Nephrotic Syndrome Treatment & Management

Updated: Nov 23, 2021
  • Author: Ramapriya Sinnakirouchenan, MD, MBBS; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Approach Considerations

Specific treatment of nephrotic syndrome depends on its cause. These are detailed in the Medscape articles specific to each of these disorders. Treatment varies between adult and pediatric patients. Kidney Disease Improving Global Outcomes (KDIGO) issued guidelines in 2012 that include recommendations on treatment of nephrotic syndrome in adults and children. [43]

A study using the Cochrane database has put into question whether prednisone treatment is beneficial in adult minimal-change nephropathy. [44] Nevertheless, treatment is needed when the nephrotic syndrome causes illness such as uncomfortable edema or associated coagulopathy.

Moret et al reported that apheresis may result in remission of idiopathic nephrotic syndrome that fails to respond to pharmacologic treatment. In this retrospective study, which included 21 adult patients with focal segmental glomerulosclerosis or minimal change disease refractory to treatment with corticosteroids plus at least 1 immunosuppressive drug, 7 of the 21 patients were in complete or partial remission at 12 months follow-up. Factors significantly associated with achieving remission were need for dialysis before apheresis, age ≥50 years, a marked decrease in proteinuria, and a short time (< 12 months) between diagnosis and apheresis. [45]

The role of preventive anticoagulation in nephrotic syndrome has been reported, but there is no proof that it is beneficial.

Hyperlipidemia occurs in nephrotic syndrome, and it can be controlled with lipid-lowering agents (eg, statins—with the exception of rosuvastatin, which can worsen proteinuria [46] —bile acid sequestrants, fibrates, nicotinic acid and ezetimibe). In addition, lipoprotein apheresis, which is a second-line therapy for pediatric patients with focal segmental glomerulosclerosis, may yield clinical benefits in nephrotic syndrome. [47] Inhibitors of PCSK9 show promise as potential future therapy. [47, 46] However, the ideal therapeutic target is the proteinuria, given  the central role of proteinuria in the pathogenesis of lipid disorders in nephrotic syndrome. [46]

Specific treatment in children

For children with idiopathic nephrotic syndrome, corticosteroids are the mainstay of treatment. Alternative immunosuppressive agents (eg, cyclophosphamide, mycophenolate mofetil [MMF], calcineurin inhibitors, levamisole) are often used in children with steroid-dependent or frequently relapsing nephrotic syndrome. For steroid-resistant nephrotic syndrome, calcineurin inhibitors are the principal choice; children who fail to respond may be tried on agents such as MMF or prolonged and/or high-dose intravenous pulse corticosteroids. [48, 49, 50]

Rituximab, an antibody against B-cells, has proved an effective steroid-sparing agent in children with steroid-dependent idiopathic nephrotic syndrome. However, children dependent on both steroids and calcineurin inhibitors are less likely to achieve drug-free remission with rituximab. [51]  Rituximab may also be used in children with steroid-resistant disease. [48]

The benefits of rituximab for nephrotic syndrome were shown in a study in 10 children and 20 adults with minimal-change disease/mesangial proliferative glomerulonephritis or focal segmental glomerulosclerosis who had suffered two or more recurrences over the previous year and were in steroid-induced remission for 1 month or longer. At 1 year after receiving one or two doses of rituximab, all patients were in remission: 18 had been fully weaned from steroids and 15 had never relapsed. In addition, rituximab halted disease-associated growth deficit in the children. [52]

Maxted et al retrospectively compared 7 different rituximab dosing regimens—from 1 to 4 doses of 375 to 750 mg/m2—in 60 children with steroid-sensitive frequently relapsing nephrotic syndrome. Probability of relapse at 12 months or time to B cell reconstitution was not significantly different in children who received a single 375 mg/m2 dose than in those treated with a conventional higher dose. [53]

In children with complicated nephrotic syndrome with a history of steroid resistance who respond to rixubimab, Okutsu et al reported that an additional rituximab treatment at B cell recovery can maintain prolonged remission. The 50% relapse-free survival after B cell recovery was 954 days in the group that received prophylactic rituximab, versus 205.5 days in patients who did not (P = 0.003). [54]

A pilot study by Bonanni et al tested the new fully humanized anti-CD20 monoclonal antibody ofatumumab in four children with persistent proteinuria despite a full drug approach (including rituximab). The two patients with normal kidney function experienced remission of proteinuria—transient in one patient and persistent in the other—while the two with impaired kidney function failed to respond. This study used a low-dose two-infusion ofatumumab regimen (300+700 mg/1.73 m2 2 weeks apart); the authors suggest testing whether higher doses of ofatumumab may be effective in patients with renal impairment. [55]

In a retrospective study of 64 children with steroid-dependent nephrotic syndrome and 18 children with steroid-resistant nephrotic syndrome, treatment with cyclosporine alone or cyclosporine plus MMF resulted in remission in 14 of the 18 steroid-resistant patients (eight with cyclosporine and six with combination treatment). In the steroid-dependent group, 15 patients (23%) received no medication, cyclosporine was effective in 31 of 38 patients (82%), and MMF was effective in all patients in whom cyclosporine treatment was not successful. [56]

A Cochrane review of corticosteroid regimens in children with steroid-sensitive nephrotic syndrome concluded that continuing prednisone for more than 2 or 3 months after the initial episode offers no benefit. In addition, although corticosteroids are customarily given every other day in this setting, switching to daily dosing at the onset of an upper respiratory tract or viral infection reduces the risk of relapse. [57]

In pediatric patients with frequently relapsing nephrotic syndrome, an open-label randomized controlled trial by Yadav et al found low-dose daily dosing of prednisolone (0.2-0.3 mg/kg) was more effective than alternate-day dosing (0.5-0.7 mg/kg). Compared with patients on alternate-day therapy (n=31), patients receiving daily prednisolone (n = 30) showed significantly fewer relapses (0.55 versus 1.94 relapses/person-year), as well as higher rates of sustained remission at 1 year (60% versus 31.6%; P = 0.013), lower rates of treatment failure at 1 year (6.7 versus 57.4%; P <  0.0001), and lower prednisolone use (0.27 ± 0.07 versus 0.39 ± 0.19 mg/kg/day; P = 0.003). [58]

Congenital nephrotic syndrome (eg, from mutations in NPHS or WT1) is often treated with bilateral nephrectomy followed by dialysis and transplantation. However, Dufek et al reported that an individualized, stepwise approach with prolonged conservative management may also be effective. [59] The European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) have provided consensus recommendations for the management of congenital nephrotic syndrome. [60]

Specific treatment in adults

Treatment varies by etiology, as follows:

  • Minimal change nephropathy in adults should respond to prednisone. [61]
  • In lupus nephritis, prednisone with cyclophosphamide or mycophenolate mofetil should induce remission.
  • Secondary amyloidosis with nephrotic syndrome should improve with anti-inflammatory treatment of the primary disease.

Membranous nephropathy

In membranous nephropathy, management with angiotensin blockade but without immunosuppression can be used for the first 6 months in patients at low risk for progression (ie, those with serum creatinine level < 1.5 mg/dL and less than 4 g of proteinuria per day). Patients with renal insufficiency (serum creatinine level >1.5 mg/dL) or those with higher amounts of urine protein are at risk for loss of kidney function and should receive immunosuppressive therapy. [62]  This includes regimens that combine prednisone with cyclophosphamide or chlorambucil. Mycophenolate mofetil is not helpful in membranous nephropathy.

Rituximab is effective in membranous nephropathy in adults. In the randomized MENTOR trial, which compared rituximab with cyclosporine in 130 patients with membranous nephropathy and nephrotic syndrome who had been receiving angiotensin blockade for at least 3 months, rituximab proved noninferior. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission; at 24 months, the remission rate was unchanged in the rituximab group but had decreased to 20% (13 of 65 patients) in the cyclosporine group. [63, 35]


Acute Nephrotic Syndrome in Childhood

With good parental and patient education and close outpatient follow-up care, hospitalization is not usually necessary. Hospitalization should be considered if any of the following are present:

  • Generalized edema severe enough to cause respiratory distress
  • Tense scrotal or labial edema
  • Complications such as bacterial sepsis, peritonitis, pneumonia, or thromboembolism
  • Failure to thrive
  • Uncertainty regarding patient or family compliance with treatment

Diuretics are needed. Furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) will help when fluid retention is severe, provided no signs of renal failure or volume contraction are evident.

Achieving a satisfactory diuresis is difficult when the patient's serum albumin level is less than 1.5 g/dL. Albumin in a dose of 1 g/kg may be given intravenously (IV), followed by IV furosemide. Use of this approach is based on the premise that raising the serum albumin level will ‘pull’ fluid from the extravascular to the intravascular space. Albumin may also increase diuretic delivery to the kidney by keeping furosemide within the vascular space, decreasing its catabolism and facilitating its secretion into the tubular lumen.

Complications of using IV albumin may occur, including pulmonary edema. In addition, some evidence suggests that administration of albumin may delay the response to steroids and may even induce more frequent relapses, probably by causing severe glomerular epithelial damage. Fluid removal and weight loss remain transient unless proteinuria remits.

To prevent infection, oral penicillin can be prescribed for children with gross edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis, and any bacterial infection should be treated promptly. A non-immune patient with varicella should get immunoglobulin therapy if exposed to chickenpox, and acyclovir should be given if the patient develops chickenpox.

Depending on the cause of nephrotic syndrome, a patient may need specialty consultation. For example, an individual with lupus nephritis will benefit from rheumatologic consultation.


Acute Nephrotic Syndrome in Adults

The principles for management of adults with acute nephrotic syndrome are similar to those for children. Diuretics will be needed; furosemide, spironolactone, and even metolazone may be used. Volume depletion may occur with diuretic use, which should be monitored by assessment of symptoms, weight, pulse, and blood pressure.

Anticoagulation has been advocated for use in preventing thromboembolic complications, but its use in primary prevention is unproven.

Hypolipidemic agents may be used. If the nephrotic syndrome cannot be controlled, the patient will have persistent hyperlipidemia.

In secondary nephrotic syndrome, such as that associated with diabetic nephropathy, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers are widely used. These may reduce proteinuria by reducing the systemic blood pressure, by reducing intraglomerular pressure, and also by direct action on podocytes.


Diet and Activity

The diet in patients with nephrotic syndrome should provide adequate caloric intake and adequate protein (1 g/kg/d). Supplemental dietary protein is of no proven value.

A low-salt diet will limit the fluid retention and edema that occurs in nephrotic syndrome. A 24-hour urine collection is useful to quantify dietary intake of sodium. More than 88 mEq/day in the 24-hour urine suggests high salt intake. The help of a dietician will be useful to bring the daily sodium intake down to 2 g (88 mEq)/day or less. Fluid restriction per se is not needed.

There are no activity restrictions for patients with nephrotic syndrome. Ongoing activity, rather than bedrest, will reduce the risk of blood clots.


Long-Term Monitoring

Ongoing use and adjustment of diuretics and angiotensin antagonists are done according to the amount of edema and proteinuria that a patient has.

Follow-up care in patients with nephrotic syndrome also includes immunizations and monitoring for corticosteroid toxicity.

Routine immunizations should be delayed until the patient is free of relapses and has been off immunosuppression for 3 months. [64] Pneumococcal and influenza vaccines are recommended but are not routinely used, because their efficacy is not established. [65, 66] Children who have received immunosuppressive therapy in the preceding 3 months and are not immune to varicella should receive zoster immunoglobulin if they are exposed to chickenpox or shingles. These patients should also receive acyclovir if they develop chickenpox. [67]

Monitoring for steroid toxicity every 3 months in the outpatient clinic will detect adverse effects such as slowing of growth. Supplemental calcium and vitamin D may attenuate bone loss. A yearly checkup will detect cataracts. [68]