Nephrotic Syndrome AAFP.pdf

Diagnosis and Management of Nephrotic Syndrome in Adults CHARLES KODNER, MD, University of Louisville School of Medicine, Louisville, Kentucky Nephrotic syndrome (NS) consists of peripheral edema, heavy proteinuria, and hypoalbuminemia, often with hyper- lipidemia. Patients typically present with e...

Diagnosis and Management of Nephrotic Syndrome in Adults CHARLES KODNER, MD, University of Louisville School of Medicine, Louisville, Kentucky Nephrotic syndrome (NS) consists of peripheral edema, heavy proteinuria, and hypoalbuminemia, often with hyper- lipidemia. Patients typically present with edema and fatigue, without evidence of heart failure or severe liver disease. The diagnosis of NS is based on typical clinical features with confirmation of heavy proteinuria and hypoalbumin- emia. The patient history and selected diagnostic studies rule out important secondary causes, including diabetes mellitus, systemic lupus erythematosus, and medication adverse effects. Most cases of NS are considered idiopathic or primary; membranous nephropathy and focal segmental glomerulosclerosis are the most common histologic sub- types of primary NS in adults. Important complications of NS include venous thrombosis and hyperlipidemia; other potential complications include infection and acute kidney injury. Spontaneous acute kidney injury from NS is rare but can occur as a result of the underlying medical problem. Despite a lack of evidence-based guidelines, treatment consisting of sodium restriction, fluid restriction, loop diuretics, angiotensin-converting enzyme inhibitor or angio- tensin receptor blocker therapy, and careful assessment for possible disease complications is appropriate for most patients. Renal biopsy is often recommended, although it may be most useful in patients with suspected underly- ing systemic lupus erythematosus or other renal disorders, in whom biopsy can guide management and prognosis. Immunosuppressive treatment, including corticosteroids, is often used for NS, although evidence is lacking. Routine prophylactic treatment to prevent infection or thrombosis is not recommended. A nephrologist should be consulted about use of anticoagulation and immunosuppressants, need for renal biopsy, and for other areas of uncertainty. (Am Fam Physician. 2016;93(6):479-485. Copyright © 2016 American Academy of Family Physicians.) N CME This clinical content ephrotic syndrome (NS) con- account for approximately 15% of cases. The conforms to AAFP criteria sists of peripheral edema, heavy remaining 10% of cases are secondary to an for continuing medical education (CME). See proteinuria, and hypoalbumin- underlying medical condition.1 CME Quiz Questions on emia, often with hyperlipid- page 449. emia. Patients typically present with edema Causes Author disclosure: No rel- and fatigue, without heart failure or severe Assessing the cause of NS is important evant financial affiliations. liver disease. Although there is limited evi- in guiding management decisions. Many Patient information: dence to guide management decisions, recent underlying systemic conditions can cause ▲ A handout on this topic, expert consensus guidelines and systematic NS, although type 2 diabetes mellitus and written by the author of reviews provide updated recommendations. systemic lupus erythematosus are most this article, is available at http://www.aafp.org/ This article focuses on diagnosis and man- common. NS may not present as a primary afp/2016/0315/p479-s1. agement of NS in adults, which is different diagnosis, but instead as one of multiple dis- html. from that in children. ease manifestations, particularly in systemic lupus erythematosus. A published case report Epidemiology of a 29-year-old pregnant woman with lupus The annual incidence of NS in adults is nephritis, preeclampsia, NS, and hemolytic three per 100,000 persons. Approximately anemia illustrates this scenario.2 Secondary 80% to 90% of NS cases in adults are idio- causes of NS are listed in Table 1.1,3 pathic. Membranous nephropathy is the most common cause in whites, and focal Pathophysiology segmental glomerulosclerosis is most com- The mechanism of edema formation in NS mon in blacks; each of these disorders is unclear. The primary defect seems to accounts for approximately 30% to 35% of be increased glomerular permeability to NS cases in adults. Minimal change disease albumin and other plasma proteins. Pri- and immunoglobulin A nephropathy each mary renal sodium retention and decreased March 15, 2016 Downloaded from ◆theVolume 93,Family American Number 6 website at www.aafp.org/afp. Physician www.aafp.org/afp American Copyright © 2016 American Academy of Family Family Physicians. For thePhysician 479 private, noncom- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Nephrotic Syndrome Table 1. Secondary Causes of Nephrotic Syndrome Metabolic Medication/drug use Infection (continued) Amyloidosis Heroin Viral Diabetes mellitus Interferon alfa Epstein-Barr virus Immunologic Lithium Hepatitis B and C Cryoglobulinemia Nonsteroidal anti-inflammatory Herpes zoster Erythema multiforme drugs Human immunodeficiency virus Henoch-Schönlein purpura Pamidronate Allergic Microscopic polyangiitis Infection Antitoxins Polyarteritis nodosa Bacterial Insect stings, venomous snake bites Sjögren syndrome Infective endocarditis Poison ivy or oak Systemic lupus erythematosus Leprosy Genetic syndromes Idiopathic/primary Syphilis Congenital nephrotic syndrome (Finnish type) Neoplastic Protozoan Familial focal segmental glomerulonephritis Carcinoma (e.g., bronchus, breast, Filariasis Hereditary nephritis (Alport syndrome) colon, stomach, kidney) Helminthiasis Other Leukemia, lymphomas Malaria Castleman disease Melanoma Schistosomiasis Chronic allograft nephropathy Multiple myeloma Malignant hypertension Preeclampsia Sarcoidosis Information from references 1 and 3. oncotic pressure from hypoalbuminemia from a single urine sample is commonly used lead to increased extravasation of fluid from to diagnose nephrotic-range proteinuria. the intravascular space into the interstitial Although this spot test has limited accuracy space, resulting in edema.4 in patients who exercise heavily, are gaining The pathophysiology of thrombogenesis or losing muscle mass, or have similar fac- in NS is also not completely understood but tors, in general, it is sufficient for diagnosing seems to be multifactorial, involving loss of heavy proteinuria.1 coagulation regulatory proteins and a shift Further diagnostic assessment of patients in the hemostatic balance toward a pro- with NS has three goals: to assess for com- thrombotic milieu.5 Patients with NS and plications, identify underlying disease, and prothrombotic genetic mutations have a fur- potentially determine the histologic type of ther increased risk of thrombosis. idiopathic NS. The role of renal biopsy in patients with NS is controversial, and there Diagnostic Evaluation are no evidence-based guidelines regarding New-onset edema, particularly in the lower indications for biopsy. Whether biopsy is extremities, is the most common presenting performed often depends on the preferences symptom of NS. Depending on disease sever- of consulting nephrologists. In patients with ity, patients may have edema extending to the NS from a known secondary cause and who proximal lower extremities, lower abdomen, are responding to treatment appropriately, or genitalia. Ascites, periorbital edema, hyper- biopsy will likely add little to treatment. tension, and pleural effusion are also pos- Biopsy may be more useful for treatment sible presenting features. Patients may report and prognosis in patients with idiopathic foamy urine, exertional dyspnea or fatigue, NS of an unknown histologic disease type and significant fluid-associated weight gain.1,3 or with suspected underlying systemic lupus The diagnostic criteria for NS are listed erythematosus or other renal disorders. in Table 2.1 Confirmation of proteinuria via 24-hour urine collection is cumbersome for Complications patients, and the specimen can be collected Various systemic complications are com- incorrectly. The protein-to-creatinine ratio monly associated with NS. These are thought 480 American Family Physician www.aafp.org/afp Volume 93, Number 6 ◆ March 15, 2016  Nephrotic Syndrome to result from overproduction of hepatic 7%.7 Unless the patient’s history suggests a proteins and loss of low-molecular-weight thromboembolic complication, screening proteins in the urine, although the specific otherwise asymptomatic patients for throm- mechanisms have not been fully described.5 boembolic events is not indicated. It is generally not necessary to screen other- INFECTION wise asymptomatic patients for these com- plications. Figure 1 is an algorithm for the Bacterial infections, especially cellulitis, are diagnosis and management of NS.1 a potential complication of NS. A Cochrane review found no relevant studies of infec- VENOUS THROMBOSIS tions in adults with NS.8 There are no reli- Venous thrombosis is one of the most able data on the incidence of infection as a important complications of NS, but the true complication of NS and no current guide- incidence and risk are difficult to determine lines for the use of prophylactic antibiotics because of the heterogeneity of the clini- in adults with NS. cal manifestations and causes of NS. The RENAL FAILURE most common sites of venous thrombosis in adults are in the deep veins of the lower Acute kidney injury is considered a rare spon- limbs, although thrombosis can also occur taneous complication of NS. It can coexist in the renal veins and can cause pulmonary with NS when it is caused by the same factors embolism. Arterial thrombosis is rare in that lead to edema and proteinuria, such as patients with NS.1 lupus nephritis and drug-induced interstitial In a historical case series of patients nephritis.1,9 Although acute kidney injury with NS, venous thrombosis of the lower is uncommon in NS, tests for renal func- limb occurred in 8% of patients, and renal tion, quantification of proteinuria, serum venous thrombosis occurred in up to 25% of chemistry, and lipid profile are appropriate patients. However, more recent data suggest to assess renal function and determine the a much lower risk of venous thrombosis in degree of hyperlipidemia. Table 3 shows the patients with NS.6 In a retrospective study, differential diagnosis of acute kidney injury deep venous thrombosis occurred in 1.5% of in patients with NS.3 adults with NS, and renal venous thrombosis HYPERLIPIDEMIA occurred in 0.5% of adults with NS.6 Venous thrombosis is much more common in adults Elevated lipid levels (potentially markedly than in children and is more common in elevated) are a common feature of NS. Any adults with membranous nephropathy than subtype of lipoprotein concentrations can be other histologies,5 with an incidence of up to elevated. There are no recent epidemiologic Table 2. Diagnostic Criteria for Nephrotic Syndrome Factor Criteria Heavy proteinuria Spot urine showing a protein-to-creatinine ratio of > 3 to 3.5 mg protein/ mg creatinine (300 to 350 mg/mmol), or 24-hour urine collection showing > 3 to 3.5 g protein Hypoalbuminemia Serum albumin < 2.5 g per dL (25 g per L)* Edema Clinical evidence of peripheral edema Hyperlipidemia (not Severe hyperlipidemia, total cholesterol is often > 350 mg per dL required for diagnosis) (9.06 mmol per L) *—Some experts use a cutoff of < 3.0 g per dL (30 g per L). Adapted with permission from Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185. March 15, 2016 ◆ Volume 93, Number 6 www.aafp.org/afp American Family Physician 481  Diagnosis of Nephrotic Syndrome in Adults Positive result on urine dipstick testing (2/3/4+) Early morning urinary protein measurement; protein-to- Step 1: Confirm nephrotic syndrome creatinine ratio is typically > 3 to 3.5 mg protein/mg creatinine (300 to 350 mg/mmol) in nephrotic syndrome Serum albumin measurement Urinalysis: Hematuria or casts suggest nephritis Blood counts and coagulation panel: Abnormal results may suggest a bleeding disorder Renal function and electrolytes: An elevated creatinine level Step 2: Assess for common causes may indicate acute kidney injury and indicates reduced GFR Liver panel: Elevated transaminase levels may suggest viral hepatitis Glucose tests for diabetes mellitus Focused testing for disorders suggested by history and physical examination Antinuclear antibody, anti–double-stranded DNA antibody, and complement values (C3 and C4) if connective tissue disorder is suspected Step 3: Assess for underlying conditions Chest radiography if pleural effusion is suspected Echocardiography if heart failure is suspected Abdominal ultrasonography if ascites is suspected Renal ultrasonography if GFR is reduced Viral hepatitis panel if transaminase levels are abnormal Consideration of focused testing for disorders suggested by history and physical examination Renal ultrasonography if GFR is reduced Step 4: Assess for disease complications Lower extremity Doppler ultrasonography, chest computed tomography, or lung ventilation/perfusion scan if venous thrombosis or pleural effusion is suspected Nephrologist consultation if biopsy is considered Step 5: Consider renal biopsy Renal biopsy should be considered if it will inform management, or for severe disease, lack of response to treatment, or steroid resistance Figure 1. Algorithm for the diagnosis of nephrotic syndrome in adults. (GFR = glomerular filtration rate.) Information from reference 1. data to indicate how common or severe this correction of treatable causes, management complication is, and no recent data regard- includes general measures to treat symp- ing the impact of treatment for dyslipidemia toms such as edema and, in some cases, associated with NS. However, resolving pro- immunosuppressant treatment of the renal teinuria and any underlying disease pro- pathology. cess is believed to improve or resolve the GENERAL TREATMENT MEASURES dyslipidemia.1,10 Because of the possible pathophysiologic Management role of sodium retention, some experts Management of NS is limited by a lack of recommend that routine treatment of clear evidence-based guidelines, although patients with NS include restricting dietary recent expert consensus guidelines provide sodium to less than 3 g per day and restrict- useful recommendations.11 In addition to ing fluid to less than 1,500 mL per day.1 482 American Family Physician www.aafp.org/afp Volume 93, Number 6 ◆ March 15, 2016  Nephrotic Syndrome Table 3. Differential Diagnosis of Acute Kidney Injury in Nephrotic Syndrome Acute allergic interstitial nephritis secondary to use of various drugs, TREATING EDEMA including diuretics Patients with nephrosis are resistant to Acute tubular necrosis caused by volume depletion or sepsis diuretics, even if the glomerular filtration Adverse effects of drug therapy rate is normal. Loop diuretics act in the renal Hemodynamic response to nonsteroidal anti-inflammatory drugs, tubule and must be protein-bound to be angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers effective. Serum proteins are reduced in NS, Intrarenal edema limiting the effectiveness of loop diuretics, Prerenal failure caused by volume depletion and patients may require higher-than-normal Renal venous thrombosis doses.3 Other mechanisms for diuretic resis- Transformation of underlying glomerular disease (e.g., crescentic nephritis superimposed on membranous nephropathy) tance are also possible. Oral loop diuretics with twice-daily administration are usually Information from reference 3. preferred because of the longer duration of action. However, with severe NS and edema, gastrointestinal absorption of the diuretic be made individually.13 Although the ben- may be uncertain because of intestinal wall efits of anticoagulation may outweigh the edema, and intravenous diuretics may be risks in selected patients at high risk of necessary. Diuresis should be relatively grad- venous thrombosis (e.g., those with known ual and guided by daily weight assessment, prothrombotic tendency or a history of with a target of 2 to 4 lb (1 to 2 kg) per day.3 venous thrombosis), anticoagulation is not Furosemide (Lasix) at 40 mg orally twice routinely used for primary prevention of daily or bumetanide at 1 mg twice daily is thrombotic events in patients with NS.6 a reasonable starting dosage, with approxi- TREATING AND PREVENTING INFECTION mate doubling of the dose every one to three days if there is inadequate improvement in Infection has been reported in up to 20% of edema or other evidence of fluid overload.3 adults with NS, although it is unclear if NS An approximate upper limit for furosemide is causative or if the infection is a result of is 240 mg per dose or 600 mg total per day,12 hospitalization, corticosteroid use, or other but there is no clear evidence or rationale factors.1 A Cochrane review found no strong for this limit. If there is still an inadequate evidence to recommend a specific interven- clinical response, patients may be treated tion to prevent infection in adults with NS.8 by changing to intravenous loop diuretics, TREATING DYSLIPIDEMIA adding oral thiazide diuretics, or giving an intravenous bolus of 20% human albumin A recent Cochrane review found insuffi- prior to an intravenous diuretic bolus.3 cient evidence to determine if lipid-lowering agents are helpful in managing dyslipidemia ANTICOAGULATION FOR VENOUS THROMBOSIS in adults with NS and no other indications Despite the known risk of venous throm- for treatment based on previously obtained bosis in patients with NS, there are no ran- lipid levels.10 domized controlled trials to guide whether ANTIPROTEINURIC TREATMENT prophylactic anticoagulation should be used and for how long.1 Treatment with angiotensin-converting Adult patients with NS should be assessed enzyme inhibitors or angiotensin receptor individually for underlying disease. Addi- blockers appears to reduce the risk of venous tional considerations are the severity of NS thrombosis, although this has not been (i.e., serum albumin less than 2.0 to 2.5 g confirmed.14 Treatment with angiotensin- per dL [20 to 25 g per L] may be more likely converting enzyme inhibitors or angioten- to prompt anticoagulation prophylaxis7), sin receptor blockers is often recommended preexisting thrombophilic states, and the for patients with NS because of their known overall likelihood of serious bleeding events antiproteinuric effects. However the degree from the use of oral anticoagulation. The of benefit for specific outcomes, such as renal decision to treat with anticoagulants should failure or recovery, improvement in edema, March 15, 2016 ◆ Volume 93, Number 6 www.aafp.org/afp American Family Physician 483  SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Spot urine protein-to-creatinine ratio should be used instead of 24-hour C 1 urine collection to confirm nephrotic-range proteinuria. Although venous thrombosis is a common complication of NS, there is no C 6, 7, 13 evidence that anticoagulation is indicated in all patients with NS. Although hyperlipidemia is a common complication of NS, there is no A 10 evidence that lipid-lowering therapy should be initiated solely to treat the manifestations of NS. Therapy with sodium restriction, fluid restriction, loop diuretics, and C 1, 3 angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is a conservative management approach appropriate for most patients with NS. Corticosteroids and other immunosuppressant drugs may have some benefit B 15 in patients with NS, but the potential risks are significant and there is no evidence or guideline recommending use of these drugs in all patients. NS = nephrotic syndrome. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; 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. or need for dialysis, is unproven, and the has no proven benefit for most adults with evidence supporting the routine use of these idiopathic NS, and the potential risks may medications is conflicting. outweigh any benefits. The role of such treatment and specific treatment decisions, IMMUNOSUPPRESSIVE THERAPY such as type and duration of therapy, depend Corticosteroids are often used in the treat- on clinical factors and potentially on the ment of NS despite an absence of support- histologic diagnosis identified on biopsy. If ing data. In recent years, corticosteroids and NS is steroid-resistant or does not improve, other immunosuppressive treatments have other immunosuppressive treatments been investigated for use in NS (Table 4).15 should be considered in cooperation with a A Cochrane review showed that combining nephrologist. Immunosuppressive therapy an alkylating agent with a corticosteroid for NS secondary to systemic lupus erythe- has short- and long-term benefits for mem- matosus is highly effective and supported by branous nephropathy in adults with NS.15 multiple studies, and may lead to partial or In general, immunosuppressive treatment complete remission in patients with mini- mal change disease or primary focal seg- mental glomerulosclerosis. Table 4. Potential Immunosuppressive Agents for Nephrotic Prognosis Syndrome Due to Idiopathic Membranous Nephropathy The prognosis for NS is highly dependent on Adrenocorticotropic hormone the underlying cause, the disease histology, Alkylating agents (chlorambucil [Leukeran], cyclophosphamide) and patient clinical factors. Although many Azathioprine (Imuran) patients improve with appropriate sup- Biologics (rituximab [Rituxan], eculizumab [Soliris]) portive care and do not require any specific Calcineurin inhibitors (cyclosporine [Sandimmune], tacrolimus [Prograf]) therapy, others worsen despite aggressive, High-dose immune globulin specific therapy and may require dialysis. Mycophenolate mofetil (Cellcept) In one study, routine treatment with an Tripterygium wilfordii (thunder god vine; traditional Chinese angiotensin-converting enzyme inhibitor or immunosuppressive therapy) angiotensin receptor blocker, plus selective use of corticosteroids or other immunosup- Information from reference 15. pressants, led to a remission rate of 76%, with 12% of patients requiring hemodialysis.16 484 American Family Physician www.aafp.org/afp Volume 93, Number 6 ◆ March 15, 2016  Nephrotic Syndrome Idiopathic membranous nephropathy is REFERENCES one of the most common forms of primary 1. Hull RP, Goldsmith DJ. 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J Thromb Hae- This review updates a previous article on this topic by the most. 2011;9(12):2416-2423. author.18 15. Chen Y, Schieppati A, Chen X, et al. Immunosuppres- sive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database The Author Syst Rev. 2014;(10):CD004293. 16. McQuarrie EP, Stirling CM, Geddes CC. Idiopathic mem- CHARLES KODNER, MD, is an associate professor in the branous nephropathy and nephrotic syndrome. Nephrol Department of Family and Geriatric Medicine at the Uni- Dial Transplant. 2012;27(1):235-242. versity of Louisville (Ky.) School of Medicine. 17. Korbet SM. Treatment of primary FSGS in adults. J Am Address correspondence to Charles Kodner, MD, Univer- Soc Nephrol. 2012;23(11):1769-1776. sity of Louisville School of Medicine, Med Center One 18. Kodner C. Nephrotic syndrome in adults: diagnosis Bldg., Louisville, KY 40292. Reprints are not available and management. Am Fam Physician. 2009; 80(10): from the author. 1129-1134. March 15, 2016 ◆ Volume 93, Number 6 www.aafp.org/afp American Family Physician 485