APPROACH TO A PATIENT WITH PROTEINURIC RENAL DISEASE

PHYSIOLOGY AND PATHOPHYSIOLOGY OF PROTEIN EXCRETION

Physiology/Pathophysiology l Protein flow through renal arteries = 121,000 g/day l Protein filtered through glomerulus = 1-2 g/day (< 0.001%) l Protein excreted in urine < 150 mg/day (<1% of filtered) l Composition of normal urine: Tamm- Horsfall protein 60-80%, albumin 10-20%.

Physiology/Pathophysiology Schematic 1. Filtration 2. Reabsorption/Catabolism 3. Secretion 4. Excretion

Physiology and Pathophysiology Etiologies of Proteinuria l Overflow: excess serum concentrations of protein overwhelm nephron’s ability to reabsorb. Ex.-light chain disease. l Tubular: deficiency reabsorption of proteins in proximal tubule causing mostly LMW proteinuria. Exs.-interstitial nephritis, Fanconi’s syndrome. l Glomerular: defect causing albuminuria (>70%) and HMW proteinuria. Exs.- orthostatic proteinuria, glomerulonephritis.

DIFFERENTIAL DIAGNOSIS

Differential Diagnosis General Categories l Transient proteinuria l Orthostatic proteinuria l Persistent proteinuria

Differential Diagnosis Transient Proteinuria l Proteinuria caused by non-renal causes: fever, exercise, CHF, seizures. l Resolves when condition resolves. No further work-up indicated. l Intermittent proteinuria: no clear etiology, benign condition with excellent prognosis.

Differential Diagnosis Orthostatic Proteinuria l Proteinuria caused by upright position. l Subjects < age 30 with proteinuria < 1.5 g/day. l Diagnosis: split day/night urine collections. (Or spot protein/creatinine ratio first AM void and mid afternoon).

Differential Diagnosis Orthostatic Proteinuria l The most important point is the morning collection, or first AM void spot protein/creatinine ratio, should be NORMAL (extrapolating to <150 mg/d over 24 hours, or a ratio of <0.15), not just lower than the afternoon collection. l Once diagnosis established, excellent long- term prognosis. l Annual follow-up recommended.

Differential Diagnosis Persistent Proteinuria l Subnephrotic: 3.5 g/day/1.73 m 2. l Distinction has diagnostic, prognostic, and therapeutic implications but actual value is arbitrary. l No practical distinction between nephrotic syndrome and nephrotic- range proteinuria.

Differential Diagnosis Subnephrotic Proteinuria l Transient or orthostatic proteinuria l Hypertensive nephrosclerosis l Ischemic renal disease/renal artery stenosis l Interstitial nephritis l All causes of nephrotic-range proteinuria

Differential Diagnosis Nephrotic Syndrome l Def: nephrotic-range proteinuria, lipiduria, edema, hypoalbuminemia, hyperlipidemia. l Implies glomerular origin of proteinuria. Clinical manifestations: edema, hypercoagulability, immunosuppression, malnutrition, +/  hypertension, +/  renal failure.

Differential Diagnosis Nephrotic Syndrome (cont.) l 75% have primary glomerular disease l 25% have secondary glomerular disease Medications: NSAIDs, heavy metals, “street” heroin, lithium, penicillamine,  -INF n Infections: post-strep, HIV, hepatitis B/C, malaria, schistosomiasis n Neoplasms: solid tumors, leukemias, lymphomas, multiple myeloma n Systemic diseases: diabetes mellitus, SLE, amyloidosis

Differential Diagnosis Diabetic Nephropathy l #1 cause of ESRD (~35% of all ESRD). l ~ 40% of all diabetics (type I and II) will develop nephropathy. l Microalbuminuria (> 30 mg/day) develops after ~ 5 years. Proteinuria after years. l Progression to ESRD ~15-30 years.

EVALUATION OF THE PATIENT WITH PROTEINURIA

Clinical Evaluation History l Onset: acuity, duration l Diabetic history if applicable, esp. h/o retinopathy/neuropathy l Renal ROS: edema, HTN, hematuria, foamy urine, renal failure l Constitutional sxs: fever, nausea, appetite, weight change l Sxs of coagulopathy: DVT/RVT/P.E.

Clinical Evaluation History (cont.) l Rheumatological ROS l Malignancy ROS l Medications including OTC and herbals l Family hx of renal disease l Exposure to toxins

Clinical Evaluation Physical Examination l BP and weight l Fundoscopic exam l Cardiopulmonary exam l Rashes l Edema

Clinical Evaluation Labs and Studies l Required: Chem-16, CBC, U/A, 24-hr urine or spot urine for protein/creatinine l As clinically indicated: SPEP/UPEP, fasting lipid panel, glycosylated Hg, ANA, C3/C4, urine eosinophils, hepatitis B/C, ophthalmology exam, review of HCM, renal ultrasound +/- Doppler study of veins l Renal biopsy as indicated

Clinical Evaluation Urine dipstick l Most sensitive to albumin, least sensitive to LWM proteins. l Sensitivity ~ 10 mg/dL (~ 300 mg/day). Coefficient of variability high. l False negatives: small and positively- charged proteins (light chains), dilute urine. l False positives: radiocontrast dye, Pyridium, antiseptics, pH > 8.0, gross hematuria.

Clinical Evaluation Sulfosalicylic Acid (SSA) Assay l Turbidimetric assay based on precipitation of proteins. l Measures all proteins.

Test sample

Clinical Evaluation Urine Sediment l Red cell casts or dysmorphic RBCs suggest glomerulonephritis. l WBCs suggest interstitial nephritis or infection. l Lipid bodies, oval fat bodies, Maltese crosses suggest hyperlipidemia and possible nephrotic syndrome.

Clinical Evaluation Quantitation of Proteinuria l 24-hr urine is gold standard, however is often not easily obtained. l Spot urine protein/creatinine ratio is easier to get, nearly as accurate. l ALWAYS GET A CREATININE WITH ANY QUANTITATIVE MEASURE OF URINE! l 24-hr urines: Cr Index = mg/kg/day for men, mg/kg/day for women.

Clinical Evaluation Spot Urine Protein/Creatinine Ratio Proteinuria, g/day/1.73 m 2 Urine P/C ratio Adapted from Ginsberg et al., NEJM, 309:1543, 1983.

Clinical Evaluation When to Refer to Nephrology l Option 1: refer everybody. l Option 2: refer patients after evaluation for transient and orthostatic proteinuria (unless underlying systemic disease). Diabetics referred at time of microalbuminuria.

Clinical Evaluation Who To Biopsy l Non-diabetic nephrotic syndrome l SLE for classification l Planned use of immunosuppressive agents in primary GNs (renal insufficiency, severe edema, hypertension) l Diagnosis of plasma cell dyscrasias l < 2 gms proteinuria without other signs: conservative therapy (biopsy resulted in management change in only 3/24 patients in prospective trial)

MANAGEMENT OF PROTEINURIA

Management Specific vs. Nonspecific Therapies l Proteinuria is not just a marker of kidney disease, but also a culprit in its progression. l Control of proteinuria is seen to ameliorate or arrest glomerular disease independent of the underlying etiology. l Treatment of secondary causes is treatment of the underlying disorder plus supportive care.

Management Specific vs. Nonspecific Therapies l Specific therapies on primary glomerulonephritis depending on diagnosis: glycemic control, immunosuppresive agents (corticosteroids, cyclophosphamide, chlorambucil, cyclosporine A, fish oil) l Nonspecific therapies independent of diagnosis: blood pressure and metabolic control and toward supportive care.

Management Blood Pressure Control l Diabetics: control of BP shown to slow progression of nephropathy in several studies. l Non-diabetics: BP control to MAP < 92 vs. 107 associated with less progression of disease. Benefit greatest in nephrotic patients. l Gains in stroke and heart disease due to BP control have not been seen in renal disease.

Management ACE Inhibitors l Have benefit over and above blood pressure control. l Type I Diabetes: Captopril use associated with slower progression, less proteinuria without or without co-existing HTN (Lewis et al, 1993, Viberti et al, 1994) l Type II Diabetes: Enalapril use associated with slower progression, less proteinuria. (Ravid et al, 1993, 1996).

Management ACE Inhibitors l Nondiabetic disease: use of benazepril vs. placebo reduced by 38% the 3-yr progression of renal failure in various diseases. Reduction greater with higher proteinuria (Maschio et al, 1996). l Similar data emerging for angiotensin II receptor antagonists.

Management Calcium-Channel Blockers l No benefit with nondihydropyridine agents. l Diabetes: meta-analysis suggests Non- dihydropyridine blockers may have antiproteinuric effect (Gansevoort et al, 1995). l Would recommend as second-line agent behind ACE inhibitors.

Management Lipid Control l Hypoalbuminemia caused increased lipoprotein synthesis by the liver. l May increase cardiovascular morbidity/mortality. l Diabetes: small trial suggests that use of lovastatin has beneficial effect on rate of renal progression (Lam et al., 1995).

Management Glycemic Control l Type I diabetes: intensive glucose control (HbA1c < 7%) reduced microalbuminuria by 39% and frank albuminuria by 54% (DCCT Study, 1993). l Type II diabetes: some studies

Diabetic Nephropathy and Proteinuria l End stage renal disease is a major cause of death and disability among diabetics l Blood pressure reduction is an important initial step in slowing the progression of diabetic nephropathy l Randomized, blinded outcomes trials that demonstrate a clear renoprotective benefit of ACE inhibitors in diabetes have been conducted in type 1 diabetics l Three recently completed randomized blinded trials address the previously unanswered questions of whether ARBs delay the progression of diabetic nephropathy (RENAAL, IDNT) or reduce proteinuria (IRMA II) in patients with type 2 diabetes

ARBs in Type 2 DM With Nephropathy Progression of Renal Insufficiency Primary Endpoint: Composite of doubling of serum creatinine, end stage renal disease, or death Average Duration RENAAL (n=1,514) Losartan mg vs placebo*  16% (p=0.02) 3.4 yrs IDNT (n=1,715) Irbesartan mg vs placebo*  20% (p=0.02) 2.6 yrs Irbesartan mg vs Amlodipine*  23% (p=0.006) Brenner BM, et al. N Engl J Med. 2001;345(12): Lewis EJ, et al. N Engl J Med. 2001;345(12):

ARBs in Type 2 Diabetics Progression of Microalbuminuria† Primary Outcome: Development of clinical proteinuria‡ Duration IRMA II (n=590) Irbesartan 150mg vs placebo*  39% (P=0.080) 2 yrs Irbesartan 300mg vs placebo*  70% (P<0.001) † Albumin excretion rate of 20 to 200 g per minute in 2 of 3 consecutive, sterile, overnight urine samples ‡ Urinary albumin excretion rate >200 g per minute and at least 30% higher than baseline in at least 2 consecutive measurements *In combination with conventional antihypertensive therapy (excluding ACE inhibitors) Parving HH, et al. N Engl J Med. 2001;345(12): IRMA II=The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study

ARBs in Type 2 Diabetes and Nephropathy Summary of Findings (I) l RENAAL, IDNT and IRMA II present the strongest evidence to date for the efficacy of specific types of treatment to slow the progression of nephropathy in type 2 diabetes n The ARBs losartan and irbesartan compared to placebo* have been shown to reduce the progression of renal insufficiency beyond the benefit of similarly achieved blood pressures n Irbesartan compared to placebo* has been shown to reduce the progression of microalbuminuria to diabetic nephropathy Brenner BM, et al. N Engl J Med. 2001;345(12): Lewis EJ, et al. N Engl J Med. 2001;345(12): Parving HH, et al. N Engl J Med. 2001;345(12): *In combination with conventional antihypertensive therapy (excluding ACE inhibitors)

l Good blood pressure control in earlier studies has proven critical to slow the progression of nephropathy in type 2 diabetes l New guidelines for good blood pressure control are: –<130/80 mmHg (American Diabetes Association) –<125/75 mmHg for patients with renal insufficiency with greater than 1 g/d of proteinuria (JNC VI) l Multiple antihypertensive agents will be needed to achieve good blood pressure control l ARBs now are indicated for the treatment of type 2 diabetes with nephropathy ARBs in Type 2 Diabetes and Nephropathy Summary of Findings (II)

Management Dietary Protein Restriction l Experimental data suggests reduced metabolic load slows progression of disease. l Clinical data is underwhelming (MDRD*: no benefit seen except in secondary analysis). l Probably at most, a small benefit exists. l Must balance potential benefit of protein restriction with nutritional status. *Modification of Diet in Renal Disease Study

Management Supportive Care l Edema: Cause of significant morbidity. Rx- -diuretics, sodium restriction. l Thromboembolism in nephrotic syndrome: RVT* ~35% incidence, other complications ~20% incidence. Prophylactic anticoagulation not recommended. l Infection: may have low Ig levels, defective cell-mediated immunity. Consider Pneumovax. *Renal vein thrombosis

PROGNOSIS OF PERSISTENT PROTEINURIA

Prognosis l Diabetic nephropathy: progression to ESRD over years after onset of proteinuria. l Isolated non-nephrotic proteinuria: 20-yr follow-up shows incidence ~40% renal insufficiency, ~50% HTN. l Nephrotic syndrome: variable but poorer overall prognosis.

RECOMMENDATIONS

Recommendations Evaluation l R/O transient and orthostatic proteinuria. l Clinical evaluation for systemic diseases, medications, infections, and malignancies as causes of secondary glomerular disease. l Diabetics: regular screening for microalbuminuria, early use of ACE inhibitors/ARBs, early referral to nephrology.

Recommendations Non-specific Treatment l BP control: < 130/80 for nondiabetics, < 125/75 for diabetics. l Maximization of ACE inhibitors/AII receptor antagonists and non- dihydropyridine calcium-channel blockers as tolerated. l Lipid control: TChol < 200, LDL < 100 with HMG Co-A reductase inhibitors. l Glycemic control for diabetics: A1C < 7%.

Recommendations Treatment l Moderate dietary protein restriction: 0.8 mg/kg/day + urine protein losses, careful monitoring of nutritional status. l Edema: diuretics, sodium restriction l Specific immunosuppressive therapies for primary glomerular diseases as indicated.

TAKE HOME MESSAGE DON’T LET PERSISTENT PROTEINURIA GO UNQUANTIFIED OR UNEVALUATED!