Medication Summary
Corticosteroids (prednisone), cyclophosphamide, and cyclosporine are used to induce remission in nephrotic syndrome. Diuretics are used to reduce edema. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers can reduce proteinuria.
Treatment should be dictated by the type of renal pathology causing nephrotic syndrome.
Minimal-change disease has an excellent response to corticosteroids, while in focal glomerulosclerosis, only 20% of patients respond well to corticosteroids. Kidney biopsy is very helpful to differentiate minimal-change disease and its variants such as IgM nephropathy and C1q nephropathy. Very few randomized trials are available to guide treatment for minimal-change disease in adults. Prednisone in short courses from 12-20 weeks’ duration remains the mainstay of treatment for patients with minimal-change disease.
Immunosuppressive medications other than steroids are usually reserved for patients with steroid-resistant disease with persistent edema, or for steroid-dependent patients with significant steroid-related adverse effects.
Cyclophosphamide may benefit patients who have frequently relapsing steroid-sensitive nephrotic syndrome. Associated complications include bone marrow suppression, hair loss, reduced sperm counts, hemorrhagic cystitis, malignancy, and infertility.
Cyclosporine is indicated when relapses occur after cyclophosphamide treatment. Cyclosporine may be preferable in a pubertal male who is at risk of developing cyclophosphamide-induced azoospermia. Cyclosporine is a highly effective maintenance therapy for patients with steroid-sensitive nephrotic syndrome who are able to stop steroids or take lower doses, but some evidence suggests that although remission is maintained as long as cyclosporine is administered, relapses are frequent when treatment is discontinued. However, cyclosporine can be nephrotoxic and can cause hirsutism, hypertension, and gingival hypertrophy.
For focal glomerulosclerosis, prednisone, cyclosporine, and cyclophosphamide have all been used in treatment. Corticosteroids should be the first-line agent, with cyclophosphamide or cyclosporine as backup for steroid-resistant cases. Mycophenolate and rituximab have also been used in treating focal glomerulosclerosis. However, data on the use of these latter two agents are not convincing.
For idiopathic membranous nephropathy, prednisone along with chlorambucil or cyclophosphamide remains important for treatment. Other agents that have been used include cyclosporine, synthetic corticotropin, and rituximab.
A Cochrane review of immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome concluded that combination treatment with an alkylating agent and a corticosteroid has both short- and long-term benefits, and that cyclophosphamide is a safer alkylating agent than chlorambucil. Cyclosporine or tacrolimus are recommended as alternatives. [73]
Rituximab has been effective in some cases of nephrotic syndrome that relapse after prednisone treatment or in cases resistant to prednisone treatment. [74] This drug is a chimeric murine/human antibody against the CD20 antigen of B cells. It presumably exerts its benefit by suppressing antibody production. Its adverse effect to cause immunosuppression cannot be ignored.
Natural, highly purified corticotropin gel formulation (repository corticotropin injection) is also a potential treatment option for steroid-resistant nephrotic syndrome and has shown some results in reducing proteinuria. However, reported data are based solely on retrospective and observational studies, and, hence, this therapy should be tested further in controlled trials. [75, 76] The mechanism by which this drug decreases proteinuria is unclear. It is presumed to have an anti-inflammatory action. Its adverse effect profile is similar to steroids, but the most striking disadvantage is its cost.
Corticosteroids
Class Summary
Corticosteroids have anti-inflammatory properties and modify the body's immune response to diverse stimuli.
Prednisone
Prednisone is an immunosuppressant used in treatment of autoimmune disorders. This agent may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. It may be administered as a single dose in the morning or as divided doses; once-daily dosing is equally effective and greatly improves compliance.
Immunomodulators
Class Summary
These agents regulate key steps of the immune system.
Cyclophosphamide
Cyclophosphamide is a cyclic polypeptide that suppresses some humoral immune activity. It is chemically related to nitrogen mustards. In the liver, this agent is biotransformed by the cytochrome P-450 system to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which interferes with growth of normal and neoplastic cells.
The mechanism of action of cyclophosphamide in autoimmune diseases is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.
In high doses, cyclophosphamide affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, it affects T cell functions.
Cyclophosphamide has been successfully used in conditions that require immunosuppression. It is effective for frequently relapsing steroid-sensitive nephrotic syndrome.
Cyclosporine (Sandimmune, Neoral, Gengraf)
Cyclosporine is a cyclic polypeptide that suppresses cell-mediated immune reactions. Tacrolimus (Prograf) has a similar effect. [52, 53]
For children and adults, base dosing on ideal body weight
Rituximab (Rituxan)
Rituximab is a chimeric humanized murine monoclonal antibody against CD20 antigen found on the surface of lymphocytes.
Immunosuppressants
Mycophenolate (CellCept, Myfortic)
Mycophenolate inhibits inosine monophosphate dehydrogenase and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production.
Diuretics
Class Summary
These agents are used for symptomatic treatment of edema.
Furosemide (Lasix)
Furosemide increases urine output by inhibiting sodium transport in the ascending loop of Henle . The dose must be individualized. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs.
Spironolactone (Aldactone)
Spironolactone is used for management of edema resulting from excessive aldosterone excretion. It competes with aldosterone for receptor sites in the distal nephron, thus enhancing sodium excretion.
Angiotensin-converting Enzyme (ACE) Inhibitors
Class Summary
ACE inhibitors block conversion of angiotensin I to angiotensin II and prevent secretion of aldosterone from the adrenal cortex.
Captopril
Captopril inhibits angiotensin converting enzyme (ACE), which blunts the conversion of angiotensin I to angiotensin II, resulting in less vasoconstriction and lower aldosterone secretion.
Enalapril (Vasotec)
Enalapril inhibits angiotensin converting enzyme (ACE), which blunts the conversion of angiotensin I to angiotensin II, resulting in less vasoconstriction and lower aldosterone secretion.
Lisinopril (Prinivil, Zestril)
Lisinopril inhibits angiotensin converting enzyme (ACE), which blunts the conversion of angiotensin I to angiotensin II, resulting in less vasoconstriction and lower aldosterone secretion.
Angiotensin II receptor antagonists
Class Summary
ARBs antagonize the action of angiotensin II at the type 1 receptor, reducing systemic arterial blood pressure and blunting the intrarenal effect of angiotensin II. If ACE inhibitors cause cough, ARBs may be substituted.
Valsartan (Diovan)
Valsartan directly antagonizes type 1 angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. It does not affect bradykinin and is less likely to be associated with cough and angioedema. Valsartan is useful in patients who are unable to tolerate ACE inhibitors.
Losartan (Cozaar)
Losartan directly antagonizes type 1 angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. It does not affect bradykinin and is less likely to be associated with cough and angioedema. Valsartan is useful in patients who are unable to tolerate ACE inhibitors.
Adrenocorticotropic Hormone (ACTH) Analogue
Class Summary
Consider use of corticotropin to induce diuresis or a remission of proteinuria.
Corticotropin (HP Acthar Gel)
HP Acthar Gel is a synthetic corticotropin that stimulates corticotropin production. It may induce remission of proteinuria in nephrotic syndrome.
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Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Courtesy of the American Physiological Society (www.the-aps.org) and reproduced from Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008 Apr;88(2):451-87.
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Incidence of important causes of nephrotic syndrome, in number per million population. The left panel shows systemic causes, and the right panel lists primary renal diseases that can cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy, min change = minimal-change nephropathy. Data are in part from Swaminathan et al and Bergesio et al.
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A schema of the average patient age at presentation in various common forms of nephrotic syndrome. (Timeline not to scale.)
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Forces determining capillary filtration
