Proteinuira & Glomerular Disease, Dr. Sara Arnold, 11/8/14
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This document provides an overview of glomerular disease and proteinuria in dogs. It begins with a discussion of laboratory evaluation of proteinuria including urinalysis and urine protein to creatinine ratio testing. Pathophysiology of proteinuria is then reviewed including mechanisms in the glomerulus, tubules, and factors causing extra-renal proteinuria. Common causes of pathologic renal proteinuria are listed. The diagnostic workup for proteinuria is outlined including recommendations for additional testing based on urinary protein levels and presence of azotemia. Renal biopsy indications and contraindications are reviewed. Treatment options including ACE inhibitors, diet, immunosuppression, and managing hypertension are summarized. Factors impacting prognosis like severity
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Proteinuira & Glomerular Disease, Dr. Sara Arnold, 11/8/14
- 1. GLOMERULAR DISEASE AND PROTEINURIA November 8, 2014 Sara Arnold, DVM, DACVIM
- 2. Outline: Laboratory evaluation Methodology Pathophysiology of proteinuria Glomerulus Tubule Pre-renal Diagnostic workup Renal biopsy Treatment ACE and ARB Immunosuppression Hypertension Prognosis Nephrotic syndrome
- 3. Laboratory evaluation of proteinuria Urinalysis Dipstick >30mg/dl Alkalinuria (pH > 7.5) Hypersthenuria Sulfasialacylic acid Bence jones proteins False +: radiocontrast agents, penicillins, sulfasoxazole, cephaloridine
- 5. 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
- 6. Predisposed Breeds Beagles: Amyloidosis, membranoproliferative glomerulonephritis Bernese: Mesangiocapillary glomerulonephritis Bull Terrier: Hereditary nephritis Cocker Spaniel: Hereditary nephritis Dalmatian: Hereditary nephritis Doberman: Glomerulosclerosis, cystic glomerular atrophy English foxhound:Amyloidosis Greyhound: Glomerular vasculopathy and necrosis Newfoundland: Glomerulosclerosis Pembroke Corgi: Cystic glomerular atrophy Rottweiler : Atrophic glomerulopathy Samoyed: Hereditary nephritis Shar Pei: Amyloidosis SC Wheaten: Proliferative and sclerosing glomerulonephritis Vanden S and Grauer G “Glomerular Disease.” Nephrology and Urology of Small Animals.
- 8. 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?
- 10. The glomerulus Filtration barrier Endothelium Basement membrane Podocytes Negative charge Minimal change nephropathy Glomerular filtration rate Sympathetic nervous system Hormonal regulation
- 11. The glomerulus Hormonal regulation of GFR Vasoconstriction – decreased GFR Norepinephrine and Epinephrine Endothelin Angiotensin II Vasodilation – increased GFR Nitric oxide Prostaglandins Bradykinin
- 12. The proximal tubule Protein absorption 1.5mM/min Proteinuria and tubular damage Mesangial toxicity Tubular overload and hyperplasia Toxicity Up-regulation of inflammation
- 13. 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
- 14. 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.
- 18. 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
- 19. 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
- 20. Littman, M. P. (2011). "Protein- losing Nephropathy in Small Animals." Veterinary Clinics of North America: Small Animal Practice 41(1): 31-62. ProposedProposed workup?workup?
- 21. 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
- 22. 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
- 23. 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
- 24. Renal Biopsy
- 25. 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
- 26. IRIS Guidelines Biopsy analysis Light microscopy Electron microscopy Immunofluorescence For biopsy kit and sample submission: International Veterinary Renal Pathology Service Department of Veterinary Biosciences The Ohio State University Columbus, OH 43210 Dr. Rachel Cianciolo rachel.cianciolo@cvm.osu.edu
- 27. Treatment
- 28. 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
- 29. 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
- 30. 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
- 31. 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
- 32. IRIS Guidelines: Standard Therapy Antithrombotic Aspirin 0.5 - 5mg/kg/day Plavix 1-3mg/kg/day Heparin? Works via enhancement of antithrombin
- 33. 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)
- 34. 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
- 35. Treatment: Hypertension Geigy C. “Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate.” JSAP, (2011) 52, 340–346
- 36. Prognosis
- 37. Prognosis Klosterman (2011). "Comparison of Signalment, Clinicopathologic Findings, Histologic Diagnosis, and Prognosis in Dogs with Glomerular Disease with or without Nephrotic Syndrome." JVIM
- 38. 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
- 39. 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)
- 40. 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
- 41. 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.
- 42. 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.
- 43. Questions?
- 44. Guardian Continuous Glucose Monitor Stay Tuned….
Editor's Notes
- False positives on the urine dipstick can occur with alkalinuria and highly concentrated urine Common sense regarding workup and degree of proteinuria Beatrice 2010 JAVMA – inactive urine sediment ( &lt; 5RBC / Hpf, &lt; 5WBC / hpf and no visible bactiuria or increased cellularity) FC sample was acceptable for UPC
- Microalbuminuria is defined as a protein level greater than normal but lower than can be detected by other standard assays. The problem is we don’t know what normal is. In humans, urine albumin : creatinine ratios greater than 0.03 are considered abnormal
- Mechanism behind physiologic proteinuria is not completely understood but it is thought to be a combination f renal vasoconstriction, ischemia and congestion Renal neoplasia, pyelonephritis and leptospirosis may also produce active urine sediments but be causes of true renal proteinuria and they cause direct damage to the glomerulus and tubules
- Filtration barrier is composed of: endothelium, basement membrane and podocytes
- The filtration slits are thought to be 8nm in diameter and albumin is only 6nm, it is the negative charge that prevents its filtration
- Epinephrine and norepinephrine are elevated in times of high sympathetic tone – only have a real effect on GFR in extreme situations (severe hemorrhage) Endothelin – released in response to endothelial damage, can be systemically elevated during acute renal failure, chronic uremia, pregnancy toxemia Angiotensin II – preferentially constricts the efferent arteriole; is secreted in times of decreased arterial pressure and volume depletion in order to prevent decreases in the glomerular hydrostatic pressure and GFR; Constriction of the efferent arteriole increases the filtration fraction in the glomerulus and thereby increases the concentrations of proteins and the colloid osmotic pressure that is delivered to the proximal tubule. Prostaglandins – oppose vasoconstriction of the afferent arteriole and thereby prevent excessive reduction of GFR
- Toxicity – specific proteins, transferrin and iron, may be directly toxic to the tubular epithelial cells Inflammation may be up regulated by the proteins that accumulate in the proximal tubular cells, also complement components that are filtered through the glomerulus may cause interstitial injury
- Monitoring for progression of azotemia in mildly azotemic dogs or non – azotemic dogs serves to provide prognotic information – ongoing kidney damage or stable proteinuria? UPC can vary up to 40% in dogs and up to 90% in cats from day to day
- 2011 veterinary parasitology article – naturally and experimentally infected cats with heartworm, the majority had microalbuminuria and 9/10 had UPC &gt; 0.4; unfortunately no UPC data was available for naturally infected but they did test positive for proteinuria via dipstick and there was a weak correlation of the magnitude of infection with degree of proteinuria
- ** lepto causes primarily tubular proteinuria but the hypoalbuminemia associated with this disease can mimic glomerular disease. **Potential cross Rxn between Lyme and lepto antibodies.
- Humans with chronic kidney disease have an increased complication rate with biopsy Primarily indicated for episodes of acute renal failure or with glomerulonephritis - acute renal failure – intact basement membrane is a good indicator for return of renal function but without this the prognosis is much poorer Complication rate of 15 – 18% - Vaden 2005, most common complication was hemorrhage
- Angiotensin receptor blockers act synergistically with ACE inhibitors and can decrease proteinuria by 60% more than either drug alone. However studies in people have shown a higher mortality in elderly patients when given these medications in combination. Goal is a UPC reduction by 50% or more
- Mycophenolate is more widely used for glomerular disease in people and is at least as effective as protocols employing azathioprine, cyclophosphamide and cyclosporine
- There was no difference in survival between azotemic dogs with or without nephrotic syndrome Syme 2006 – used UPC cutoffs of &gt;0.2 and &lt; 0.4 – 3 times more likely to die; &gt;0.4 were 4 times more likely Based on their graphs, cats with elevated UPC had a 400 – 500 day median survival vs. 1000 d for &lt;0.2 UPC
- Only 45 dogs in the entire study. Also appeared to be an association with progressively elevating creatinine and elevated UPC. Time to first uremic crisis was also significantly shorter for dogs with elevated UPC.