDOSIS

FRACTIONAL EXCRETION OF ELECTROLYTES AMOUNT EXCRETED/AMOUNT FILTERED (%)

(UX x V) x 100 % (PX x GFR) (UX x V) x PCr x 100 % PX UCr x V UX x PCr PX UCr

FRACTIONAL EXCRETION OF ELECTROLYTES AMOUNT EXCRETED/AMOUNT FILTERED (%)

An indicator of tubular function FENa and FEP used most often

x 100 %

GLUCOSURIA

INCREASED FILTERED LOAD

? TUBULAR REABSORPTION DEFECT

11/21/2015

SPILL-OVER GLUCOSURIA INCREASED FILTERED LOAD

RENAL GLUCOSURIA

STRESS, DIABETES MELLITUS

TUBULAR DEFECT

AMINOACIDURIA

CARRIER-MEDIATED TRANSPORT

CYSTINURIA

RENAL TUBULAR ACIDOSIS

REDUCED PLASMA HCO3 (Total CO2)

TYPE I

DISTAL DEFECT SEVERELY REDUCED TOTAL CO2 URINE pH NOT MAXIMALLY ACIDIC

11/21/2015

RENAL TUBULAR ACIDOSIS TESTS OF TUBULAR FUNCTION TYPE II Usually the patients present with: Glucosuria Cystine Uroliths Metabolic Acidosis (normal anion gap)

MUST RECOGNIZE THE POSSIBILITIES

RENAL BIOPSY (NEEDLE)

CYSTOMETROGRAM

Pressure Transducer

NO!

Infusion Pump

Bladder

Urethra

URODYNAMIC STUDIES

Catheter

URETHRAL PRESSURE PROFILE

CYSTOMETROGRAM

Side Hole

Pressure Transducer

Infusion Pump

Bladder Urethra

Catheter

Catheter Puller

11/21/2015

URODYNAMIC STUDIES URETHRAL PRESSURE PROFILE

11/21/2015

Interpretation of the MATULA

URINALYSIS David F. Senior dfsenior37@cox.net

URINE COLLECTION Lettsom, 1776.

“A gentleman through mistake carried a glass of Lisbon wine instead of his wife’s urine to Dr. Meyersback, who told by it the lady’s complaint, which according to him are…. a disorder of the womb.”

URINE COLLECTION

Catheter

Voided Urine Screening tests S.G.: uroliths pH: uroliths UTI Blood: FLUTD Glucose: diabetes

Void Catheter Cystocentesis

URINE COLLECTION

Poor for culture

Void Catheter Cystocentesis

11/21/2015

URINE COLLECTION

Void Catheter Cystocentesis

URINE COLLECTION

Void Catheter Cystocentesis

URINE COLLECTION

Void Catheter Cystocentesis

11/21/2015

Fundamentals of urinalysis Dipstick tests

Appearance

pH protein glucose ketones bilirubin heme-protein nitrite urobilinogen

Concentration

Sediment exam

Appearance of urine Color Cloudiness (turbidity) Odor

Color Cloudiness (turbidity) Odor

Odor putrefaction ammonia urease producers

Color: Pale: Dark: Red: Orange: Brown: Green: Blue:

dilute concentrated blood azulfidine bilirubin Pseudomonas methylene blue

Appearance of urine Color Cloudiness (turbidity) Odor

Appearance of urine

Cloudiness cells (RBC, WBC) bacteria crystals fat

Should urine be tasted? Greenfield’s “Grounds of Phisik” (1917)

Question: “Is it within the physician’s dignity to taste the urine?” Answer: “No! that should be done by the patient or the patient’s servant and if that cannot be done the physician had better enquire nothing about it.”

11/21/2015

Urine specific gravity (osmolality)

Concentration

Urine specific gravity (osmolality)

Urine specific gravity (osmololity)

Dipstick tests

Normal values Dog: (osm)

Low 1.000 (50)

Usual 1.040 (1600)

High 1.065 (2400)

Cat: (osm)

1.000 (50)

1.060 (2200)

1.085 (3000)

pH protein glucose ketones bilirubin blood urobilinogen

Factors affecting urine pH

Normal values: 5.0-8.5

urine storage diet post-prandial effect excitement bacterial infection tubular defects

urine storage diet post-prandial effect excitement bacterial infection

11/21/2015

Urease producing infection Staphylococcus intermedius Proteus spp.

RENAL TUBULAR ACIDOSIS TYPE I

(urease)

H2O + NH2-CO-NH2  2NH3 + CO2. Further hydrolysis yields:

DISTAL DEFECT

NH3 + H2O  NH4+ + OH-

SEVERELY REDUCED TOTAL CO2 URINE pH NOT MAXIMALLY ACIDIC

PROTEINURIA

RENAL TUBULAR ACIDOSIS TYPE II

Pre-Renal Abnormally high filtered protein in plasma

DISTAL DEFECT

Renal Glomerular Functional Pathological Tubular (Impaired reabsorption)

SEVERELY REDUCED TOTAL CO2 URINE pH MAXIMALLY ACIDIC

Protein

Post-Renal Lower UT inflammation Genital source

Limits of sensitivity Dipstick: E.R.D. ScreenTM:

> 30 mg/dl 1-30 mg/dl

Protein False positive on dipstick Alkaline urine

11/21/2015

Tests for Proteinuria

Sulfosalicylic acid Turbidimetric test

24 hr Protein Excretion ï&#x201A;µ UPr/Cr

UPr/Cr Ualbumin/Cr

24 hr Protein Excretion and Urine Protein/Creatinine ratio UPr/Cr

PROTEINURIA

POST-RENAL

INFLAMMATION/HEMORRHAGE

24 hr P. Excr. (mg/kg/day)

NORMAL

20-30

GLOMERULAR DISEASE

> 40-60

PROTEINURIA

GLUCOSURIA

An important indicator of renal function INCREASED FILTERED LOAD

Indicates integrity of the glomerular sieve UPr/Cr is proportional to 24-hour protein excretion UPr/Cr is only accurate once other major sources of urine protein have been eliminated: e.g., UTI, hematuria

? TUBULAR REABSORPTION DEFECT

11/21/2015

SPILL-OVER GLUCOSURIA

RENAL GLUCOSURIA

INCREASED FILTERED LOAD

TUBULAR DEFECT

STRESS, DIABETES MELLITUS

Bilirubin

Hard to read in bloody urine

unconjugated bilirubin

LIVER

KIDNEY

conjugated bilirubin

URINE SEDIMENT

HEME-PROTEIN Hemoglobin erythrocytes free hemoglobin Myoglobin

HEMOGLOBINURIA SERUM PINK MYOGLOBINURIA SERUM NORMAL

Urine sediment - Preparation

Epithelial cells Erythrocytes Leukocytes Bacteria Casts Crystals Mucoid threads Fat droplets Parasites

11/21/2015

Epithelial cells

Erythrocytes

Oval fat body

Macrophage

11/21/2015

Leukocytes

Bacteria Proteus sp. Infection

Bacteriuria (cat)

CASTS Tamm-Horsfall protein

Hyaline cast Granular cast

11/21/2015

Granular cast

Granular casts

Cellular cast

White blood cell cast

11/21/2015

White blood cell cast

Wide cast Fatty cast

Waxy cast

Wide fatty cast

Waxy cast

Pyelonephritis

CRYSTALS

11/21/2015

Urine Concentration Struvite crystals (cat) LABILE SUPERSATURATION Formation Product

INCREASING URINE CONCENTRATION (Activity Product)

METASTABLE SUPERSATURATION

Ksp Solubility Product UNDERSATURATION

Struvite crystal Sperm

Struvite crystal

Hematuria and struvite crystals (cat)

Ammonium urate

11/21/2015

Cystine

Calcium oxalate monohydrate

Calcium oxalate dihydrate (cat)

Hematuria, Crystalluria (cat)

Fat droplets

Fat droplet

11/21/2015

Talc crystal

Aspergillosis

Images courtesy of Heather Walmsley

Candidiasis

Microfilaria

Images courtesy of Heather Walmsley

Capillaria plica egg

Capillaria plica

11/21/2015

Drug Crystals

Images courtesy of Heather Walmsley

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Upper urinary tract Urinary Tract Imaging Images by:

Nathalie Rademacher, LSU Lorrie Gaschen, LSU Johann Lang, Vetsuisse Chris Lamb, RVC

Survey radiographs position, topography size shape, borders opacity

David F. Senior dfsenior37@cox.net

Renal size – Length on VD view

Location VD View

T12-L1 L1-L4 L2-L5

CAT

L1-L3

Cat: Neutered: 1.9-2.6 x L2 Intact: 2.1-3.2 x L2 or: 3.5 - 4.5 cm

Dog: 2.5-3.5 x length ofL2

DOG

11/21/2015

Changes in kidney size  Large  Cyst  Hydronephrosis  Neoplasia  Lymphosarcoma, other

      

Trauma Peri-renal cyst Acute glomerulonephritis Acute pyelonephritis Hypertrophy (compensatory) Amyloidosis Abscess

 Small      

Chronic pyelonephritis Chronic glomerulonephritis Infarct Dysplasia Hypoplasia Neoplasia  Adenocarcinoma

 Lymphosarcoma

Renomegaly

Changes in kidney shape  Smooth, regular borders  Acute inflammation  Pyelonephritis  Glomerulonephritis  Hypoplasia  Lymphosarcoma, FIP  Hydronephrosis due to obstruction  Peri-nephric cysts

 Irregular, focal or generalized  Chronic diseases  Focal cysts, tumors, abscesses, hematomas or infarcts  Dysplasia  Tumors  Polycystic kidney disease  FIP

11/21/2015

Plain radiographs

IVP (EU)

 Advantages

 Intravenous Pyelography (Excretory Urography)

Fast, easy performed Accessable Anatomical survey

 Disadvantages

 IV administration of iodinated contrast medium  Excretion by glomerular filtration

No evaluation about function or architecture Ureters not visible

Indications for IVP (EU)  Renal abnormalities on PE or abdominal radiographs*  Suspected renal or ureteral trauma  Uroperitoneum or uroretroperitoneum  Mass lesion of suspected renal origin*  Prior to unilateral nephrectomy or nephrotomy  Ureter evaluation  Evaluate bladder when catheterization of bladder impossible*

IVP (EU) - Contraindications  Patient dehydration  Uncontrolled congestive heart failure or debilitating disease  Sensitivity to contrast material  Severe renal failure

* Abdominal ultrasound better, if available

11/21/2015

IVP (EU)- Information gained Morphology and Function

Technique: IVP (EU)  Ionic iodinated contrast medium  400mg l/lb (880mg l/kg)  Roughly 2ml/kg volume (370mg I/ml agent)

 Survey radiography (fasted, enema)  If suspect ectopic ureters, fill bladder with negative contrast prior to injection  VD view  Bolus injection and immediate radiograph

Size and shape, uni- or bilateral Contrast enhancement Uniform, filling defects, timing of phases Estimates function

Pelvis and ureter assessment

 See arterial phase

 Then VD and Lateral views at 5, 15 and 30-40 minutes post injection  Oblique view at 5 minutes to see ureters entering bladder

Dilation, filling defects, ectopic ureters, ruptures

normal urography does NOT exclude pathology

Arterial phase (0sec)

Nephrogram phase (30 sec)

Pyelogram phase (5 min)

Analysis of the pelvis and ureters Small, irregular kidney with deformed pelvis

Normal

Chronic pyelonephritis

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Survey IVP

Normal ureters

Ureters – Assesment • • • • • •

Diameter 2-3 mm Frequent peristalsis Trigonum dorsal Fill bladder with gas for contrast Oblique Views DV!!

11/21/2015

Rasco – Gun shot

Ureter – Dilatation Unilateral • • • •

Inflammation Ectopic Ureter Trauma Stricture/obstruction

Bilateral • • • •

Ectopic Ureters Trauma Bladder neoplasia Inflammation

Ectopic Ureter • • • • • • •

Congential defect Bilateral or unilateral Emptying into vagina or urethra Female more common Urinary incontinence Commonly intramural Extramural rare

11/21/2015

Renal Ultrasound-Advantages      

kidney architecture solid masses-fluid filled structures vessels, flow and perfusion other abdominal structures US guided FNA/biopsy nephropyelocentesis and antegrade ureterography

Renal echogenicity

Anatomy

versus spleen or liver

K K

Dorsal

Transverse

Sagittal

size - shape - borders - architecture

Echogenicity is relative and depends on frequency!

Kidney Size and Shape

Echogenicity and architecture

Cat

kidney size of 2.7cm

Cat

kidney size of >6cm

Focal hyperechoic zone Infarct

Focal hyperechogenicity with shadowing Mineralization

Hyperechoic corticomedullary ring Normal, tubular mineralization, ethylene glycol toxicity

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solid

versus

fluid filled lesions

pyelonephritis versus hydronephrosis

normal kidney

mild pyelectasia

Nephrolithiasis

specificity of solid lesions?

Ureter imaging

requires biopsy

radiography

sonography

 invisible

 in the near region of kidneys detectable, if dilated

 examination requires excretory urography

 between kidney and bladder visible only if markedly dilated  ureterovesical junction flow into bladder detectable

11/21/2015

Indication: trauma with suspected rupture of urinary tract Contrast radiography is in most cases method of choice • fast • safe • sensitive

Summary • Information provided by radiography and sonography are often complementary

Lower urinary tract

• Sonography method of choice for internal architecture • Scintigraphy of kidney is an excellent method for functional studies on individual kidneys

Anatomy - bladder  cranial to pubis, ventral to colon  Size dependent on filling  Ovoid shape  Soft tissue opacity

Indications for Bladder Imaging Hematuria Dysuria Straining, polakiuria, etc..

Abdominal Trauma Mass in the caudal abdomen Uroabdomen Chronic cystitis Determine position of bladder and size

11/21/2015

Urinary bladder Content, wall, position, size, shape on radiographs ď Źonly gas, radio-opaque calculi and mineralized lesions are visualized ď Źevaluation of content and the wall requires contrast cystography or US

11/21/2015

contrast studies of the lower urinary tract:

cystography

negative-contrast cystography positive-contrast cystography double-contrast cystography

which method and when?

Contrast studies of the lower urinary tract:

cystography

 negative contrast (CO2, N2O, air) contrast media for EU/demonstration of the ureters localization of the urinary bladder bladder wall (concrements)

not method of choice when rupture of the bladder is suspected

choice of contrast media negative-

positive contrast

positive-contrast-cystography localization suspicion of rupture (wall)

concrements or coagula are not readily visualized

contrast studies of the lower urinary tract:

cystography double-contrast cystography wall thickness, borders abnormal content stones - coagula – concrements, air bubbles

filling defects: free in the lumen attached to wall

11/21/2015

Double contrast cystography concrements: normally located in center, irregular, well defined-sharp margins blood clots: anywhere, can stick to wall, round - irregular, ill-defined margins

Hematuria

air bubbles: at border of CM-pool, round, on sites of contact flattened (look like soap bubbles) Oxalate stones

double contrast cystography

diverticula

lesions of the wall

congenital acquired

thickening cystitis - tumor

diverticula congenital acquired

cystitis versus tumor

 cystitis rather flat thickening diffuse or cranio-ventral bladder often small stones frequent

Cystogram

 tumor focal thickening, sessile masses variable location, often neck obstruction frequent ± enlarged regional Lnn (US!)

11/21/2015

hematuria

sonography examination in lateral- or dorsal recumbency bladder moderately filled (wall thickness!!)

Modalities for diagnosis of diseases of the bladder and the distal ureter  wall thickening cystitis, tumor

C-Rx/US

abnormal content stones, coagula...

C-Rx/US

dilatation of ureter

C-Rx/US

abnormal orifice of ureter

C-Rx/US

enlarged regional lnn.

11/21/2015

lateral approach to bladder

ventral approach

midline, dog symmetric

ventral to colon transducer vertically

gas and stones can look similar

Sediment mineralized

cellular debris

courtesy of Chris Lamb

diffuse thickening of bladder wall

courtesy of Chris Lamb

11/21/2015

diffuse

focal

Contrast studies :

retrograde urethrography Indications Straining to urinate, hematuria, detect stones, detect ruptures

Narrowing of the urethral lumen due to: urolithiasis tumors urethritis strictures malformations

courtesy of Chris Lamb

functional stenosis cave air bubbles!

Filling defects

urethra - positionings of legs in male dogs

Stone and Stricture

Many small stones

11/21/2015

Summary sonography vs. contrast radiography information and sensitivity comparable ultrasound much more convenient, less invasive Contrast radiography the method of choice for detecting urinary tract obstruction or rupture

11/21/2015

URINARY TRACT INFECTION David F. Senior dfsenior37@cox.net

PYELONEPHRITIS

CYSTITIS CYSTITIS PROSTATITIS

URETHRITIS

ETIOLOGY Bacterial isolates in canine UTI • UTI is due to ascending infection from the perineum of GI flora

Dogs* (%)

Dogs** Cats*** (%) (%)

Coliforms (mostly E. coli) Staphylococcus spp. Proteus mirabilis Streptococcus/Enterococcus spp. Klebsiella pneumoniae Pseudomonas aeruginosa Enterobacter spp.

37.8 14.5 12.4 10.7 8.1 3.4 2.6

54.8 14.7 7.2 14.7 2.2 4

37.3 19.8 (S. felis)

• UTI may be confined to the lower urinary tract

• The upper urinary tract could be involved as well

Number of isolates:

1,400

1,037

126

*Ling, G.V. et al. Vet. Clin. North Amer. 1979;9:617-630 **Hall, J.L. et al. Vet Rec. 2013, 173:549 *** Litster A et al. Vet Microbiol. 2007;121(1-2):182-8

• In intact male dogs, the prostate is usually involved • E coli is the most common isolate in UTI in both dogs and cats

11/21/2015

Bacterial Virulence vs. Host Defenses

Normal Flora

Sterile CYSTITIS PROSTATITIS

Bladder

Urethra

HOST DEFENSE MECHANISMS

Virulence vs. Defense Bacterial Virulence

Bladder

Urethra

Frequent, complete voiding Normal

Residual volume

100 ml

100 ml 20 ml 1

Host Defenses

HOST DEFENSE MECHANISMS

NORMAL VAGINAL AND PREPUTIAL FLORA Bacterial Virulence

Bladder

Urethra

Occupy binding sites Produce Aerobactins Compete for iron

Host Defenses Vulval Involution

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HYPOSPADIAS

VULVAL INVOLUTION

HOST DEFENSE MECHANISMS

URETERO-VESCICAL JUNCTION

HOST DEFENSE MECHANISMS

ECTOPIC URETER

URETER BLADDER WALL BLADDER LUMEN

HOST DEFENSE MECHANISMS

sIgA and Adherence

Mucosal Protection by GAGâ&#x20AC;&#x2122;s

Bladder Wall GAG layer Fixed H2O Urine

Trinchieri A et al Urol Res 1990;18:305-8

11/21/2015

Mucosal Protection by GAG’s -+ -

so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 + so4 +

UROEPITHELIUM

HOST DEFENSE MECHANISMS

Disruption of the GAG Layer Tumor Ulceration

- URINE ---- ---- --- --- --- --- --- -

HOST DEFENSE MECHANISMS

Bladder Wall GAG layer Fixed H2O Urine

Bacterial Attachment

PATHOGENESIS

Antimicrobial Properties of Urine Hyperosmololality/High Urea pH: Low: inhibits Proteus spp. High: inhibits fungal growth Hepcidin: (human and canine urine)* cysteine-rich peptides hepatic synthesis antifungal/antibacterial

Major host defenses include: • • • • • •

Frequent complete voiding Normal anatomical structures Mucosal GAGs Secretory IgA production Urine hyperosmolality, pH Hepcidin?

* Park CH et al J Biol Chem 2001; 276:7806-10

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BACTERIAL VIRULENCE

Virulence Factors

BACTERIAL VIRULENCE

FIMBRIAL ATTACHMENT OF E. COLI

• Fimbrial expression – Type 1 – P-fimbriae – S-fimbriae – Afimbrial adhesin

• Alpha-hemolysin • Aerobactin • Cytotoxic Necrotizing Factor 1

BACTERIAL VIRULENCE

PATHOGENESIS

Fimbrial adhesin/receptor attachment

Urothelial cell wall

• Most UTI is caused by an ascending infection • Invading bacteria are from the GI tract • UTI is determined by bacterial virulence vs. host defenses • Adherence is a major bacterial virulence factor • Host defenses are vital to prevention of UTI

Coliform Bacteria

CLINICAL SIGNS

DIAGNOSIS LOWER URINARY TRACT INFLAMMATION

UTI

UROLITHIASIS

TUMOR

11/21/2015

DIAGNOSIS

URINALYSIS

DIAGNOSIS

URINALYSIS

METHODS OF COLLECTION FOR URINE CULTURE VOID MISLEADING CATHETER OK CYSTOCENTESIS BEST

DIAGNOSIS

ANTIMICROBIAL SENSITIVITY

KIRBY-BAUER DISC DIFFUSION

DIAGNOSIS

MINIMUM INHIBITORY CONCENTRATION

ANTIMICROBIAL SENSITIVITY

DIAGNOSIS

KIRBY-BAUER DISC DIFFUSION

DIAGNOSIS

ANTIMICROBIAL SENSITIVITY

MUC SHOULD BE 4x MIC MINIMUM INHIBITORY CONCENTRATION MINIMUM INHIBITORY CONCENTRATION

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DIAGNOSIS

LOCALIZATION OF INFECTION Localization of Infection Pyelonephritis CYSTITIS

PYELONEPHRITIS

URINE S.G.:

HIGH

LOW

CASTS:

ABSENT

PRESENT

IVP:

NORMAL

ABNORMAL

ULTRASOUND:

NORMAL

ABNORMAL

Pyelonephritis

DIAGNOSIS

LOCALIZATION OF INFECTION

ABNORMAL IVP

DIAGNOSIS

PROSTATE

LOCALIZATION OF INFECTION

DIAGNOSIS

• UTI is often clinically silent

WASH ASPIRATE BIOPSY

• Method of collection changes U/A and C/S

IF UTI: 90 % POS.

• MIC is better that K-B for A/B sensitivity tests

• Cystocentesis is the best method of collection – (Lower UTI in Females and castrated Males)

• Pyelonephritis is hard to diagnose in the dog and cat • Prostatic involvement can be assumed in intact males

11/21/2015

TREATMENT

FIRST TIME INFECTIONS No Previous Antimicrobial Treatment

ACIDIC URINE RODS IN SEDIMENT E. COLI KLEBSIELLA PSEUDOMONAS

ALKALINE URINE

RODS IN SEDIMENT E. COLI* KLEBSIELLA* PSEUDOMONAS

PROTEUS*

* 90% SENSITIVE TO AMOXICILLIN OR AMPICILLIN PROTEUS AND STAPH. NEED -LACTAMASE INHIBITOR IN MALES: SULFA WITH TRIMETHOPRIM

FIRST TIME INFECTIONS No Previous Antimicrobial Treatment

ACIDIC URINE RODS IN SEDIMENT E. COLI KLEBSIELLA PSEUDOMONAS*

FIRST TIME INFECTIONS No Previous Antimicrobial Treatment

ACIDIC URINE

COCCI IN THE SEDIMENT STREPTOCOCCUS* STAPHYLOCOCCUS*

TREATMENT

ALKALINE URINE PROTEUS

COCCI IN THE SEDIMENT STREPTOCOCCUS STAPHYLOCOCCUS * UNPREDICTABLE MUST PERFORM SENSITIVITY TEST

TREATMENT

DURATION OF TREATMENT

LOWER UTI FEMALE

14 DAYS

UPPER UTI LOWER UTI MALE

30 DAYS

STRUVITE UROLITH DISSOLUTION

DURATION OF DISSOLUTION

COCCI IN THE SEDIMENT STREPTOCOCCUS STAPHYLOCOCCUS

* AMINOGLYCOSIDES AND FLUOROQUINOLONES

Effect of pKa on Prostatic Penetration Antimicrobial pKa = 8.4 Interstitium pH 7.4

(1) B

Prostatic Acinus pH 6.4

B (1)

(10) HB+

HB+ (100)

Weak Base

Antimicrobial pKa = 5.4 Interstitium pH 7.4

Prostatic Acinus

Prostatic Penetration • High pKa (Weak base) • High free plasma levels (Not protein bound) • Non-ionized (Lipid soluble)

pH 6.4

HA (1)

A- (100)

A- (10)

• Fluoroquinolones • Trimethoprim • Doxycycline, Tetracycline HCl • Chloramphenicol

Weak Acid

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Prostatic abscess

TREATMENT

• First time infections (No Previous Antimicrobial Rx) • Cocci/Rods in alkaline urine: predicable sensitivity • Rods in acidic urine: unpredictable • Repeat treatment: Always get sensitivity • Duration of treatment varies • Prostatic penetration • Weak bases • Lipid soluble • High free plasma levels

TREATMENT FAILURE

1. Inappropriate drug, dose or duration of treatment 2. Failure to reach therapeutic concentrations in urine 3. Presence of a nidus of infection with post-treatment recolonization 4. Anatomical or functional defects that predispose to re-infection

TREATMENT FAILURE

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TREATMENT FAILURE

• Check dose and duration of treatment • Check sensitivity • Perform workup • Look for breakdown of host defenses

TREATMENT OF RECURRENT UTI

LONG-TERM LOW-DOSE TREATMENT

LONG-TERM TREATMENT

1. Full course of treatment based on sensitivity

Methenamine mandalate

2. Continue at 30-50% of usual dose

10 mg/kg PO q6h

3. Single dose at night after the last void

**NH4Cl to acidify urine

4. Continue for 6 months

Cranberry Extract?

5. Drugs used: amoxicillin, amoxi/clav., cephalexin cefadroxil, potentiated sulfas

LEAVE UNTREATED?

11/21/2015

TREATMENT OF RECURRENT UTI

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

11/21/2015

Urine Concentration

UROLITHIASIS David F. Senior dfsenior37@cox.net

Composition of Uroliths Mineral Matrix

Urine Concentration

APSTRUVITE = [Mg2+][NH4+][PO43-] LABILE SUPERSATURATION

LABILE SUPERSATURATION

Formation Product

INCREASING URINE CONCENTRATION (Activity Product)

Formation Product

METASTABLE SUPERSATURATION

AP > Ksp Ksp Solubility Product UNDERSATURATION

Homogeneous Nucleation

AP = Ksp

Ksp Solubility Product

AP < Ksp

UNDERSATURATION

Heterogeneous Nucleation

Dissolution

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APSTRUVITE = [Mg2+][NH4+][PO43-]

Composition can vary within a urolith

LABILE SUPERSATURATION

Initially

Subsequently

Formation Product

Urease-producing Infection

METASTABLE SUPERSATURATION

AP > Ksp

Relative Supersaturation (RSS)

RSS = AP/Ksp

Ksp Solubility Product

AP = Ksp

UNDERSATURATION

AP < Ksp

Factors Contributing to Urolith Formation

Mineral composition and frequency of uroliths in dogs and cats

1. High urinary supersaturation 2. Availability of a nidus 3. Reduced concentration of inhibitors in urine 4. Constraints on normal crystal movement 5. Simple crystal growth or with aggregation

Predominant mineral Struvite Calcium oxalate Urate Cystine Silica Calcium phosphate Compound/Mixed/Matrix/Other

Dog % of total n = 32,885 (2005)

Cat % of total n = 8,711 (2004)

38 41 5 1 <1 <1 15

44.9 44.3 4.4 <1 <1 <1 5

Data from: Minnesota Urolith Center.

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Pathogenesis - Struvite Struvite and calcium oxalate are the most common uroliths in dogs and cats

MgNH4PO4.6H2O INPUT

Urolith formation is due to urine hyperosmolality

OUTPUT

The driving force for urolith formation is supersaturation Undersaturation induces dissolution in some minerals

Body Fluid

Oral Mg2+

The rate of growth and dissolution depends on the degree of supersaturation and undersaturation respectively RSS is a convenient indicator of the degree of supersaturation undersaturation

Urinary Mg2+

Pathogenesis - Struvite

MgNH4PO4.6H2O

MgNH4PO4.6H2O INPUT

OUTPUT

NH3 + H+ ↔ NH4+ Oral PHOSPHORUS

Body Fluid

Urinary NH4+ Urinary PO43-

Pathogenesis - Struvite

Oral Mg2+ Body Fluid

CATS: No Urease infection

MgNH4PO4.6H2O

DOG: Urease producing infection Staphylococcus intermedius Proteus spp.

(urease)

H2O + NH2-CO-NH2  2NH3 + CO2. Further hydrolysis yields:

NH3 + H+  NH4+

NH3 + H2O  NH4+ + OHH3PO4 

H+

+ H2PO4

pK = 2.12

H2PO4-  H+ + HPO42-

pK = 7.21

HPO42-  H+ + PO43-

pK = 12.67 Urinary Mg2+

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Pathogenesis - Struvite

NH3 + H2O  NH4+ + OH-

MgNH4PO4.6H2O H3PO4  H+ + H2PO4-

pK = 2.12

H2PO4 

pK = 7.21

H+

+ HPO4

HPO42-  H+ + PO43-

Pathogenesis - Calcium Oxalate

pK = 12.67

Risk Factors for Ca Ox Urolithiasis in Cats

Promotion Degree of Supersaturation Hypercalciuria* Hyperoxaluria

Inhibition Nephrocalcin Citrate Ribonucleic acid Glycosaminoglycans Magnesium Pyrophosphate

• Acidifying diet Unvaried with no treats and table scraps • Age Older than 5 years • Males (neutered) • Certain breeds Persian, Himalayan • Indoors only

Pathogenesis - Calcium Oxalate Dogs with CaOx Uroliths Hypercalciuria: Intestinal hyperabsorption Renal calcium “leak”

 -HYDROXYLASE

 CALCITRIOL

 PTH

 INTESTINAL ABSORPTION

11/21/2015

Pathogenesis - Calcium Oxalate Delayed Transit of Crystals Nephroliths/Ureteroliths Tubular epithelial damage Interstitial mineralization + epithelial erosion (Randall’s plaques) Bladder uroliths Infrequent and incomplete bladder emptying Atonic bladder Urethral stricture

Etiology - Calcium Oxalate Urolithiasis in Dogs and Cats Dogs: Hyperadrenocorticism Hypercalciuria Diet Intestinal hyperabsorption Renal Calcium “leak” Hyperoxaluria Diet Absence of GI Oxalobacter formigenes?

Cats Formation of Randall’s plaques? Diet Absence of GI Oxalobacter formigenes?

Clinical Signs

The causes of extreme supersaturation vary with each mineral type and between species The conditions predisposing to each mineral type must be understood for appropriate treatment and prevention

Clinical Signs

DIAGNOSIS LOWER URINARY TRACT INFLAMMATION

Lower Urinary Tract Inflammation Urgency Pollakiuria Hematuria Stranguria Crepitus

UTI

TUMOR UROLITHIASIS

11/21/2015

NON-OBSTRUCTIVE FLUTD

Etiology

Frequency of Occurrence for Causes Associated With Urethral Obstruction in Male Cats Characteristic

Kruger 1991 Barsanti 1996 Gerber 2008

Urethral plugs

59%

42%

18%

Idiopathic

29%

42%

53%

Uroliths

12%

29%

Strictures

11%

Diagnosis

Cystine Urate Struvite CaOx

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Diagnosis

Diagnosis Epidemiological factors can provide evidence of a particular mineral type within a urolith Crystalluria is helpful but not definitive Radiographic density can be helpful The gold standard for identification is quantitative analysis Crystallography X-ray diffraction Infrared spectroscopy Mineral composition can vary within uroliths

Treatment and Prevention

MEDICAL DISSOLUTION

Urethral obstruction

Bladder

LABILE SUPERSATURATION

Ureteral obstruction

Kidney

Formation Product

? SURGERY/ LITHOTRIPSY/ FLUSH

MEDICAL DISSOLUTION

METASTABLE SUPERSATURATION

AP > Ksp

Relative Supersaturation (RSS)

RSS = AP/Ksp< 1

Ksp Solubility Product

AP = Ksp

UNDERSATURATION

AP < Ksp

11/21/2015

Treatment and Prevention - Struvite - CAT TREATMENT 1. Special diet Acidified Low magnesium Low phosphate

Treatment and Prevention - Calcium oxalate Treatment: Surgery Lithotripsy Urohydopropulsion

PREVENTION Many diets

(antimicrobials unnecessary) 2. Regular rechecks (urine pH) 3. Continue for 4 weeks after uroliths not apparent on recheck

Treatment and Prevention - Calcium oxalate 1. Dietary Adjustment Reduced RSS CaOx Dogs: CKD diet Low: Protein, Na Replete: Mg, Ca, P Cats: 2 Strategies High Na or Mineral and pH balance

Urohydropropulsion

2. Potassium citrate 45-75 mg/kg po bid Goal: Urine pH 7.0-7.5 3. Hydrochlorothiazide 2-4 mg/kg po bid

Many uroliths must be treated surgically Dissolution and prevention of struvite uroliths are well worked out Calcium oxalate uroliths cannot be dissolved clinically

4. Increase water consumption KCl?

Where possible regular rechecks should ensure that treatment and prevention goals are being met

Lithotripsy

E l e c t r o h y d r a u l i c S h o c k W a v e L i t h o t r i p s y u r o l i t h

s p a r k s h o c k w a v e e n e r g y

e l e c t r o d e p r o b e

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Lithotripsy E x t r a c o r p o r e a l S h o c k W a v e L i t h o t r i p s y

b o d y o f p a t i e n t

u r o l i t h

s h o c k w a v e e n e r g y

s p a r k

e l i p s o i d f o c u s i n g a r c

Pathogenesis - Ammonium Urate

HYPOXANTHINE NUCLEIC ACID METABOLISM

XANTHINE OXIDASE

XANTHINE

URIC ACID

ALLANTOIN

URICASE

EXCRETED METABOLITES OF PURINE BASES IN HUMANS AND DOGS Urate Urate/day Allantoin (%) (mg) (%) _____________________________________________ Humans 100 264-588 0 Mongrel Dog 10-20 60-100 80-90 Dalmatian Dog* 40-80 400-600 20-60 _____________________________________________ *Genetic mutation: SLC2A9 gene

Pathogenesis - Ammonium Urate

Acidic meat protein diet

Hyperuraturia

NH4URATE

11/21/2015

Pathogenesis - Ammonium Urate HYPERAMMONEMIA

Porto-Systemic Shunt

URIC ACID

Pathogenesis - Ammonium Urate

Porto-Systemic Shunt

ALLANTOIN

URICASE Impaired

NH4URATE

Pathogenesis - Cystine Normal

Cystinuric 80%

97%

Diagnosis

Pathogenesis - Cystine

20%

Diagnosis

11/21/2015

Treatment and Prevention - Urate - DOG HYPOXANTHINE NUCLEIC ACID METABOLISM

XANTHINE OXIDASE

XANTHINE

URIC ACID

ALLANTOIN

URICASE

Treatment and Prevention - Urate - Dalmatians 1. Feed ultra low protein (renal failure) diet (Continue for prevention) 2. Potassium citrate 40-75 mg/kg po bid

Treatment and Prevention - Cystine Often obstructed: Surgery (Urohydropropulsion)

3. Allopurinol 7-10 mg/kg po tid (Half dose for subsequent prevention) Donâ&#x20AC;&#x2122;t give unless feeding a low protein diet!! Goals for Success: Reduce urate excretion to 200-300 mg/day Urine pH 7.0-7.5

Treatment and Prevention - Cystine

1. Tiopronin 15-20 mg/kg po tid Reduce renal cystine excretion

2. Potassium citrate 75 mg/kg po bid Urine pH > 7.5

11/21/2015

Treatment and Prevention - Cystine

1. Tiopronin 15-20 mg/kg po tid Reduce renal cystine excretion 2. Potassium citrate 75 mg/kg po bid Urine pH > 7.5 3. Ultra-low protein (renal failure) diet Reduce renal cystine excretion 4. Increase urine volume

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx