GLOMERULAR DISEASE AND PROTEINURIA

November 8, 2014 Sara Arnold, DVM, DACVIM

Outline: Laboratory evaluation

Methodology Pathophysiology of proteinuria

Glomerulus Tubule Pre-renal

Diagnostic workup Renal biopsy

Treatment ACE and ARB Immunosuppression Hypertension

Prognosis Nephrotic syndrome

Laboratory evaluation of proteinuria

Urinalysis Dipstick

>30mg/dl Alkalinuria (pH > 7.5) Hypersthenuria

Sulfasialacylic acid Bence jones proteins False +: radiocontrast

agents, penicillins, sulfasoxazole, cephaloridine

ACVIM consensus statement

Microalbuminuria Testing

If the patient is predisposed to the development of proteinuria

Chronic illness Drug administration Breed predisposition

Conventional testing is equivocal or conflicting Dogs > 6 years old and cats > 8 years old where increased

vigilance is desired by the veterinarian or owner

Predisposed BreedsBeagles: Amyloidosis, membranoproliferative glomerulonephritisBernese: Mesangiocapillary glomerulonephritisBull Terrier: Hereditary nephritisCocker Spaniel: Hereditary nephritisDalmatian: Hereditary nephritisDoberman: Glomerulosclerosis, cystic glomerular atrophyEnglish foxhound:AmyloidosisGreyhound: Glomerular vasculopathy and necrosisNewfoundland: GlomerulosclerosisPembroke Corgi: Cystic glomerular atrophyRottweiler : Atrophic glomerulopathySamoyed: Hereditary nephritisShar Pei: AmyloidosisSC Wheaten: Proliferative and sclerosing glomerulonephritis

Vanden S and Grauer G “Glomerular Disease.” Nephrology and Urology of Small Animals.

Pathophysiology

Extra-renal proteinuria Physiologic proteinuria

Pyrexia Strenuous exercise Seizures Extreme hyper / hypothermia

Pre-renal proteinuria Dysproteinemia (bence jones) Hemoglobin myoglobin

Post-renal proteinuria Prostatitis Metritis Urinary tract infection Neoplasia Bladder stones?

The glomerulus

The glomerulus

Filtration barrier Endothelium Basement membrane Podocytes

Negative charge Minimal change nephropathy

Glomerular filtration rate Sympathetic nervous system Hormonal regulation

The glomerulus

Hormonal regulation of GFR Vasoconstriction – decreased GFR

Norepinephrine and Epinephrine Endothelin Angiotensin II

Vasodilation – increased GFR Nitric oxide Prostaglandins Bradykinin

The proximal tubule

Protein absorption 1.5mM/min

Proteinuria and tubular damage Mesangial toxicity Tubular overload and hyperplasia Toxicity Up-regulation of inflammation

Tubular Proteinuria

Proteinuria is mild UPC < 3

Can occur as a result of systemic disease and tubular insult

Fanconi’s syndrome Glycosuria* in the face of euglycemia Hypokalemia Hypophosphatemia Metabolic acidosis Proteinuria

Summary: Initial Evaluation of Proteinuria

Urinalysis Urine culture

If patient is currently on antibiotics – consider culture 5 to 7 days after antibiotics

Penicillins can cause false + urine protein on dipstick

UPC

Blood pressure?

Beatrice, L., F. Nizi, et al. (2010). "Comparison of urine protein-to-creatinine ratio in urine samples collected by cystocentesis versus free catch in dogs." JAVMA UPC from free catch urine with an inactive sediment was equivalent to samples obtained by cystocentesis.

Diagnostic Workup

ACVIM consensus statement

Non-azotemic UPC >0.5 but <1.0 – monitor UPC > 1.0 – investigate UPC > 2.0 – treat

Azotemic dogs UPC > 0.5 – investigate and treat

Azotemic cats UPC > 0.4 – investigate and treat

Etiology of pathologic renal proteinuria

Infectious disease: Infectious canine hepatitis Endotoxemia Bacteremia: endocarditis Tick borne disease –

ehrlichiosis, RMSF, anaplasmosis, Lyme, babesia

Bartonella Fungal disease –

coccidiomycosis Leishmaniasis Arthropod borne viral infections Heartworm disease FIP Toxoplasmosis Felv Etc…

Neoplasia Congenital Primary hypertension Endocrine:

Hyperadrenocorticism Diabetic nephropathy

Immune mediated: Lupus IMHA

Littman, M. P. (2011). "Protein-losing Nephropathy in Small Animals." Veterinary Clinics of North America: Small Animal Practice 41(1): 31-62.

Proposed Proposed workup?workup?

IRIS Guidelines:Consensus Recommendations for the Diagnostic Investigation of Dogs

with Suspected Glomerular Disease

Tier System Tier 1 –Renal proteinuria without hypoalbuminemia

Tier 1a – subclinical Tier 1b – with hypertension +/- target organ damage

Tier 2 – Renal proteinuria with hypoalbuminemia, nonazotemic Tier 2a – without hypertension Tier 2b – with hypertension

Tier 3 – Renal proteinuria with renal azotemia Tier 3a – normotensive, normal albumin Tier 3b – hypertensive, normal albumin Tier 3c – hypoalbuminemic +/- hypertension

Recommendations for all patients CBC, Chemistry panel (including electrolytes), Urinalysis, Urine culture UPC 4DX (+/- quant C6), leptospirosis titers “Appropriate, problem-specific investigation of any

concomitant extra-renal diseases or abnormalities identified by the minimum evaluation”

Samples to consider saving: EDTA whole blood *Prior to antibiotic therapy* Serum Urine

IRIS Guidelines:Consensus Recommendations for the Diagnostic Investigation of Dogs

with Suspected Glomerular Disease

If UPC > 3.5, hypertension, hypoalbuminemia or Azotemia are present Imaging: Abdominal ultrasound, 3v thoracic

radiographs If hypertensive: testing for Cushing’s disease,

consider drug side effects (Proin, EPO), pheochromocytoma, hyperaldosteronism, fluid overload, echocardiogram (left ventricular hypertrophy)

If hypoalbuminemic Rule out other causes – liver disease, PLE

Consider additional infectious diseases: Babesia, Bartonella, RMSF

IRIS Guidelines:Consensus Recommendations for the Diagnostic Investigation of Dogs

with Suspected Glomerular Disease

Renal Biopsy

Renal Biopsy Contraindications

CKD IRIS stage 4 Severe azotemia (creatinine > 5mg/dl) Severe anemia

Uncorrectable coagulopathy Discontinue anti-thrombotics for 3d prior to Bx

Recent NSAID administration Uncontrolled hypertension Severe hydronephrosis Large or multiple renal cysts Perirenal abscess Extensive pyelonephritis Inexperienced operator Incomplete patient immobilization

Cathy Brown, 2007 ACVIM Conference Proceedings

IRIS Guidelines

Biopsy analysis Light microscopy Electron microscopy Immunofluorescence

For biopsy kit and sample submission: International Veterinary Renal Pathology Service

Department of Veterinary BiosciencesThe Ohio State UniversityColumbus, OH 43210

Dr. Rachel Cianciolo rachel.cianciolo@cvm.osu.edu

Treatment

Treatment: IRIS Guidelines

Consensus Recommendations for Standard therapy of Glomerular Disease in Dogs

Consensus Guidelines for Immunosuppressive Treatment of Dogs with Glomerular disease Absent a Pathologic diagnosis

Consensus Recommendations for Immunosuppressive Treatment of Dogs with Glomerular Disease Based on Established Pathology

Consensus Recommendations for Treatment for Dogs with Serology Positive Glomerular Disease

Iris Guidelines: Standard Therapy

ACE inhibitor Caution is warranted with IRIS stage 4 Benazepril vs. Enalapril Max dose – 2mg/kg/day

Angiotensin Receptor Blockers Losartan – 0.125mg/kg/d (azotemic), 0.5mg/kg/d

(nonazotemic) Telmisartan - 1mg/kg/d

more lipophilic longer half life higher affinity for Angiotensin I receptor

IRIS Guidelines: Standard Therapy

Monitor for side effects Hyperkalemia Azotemia

IRIS stage 1 & 2 – up to 30% increase in creatinine without modifying therapy

IRIS stage 3 & 4 are less tolerant of worsening azotemia

Dietary Therapy Renal diet Omega 3 fatty acids

300mg EPA + DHA / 10# BW 0.25 – 0.5g EPA + DHA/kg BW

Salt restriction Nephrotic syndrome

IRIS Guidelines: Standard Therapy

IRIS Guidelines: Standard Therapy

Antithrombotic Aspirin 0.5 - 5mg/kg/day Plavix 1-3mg/kg/day Heparin?

Works via enhancement of antithrombin

IRIS Guidelines: Immunosuppression Absence of Renal Biopsy

Immunosuppression is contraindicated Familial Nephropathy Infectious disease Amyloidosis

Immunosuppression should be considered Serum Creatinine >3mg/dL Azotemia is progressive Hypoalbuminemia is severe (Albumin <2g/dl)

Drug options Glucocorticoids Mycophenolate Azathioprine Cyclophosphamide Chlorambucil

Peracute or Rapidly progressive glomerular disease Mycophenolate** +/- prednisolone Cyclophosphamide +/- prednisolone

Minimum therapy 8 weeks of rapidly acting drug therapy 8 – 12 weeks of slowly acting drug therapy

IRIS Guidelines: Immunosuppression

Treatment: Hypertension

Geigy C. “Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate.” JSAP, (2011) 52, 340–346

Prognosis

Prognosis

Klosterman (2011). "Comparison of Signalment, Clinicopathologic Findings, Histologic Diagnosis, and Prognosis in Dogs with Glomerular Disease with or without Nephrotic Syndrome." JVIM

Prognosis

Syme (2006). "Survival of Cats with Naturally Occurring Chronic Renal Failure Is Related to Severity of Proteinuria." JVIM UPC was significantly associated with survival

Prognosis

Jacob (2005). "Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure." JAVMA At initial diagnosis of CKD, dogs with a UPC > 1.0 have significantly shortened survival relative to dogs with a UPC <1.0 (300d vs. 600d until renal associated death)

References Lees, G.E., et al., Assessment and Management of

Proteinuria in Dogs and Cats: 2004 ACVIM Forum Consensus Statement (Small Animal). Journal of Veterinary Internal Medicine, 2005. 19(3): p. 377-385.

IRIS consensus statements. Journal of Veterinary Internal Medicine, 2013; 27: p S27 – S43

Open access www.acvim.org

JVIM Consensus Statements – Wiley Online

References Littman, M.P., Protein-losing Nephropathy in Small Animals. Veterinary Clinics of North America: Small Animal Practice, 2011. 41(1): p. 31-62. Klosterman, E.S., et al., Comparison of Signalment, Clinicopathologic Findings, Histologic Diagnosis, and Prognosis in Dogs with Glomerular Disease with or without

Nephrotic Syndrome. Journal of Veterinary Internal Medicine, 2011: p. no-no. Atkins, C.E., et al., Renal effects of Dirofilaria immitis in experimentally and naturally infected cats. Veterinary Parasitology, 2011. In Press, Corrected

Proof. Zatelli, A., et al., Evaluation of a urine dipstick test for confirmation or exclusion of proteinuria in dogs. American Journal of Veterinary Research, 2010. 71(2): p.

235-240. Smets, P.M.Y., et al., Urinary Markers in Healthy Young and Aged Dogs and Dogs with Chronic Kidney Disease. Journal of Veterinary Internal Medicine, 2010.

24(1): p. 65-72. Smets, P.M.Y., et al., Effect of sampling method and storage conditions on albumin, retinol-binding protein, and N-acetyl-{beta}-D-glucosaminidase concentrations in canine

urine samples. J Vet Diagn Invest, 2010. 22(6): p. 896-902. Raila, J., et al., Influence of kidney function on urinary excretion of albumin and retinol-binding protein in dogs with naturally occurring renal disease. American Journal

of Veterinary Research, 2010. 71(11): p. 1387-1394. Lyon, S.D., et al., Comparison of urine dipstick, sulfosalicylic acid, urine protein-to-creatinine ratio, and species-specific ELISA methods for detection of albumin in urine

samples of cats and dogs. Journal of the American Veterinary Medical Association, 2010. 236(8): p. 874-879. Lien, Y.-H., T.-Y. Hsiang, and H.-P. Huang, Associations among systemic blood pressure, microalbuminuria and albuminuria in dogs affected with pituitary- and

adrenal-dependent hyperadrenocorticism. Acta Veterinaria Scandinavica, 2010. 52(1): p. 61. Lavoué, R., et al., Progressive Juvenile Glomerulonephropathy in 16 Related French Mastiff (Bordeaux) Dogs. Journal of Veterinary Internal Medicine, 2010.

24(2): p. 314-322. Glassock, R.J., The Pathogenesis of Idiopathic Membranous Nephropathy: A 50-Year Odyssey. American Journal of Kidney Diseases, 2010. 56(1): p. 157-167. Beatrice, L., et al., Comparison of urine protein-to-creatinine ratio in urine samples collected by cystocentesis versus free catch in dogs. Journal of the American

Veterinary Medical Association, 2010. 236(11): p. 1221-1224. Bacic, A., et al., Evaluation of albuminuria and its relationship with blood pressure in dogs with chronic kidney disease. Veterinary Clinical Pathology, 2010. 39(2):

p. 203-209.

References Alchi, B. and D. Jayne, Membranoproliferative glomerulonephritis. Pediatric Nephrology, 2010. 25(8): p. 1409-1418. Jepson RE, B.D., Vallance C, Syme HM, Elliott J., Evaluation of predictors of the development of azotemia in cats. Journal of

Veterinary Internal Medicine, 2009. 23(4): p. 806 - 13. White, J.D., et al., Persistent haematuria and proteinuria due to glomerular disease in related Abyssinian cats. Journal of Feline

Medicine & Surgery, 2008. 10(3): p. 219-229. Whittemore, J.C., et al., Association of microalbuminuria and the urine albumin-to-creatinine ratio with systemic disease in cats.

Journal of the American Veterinary Medical Association, 2007. 230(8): p. 1165-1169. Nabity, M.B., et al., Day-to-Day Variation of the Urine Protein: Creatinine Ratio in Female Dogs with Stable Glomerular

Proteinuria Caused by X-Linked Hereditary Nephropathy. Journal of Veterinary Internal Medicine, 2007. 21(3): p. 425-430. King, J.N., et al., Prognostic Factors in Cats with Chronic Kidney Disease. Journal of Veterinary Internal Medicine, 2007.

21(5): p. 906-916. Whittemore, J.C., et al., Evaluation of the association between microalbuminuria and the urine albumin-creatinine ratio and systemic

disease in dogs. Journal of the American Veterinary Medical Association, 2006. 229(6): p. 958-963. Syme, H.M., et al., Survival of Cats with Naturally Occurring Chronic Renal Failure Is Related to Severity of Proteinuria.

Journal of Veterinary Internal Medicine, 2006. 20(3): p. 528-535. Vaden, S.L., et al., Renal Biopsy: A Retrospective Study of Methods and Complications in 283 Dogs and 65 Cats. Journal of

Veterinary Internal Medicine, 2005. 19(6): p. 794-801. Jacob, F., et al., Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally

occurring chronic renal failure. Journal of the American Veterinary Medical Association, 2005. 226(3): p. 393-400. D'Amico, G. and C. Bazzi, Pathophysiology of proteinuria. Kidney International, 2003. 63(3): p. 809-825. Grauer, G.F., et al., Effects of Enalapril versus Placebo as a Treatment for Canine Idiopathic Glomerulonephritis. Journal of

Veterinary Internal Medicine, 2000. 14(5): p. 526-533. Brown, C. Renal Biopsy: Who, When and How? in ACVIM Forum. 2007. Seattle, WA. Bonagura, J.T., David, ed. Kirk's Current Veterinary Therapy. 14 ed. 2009, Elsevier: St. Louis. Greene, C.E., ed. Infectious Diseases of the dog and cat. 3 ed. 2006, Elsevier: St. Louis.

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