Nephrotic syndrome (aka totality of proteinuria)

Thanks Curtis for presenting an excellent case! Also many thanks to Robert Rope for attending and his knowledge bombs on nephrotic syndrome. This was a case of a patient with soft tissue sarcoma on chemotherapy with gemcitabine, well-controlled diabetes, presenting with subacute progressive bilateral lower extremity swelling found to have nephrotic syndrome thought due to membranous nephropathy vs minimal change disease secondary to the patient’s malignancy.


(Img: N Engl J Med 2013; 368:956-958)

Main points:

  • 1) Bilateral lower extremity edema is most commonly secondary to heart failure, liver failure, or renal failure/ nephrotic syndrome.
  • 2) Nephrotic syndrome is defined as the triad of (1) nephrotic range proteinuria (>3.5g/day), (2) hypoalbuminemia (serum albumin < 3) and (3) edema
  • 3) A complication of nephrotic syndrome is thromboembolism so if there is any suspicion for renal vein thrombosis, get a renal ultrasound with dopplers!

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Approach to bilateral lower extremity edema

  • 1) Most common causes: heart failure, liver failure, or renal failure/ nephrotic syndrome
  • 2) Less common/ don’t miss: hypoalbuminemia (2/2 malnutrition/ malabsorption), venous stasis, thromboembolism, refeeding syndrome, hypothyroidism, vasodilated state (sepsis, burns, severe allergic reaction), medications (anti-hypertensives, NSAIDs, vasodilators, steroids)

Approach to nephrotic syndrome

Nephrotic syndrome can be thought of as a primary condition or secondary to systemic disease. Rob Rope suggested a brief 5-item differential of: FSGS, membranous, minimal change, inflammatory (infection, malignancy, autoimmune) and meds. See this excellent former chief resident blog post on a more detailed approach to nephrotic syndrome.

Given this workup, consider ordering the following labs: A1C, lipid panel (HLD/lipiduria is common complication), coags, ANA, complements, SPEP/SFLC/UPEP, HIV, Hepatitis B and C Abs, RPR, renal ultrasound with dopplers… and don’t forget that usually you will need a kidney biopsy to make the definitive diagnosis!

Mini EBM: Nephrotic syndrome and cancer mortality

Curtis found a retrospective cohort study out of a National Danish registry of ~4000 patients with nephrotic syndrome as per ICD coding from 1980-2010. Of these, ~300 were diagnosed with cancer subsequently. This study tried to address whether the patients with nephrotic syndrome with subsequent cancer had an increased 5-year mortality as compared to those without nephrotic syndrome and cancer. It identified a comparison cohort from a Danish cancer registry of patients with cancer. The study used a cox regression adjustment for age, gender and comorbidity. It did not pre-define its endpoints, adjust for multiple hypothesis testing, propensity score match, or perform sensitivity analysis. At 5 years, 69% of patients with prior nephrotic syndrome died whereas 63% of patients without prior nephrotic syndrome died. It concluded that the adjusted hazard ratio was 1.20 for 5 year mortality (95% CI 1.02-1.42).