Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 22-15: Nephrotic Spectrum Glomerular Diseases + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Bland urine sediment (few if any cells or cellular casts) Nephrotic syndrome manifestations: Heavy proteinuria (urine protein excretion > 3 g per 24 hours) Hypoalbuminemia (albumin < 3 g/dL) Peripheral edema Hyperlipidemia Oval fat bodies may be seen in the urine +++ General Considerations ++ Causes Diabetes mellitus (most common) Minimal change disease FSGS Membranous nephropathy Amyloidosis Any of these entities can present on the less severe end of the nephrotic spectrum with a bland urinalysis and proteinuria, or with the most severe presentation of the nephrotic syndrome Serum creatinine may be abnormal at the time of presentation, depending on the severity and acuity of the disease +++ Clinical Findings ++ Patients with subnephrotic range proteinuria do not manifest symptoms of the kidney disease In those with the nephrotic syndrome, peripheral edema is present and is most likely due to sodium retention and hypoalbuminemia-induced low plasma oncotic pressure Edema May develop solely in dependent regions, such as the lower extremities May become generalized and include periorbital edema Dyspnea due to pulmonary edema, pleural effusions can occur Diaphragmatic compromise due to ascites can also occur + Diagnosis Download Section PDF Listen +++ +++ Laboratory Findings ++ Urinalysis Urinary dipstick is a good screening test for proteinuria; however, it detects only albumin A spot urine protein to urine creatinine ratio ([Uprotein]/[Ucreatinine]) gives a reasonable approximation of grams of protein excreted per day (ratio < 0.2 is normal and corresponds to excretion of < 200 mg/24 hours); a 24-hour urine sample for protein excretion is rarely needed Microscopically, the urinary sediment has relatively few cellular elements or casts However, if marked hyperlipidemia is present, urinary oval fat bodies may be seen Appear as "grape clusters" under light microscopy Appear as "Maltese crosses" under polarized light Blood chemistries Hypoalbuminemia (< 3 g/dL [30 g/L]) Hypoproteinemia (< 6 g/dL [60 g/L]) Hyperlipidemia Occurs in over 50% of patients with early nephrotic syndrome Becomes more frequent and worsens in degree as the severity of the nephrotic syndrome increases Patients may become deficient in vitamin D, zinc, and copper from loss of binding proteins in the urine Laboratory testing to determine the underlying cause may include Complement levels Serum and urine protein electrophoresis Serum free light chains Antinuclear antibodies PLA2R antibody titers Serologic tests for viral hepatitides +++ Diagnostic Procedures ++ Kidney biopsy Often performed in adults with new-onset idiopathic nephrotic syndrome if a primary renal disease that may require immunosuppressive therapy is suspected Chronically and significantly decreased GFR indicates irreversible kidney disease mitigating the usefulness of kidney biopsy In the setting of long-standing diabetes mellitus type 1 or 2, proteinuric renal disease is rarely biopsied unless Atypical features (such as significant glomerular hematuria or cellular casts) are also present There is other reason to suspect an additional renal lesion + Treatment Download Section PDF Listen +++ ++ Protein loss In those with subnephrotic proteinuria or mild nephrotic syndrome, dietary protein restriction may be helpful in slowing progression of kidney disease In those with proteinuria > 10 g/day, protein malnutrition may occur and daily protein intake should replace daily urinary protein losses In both diabetic and nondiabetic patients, ACE inhibitors and ARBs Lower urine protein excretion by reducing glomerular capillary pressure Have antifibrotic effects These agents can be used in patients with reduced GFR as long as significant hyperkalemia (potassium > 5.2–5.5 mEq/L or mmol/L) does not occur and serum creatinine rises < 30% Patients should be monitored closely to avoid AKI and hyperkalemia Combination therapy of an ARB and an ACE inhibitor increases risk for AKI and hyperkalemia and is not recommended Edema Dietary salt restriction is essential for managing edema Most patients also require diuretic therapy Both thiazide and loop diuretics are highly protein bound; therefore, with hypoalbuminemia and decreased GFR, diuretic delivery to the kidney is reduced, and patients often require larger doses A combination of loop and thiazide diuretics can potentiate the diuretic effect and may be needed for patients with refractory fluid retention Hyperlipidemia Dietary modification and exercise should be advocated; however, effective lipid-lowering usually also requires pharmacologic treatment There is significant risk of rhabdomyolysis in patients with CKD who take gemfibrozil in combination with statins Combining fenofibrate or niacin with a statin may be safer Hypercoagulable state Patients with serum albumin < 2 g/dL (20 g/L) can become hypercoagulable Patients with nephrotic syndrome Have urinary losses of antithrombin, protein C, and protein S and increased platelet activation Are prone to renal vein thrombosis, pulmonary embolus, and other venous thromboemboli, particularly with membranous nephropathy Anticoagulation therapy with warfarin is warranted for at least 3–6 months in patients with evidence of thrombosis in any location Patients with renal vein thrombosis, pulmonary embolus, or recurrent thromboemboli require indefinite anticoagulation + Outcome Download Section PDF Listen +++ +++ When to Refer ++ Any patient with the nephrotic syndrome should be referred immediately to a nephrologist for Volume and blood pressure management Assessment for kidney biopsy Treatment of the underlying disease Proteinuria of more than 1 g/24 hours without the nephrotic syndrome also merits nephrology referral, though with less urgency +++ When to Admit ++ Patients with edema refractory to outpatient therapy Patients with rapidly worsening kidney function that may require inpatient interventions + References Download Section PDF Listen +++ + +Agrawal S et al. Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. Nat Rev Nephrol. 2018 Jan;14(1):57–70. [PubMed: 29176657] + +Fallahzadeh MA et al. Acetazolamide and hydrochlorothiazide followed by furosemide versus furosemide and hydrochlorothiazide followed by furosemide for the treatment of adults with nephrotic edema: a randomized trial. Am J Kidney Dis. 2017 Mar;69(3):420–7. [PubMed: 28043731] + +McCloskey O et al. Diagnosis and management of nephrotic syndrome. Practitioner. 2017 Feb;261(1801):11–5. [PubMed: 29020719] + +Sexton DJ et al. Direct-acting oral anticoagulants as prophylaxis against thromboembolism in the nephrotic syndrome. Kidney Int Rep. 2018 Mar 3;3(4):784–93. [PubMed: 29989039] + +Snyder S et al. Workup for proteinuria. Prim Care. 2014 Dec;41(4):719–35. [PubMed: 25439530] + +Torban E et al. From podocyte biology to novel cures for glomerular disease. Kidney Int. 2019 Oct;96(4):850–61. [PubMed: 31420194]