Proteinuria Treatment & Management

Updated: Dec 14, 2021
  • Author: Beje Thomas, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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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

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.

As an example of specific treatment, sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin, empagliflozin) have gained wide use in the management of type 2 diabetes mellitus and have effects beyond glucose lowering that include reducing the risk of development or worsening of albuminuria. [35] A meta-analysis concluded that although SGLT2 inhibitors did not have a statistically significant effect on estimate glomerular filtration rate (eGFR) in patients with type 2 diabetes, compared with monotherapy, the combination of SGLT2 inhibitors with other hypoglycemic agents can reduce albuminuria levels (SMD - 0.13, 95% CI - 0.19, - 0.06, p <  0.0001). [36]

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, support 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. [37, 38]

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. A second dose of PPSV23 is given at least 5 years after the first. [39]


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:

  • Proteinuria
  • Presence or absence of other indicators of kidney disease
  • Complications of nephrotic syndrome
  • Treatment effectiveness
  • Adverse effects

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 [40] 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. [40, 41] These classes of drugs have a proteinuria-reducing effect independent of their antihypertensive effect. [42]

Other hemodynamic and nonhemodynamic effects of ACE inhibitors that may partly explain the renoprotective properties of these drugs include the following [43] :

  • Reduced breakdown of bradykinin (an efferent arteriolar vasodilator)
  • Restoration of size and charge selectivity to the GCW
  • Reduced production of cytokines that promote glomerulosclerosis and fibrosis, such as transforming growth factor (TGF)–beta.

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. [44]

Immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive kidney insufficiency or with vasculitic lesions on kidney biopsy. [45]


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.


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, 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. [46]

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. [47, 48]

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. [49, 50]  

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. [51] 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. [52]


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. [53, 54] Dyslipidemia usually improves once the proteinuria resolves or immunosuppression is started.



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. [55]  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). [56, 57]