Proteinuria Treatment & Management
- Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Medical management of proteinuria has the following two components:
Nonspecific treatment - Treatment that is applicable irrespective of the underlying cause, assuming the patient has no contraindications to the therapy
Specific treatment - Treatment that depends on the underlying renal or nonrenal cause and, in particular, whether or not the injury is immune mediated
If a patient is not being monitored by a nephrologist, transfer to a nephrologist is indicated if he or she develops proteinuria, any adverse prognostic markers (eg, rise in albumin excretion of > 1 g/day), or any worsening in renal function.
Patients with nephrotic syndrome are at increased risk of infection. The risk is greatest for bacterial infection (including spontaneous bacterial peritonitis) due to renal losses of immunoglobulin and complement components. No data, however, advocates the routine use of prophylactic antibiotics or immunoglobulin infusions.
Patients with nephrotic syndrome are at increased risk of infection. Both humoral and cell mediated immunity are affected. Renal losses of immunoglobulin and complement, as well as a decrease in the number of circulating T lymphocytes, place nephrotic patients at a very high risk for bacterial infection, including spontaneous bacterial peritonitis.[21, 22]
No data support the routine use of prophylactic antibiotics or immunoglobulin infusions. However, the Advisory Committee on Immunization Practices (ACIP) recommends immunization with 13-valent pneumococcal conjugate vaccine (PCV13), followed by a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) at least 8 weeks later, in patients with nephrotic syndrome.
Inpatient care is necessary only if the patient develops complications of severe nephrotic syndrome.
Patients may require regular follow-up care by a family physician, general internal medicine specialist, or nephrologist, depending on the cause and setting of proteinuria. Monitoring of proteinuria, the presence or absence of other indicators of renal disease, complications of nephrotic syndrome, treatment effectiveness, and adverse effects is required.
Pharmacologic Therapy in Nonspecific Treatment
ACE inhibitors and ARBs
The degree of proteinuria depends on the integrity (charge and size selectivity) of the glomerular capillary wall (GCW) and the intraglomerular pressure. Intraglomerular pressure is controlled by the afferent arteriole, which transmits systemic blood pressure to the glomerulus, and the efferent arteriole.
Normalization of systemic blood pressure in a patient with hypertension should result in a reduction in intraglomerular pressure and a fall in albuminuria.
Some vasodilatory antihypertensives (eg, hydralazine, nifedipine) dilate the afferent arteriole, which may attenuate the reduction in intraglomerular pressure despite the fall in arterial blood pressure. As a consequence, these agents may not reduce proteinuria to the same degree, particularly if systemic blood pressure is not adequately reduced at the same time that the afferent arteriole is dilated.
Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure by inhibiting angiotensin II ̶ mediated efferent arteriolar vasoconstriction.[24, 25] These groups of drugs have a proteinuria-reducing effect independent of their antihypertensive effect.
Other hemodynamic and nonhemodynamic effects of ACE inhibitors may partly explain the renoprotective properties of this group of drugs, such as reduced breakdown of bradykinin (an efferent arteriolar vasodilator), restoration of size and charge selectivity to the GCW, and reduced production of cytokines that promote glomerulosclerosis and fibrosis, such as transforming growth factor (TGF)–beta.
Target blood pressure is less than 125/75 mm Hg. The dose of ACE inhibitor should be increased as tolerated until this blood pressure is achieved.
Normotensive patients with proteinuria also should be given ACE inhibitors, because low doses usually are well tolerated and do not usually cause symptomatic hypotension.
Patients who develop adverse effects from ACE inhibitors, such as cough, should be given an ARB. Patients also may develop angioedema, due to the increase in bradykinin levels that accompany the use of ACE inhibitors. This adverse effect also warrants cessation of treatment. An ARB may be used instead. Patients with mild hyperkalemia should receive dietary counseling. Those with significant hyperkalemia should have the medication immediately discontinued and should be treated with a potassium-binding resin.
When treatment with an ACE inhibitor or ARB does not adequately control proteinuria in a patient with chronic kidney disease (eg, diabetic nephropathy), a further reduction in proteinuria can be achieved by adding a mineralocorticoid receptor antagonist (MRA) such as eplerenone or spironolactone. However, MRA is associated with a three- to eightfold increased risk for hyperkalemia. In a phase 2 trial of finerenone, a nonsteroidal MRA, this new agent reduced proteinuria while producing lower rates of hyperkalemia than have been seen with other MRAs.
Patients with moderate to severe proteinuria are usually fluid overloaded and require diuretic therapy along with dietary salt restriction. In spite of good kidney function, these patients may not respond to normal doses of diuretics and may require increased doses for the drug to be delivered to renal tubule.
If fluid overload becomes refractory to therapy with a single diuretic agent, a combination of diuretics acting at different sites of the nephron can be tried. If the edema is due to marked hypoalbuminemia, aggressive diuresis may put the patient at risk of acute renal failure due to intravascular volume depletion.
The routine use of albumin infusion combined with diuretics is not advocated in patients with nephrotic syndrome. Treatment with a loop diuretic or a combination of diuretics produces diuresis in most patients. The addition of albumin may improve natriuresis in patients with refractory salt and water retention, but the potential benefits must be weighed against the cost and risks of albumin infusion, which include the possibility of exacerbating fluid overload.
Patients with proteinuria tend to be hypercoagulable due to urinary losses of coagulation inhibitors, such as antithrombin III and protein S and C. The risk of thrombosis appears to be highest in patients with membranous glomerulonephritis. Numerous case reports have described renal vein thrombosis (which usually presents as acute onset of gross hematuria and back pain) in patients with membranous glomerulonephritis.
There are no randomized controlled trials supporting the use of prophylactic anticoagulation in patients with nephrotic syndrome. However, guidelines published by Kidney Disease – Improving Global Outcomes (KDIGO) in 2012 recommend treatment with warfarin in patients with nephrotic syndrome who have a low serum albumin level (<2.5 g/dL), especially if the patient has other risk factors for thrombosis.
Vitamin D and proteinuria
In animal studies, vitamin D and vitamin D analogues decrease inflammatory mediators and may act as immunosuppressive agents. Vitamin D may play a role in down-regulating prorenin gene expression and thereby enhancing renin-angiotensin-aldosterone system (RAAS) blockade.
A randomized controlled trial showed a reduction in proteinuria of around 20% in diabetic patients with paricalcitol. A similar conclusion was reached in a systematic review by Borst et al, which found that treatment with active vitamin D reduced proteinuria even in the setting of RAAS blockade in most patients.
Treatment of Lipid Abnormalities
Lipid abnormalities are quite common in patients with nephrotic syndrome. No evidence-based recommendations are available for the treatment of hyperlipidemia associated with nephrotic syndrome. Since, the presence of proteinuria and hyperlipidemia may increase the risk for atherosclerotic disease, it should be treated in the same way as general population.
Dietary measures are usually not very effective and most of these patients do require medication. The treatment of choice is statin therapy. Some studies have reported statins to be renoprotective.[31, 32] Dyslipidemia usually improves once the proteinuria resolves or immunosuppression is started.
Patients with nephrotic syndrome and fluid overload should have a salt-restricted diet. A "no-added-salt" diet usually is sufficient, although some patients may need restrictions of up to 40 mmol/day.
Vegter et al found that for nondiabetic patients with chronic kidney disease, high dietary salt (>14 g daily) appeared to blunt the antiproteinuric effect of ACE-inhibitor therapy and increase the risk for end-stage renal disease, independent of blood pressure control.
The issue of dietary protein restriction is controversial. Evidence indicates that protein restriction may slow the rate of deterioration in the GFR in patients with glomerular diseases, including diabetic nephropathy. The presumed mechanism is a reduction in intraglomerular pressure.
However, concern exists that protein-restricted diets may increase the risk of protein malnutrition. Other methods of reducing intraglomerular pressure, such as the use of ACE inhibitors, may be safer than protein restriction. Most nephrologists recommend no restrictions or only mild restriction in protein intake (0.8-1 g/kg daily).[34, 35]
Springberg PD, Garrett LE Jr, Thompson AL Jr. Fixed and reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med. 1982 Oct. 97(4):516-9. [Medline].
Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, et al. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int. 2004 Jan. 65(1):30-9. [Medline].
Eremina V, Baelde HJ, Quaggin SE. Role of the VEGF--a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol. 2007. 106(2):p32-7. [Medline].
Schlöndorff D, Banas B. The mesangial cell revisited: no cell is an island. J Am Soc Nephrol. 2009 Jun. 20(6):1179-87. [Medline].
Burton C, Harris KP. The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis. 1996 Jun. 27(6):765-75. [Medline].
Hebert LA, Birmingham DJ, Shidham G, et al. Random spot urine protein/creatinine ratio is unreliable for estimating 24-Hour proteinuria in individual systemic lupus erythematosus nephritis patients. Nephron Clin Pract. 2009 Aug 12. 113(3):c177-c182. [Medline]. [Full Text].
Jones CA, Francis ME, Eberhardt MS, Chavers B, Coresh J, Engelgau M, et al. Microalbuminuria in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2002 Mar. 39(3):445-59. [Medline].
Bryson CL, Ross HJ, Boyko EJ, Young BA. Racial and ethnic variations in albuminuria in the US Third National Health and Nutrition Examination Survey (NHANES III) population: associations with diabetes and level of CKD. Am J Kidney Dis. 2006 Nov. 48(5):720-6. [Medline].
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7. 298(17):2038-47. [Medline].
Friedman DJ, Kozlitina J, Genovese G, Jog P, Pollak MR. Population-Based Risk Assessment of APOL1 on Renal Disease. J Am Soc Nephrol. 2011 Nov. 22(11):2098-105. [Medline].
Ruggenenti P, Perna A, Mosconi L. Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). Kidney Int Suppl. 1997 Dec. 63:S54-7. [Medline].
Jackson CE, Solomon SD, Gerstein HC, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet. 2009 Aug 15. 374(9689):543-50. [Medline].
Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, et al. Microalbuminuria, cardiovascular risk factors and cardiovascular morbidity in a British population: the EPIC-Norfolk population-based study. Eur J Cardiovasc Prev Rehabil. 2004 Jun. 11(3):207-13. [Medline].
Rein P, Saely CH, Zanolin D, Vonbank A, Drexel H. Albuminuria significantly predicts cardiovascular events in patients with type 2 diabetes independently from the baseline coronary artery state. European Heart Journal. Available at http://eurheartj.oxfordjournals.org/content/34/suppl_1/P5175. Accessed: November 12, 2014.
Ruggenenti P, Porrini E, Motterlini N, Perna A, Ilieva AP, Iliev IP, et al. Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes. J Am Soc Nephrol. 2012 Oct. 23(10):1717-24. [Medline]. [Full Text].
Chiu YW, Adler SG, Budoff MJ, et al. Coronary artery calcification and mortality in diabetic patients with proteinuria. Kidney Int. 2010 Mar 17. [Medline].
Sandsmark DK, Messé SR, Zhang X, Roy J, Nessel L, Lee Hamm L, et al. Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease: Chronic Renal Insufficiency Cohort Study. Stroke. 2015 Aug. 46 (8):2075-80. [Medline].
Methven S, Macgregor MS, Traynor JP, et al. Assessing proteinuria in chronic kidney disease: protein-creatinine ratio versus albumin-creatinine ratio. Nephrol Dial Transplant. 2010 Mar 17. [Medline].
Cirillo M. Evaluation of glomerular filtration rate and of albuminuria/proteinuria. J Nephrol. 2010 Mar-Apr. 23(2):125-32. [Medline].
Krensky AM, Ingelfinger JR, Grupe WE. Peritonitis in childhood nephrotic syndrome: 1970-1980. Am J Dis Child. 1982 Aug. 136(8):732-6. [Medline].
Chapman S, Taube D, Brown Z, Williams DG. Impaired lymphocyte transformation in minimal change nephropathy in remission. Clin Nephrol. 1982 Jul. 18(1):34-8. [Medline].
Pneumococcal ACIP Vaccine Recommendations. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/pneumo.html. Accessed: November 13, 2014.
Roozbeh J, Banihashemi MA, Ghezlou M, et al. Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. Ren Fail. 2010 Jan. 32(2):172-8. [Medline].
Robles NR, Romero B, de Vinuesa EG, et al. Treatment of proteinuria with lercanidipine associated with renin-angiotensin axis-blocking drugs. Ren Fail. 2010 Jan. 32(2):192-7. [Medline].
Lewis EJ, Hunsicker LG, Bain RP. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group [published erratum appears in N Engl J Med 1993 Jan 13;330(2):152]. N Engl J Med. 1993 Nov 11. 329(20):1456-62. [Medline].
Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. ALYSIS. 1997 Sep 1. 127(5):337-45. [Medline].
Bakris GL, et al; Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA. 2015 Sep 1. 314 (9):884-94. [Medline].
de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010 Nov 6. 376(9752):1543-51. [Medline].
de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ. Active vitamin D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol. 2013 Nov. 24(11):1863-71. [Medline]. [Full Text].
Nakamura T, Sato E, Fujiwara N, et al. Co-administration of ezetimibe enhances proteinuria-lowering effects of pitavastatin in chronic kidney disease patients partly via a cholesterol-independent manner. Pharmacol Res. 2009 Aug 7. [Medline].
Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis. 2003 Mar. 41(3):565-70. [Medline].
Vegter S, Perna A, Postma MJ, et al. Sodium Intake, ACE Inhibition, and Progression to ESRD. J Am Soc Nephrol. 2012 Jan. 23(1):165-73. [Medline].
Klahr S, Levey AS, Beck GJ. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994 Mar 31. 330(13):877-84. [Medline].
Robertson L, Waugh N, Robertson A. Protein restriction for diabetic renal disease. Cochrane Database Syst Rev. 2007 Oct 17. CD002181. [Medline].
Burton C, Harris KP. The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis. 1996 Jun. 27(6):765-75. [Medline].
Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient. Kidney Int. 2012 Oct. 82(8):840-56. [Medline].
Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int. 1980 Sep. 18(3):395-406. [Medline].
Wu Y, Chen Y, Chen D, et al. Presence of foam cells in kidney interstitium is associated with progression of renal injury in patients with glomerular diseases. Nephron Clin Pract. 2009 Aug 12. 113(3):c155-c161. [Medline].