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Home , Nephrotic syndrome, Proteinuria

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

Nephrotic syndrome (NS) consists of peripheral , heavy , and , often with hyper- lipidemia. Patients typically present with edema and fatigue, without evidence of or severe 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 mellitus, systemic erythematosus, and medication adverse effects. Most cases of NS are considered idiopathic or primary; membranous nephropathy and focal segmental are the most common histologic sub- types of primary NS in adults. Important complications of NS include venous and ; other potential complications include and injury. Spontaneous 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 restriction, fluid restriction, loop , angiotensin-converting enzyme inhibitor or angio- tensin receptor blocker therapy, and careful assessment for possible disease complications is appropriate for most patients. 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 , 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.)

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 1 education (CME). See proteinuria, and hypoalbumin- underlying medical condition. CME Quiz Questions on emia, often with hyperlipid- page 449. Nemia. 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 of a 29-year-old pregnant woman with lupus The annual incidence of NS in adults is , preeclampsia, NS, and hemolytic three per 100,000 persons. Approximately 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. and other plasma . Pri- and immunoglobulin A nephropathy each mary renal sodium retention and decreased

MarchDownloaded 15, 2016 from ◆the Volume American 93, Family Number Physician 6 website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2016 American Academy of FamilyAmerican Physicians. Family For the Physician private, noncom 479- 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/ use Infection (continued) Viral Diabetes mellitus Interferon alfa Epstein-Barr virus Immunologic Lithium B and C Cryoglobulinemia Nonsteroidal anti-inflammatory Herpes zoster Erythema multiforme Human immunodeficiency virus Henoch-Schönlein purpura Pamidronate Allergic Infection Antitoxins Bacterial Insect stings, venomous snake bites Sjögren syndrome Infective endocarditis Poison ivy or oak Systemic lupus erythematosus Leprosy Genetic syndromes Idiopathic/primary Congenital nephrotic syndrome (Finnish type) Neoplastic Protozoan Familial focal segmental Carcinoma (e.g., bronchus, breast, Filariasis Hereditary nephritis () colon, stomach, kidney) Helminthiasis Other Leukemia, Malaria Castleman disease Melanoma Chronic allograft nephropathy Malignant Preeclampsia

Information from references 1 and 3.

from hypoalbuminemia from a single 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. , periorbital edema, hyper- biopsy will likely add little to treatment. tension, and 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 -to- ratio monly associated with NS. These are thought

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to result from overproduction of hepatic 7%.7 Unless the patient’s history suggests a proteins and loss of low-molecular-weight thromboembolic , 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- wise asymptomatic patients for these com- INFECTION plications. Figure 1 is an algorithm for the Bacterial , especially cellulitis, are diagnosis and management of NS.1 a potential complication of NS. A Cochrane review found no relevant studies of infec- 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 because of the heterogeneity of the clini- in adults with NS. cal manifestations and causes of NS. The most common sites of venous thrombosis RENAL FAILURE 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 . Arterial thrombosis is rare in that lead to edema and proteinuria, such as patients with NS.1 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, 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, of acute kidney injury deep venous thrombosis occurred in 1.5% of in patients with NS.3 adults with NS, and renal venous thrombosis occurred in 0.5% of adults with NS.6 Venous HYPERLIPIDEMIA 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 concentrations can be other ,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 < 2.5 g per dL (25 g per L)* Edema Clinical evidence of peripheral edema Hyperlipidemia (not Severe hyperlipidemia, total 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: or casts suggest nephritis Blood counts and coagulation panel: Abnormal results may suggest a bleeding disorder Renal function and : 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 tests for diabetes mellitus

Focused testing for disorders suggested by history and physical examination Antinuclear , 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 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 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 dyslipidemia.1,10 GENERAL TREATMENT MEASURES 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 are resistant to caused by volume depletion or 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 resis- Transformation of underlying glomerular disease (e.g., crescentic nephritis tance are also possible. Oral loop diuretics superimposed on membranous nephropathy) 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 (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- mate doubling of the dose every one to three TREATING AND PREVENTING INFECTION 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, 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, adding oral thiazide diuretics, or giving an TREATING DYSLIPIDEMIA 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 prophylactic anticoagulation should be used ANTIPROTEINURIC TREATMENT 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 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 , 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 the underlying cause, the disease , Adrenocorticotropic and patient clinical factors. Although many Alkylating agents ( [Leukeran], ) patients improve with appropriate sup- Azathioprine (Imuran) portive care and do not require any specific Biologics (rituximab [Rituxan], eculizumab [Soliris]) therapy, others worsen despite aggressive, inhibitors (cyclosporine [Sandimmune], tacrolimus [Prograf]) specific therapy and may require dialysis. High-dose immune In one study, routine treatment with an Mycophenolate mofetil (Cellcept) angiotensin-converting enzyme inhibitor or Tripterygium wilfordii (thunder god vine; traditional Chinese 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

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Idiopathic membranous nephropathy is REFERENCES one of the most common forms of primary NS in adults, and has a generally favorable 1. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185-1189. 15 prognosis. The prognosis for this illness 2. Williams WW Jr, Ecker JL, Thadhani RI, Rahemtullah A. roughly follows a “rule of thirds”: about one- Case records of the Massachusetts General Hospital. third of patients have a benign course with a Case 38-2005. A 29-year-old pregnant woman with the nephrotic syndrome and hypertension. N Engl J Med. high rate of remission; one-third have ongo- 2005;353(24):2590-2600. ing evidence of proteinuria or edema but 3. Floege J. Introduction to glomerular disease: clinical maintain normal renal function; and some- presentations. In: Johnson RJ, Feehally J, Floege J, eds. what less than one-third of patients progress Comprehensive Clinical . 5th ed. Philadel- phia, Pa.: Elsevier Saunders; 2015. toward end-stage renal disease within 10 4. Siddall EC, Radhakrishnan J. The pathophysiology of 15 years. edema formation in the nephrotic syndrome. Kidney Adults with primary focal segmental Int. 2012;82(6):635-642. glomerulosclerosis, however, tend to have 5. Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associated a poorer prognosis, and the degree of pro- thromboembolic disease. Clin J Am Soc Nephrol. 2012;​ teinuria is a significant prognostic factor. 7(3):513-520. Although about one-half of patients with 6. Kayali F, Najjar R, Aswad F, Matta F, Stein PD. Venous nephrotic-range proteinuria progress to thromboembolism in patients hospitalized with nephrotic syndrome. Am J Med. 2008;121(3):226-230. end-stage renal disease over five to 10 years, 7. Pincus KJ, Hynicka LM. Prophylaxis of thromboembolic patients with very heavy proteinuria (10 to 14 events in patients with nephrotic syndrome. Ann Phar- g per day) will develop end-stage renal dis- macother. 2013;47(5):725-734. ease on average within two to three years.17 8. Wu HM, Tang JL, Cao L, Sha ZH, Li Y. Interventions for preventing infection in nephrotic syndrome. Cochrane Database Syst Rev. 2012;(4):CD003964. Subspecialist Consultation 9. Koomans HA. Pathophysiology of acute renal failure in Consultation with nephrologists should idiopatic nephrotic syndrome. Nephrol Dial Transplant. guide decisions about use of anticoagulation 2001;16(2):221-224. and immunosuppressants, need for renal 10. Kong X, Yuan H, Fan J, Li Z, Wu T, Jiang L. Lipid-lowering agents for nephrotic syndrome. Cochrane Database biopsy, and for other areas of uncertainty. Syst Rev. 2013;(12):CD005425. 11. Radhakrishnan J, Cattran DC. The KDIGO practice Data Sources: A Medline literature search was con- guideline on glomerulonephritis: reading between the ducted using the key term nephrotic syndrome. The (guide)lines—application to the individual patient. Kid- search was limited to English, human, core clinical ney Int. 2012;82(8):840-856. journals (Abridged Index Medicus), and publication 12. Furosemide dosage. Drugs.com. http://www.drugs. years between 2005 and 2015. Additional searches were com/dosage/furosemide.html. Accessed January 13, conducted combining the baseline nephrotic syndrome 2016. search with other relevant key words, such as venous 13. Glassock RJ. Prophylactic anticoagulation in nephrotic thrombosis, hyperlipidemia, infection, and acute kidney syndrome. J Am Soc Nephrol. 2007;18(8):2221-2225. injury. Relevant original articles cited in reviews were used as the sources for cited data. Search dates: January 14. Mahmoodi BK, Mulder AB, Waanders F, et al. The 25, 2015, and December 10, 2015. impact of antiproteinuric therapy on the prothrombotic state in patients with overt proteinuria. 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. CHARLES KODNER, MD, is an associate professor in the 16. McQuarrie EP, Stirling CM, Geddes CC. Idiopathic mem- 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.

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