10/1/11 Shanna Pace, DVM Practice Limited to Internal Medicine VCA Veterinary Specialty Center of Seattle October 16, 2011 seejanenurse.wordpress.com               Significance of proteinuria Renal and glomerular anatomy Pathophysiology of glomerular inflammation Types of proteinuria Specific glomerular diseases Methods of detecting proteinuria Assessment and management of proteinuria nephrons.org In humans       Persistent proteinuria is a strong independent risk factor for progression to end-stage chronic kidney disease (CKD) Hypertension and diabetes are the two biggest risk factors for proteinuria Early intervention after detection can prevent/ prolong progression to renal failure 1 10/1/11 Dog and Cats   Proteinuria is the hallmark of glomerular disease   Glomerular disease is an important cause of renal failure   Protein-losing nephropathy may be seen in ◦  infectious, inflammatory, metabolic, neoplastic diseases   Proteinuria is associated with a more rapid progression of CKD and a higher frequency uremic crises   Most common cause of end stage renal failure worldwide in humans Most present with one of five syndromes   ◦  Asymptomatic hematuria ◦  Acute glomerulonephritis (GN) ◦  Rapidly progressing GN ◦  Nephrotic syndrome ◦  Chronic glomerulonephritis         Affects dogs more than cats Can occur at any age depending on cause Can be primary (familial, congenital) or secondary Clinical signs variable ◦  Dependent on degree of proteinuria ◦  Dependent on presence or absence of renal failure ◦  Dependent on signs related to underlying disease 2 10/1/11               Significance of proteinuria Renal and glomerular anatomy Pathophysiology of glomerular inflammation Types of proteinuria Specific glomerular diseases Methods of detecting proteinuria Assessment and management of proteinuria nephrons.org •  Nephron – functional unit of the kidney •  Renal corpuscle, proximal tubule, loop of henle and distal tubule •  Renal corpuscle  Glomerulus + Bowman’s capsule courses.stu.qmul.ac.uk sharinginhealth.ca 3 10/1/11 Capillary Basement membrane Epithelium www.bu.edu   115 liters of glomerular filtrate per day   Potential   Actual loss of 3.73kg of albumin/day albumin loss ONLY 75 mg/day ◦  99% exclusion Courtesy of research done by Dr. Scott Brown, DVM, DACVIM, University of Georgia ? Glomerular inflammation Increased serum proteins (overflow proteinuria) Proximal tubule defects (low reabsorption – Faconi syndrome, etc) 4 10/1/11     Both humoral and cell mediated immune mechanisms play a role Two mechanisms of antibody mediated injury ◦  Type II hypersensitivity reaction   Abs develop against GBM components ◦  Type III hypersensitivity reaction   AG-AB complexes escape clearance from reticuloendothelial system   Cell-mediated response ◦  Involves activation of macrophages, NK cells and cytotoxic T lymphocytes ◦  Attacks cells displaying antigen or invaded with intracellular pathogens ◦  Release cytokines in response to antigen ◦  Cytokines mediate destruction and maladaptive proliferative events   Complement, coagulation cascade, leukocyte invasion, proteolytic enzymes, growth factors   Role of platelets ◦  Activation and aggregation secondary to endothelial damage ◦  Exacerbate damage by releasing vasoactive and inflammatory substances   Also facilitate coagulation cascade   Release growth stimulating factors   Glomerulus responds by thickening of GBM   Increased urinary levels of platelet derived thromboxane A2 detected in experimental GN ◦  Eventually leads to hylanization and sclerosis 5 10/1/11       Damaged glomerulus leads to non-functional nephron Fibrosis and scarring may look like interstitial inflammation GFR progressively declines ◦  Remaining nephrons compensate with hyperfiltration   Hyperfiltration and proteinuria in remaining nephrons results in progressive nephron loss Immune complexes deposition or in situ formation Complement activation Proinflammatory molecules Endothelial damage Platelet aggregation Vasoactive substances Coagulation system activation Intraglomerular hypertension Fibrin production Glomeruloscelerosis proliferative and/or membranous response Proteinuria healthhype.com 6 10/1/11     Significance of proteinuria Renal and glomerular anatomy nephrons.org ◦  Glomerular structure ◦  Glomerular function   Pathophysiology of glomerular inflammation Types of proteinuria Specific glomerular diseases Methods of detecting proteinuria Assessment and management of proteinuria   Prerenal proteinuria         ◦  Normal kidney structure and function ◦  Excessive hemoglobin, myoglobin, Bence Jones proteins, genital disorders ◦  Proteinuria is of low magnitude   Functional proteinuria ◦  Low magnitude proteinuria           Seizures Fever Excessive exercise Stress Transient change ◦  Filtration barrier structure ◦  Electrical charge ◦  Hydrostatic pressure 7 10/1/11   Pathological         High magnitude proteinuria Decreased glomerular permselectivity (increased permeability of capillary wall) Decreased tubular reabsorption (ie: Faconi’s syndrome) Interstitial abnormalities (exudation of proteins to the urinary space)     Pyelonephritis, nephritis, neoplasia Protein enters urine after renal pelvis ◦  Uroliths ◦  Metritis, pyometra, vaginitis, neoplasia ◦  Paraprostatic cysts, prostatitis, neoplasia Non-immune-mediated glomerulonephropathies   Amyloidosis (cortical) ◦  Shar Pei, Abyssian cats   Familial   Intraglomerular hypertension ◦  X-linked nephropathy (collagen deficit) ◦  ◦  ◦  ◦  ◦  Hyperadrenocorticism Chronic glucocorticoid administration Diabetes mellitus Systemic arterial hypertension Chronic renal disease 8 10/1/11 Immune-mediated glomerulonephropathies   Primary (familial) ◦  Bernese Mountain Dog, Bull Terrier, Cocker Spaniel, SCWT   Secondary ◦  Deposition of immune complexes in glomerular capillary wall ◦  Membranoproliferative glomerulonephritis, Membranous nephropathy, Proliferative glomerulonephritis   Infectious   Inflammatory ◦  Viral, bacteria, rickettsial, fungal, protozoal, parasitic diseases ◦  Dental, skin, GI tract, joint disease ◦  IMHA, ITP, SLE   Neoplastic   Significance of proteinuria Renal and glomerular anatomy   nephrons.org ◦  Glomerular structure ◦  Glomerular function           Pathophysiology of glomerular inflammation Types of proteinuria Specific glomerular diseases Methods of detecting proteinuria Assessment and management of proteinuria 0 1 mg/dL ____Normal_ Microalbuminuria 30 mg/dL __Overt Proteinuria_ Albuminuria------------ ------------------------------ Microalbuminuria test + Dipstick + UP:C increased 9 10/1/11   Dipstick   Advantages ◦  Inexpensive ◦  Easy to use ◦  Not affected by urine turbidity   Disadvantages ◦  Subjective grading ◦  Specificity poor Dogs: dipstick false-positive rate of 32% Cats: dipstick false-positive rate of 69% findmeacure.com   Advantages ◦  ◦  ◦  ◦    Inexpensive Easy to use ↑ Sensitivity for protein ↑ Specificity for protein Disadvantages ◦  More labor/time compared with the dipstick ◦  Subjective grading ◦  ↓ Specificity for albumin ahdc.vet.cornell.edu •  1 to 30 mg/dL – albumin •  Semi-quantitative (provided urine diluted to USG 1.010) –  no false positive results in 16 month field trial Negative Positive Low Medium High Very high www.heska.com 10 10/1/11   Indexes protein content to urine dilution readily available index of magnitude of proteinuria   Best ◦  To guide clinical decisions ◦  To monitor trends Good to use to monitor treatment bod.com   UP:C > 0.5 is abnormal (urine sample must be free of inflammation, bacteria & macroscopic hematuria)   Day to day variation occurs  especially in dogs with a UP:C > 4   Assess trends over time   False positives ◦  Gross hematuria ◦  Active urine sediment/ UTI ◦  Puppies < 4 months   Significant change if: ◦  High UP:C >12  change by at least 35% day to day ◦  Lower UP:C >/= 0.5  change by 50 - 80% day to day   A reduction in UP:C near these reported magnitudes WITHOUT an increase in the serum creatinine concentration is required to indicate improvement or response to therapy 11 10/1/11 1.  Can be detected before increases in UP:C 2.  Magnitude of microalbuminuria increased over time in dogs that eventually developed an increased UP:C 3.  Persistent microalbuminuria of increasing magnitude should be assessed as having an injurious process to the glomerular filtration barrier & may eventually lead to overt proteinuria   UP:C gives MORE THOROUGH information than microalbuminuria assay   Microalbuminuria assay does not differentiate between functional and pathologic proteinuria   Does not alleviate the need for chronic monitoring   When conventional tests for proteinuria are negative ◦  Especially if animal has serious disease that might cause a PLN   Healthy animals when the most sensitive available test is desired ◦  Dogs ≥ 6 years of age ◦  Cats ≥ 8 years of age 12 10/1/11   In all situations that prompt complete laboratory testing (CBC, chemistries, urinalysis) ◦  Animals with serious illnesses ◦  Routine wellness evaluations   During management of chronic diseases known to cause PLN or “at risk” breeds (Wheaten terriers, Bull terriers, Dalmations, English Cockers) ◦  At ≤ 6 month intervals   Dipstick ◦  Poor Specificity (Many false positives) ◦  Fair sensitivity (>30 mg/dL will be detected)   SSA ◦  Moderate Specificity (Few false positives) ◦  Moderate Sensitivity ◦  Generally used as confirmatory test for dipstick   UP:C ◦  Good Specificity (Few false positives) ◦  Good Sensitivity (>5 mg/dL can be detected though ratio is used to adjust for concentration) ◦  Semi-quantitative   Microalbuminuria Tests ◦  High Specificity (Rare false positives) ◦  High Sensitivity (>1 mg/dL can be detected)   Localize proteinura ◦  Pre-, renal or post-renal   Make sure it is persistent ◦  Positive result (any method) on 3 occasions, at least 2 weeks apart   Identify magnitude of proteinuria ◦  Semi-quantitative microalbuminuria ELISA or UPC ◦  Influence case management ◦  Monitor trends/ progression ◦  Monitor response to therapy 13 10/1/11   Progressive microalbuminuria or develop overt proteinuria If stable – every 3-6 months   UP:C, body weight + body condition score   Serum albumin + creatinine   Systolic BP ± urine culture and sensitivity If progressive/changing therapy – every 1-3 months   UP:C, systemic BP, body weight and BCS   Response to therapy ◦  reassess 2 - 4 weeks after introduction/ change of therapy Grauer. 2005 J Small Anim Prac 46: 469 Brunker. 2005 Compendium 27: 686 14 10/1/11 Cats Dogs Interpretation (IRIS substage) < 0. 2 < 0.2 Nonproteinuric (NP) 0.2 – 0.4 0.2 – 0.5 Borderline Proteinuric (BP) 0.4 – 2.0 > 0.5 1. Nonazotemic cats and dogs Proteinuric (P) • Associated with poor PX • Rule of thumb: UPC>2.0 most likely glomerular disease Intervene Investigate Monitor MA, UPC ≥ 0.5 UPC ≥ 1.0 2. Azotemic dogs UPC ≥ 2.0 Intervene Investigate Monitor UPC < 0.5 3. Azotemic cats UPC ≥ 0.5 Intervene Investigate Monitor UPC < 0.4 UPC < 0.2 UPC ≥ 0.4 www.iris-kidney.com 15 10/1/11   Treat underlying disease and re-assess ◦  Monitor to make sure proteinuria is persistent Dietary management ACE inhibitors   ± Anti-hypertensives – amlodipine   Omega-3 fatty acids   ± Aspirin     villageanimalclinicllc.com   Feed a “renal failure” diet ◦  Low protein ◦  Low sodium (↓hypertension, ↓fluid retention) ◦  Calorically dense ◦  Increased palatability ◦  Vitamins / minerals ◦  Fish oil (omega 3 PUFAs) Burkholder et al. 2004 JVIM 18: 165 fishoilomega.com   When do you start antiproteinuric therapy (ACE inhibitors) – IRIS substage P ◦  CKD with UPC: ≥ 0.4 in cats; ≥ 0.5 in dogs   Enalapril (0.25 –0.5 mg/kg PO q 12-24h)   Benazapril (0.5 mg/kg PO q 12-24h) ◦  ↓ efferent glomerular arteriole pressure ◦  ↓ glomerular capillary endothelial pore size ◦  ↓ glomerular mesangial hypertrophy 16 10/1/11 When starting Benazepril or Enalapril   Monitor renal parameters within 7-14 days ◦  ↓ renal blood flow may cause ↓ GFR   Assess efficacy after 2-4 weeks Aim to ↓ UPC by 50% without ↑ serum creatinine   Systolic BP > 160 mmHg despite ACE inhibitor therapy   Amlodipine (0.05-0.25 mg/kg PO q 24h) 1   ◦  Thoretically worsen proteinuria by dilation of afferent arteriole vs overall decrease in systolic BP   Activates renin-angiotensin-aldosterone system in dogs 2   Decrease dose if BP <120 mmHg and/or clinical signs 1. www.iris-kidney.com 2. Atkins et al. 2007 J Vet Pharm Therap 30: 394 projectswole.com 17 10/1/11   Most renal diets ◦  n6:n3 ratio = 5:1   Aim for ratio of 1:1   Supplement with fish oil capsules ◦  0.25 gm n-3 PUFA/kg thebeautybrains.com   0.05-0.5 mg/kg/day Ultralow dose inhibits platelet activation without causing vasoconstriction or decreased renal medullary perfusion Efficacy not proven   Severe PLN   Use if serum albumin < 2.0 g/dl     ◦  anti-coagulant action if significant loss of anti-thrombin www.iris-kidney.com   Angiotensin receptor blockers (ARB) ◦  ↓ effect of angiotensin II from alternate sources ◦  Compensatory ↑ in renin, so best combined with ACEi   Aldosterone receptor inhibitors e.g. spironolactone ◦  ↓ proteinuria in people treated with ACEi + ARB   Renin inhibitors 18 10/1/11   Dogs ◦  Renal diet, ACE inhibitors, ± amlodipine, essential fatty acids, ± aspirin ◦  Monitoring frequency depends on stability, changes in therapy   Cats ◦  Proteinuria may be cause or effect of chronic renal dz ◦  Use amlodipine first if hypertensive, then ACE inhibitors ◦  No aspirin or essential fatty acids ◦  See IRIS recommendations for treatment/management of CRD   Poor prognosis in humans associated with ◦  ◦  ◦  ◦    Azotemia Severe proteinuria Systemic hypertension Severe tubulointerstitial lesions Specific prognostic factors in dogs unknown ◦  ◦  ◦  ◦  Magnitude of proteinuria Underlying systemic disease Severity of renal dysfunction Response to therapy   Proteinuria associated with increased renal morbidity, mortality and mortality of all causes   Outcome is proportional to magnitude of proteinuria   Glomerular renal failure disease is a significant cause of ◦  Glomerular proteinuria – immune and nonimmune causes 19 10/1/11   Assess ◦  Localization, persistence and magnitude of proteinuria   Microalbuminuria ◦  Use for screening, and monitoring stable cases   UP:C ◦  Use if starting and/or monitoring response to therapy   Treatment   Prognosis   options mainly supportive variable and difficult to predict References ◦  Ettinger and Feldman, Textbook of Veterinary Internal Medicine 7th ed,Vl 2, 2010, p. 2021 – 2036. ◦  MacDougall DF, et al: Canine chronic renal disease: prevalence and types of glomerulonephritis in the dog. Kidney Int 1986; 29:1144-1151 ◦  Jennette JC, et al: Heptinstall's pathology of the kidney. ed 5. Philadelphia, LippincottRaven, 1998. ◦  Jarad G, et al: Proteinuria precedes podocyte abnormalities in Lamb2−/− mince, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest 2006; 116:2272-2279. ◦  Russo LM, et al: Renal handling of albumin: a critical review of basic concepts and perspective. Am J Kidney Dis 2002; 39:899-919. ◦  Cook AK, et al: Clinical and pathological features of protein-losing glomerular disease in the dog: a review of 137 cases (1985-1992). J Am Anim Hosp Assoc 1996; 31:313-322. ◦  DiBartola SP, et al: Clinicopathologic findings in dogs with renal amyloidosis: 59 cases (1976-1986). J Am Vet Med Assoc 1989; 195:358-364 ◦  Biewenga WJ, et al: Proteinuria in the dog: a clinicopathological study in 51 proteinuric dogs. Res Vet Sci 1986; 41:257-264. ◦  Hricik DE, et al: Glomerulonephritis. N Engl J Med 1998; 339:888-899. ◦  Koeman JP, et al: Proteinuria in the dog: a pathomorphological study of 51 proteinuric dogs. Res Vet Sci 1987; 43:367-378. ◦  Grauer GF, et al: Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 2000; 14:526-533. ◦  Brown SA, et al: Beneficial effects of chronic administration of dietary omega-3 polyunsaturated fatty acids in dogs with renal insufficiency. J Lab Clin Med 1998; 131:447-455 20 10/1/11   References   Nabity MB, 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. J Vet Int Med 2007; 21:425-430.   Grauer GF, et al: Effects of a thromboxane synthetase inhibitor on established immune complex glomerulonephritis in dogs. Am J Vet Res 1992; 53:808-813.   Campbell R, et al: Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 2003; 63:1094-1103.   Abrass CK: Clinical spectrum and complications of the nephrotic syndrome. J Invest Med 1997; 45:143-153.   Eddy A: Role of cellular infiltrates in response to proteinuria. Am J Kidney Dis 2001; 37(1 suppl 2):S25-S29. 21