Proteinuria Treatment & Management: Approach Considerations, Pharmacologic Therapy in Nonspecific Treatment, Treatment of Lipid Abnormalities (original) (raw)

Approach Considerations

Medical management of proteinuria has the following two components:

Nonspecific treatment includes renin-angiotensin-system inhibitors such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. These agents are indicated in patients with proteinuria, even those without diabetes.

Referral to a nephrologist is indicated for any patient who develops proteinuria, especially those with any adverse prognostic markers (eg, rise in albumin excretion of > 1 g/day), or any worsening in kidney function.

Infection concerns

Patients with nephrotic syndrome are at increased risk of infection. Both humoral and cell-mediated immunity are impaired, with renal losses of immunoglobulin and complement, as well as a decrease in the number of circulating T lymphocytes. The risk is greatest for bacterial infection, including spontaneous bacterial peritonitis. [39, 40] No data, however, support the routine use of prophylactic antibiotics or immunoglobulin infusions.

In 2022, the Advisory Committee on Immunization Practices (ACIP) updated its pneumococcal vaccine recommendations for pneumococcal vaccination. [41] Adults aged 19–64 years with nephrotic syndrome who have not previously received pneumococcal conjugate vaccine (PCV) or whose previous vaccination history is unknown should receive 1 dose of either 20-valent pneumococcal conjugate vaccine (PCV20) or 15-valent PCV (PCV15). When PCV15 is used, it should be followed by a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23). [42]

In 2023, the ACIP updated its pneumococcal vaccine recommendations for previously vaccinated adults aged ≥19 years with nephrotic syndrome, as follows [43, 41] :

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 the following 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 [44] 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 (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce intraglomerular pressure by inhibiting angiotensin II ̶ mediated efferent arteriolar vasoconstriction. [44, 45] These classes of drugs have a proteinuria-reducing effect independent of their antihypertensive effect. [46]

Other hemodynamic and nonhemodynamic effects of ACE inhibitors that may partly explain the renoprotective properties of these drugs include the following [47] :

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. The development of angioedema, which is due to the increase in bradykinin levels that accompany the use of ACE inhibitors, also warrants cessation of treatment. and substitution of an ARB. Patients who experience 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 therapy 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. [48]

Immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive kidney insufficiency or with vasculitic lesions on kidney biopsy. [49]

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 kidney injury 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 such as a thiazide and loop diuretic 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.

No randomized controlled trials support the use of prophylactic anticoagulation in patients with nephrotic syndrome. However, updated guidelines published by Kidney Disease–Improving Global Outcomes (KDIGO) in 2021 recommend prophylactic anticoagulation therapy based on high risk of thrombotic events and the risk of bleeding complications. Patients with nephrotic syndrome who have a low serum albumin level (< 2.5 g/dL) and a high bleeding risk should recieve aspirin and those with low bleeding risk should receive either warfarin or low-molecular weight heparin (LMWH) with aspirin. [1]

Calcium channel blockers

Non-dihydropyridine calcium channel blockers (NDCCBs), diltiazem and verapamil, have been shown to decrease proteinuria greater than dihydropyridine calcium channel blockers (DCCBs). The difference between the two is thought to stem from the fact that DCCBs affect only the afferent arteriole and not the efferent, whereas NDCCBs affect both. The effect of action on the afferent arteriole only is impaired autoregulation and increased intraglomerular pressure, leading to kidney damage.

L type calcium channels are found only in the proximal tuble and are the primary channel affected by DCCBs. However, N and T type calcium channes are found in both the afferent and efferent arteriole; the newer NDCCBs such as efonidipine and benedipine work on these channels. The newer NDCCBs, used in combination with ARBs, have been shown to reduce proteinuria. [50, 51]

Endothelin Antagonists

Renal inflammation and fibrosis has been associated with endothelin activation. Endothelin A (ETA) receptor activation leads to vasoconstriction in vascular smooth muscle. ETA blockade leads to dilation of the glomerular capillaries, decreasing the permeability of albumin. Endothelin B (ETB) decreases arterial pressure by inhibiting salt and water reabsorption in the kidneys. A trial of an experimental ETA-selective antagonist, avosentan, in patients with diabetic nephropathy showed a decrease in albuminuria, but with adverse effects including fluid retention and heart failure exacerbation. Atrasentan, another experimental ETA antagonist with a better adverse effect profile than avosentan, has also been shown to reduce proteinuria. [52, 53]

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. [54] 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. [55]

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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 proteinuria and hyperlipidemia may increase the risk for atherosclerotic disease, it should be treated in the same way as in the 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 and decrease levels of proteinuria. [56, 57] Dyslipidemia usually improves once the proteinuria resolves or immunosuppression is started.

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Diet

Sodium restriction

The glomerular capillary pressure can increase in the presence of high sodium intake. 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. [58] 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 as low as 40 mmol/day.

Protein restriction

The issue of dietary protein restriction is controversial. Evidence indicates that protein restriction may slow the rate of deterioration in the glomerular filtration rate 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). [59, 60]

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Author

Coauthor(s)

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

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: Astra Zeneca
Author for: UpToDate, ACP Smart Medicine, Elsevier, McGraw-Hill, Wolters Kluwer.

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