Nephrotic Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

A clinical syndrome of heavy proteinuria (>3.5 g/1.73 m2/24 hours), hypoalbuminemia, hyperlipidemia, and edemaIncludes both primary and secondary formsAssociated with many types of kidney disease

Epidemiology

Based on definitive diagnosis:

Diabetic nephropathy: Most common cause of secondary nephrotic syndromeMinimal change disease (MCD): Most common nephrotic syndrome in children, peaks at 2–8 yearsAssociated with drugs or lymphoma in adultsAmyloidosis: Lupus nephropathy (LN): Adult women are affected about 10 × more often than men.Focal segmental glomerulosclerosis (FSGS): 25% of nephrotic syndrome in adultsMost common primary nephrotic syndrome in African AmericansHas both primary and secondary formsMembranous nephropathy: Most common primary nephrotic syndrome in CaucasiansAssociated with malignancy and infectionMembranoproliferative glomerulonephritis (MGN): May be primary or secondaryMay present in the setting of a systemic viral or rheumatic illness

Risk Factors

Drug addiction (e.g., heroin [FSGS])Hepatitis B and C, HIV, other infectionsImmunosuppressionNephrotoxic drugsVesicoureteral reflux (FSGS)Cancer (usually MGN, may be MCD)Chronic analgesic use/abusePreeclampsiaDiabetes mellitus

Genetics

Genetic factors are likely to play a role in susceptibility to the various nephrotic syndromes, though these have not been sufficiently defined to be useful clinically.

General Prevention

In general, there are few preventive measures except avoidance of known causative medications.

Pathophysiology

Increased glomerular permeability to large protein molecules, especially albuminEdema results primarily from renal salt retention, with arterial underfilling from decreased plasma oncotic pressure playing an additional role.Hyperlipidemia is thought to be a consequence of increased hepatic synthesis resulting from low oncotic pressure and urinary loss of regulatory proteins.The hypercoagulable state that can occur in some nephrotic states is likely due to loss of antithrombin III in urine.

Etiology

Primary renal disease: Minimal change diseaseFocal and segmental glomerulosclerosis (FSGS)Membranous nephropathy (MGN)IgA nephropathyMembranoproliferative glomerulonephritisSecondary renal disease (associated primary renal disease shown in parentheses): Diabetic nephropathyAmyloidosisLupus nephropathy (LN)Focal and segmental glomerulosclerosisInfections (MGN)Cancer (MCD or MGN)Drugs (MCD or MGN)

Diagnosis

History

Look for signs or symptoms of systemic disease: Joint complaint, rash, edema, infectious complaint, fevers, anorexia, oliguria, foamy urine, acute flank pain, hematuria, etc.Look for a recent drug history that may be causative, especially nonsteroidal anti-inflammatory drugs.Assess for risk factors.

Physical Exam

A complete physical exam may discover clues to systemic disease as a potential cause and/or may suggest the severity of disease:

Fluid retention: Abdominal distention, abdominal fluid shift, extremity edema, puffy eyelids, scrotal swelling, weight gain, shortness of breath: Pericardial rub and decreased breath sounds with pleural effusions may develop.HypertensionOrthostatic hypotension

Alert

The potential for thromboembolic disease leading to pulmonary embolism is one of the most life-threatening aspects of a patient who is actively nephrotic.

Diagnostic Tests & Interpretation

Lab

Initial lab tests

Confirm proteinuria is present: By urine dipstick initially, and then quantitate by 24-hour urine or urine protein to creatinine ratioRule out urine infection with urine culture.Full blood count and coagulation screenRenal function tests: Blood urea nitrogen, creatinine with estimated glomerular filtration rateGlucose to rule out overt diabetesBlood cultures to rule out a postinfectious processLipid panel to judge the relative effect of loss of protein into the urineLiver function tests to exclude liver disease or infectionLook for autoimmune disease: Antinuclear antibody and/or antidouble-stranded DNA (dsDNA) positivity would suggest lupus.Complement levels: A low C3 may suggest a postinfectious or membranoproliferative process, whereas both low C3 and C4 low point to lupus.Serum protein electrophoresis/urine immune electrophoresis to rule in a paraproteinemiaHepatitis B and C screenHIV and rapid plasma reagent: Urinalysis to evaluate for the presence of cellular casts

Imaging

Renal ultrasound to verify the presence of 2 kidneys of normal shape and sizeChest x-ray to detect presence of pleural effusion or infectionIf thrombosis suspected: Doppler ultrasound of the legsMagnetic resonance imaging or venography for renal vein thrombosisVentilation/perfusion nuclear medicine lung scan and/or computed tomography may be required to rule out pulmonary embolism.

Diagnostic Procedures/Surgery

Renal biopsy:

Rarely done in children with 1st episode of nephrotic syndrome, as minimal-change disease is common and empiric steroid therapy is the standard of care.Often required to confirm the clinical diagnosis in adults and assist with making a treatment plan

Pathological Findings

Light microscopy: May see nothing (e.g., MCD)Sclerosis (e.g., FSGS or diabetic nodules in diabetes)Diffuse hypercellularity suggests a proliferative disease such as IgA nephropathy, lupus nephritis, or postinfectious GN.Immunofluorescence: Mesangial IgA suggests IgA nephropathy, Henoch-Schönlein; other staining patterns are specific for other disease processes.Electron microscopy: The location of immunoglobulin deposits are useful in pointing to a particular diagnosis.

Differential Diagnosis

Edema and proteinuria: Edema alone: Other diseases to rule out in patients who have edema without proteinuria include: Congestive heart failure, cirrhosis, hypothyroidism, nutritional hypoalbuminemia, protein-losing enteropathy

Treatment

Medication

First Line

Edema: Salt restriction and salt-wasting diuretics (loop and thiazide diuretics): Salt restriction to <6 g of sodium chloride (<2.4 g sodium/day)Restrict fluid intake to <1.5 L/day if hyponatremic.Target weight loss of 0.5–1 kg/d (1–2 lbs/d)Statins have been shown to improve endothelial function (1)[A] and decrease proteinuria (2)[A].Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers thought to reduce proteinuria, hyperlipidemia, thrombotic tendencies, progression of renal failure (1,3)[A], and to control hypertension if presentFor steroid-responsive disease (MCD and FGS), steroids dosed in consultation with nephrologist

Second Line

Many of the nephrotic diseases will require escalation in therapy above steroids. These include rapidly relapsing forms as well as MGN, LN, and IgA nephropathy: Bolus steroids and other immunosuppressives are required in this circumstance (cyclophosphamide, mycophenolate mofetil, chlorambucil, cyclosporine).Randomized controlled data has been insufficient to determine which patients require prophylactic anticoagulation (4)[A]. One practice is to anticoagulate with heparin and then warfarin in patients who have persistent nephrotic-range proteinuria. This decision is made based on patient’s history of edema, hypoalbuminemia, history of thromboembolism, or immobility.Hypocalcemia from vitamin D loss should be treated with oral vitamin D (dihydrotachysterol) 0.2 mg/d.

Additional Treatment

Ambulation or range-of-motion exercises to lower risk of deep vein thrombosis (DVT)

Issues for Referral

Consultation with a nephrologist is often required in order to assist with renal biopsy to confirm diagnosis and to assist with management of edema. Cytotoxic medications may be called for, depending on the disease process, and this may best be handled by the nephrologists.

In-Patient Considerations

Admission Criteria

Respiratory distress, sepsis/severe infection, thromboses, renal failure, hypertension, or other complications

Discharge Criteria

Hemodynamically stable patients without complications may be managed as outpatients.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

Frequent monitoring is required for relapse, disease progression, and for detecting signs of toxicity of medical management.Reevaluate for azotemia, hypertension, edema, loss of renal function, cholesterol, and weight.

Diet

Normal protein (1 g/kg/d)Low fat (cholesterol)Reduced sodiumSupplemental multivitamins and minerals, especially vitamin D and ironFluid restriction if hyponatremic

Patient Education

Printed material for patients: National Kidney Foundation, 30 E. 33rd Street, Suite 1100, New York, NY 10016; (800) 622-9010: Childhood Nephrotic SyndromeDiabetes and Kidney DiseaseFocal GlomerulosclerosisWeb site: National Institutes of Health: Nephrotic syndrome

Prognosis

The nephrotic syndrome in children (MCD) is typically self-limited and carries a good prognosis. In the adult, the prognosis is variable. Complete remission is expected if the basic disease is treatable (infection, malignancy, drug induced); otherwise, a relapsing and remitting course is possible, with progression to dialysis seen in more aggressive forms (diabetic glomerulosclerosis).

Complications

Thromboembolism: DVT and/or renal vein thrombosis may occur.The risk appears to be greater the lower the serum albumin.Pulmonary embolism is a known complication.Pleural effusionAscitesHyperlipidemia, cardiovascular diseaseAcute renal failure, progressive renal failureProtein malnutrition/muscle wastingInfection secondary to low serum IgG concentrations, reduced complement activity, and depressed T cell function: Loss of vitamin D (vitamin D binding protein loss in urine) leading to bone disease

References

1. Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) Lancet. 1997;349:1857–63.

2. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int. 2001;59:260–9.

3. Kunz R, Friedrich C, Wolbers M, Mann JF et al. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30–48.

4. Kulshrestha S, Grieff M, Navananeethan SD. Interventions for preventing thrombosis in adults and children with nephrotic syndrome (protocol). Cochrane Database Syst Rev. 2006;(2):CD006024.

Additional Reading

Madaio MP, Harrington JT. The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med. 2001;161:25–34.

Meyrier A. An update on the treatment options for focal segmental glomerulosclerosis. Expert Opin Pharmacother. 2009;10:615–28.

Schwarz A. New aspects of the treatment of nephrotic syndrome. J Am Soc Nephrol. 2001;12(Suppl 17):S44–7.

See Also (Topic, Algorithm, Electronic Media Element)

Amyloidosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glomerulonephritis, Acute; HIV Infection and AIDS; Multiple Myeloma; Renal Failure, Acute (ARF); Renal Failure, Chronic; Lupus Erythematosus, Discoid

Codes

ICD9

581.9 Nephrotic syndrome with unspecified pathological lesion in kidney

Snomed

52254009 Nephrotic syndrome (disorder)

Clinical Pearls

Pediatric nephrotic syndrome typically carries a good prognosis and is easily treated with steroids. Recurrences are common.Nondiabetic adults with nephrotic syndrome will require a renal biopsy to determine cause.Have a high index of suspicion for symptoms that may represent an embolic event