Obtain SCr and K levels 7–10 days later after initiation of an ACEI or ARB and with changes in anti-RAAS therapy. • Increases of SCr 30% above baseline within 3 months of initiating anti-RAAS therapy may be acceptable. Greater elevations should be thoroughly investigated and may require nephrological consultation. • For baseline SCr 2.0 mg/dL, SCr increases 1.0 mg/dL may be tolerated. • Avoid sole use of dihydropyridine CCBs in proteinuric CKD patients. • Initial SBP: if 150 mmHg, begin 2-drug regimens, eg, ACEI/thiazide, ARB/thiazide, or ACEI/CCB in patients on no medications. • Sodium: intake >100 mEq/d and/or ineffective diuretic treatment are common causes of “resistant” HTN. High sodium intake reduces effectiveness of antihypertensive therapies and is determined best by a 24-h urine sodium collection. AHA sodium limit is 1500 mg/d. 22 • Loop diuretics should be generally be used twice daily, in the morning and in the mid- to late-afternoon. Once daily dosing is often ineffective due to compensatory stimulation of the RAAS with sodium retention. • Thiazide diuretics are generally ineffective, if SCr is >1.7 mg/dL or, if the eGFR is 10 mg/g) is associated with adverse cardiovascular outcomes. While ACEI (angiotensin-converting–enzyme inhibitor) and/or ARB (angiotensin-receptor blocker) therapies reduce albuminuria and are associated with reduced risk for developing ESRD (especially in diabetes and hypertension), they are underutilized. Ideally, 70% or more of patients should be treated with these drugs. Types of Proteinuria Traditionally, normal urinary protein excretion is considered to be 300 mg/g). Notably, a new classification system that eschews the terms micro- and macroalbuminuria may be established in the near future. Quantitative urinary protein (principally albuminuria) testing by UPC or UACR is recommended within 3 months of documentation of 1+ proteinuria by dipstick analysis. Two or more positive quantitative tests, preferably on first morning urine specimens, should be documented before diagnosing persistent proteinuria (see CKD PROTEINURIA EVALUATION, P. 27). The urine dipstick favors albumin detection and is relatively insensitive for tubular proteinuria, eg, immunoglobulin light chains. If tubular proteinuria is suspected, specific qualitative and quantitative examinations may be required, eg, serum free light chain analysis (Freelite™) and serum and urine immunofixation. For screening purposes, a 24-h urine is unnecessary, but if a serum monoclonal protein is detected, a 24-h urine collection for immunofixation is indicated. Consultation with a clinical laboratory expert is advised to optimize diagnostic yield in such cases. Anti-Proteinuric Therapy Anti-proteinuric therapy reduces tubulointerstitial fibrosis and thus, progression of CKD. Patients with stable, persistent proteinuria of 2 g/m2 /d; 3.0–3.5 g/24-h in adults) has an ominous prognosis and is associated with edema, hypercholesterolemia, hypoalbuminemia, anemia, lipiduria, vitamin D deficiency, and greater risk for progression to ESRD. Irrespective of the degree of proteinuria, all therapies that reduce proteinuria should be optimized for BP control of 0.5 g/d of proteinuria, UPCs >0.22, or microalbuminuria by UACR. The anti-RAAS therapies exert differential, beneficial effects on glomerular structural proteins, intraglomerular pressures, local and systemic sympathetic nervous systems, inflammatory pathways, and the systemic blood pressure. Notably, no specific agent reduces tubular proteinuria. Recently, aldosterone receptor antagonists (ARAs) and direct renin inhibitors (DRIs) have demonstrated anti-proteinuric properties. Non-dihydropyridine CCB (calcium channel blockers), diltiazem and verapamil, also reduce proteinuria and complement the anti-RAAS agents. Combinations of such agents (ACEI + ARB) frequently reduce proteinuria by an additional 25– 40%. However, dual-agent anti-RAAS therapies involving ACEIs or ARBs (VA NEPHRON-D) with other antiproteinuric agents, eg, (ACEI or ARB) + ARA or (ACEI or ARB) + DRI (ALTITUDE) should be initiated and monitored by a nephrologist. The goal of attaining target BP supersedes additional use of antiproteinuric agents. Recent data suggest that pentoxifylline and HMG-Co synthetase inhibitors, simvastatin and atorvastatin, may reduce proteinuria. 26 Finally, high sodium intake and poor glycemic control may retard BP-lowering and proteinuriareducing effects of antihypertensive agents. Sodium intake of 1500 mg daily is recommended for patients with CKD. Therapeutic Targets for Proteinuria Reduction UPC 7), gross hematuria, mucus, semen, leukocytes, radiocontrast, exogenous creatine supplementation, and contamination by certain cleansing solutions, eg, chlorhexidine or benzalkonium. • Optimal timing of urine protein determination is the first morning void following recumbency, which should help rule out orthostatic proteinuria. • UPC and UACR tests may underestimate protein excretion in muscular patients, but may overestimate excretion in cachectic patients. REFERENCES 1. G Leoncini, et al. J Hypertens 20: 1315, 2002 2. P Muntner, et al. J Am Soc Nephrol 13: 745, 2002 3. G Remuzzi, et al. New Engl J Med 346: 1145, 2002 4. S Bianchi S, et al. Am J Kidney Dis 41: 565, 2003 5. N Boudville, et al. Am J Hypertens 18: 1300, 2005 6. JA Katzmann JA.