proteinuira & glomerular disease, dr. sara arnold, 11/8/14
TRANSCRIPT
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 [email protected]
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.
Questions?
Guardian Continuous Glucose Monitor
Stay Tuned….