in Adults: Diagnosis and Management CHARLES KODNER, MD, University of Louisville School of Medicine, Louisville, Kentucky

Nephrotic syndrome may be caused by primary (idiopathic) renal disease or by a variety of secondary causes. Patients present with marked , proteinuria, , and often hyperlipidemia. In adults, mellitus is the most common secondary cause, and focal segmental and membranous nephropathy are the most common pri- mary causes. Venous thromboembolism is a possible ; acute renal failure and serious bacterial infection are also possible, but much less common. There are no established guidelines on the diagnostic workup or management of nephrotic syndrome. Imaging stud- ies are generally not needed, and blood tests should be used selectively to diagnose specific disorders rather than for a broad or unguided workup. may be useful in some cases to confirm an underlying disease or to identify idiopathic disease that is more likely to respond to corticosteroids. Treatment of most patients should include fluid and sodium restric- tion, oral or intravenous diuretics, and angiotensin-converting enzyme inhibitors. Some adults with nephrotic syndrome may benefit from corticosteroid treatment, although research data are limited. Intravenous , prophylactic , and prophylactic anticoagulation are not currently recommended. (Am Fam Physician. 2009;80(10):1129-1134, 1136. Copyright © 2009 American Academy of Family Physicians.)

▲ 2 Patient information: n nephrotic syndrome, a variety of dis- idiopathic nephrotic syndrome. Other A handout on nephrotic orders cause proteinuria, often resulting conditions, such as membranoprolifera- syndrome, written by the in marked edema and hypoalbumin- tive , are less common. author of this article, is provided on page 1136. emia. Hyperlipidemia is a common FSGS accounts for approximately 3.3 per- I associated finding. Family physicians may cent of new cases of end-stage renal dis- 2 encounter persons with nephrotic syndrome ease. A large number of secondary causes This clinical content con- from primary (idiopathic) renal disease or of nephrotic syndrome have been identified forms to AAFP criteria for a number of secondary causes, and should (Table 2),3 with diabetes mellitus being the evidence-based continu- ing medical education initiate appropriate diagnostic workup and most common. (EB CME). medical management pending specialist consultation. Pathophysiology The underlying pathophysiology of nephrotic Causes syndrome is not completely clear.4 Although Most cases of nephrotic syndrome appear to the more intuitive “underfill” mechanism of be caused by primary disease. Table 1 edema from reduced oncotic pressure caused summarizes the recognized histologic pat- by marked proteinuria may be the primary terns and features of primary nephrotic mechanism in children with acute nephrotic syndrome.1 Membranous nephropathy and syndrome, edema in adults may be caused by focal segmental glomerulosclerosis (FSGS) a more complex mechanism. Massive - each account for about one third of cases uria causes renal tubulointerstitial inflam- of primary nephrotic syndrome; however, mation, with resulting increased sodium FSGS is the most common cause of idio- retention that overwhelms the physiologic pathic nephrotic syndrome in adults.2 Mini- mechanisms for removing edema.5 Patients mal change disease and (less commonly) may have an “overfilled” or expanded plasma immunoglobulin A (IgA) nephropathy volume in addition to expanded intersti- cause approximately 25 percent of cases of tial fluid volume. This may be clinically

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Evidence Clinical recommendation rating References

Random protein/ ratio should be used to assess the C 6 degree of proteinuria in persons with nephrotic syndrome. Renal biopsy may be helpful to guide diagnosis and treatment, but is not C 13 indicated in all persons with nephrotic syndrome. Sodium and fluid restriction and high-dose diuretic treatment are C 3, 14 indicated for most persons with nephrotic syndrome. Angiotensin-converting enzyme inhibitor treatment is indicated for most C 16 persons with nephrotic syndrome. Corticosteroid treatment has no proven benefit, but is recommended C 19, 20 by some physicians for persons with nephrotic syndrome who are not responsive to conservative treatment.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

important if over-rapid diuresis leads to acute have nephrotic syndrome. Although a renal failure from reduced glomerular blood urine dipstick proteinuria value of 3+ is a flow, despite persistent edema. useful semiquantitative means of identify- ing nephrotic-range proteinuria, given the Clinical Features logistic difficulties of collecting a 24-hour Progressive lower extremity edema, weight urine sample, the random urine protein/ gain, and fatigue are typical presenting symp- creatinine ratio is a more convenient quan- toms of nephrotic syndrome. In advanced titative measure. The numeric spot urine disease, patients may develop periorbital or protein/creatinine ratio, in mg/mg, accu- genital edema, , or pleural or pericardial rately estimates protein excretion in g per effusion. Persons who present with new edema day per 1.73 m2 of body surface area, so a or ascites, without typical dyspnea of conges- ratio of 3 to 3.5 represents nephrotic-range tive heart failure or stigmata of cirrhosis, proteinuria.6 Low albumin levels should be assessed for nephrotic syndrome. (less than 2.5 g per dL [25 g per L]) and Nephrotic-range proteinuria is typically severe hyperlipidemia are also typical fea- defined as greater than 3 to 3.5 g of protein tures of nephrotic syndrome. In one study in a 24-hour urine collection; however, not of persons with nephrotic syndrome, 53 per- all persons with this range of proteinuria cent had a total cholesterol level greater than

Table 1. Histologic Patterns and Features of Primary Nephrotic Syndrome

Histologic pattern Key pathologic features Key clinical features

Focal segmental Sclerosis and hyalinosis of segments of May be associated with , renal insufficiency, glomerulosclerosis less than 50 percent of all glomeruli on and electron microscopy Membranous Thickening of the glomerular basement Peak incidence at 30 to 50 years of age; may have nephropathy membrane on electron microscopy; microscopic hematuria; approximately 25 percent of immunoglobulin G and C3 deposits patients have underlying systemic disease, such as systemic with immunofluorescent staining erythematosus, B, or malignancy, or drug- induced nephrotic syndrome Minimal change Normal-appearing glomeruli on renal Relatively mild or benign cases of nephrotic syndrome; may disease biopsy microscopy; effacement of foot occur following upper respiratory infection or immunization processes on electron microscopy

Information from reference 1.

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300 mg per dL (7.77 mmol per L) and 25 per- therapeutic drug complications, sepsis, renal cent had a total cholesterol level greater than venous thrombosis, renal interstitial edema, 400 mg per dL (10.36 mmol per L).7 and marked hypotension may cause or con- Possible complications of nephrotic syn- tribute to acute renal failure.12 drome include venous thromboembolism caused by loss of clotting factors in the urine, Diagnostic Evaluation infection caused by urinary loss of immuno- Typical clinical and laboratory features of , and acute renal failure. Throm- nephrotic syndrome are sufficient to estab- boembolism has long been recognized as a lish the diagnosis of nephrotic syndrome. complication of nephrotic syndrome.8 In a The diagnostic evaluation focuses on iden- large retrospective review, the relative risk of tification of an underlying cause and on the deep venous thrombosis (DVT) in patients role of renal biopsy. However, there are no with nephrotic syndrome was 1.7 compared published practice guidelines available about with those without nephrotic syndrome, the diagnostic evaluation of persons with with an annual incidence of DVT of 1.5 per- nephrotic syndrome.3 cent9; the risk seems highest in the first six Initial investigation should include history, months after diagnosis.10 The relative risk of physical examination, and a serum chemistry pulmonary was 1.4 and was espe- panel. Given the large number of potential cially high in persons 18 to 39 years of age causes of nephrotic syndrome and the rela- (relative risk = 6.8). Renal venous throm- tively nonspecific aspect of therapy, the diag- bosis is a possible complication of nephrotic nostic evaluation should be guided by clinical syndrome, but was uncommon in this case suspicion for specific disorders, rather than series. Membranous nephropathy and serum a broad or unguided approach to ruling out albumin levels less than 2.0 to 2.5 g per dL multiple illnesses. Table 3 lists selected diag- (20 to 25 g per L) seem to confer an increased nostic studies for some common secondary risk of DVT. Arterial thrombotic complica- tions can occur, but are rare.9 Infection is also a possible complication Table 2. Common Secondary Causes of Nephrotic Syndrome of nephrotic syndrome; however, this risk appears primarily in children and in persons Cause Key features who have relapses of nephrotic syndrome or who require longer-term corticosteroid ther- Diabetes mellitus Glucosuria, hyperglycemia, polyuria apy.11 Invasive bacterial infections, especially Systemic lupus Anemia, arthralgias, autoantibodies, photosensitivity, erythematosus pericardial or , rash cellulitis, peritonitis, and sepsis, are the most Hepatitis B or C Elevated transaminases; high-risk sexual activity, common infections attributable to nephrotic history of transfusion, intravenous drug use, or syndrome. The mechanisms of infection other risk factors for disease transmission are unclear, but may relate to the degree of Nonsteroidal anti- Causes edema, loss of serum IgG with overall pro- inflammatory drugs teinuria,1 effects of corticosteroid therapy, Cardiomyopathy, hepatomegaly, peripheral reduced complement or T cell function, or neuropathy impaired phagocytic function.3 The risk of Abnormal urine protein electrophoresis, back pain, serious bacterial infection attributable to renal insufficiency nephrotic syndrome in adults in the United HIV Pathologically similar to focal segmental glomerulosclerosis; risk factors for HIV States is unclear, but seems low. transmission, possible reduced CD4 cell count Acute renal failure is a rare, spontane- Preeclampsia Edema and proteinuria during ; elevated ous complication of nephrotic syndrome. blood pressure Although older persons, children, and those with more profound edema and proteinuria NOTE: Causes are in approximate order of most to least common. are at highest risk, there are many possible HIV = human immunodeficiency virus. causes or contributing factors to acute renal Information from reference 3. failure in this setting. Excessive diuresis,

November 15, 2009 ◆ Volume 80, Number 10 www.aafp.org/afp American Family Physician 1131 Nephrotic Syndrome Table 3. Diagnostic Evaluation in Persons with Nephrotic Syndrome

Diagnostic studies Disorder suggested likelihood that nephrotic syndrome will Baseline respond to corticosteroid treatment, there Patient history Identify medication or toxin exposure; risk factors for HIV or viral hepatitis; and are no biopsy findings that accurately pre- symptoms suggesting other causes of edema dict corticosteroid responsiveness. No Obtain history of diabetes, systemic lupus recent studies have elucidated the true erythematosus, or other systemic illness benefit of renal biopsy in guiding manage- Urine dipstick Confirm proteinuria ment; the best available evidence is from Random urine protein/ Quantify degree of proteinuria (ratio greater a prospective study in which the results of creatinine ratio than 3 to 3.5) renal biopsy changed management in 24 of Serum creatinine Rule out acute renal failure, assess glomerular 28 persons with nephrotic syndrome, pri- filtration rate marily through the addition of corticoste- Serum albumin Assess degree of hypoalbuminemia roid treatment, although the actual patient Lipid panel Assess degree of hyperlipidemia benefit is unknown.13 In most cases, fam- Additional studies suggested by patient factors ily physicians should consult specialists in HIV screening test Identify HIV renal medicine about the need for renal Hepatitis serology panel Identify hepatitis B or C biopsy in individual patients. Serum or urine protein Suggests amyloidosis or multiple myeloma electrophoresis Management Rapid plasma reagin Identify There are no clinical guidelines and few Antinuclear antibodies Identify systemic lupus erythematosus; high-quality studies on the management or complement (C3 complement levels may also be reduced in of nephrotic syndrome in adults. Recom- and C4) levels membranoproliferative disease mendations are based primarily on early HIV = human immunodeficiency virus. case series, other observational studies, and expert opinion.3

causes of nephrotic syndrome, as well as base- FLUID AND NUTRITION line evaluations that should be obtained in all Creating a negative sodium balance will help persons with nephrotic syndrome. reduce edema, presumably as the underlying Imaging studies are generally not helpful illness is treated or as renal inflammation in assessing persons with nephrotic syn- slowly resolves. Patients should limit their drome. Renal ultrasonography may identify sodium intake to 3 g per day, and may need renal venous thrombosis if suggestive fea- to restrict fluid intake (to less than approxi- tures, such as flank pain, hematuria, or acute mately 1.5 L per day). renal failure, are present. Renal biopsy is often recommended in per- DIURETICS sons with nephrotic syndrome to establish the Diuretics are the mainstay of medical man- pathologic subtype of the disease, to assess agement; however, there is no evidence to disease activity, or to confirm the diagnosis guide drug selection or dosage. Based on of diseases, such as amyloidosis or systemic expert opinion, diuresis should aim for a lupus erythematosus. There are, however, no target weight loss of 1 to 2 lb (0.5 to 1 kg) per clear guidelines on when renal biopsy is indi- day 3 to avoid acute renal failure or electrolyte cated or whether it is needed in all persons with disorders. Loop diuretics, such as furose- nephrotic syndrome. For example, in diabetic mide (Lasix) or bumetanide, are most com- nephropathy, the leading cause of secondary monly used. Large doses (e.g., 80 to 120 mg nephrotic syndrome, renal biopsy may not be of furosemide) are often required,14 and these necessary if the patient has enlarged kidneys, drugs typically must be given intravenously a bland urinary sediment without cellular because of the poor absorption of oral drugs casts, or other evidence of microvascular caused by intestinal edema.3 Low serum disease, such as proliferative retinopathy or albumin levels also limit diuretic effective- peripheral neuropathy. Although renal ness and necessitate higher doses. Thiazide biopsy is often recommended to assess the diuretics, potassium-sparing diuretics, or

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metolazone (Zaroxolyn) may be useful as on the treatment of nephrotic syndrome adjunctive or synergistic diuretics.14 in adults found no benefit for mortality or need for dialysis with corticosteroid therapy ACE INHIBITORS for membranous nephropathy or minimal Angiotensin-converting enzyme (ACE) change disease, but found a weak benefit for inhibitors have been shown to reduce pro- disease remission and proteinuria in persons teinuria and reduce the risk of progression to with membranous nephropathy.20,24 How- renal disease in persons with nephrotic syn- ever, the findings for minimal change disease drome.15,16 One study found no improvement were based on only one randomized trial, and in response when corticosteroid treatment the role of corticosteroid treatment remains was added to treatment with ACE inhibi- unclear. Many experts recommend the use of tors.17 The recommended dosage is unclear, corticosteroids, particularly for persons with and enalapril (Vasotec) dosages from 2.5 to minimal change disease1; however, adverse 20 mg per day were used. Most persons with effects from corticosteroids often lead to nephrotic syndrome should be started on discontinuation. ACE inhibitor treatment to reduce protein- Family physicians should discuss with uria, regardless of blood pressure. patients and consulting nephrologists whether treatment with corticosteroids is advisable, ALBUMIN weighing the uncertain benefits and pos- Intravenous albumin has been proposed to sibility of adverse effects. Alkylating agents aid diuresis, because edema may be caused (e.g., cyclophosphamide [Cytoxan]) also have by hypoalbuminemia and resulting oncotic weak evidence for improving disease remission pressures. However, there is no evidence to and reducing proteinuria, but may be consid- indicate benefit from treatment with albu- ered for persons with severe or resistant dis- min,18 and adverse effects, such as hyperten- ease who do not respond to corticosteroids. sion or pulmonary edema, as well as high cost, limit its use. LIPID-LOWERING TREATMENT A Cochrane review is underway to investi- CORTICOSTEROIDS gate the benefits and harms of lipid-lowering Treatment with corticosteroids remains con- agents in nephrotic syndrome.25 Some evi- troversial in the management of nephrotic syn- dence suggests an increased risk of athero- drome in adults. It has no proven benefit, but genesis or myocardial infarction in persons is recommended in some persons who do not with nephrotic syndrome, possibly related respond to conservative treatment.19,20 Treat- to increased lipid levels.25 However, the role ment of children with nephrotic syndrome of treatment for increased lipids is unknown is different, and it is more clearly established and, at present, the decision to start lipid- that children respond well to corticosteroid lowering therapy in persons with nephrotic treatment.21 Classically, minimal change dis- syndrome should be made on the same basis ease responds better to corticosteroids than as in other patients. FSGS; however, this difference is found pri- marily in children with nephrotic syndrome. ANTIBIOTICS One older study found that corticosteroid There are no data from prospective clini- treatment improved proteinuria and renal cal trials about treatment and prevention of function in persons with minimal change infection in adults with nephrotic syndrome. disease, but not membranous nephropathy or Given the uncertain risks of infection in proliferative glomerulonephritis.22 Another adults with nephrotic syndrome in the small older study found that persons with less United States, there are currently no indica- severe glomerular changes responded well to tions for antibiotics or other interventions corticosteroids.23 One case series in black per- to prevent infection in this population. Per- sons with FSGS found no benefit from corti- sons who are appropriate candidates should costeroid treatment.19 Two Cochrane reviews receive pneumococcal vaccination.

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ANTICOAGULATION THERAPY 10. Mahmoodi BK, ten Kate MK, Waandes F, et al. High absolute risks and predictors of venous and arterial There are currently no recommendations thromboembolic events in patients with nephrotic syn- for prophylactic anticoagulation to prevent drome: results from a large retrospective cohort study. thromboembolic events in persons with Circulation. 2008;117(2):224-230. nephrotic syndrome who have not had pre- 11. Wu HM, Tang JL, Sha ZH, Cao L, Li YP. Interventions for preventing infection in nephrotic syndrome. Cochrane vious thrombotic events, and clinical prac- Database Syst Rev. 2004;(2):CD003964. 26 tice varies. A Cochrane review is in process. 12. Koomans HA. Pathophysiology of acute renal failure in Physicians should remain alert for signs or idiopatic nephrotic syndrome. Nephrol Dial Transplant. symptoms suggesting thromboembolism 2001;16(2):221-224. 13. Richards NT, Darby S, Howie AJ, Adu D, Michael J. and, if it is diagnosed, these events should be Knowledge of renal histology alters patient management treated as in other patients. Persons who are in over 40% of cases. Nephrol Dial Transplant. 1994; otherwise at high risk of thromboembolism 9(9):1255-1259. (e.g., based on previous events, known coag- 14. Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6): 387-395. ulopathy) should be considered for prophy- 15. Ruggenenti P, Mosconi L, Vendramin G, et al. ACE inhi- lactic anticoagulation while they have active bition improves glomerular size selectivity in patients nephrotic syndrome. with idiopathic membranous nephropathy and per- sistent nephrotic syndrome. Am J Kidney Dis. 2000; 35(3):381-391. The Author 16. Korbet SM. Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. CHARLES KODNER, MD, is an associate professor in the Semin Nephrol. 2003;23(2):219-228. Department of Family and Geriatric Medicine at the Uni- 17. Stiles KP, Abbott KC, Welch PG, Yuan CM. Effects of versity of Louisville (Ky.) School of Medicine. angiotensin-converting enzyme inhibitor and steroid Address correspondence to Charles Kodner, MD, Univer- therapy on proteinuria in FSGS: a retrospective study in sity of Louisville School of Medicine, Med Center One a single clinic. Clin Nephrol. 2001;56(2):89-95. Building, Louisville, KY 40292. Reprints are not available 18. Dorhout Mees EJ. Does it make sense to administer from the author. albumin to the patient with nephrotic oedema? Nephrol Dial Transplant. 1996;11(7):1224-1226. Author disclosure: Nothing to disclose. 19. Crook ED, Habeeb D, Gowdy O, Nimmagadda S, Salem M. Effects of steroids in focal segmental glomeruloscle- rosis in a predominantly African-American population. REFERENCES Am J Med Sci. 2005;330(1):19-24. 1. Karnath BM, Keddis MT. The nephrotic syndrome. Hosp 20. Schieppati A, Perna A, Zamora J, Giuliano GA, Braun N, Physician. 2007;43(10):25-30. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic 2. Kitiyakara C, Kopp JB, Eggers P. Trends in the epide- syndrome. Cochrane Database Syst Rev. 2004;(4): miology of focal segmental glomerulosclerosis. Semin CD004293. Nephrol. 2003;23(2):172-182. 21. Hodson EM, Willis NS, Craig JC. Corticosteroid therapy 3. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. for nephrotic syndrome in children. Cochrane Database BMJ. 2008;336(7654):1185-1189. Syst Rev. 2009;(3):CD001533. 4. Cho S, Atwood JE. Peripheral edema. Am J Med. 2002; 22. Black DA, Rose G, Brewer DB. Controlled trial of predni- 113(7):580-586. sone in adult patients with the nephrotic syndrome. Br 5. Rodríguez-Iturbe B, Herrera-Acosta J, Johnson RJ. Inter- Med J. 1970;3(5720):421-426. stitial inflammation, sodium retention, and the patho- 23. Rashid H, Ezedum S, Morley AR, Kerr DN. Nephrotic syn- genesis of nephrotic edema: a unifying hypothesis. drome with slight proliferative changes in the glomeruli: Kidney Int. 2002;62(4):1379-1384. response to prednisone. Br Med J. 1980;281(6236): 6. Leung YY, Szeto CC, Tam LS, et al. Urine protein-to- 347-350. creatinine ratio in an untimed urine collection is a reli- 24. Palmer SC, Nand K, Strippoli GF. Interventions for mini- able measure of proteinuria in lupus . Rheuma- mal change disease in adults with nephrotic syndrome. tology (Oxford). 2007;46(4):649-652. Cochrane Database Syst Rev. 2008;(1):CD001537. 7. Radhakrishnan J, Appel AS, Valeri A, Appel GB. The 25. Fan J, Li Z, Wu T, Chen H. Lipid-lowering agents for nephrotic syndrome, lipids, and risk factors for cardio- nephrotic syndrome (intervention protocol). Cochrane vascular disease. Am J Kidney Dis. 1993;22(1):135-142. Database Syst Rev. 2009;(2):CD005425. 8. Kendall AG, Lohmann RC, Dossetor JB. Nephrotic syn- 26. Kulshrestha S, Grieff M, Navaneethan SD. Interventions drome. A hypercoagulable state. Arch Intern Med. 1971; for preventing thrombosis in adults and children with 127(6):1021-1027. nephrotic syndrome (intervention protocol). Cochrane 9. Kayali F, Najjar R, Aswad F, Matta F, Stein PD. Venous Database Syst Rev. 2009;(2):CD006024. thromboembolism in patients hospitalized with nephrotic syndrome. Am J Med. 2008;121(3):226-230.

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