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Proteinuria Treatment & Management

  • Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Dec 10, 2015
 

Approach Considerations

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.

Infection concerns

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.[23]

Inpatient care

Inpatient care is necessary only if the patient develops complications of severe nephrotic syndrome.

Follow-up

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.

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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[24] 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.[26]

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.[27]

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.[28]

Diuretics

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.

Anticoagulants

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.[29] 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.[30]

 

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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.

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Diet

Sodium restriction

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.[33]

Protein restriction

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]

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Contributor Information and Disclosures
Author

Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF Clinical Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Research Director, Internal Medicine Training Program, Advocate Christ Medical Center; Consulting Staff, Associates in Nephrology, SC

Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF is a member of the following medical societies: American Heart Association, American Medical Association, American Society of Hypertension, American Society of Nephrology, Chicago Medical Society, Illinois State Medical Society, National Kidney Foundation, Society of General Internal Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Otsuka, Mallinckrodt, ZS Pharma<br/>Author for: UpToDate, ACP Smart Medicine.

Coauthor(s)

Tejas Desai, MD Staff Nephrologist, WG (Bill) Hefner VA Medical Center

Tejas Desai, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology

Disclosure: Nothing to disclose.

Pankaj Jawa, MD Assistant Professor of Medicine, Division of Nephrology and Hypertension, The Brody School of Medicine at East Carolina University

Pankaj Jawa, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Transplantation, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Kevin McLaughlin, MBChB, PhD, MSc Associate Professor, Assistant Dean, Department of Medicine, University of Calgary Faculty of Medicine, Calgary Health Region

Kevin McLaughlin, MBChB, PhD, MSc is a member of the following medical societies: American Society of Nephrology, American Society of Transplantation, and College of Physicians and Surgeons of Alberta

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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