52-year-old man presented to the emergency department with general weakness and swelling in his legs. Symmetric swelling had begun 4 weeks earlier and had progressed to the point that it was difficult for him to wear shoes.

The nephrotic syndrome is most commonly caused by membranous nephropathy, focal segmental glomerulosclerosis, minimal-change disease, or membranoproliferative glomerular disease.

Clinical Pearls

• What are the diagnostic criteria for the nephrotic syndrome?

The diagnostic criteria for the nephrotic syndrome include nephrotic-range proteinuria (>3.5 g in 24 hours), hypoalbuminemia (<3 g of albumin per deciliter), peripheral edema, and hyperlipidemia.

• What are some of the causes of the nephrotic syndrome?

The nephrotic syndrome is most commonly caused by membranous nephropathy, focal segmental glomerulosclerosis, minimal-change disease, or membranoproliferative glomerular disease. All forms of the nephrotic syndrome may be associated with neoplasms, particularly lymphoma, which may cause a paraneoplastic-associated membranous nephropathy or minimal-change disease. Other secondary causes of the nephrotic syndrome include medications (e.g., nonsteroidal antiinflammatory agents); hepatitis or other chronic infections, including human immunodeficiency virus (HIV) infection; systemic lupus erythematosus; and amyloidosis.

Morning Report Questions

Q: Under what circumstances is hypothyroidism a possible complication of the nephrotic syndrome?

A: Hypothyroidism is an unusual complication of the nephrotic syndrome. The majority (99%) of T4 in the serum is bound to thyroid-binding proteins, including thyroid-binding globulin, transthyretin, and albumin. In patients with an intact hypothalamic-pituitary-thyroid axis, the thyroid gland compensates for urinary losses by increasing the production of T4. Consequently, despite heavy loss of proteins associated with the nephrotic syndrome, levels of biologically active free thyroid hormone are typically unaffected, and most patients with the nephrotic syndrome remain clinically euthyroid. However, patients who are reliant on a fixed exogenous source of T4 cannot compensate for the loss of T4, and thus, clinical hypothyroidism develops as a consequence of proteinuria. In patients who are dependent on exogenous thyroxine replacement, nephrotic-range proteinuria should prompt consideration of urinary loss of thyroid hormone.

Q: Describe some of the features of minimal-change disease.

A: Minimal-change disease is characterized clinically by nephrotic-range proteinuria and pathologically by diffuse effacement of epithelial foot processes on electron microscopy in the context of a relatively normal appearance on light microscopy. Although the disease has been reported after stem-cell transplantation, it is less common than membranous nephropathy in these patients. Glucocorticoids are the mainstay of drug therapy. Other immunomodulatory therapies, including calcineurin inhibitors, cytotoxic agents, rituximab, azathioprine, and mycophenolate mofetil, have been used in conjunction with low-dose glucocorticoids in patients who have unacceptable side effects with high-dose glucocorticoids or, more commonly, as glucocorticoid-sparing agents in relapsed disease. Adjunctive therapies for minimal-change disease typically include loop diuretics for edema, inhibitors of the renin-angiotensin-aldosterone system for hypertension and proteinuria, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins) for hyperlipidemia. Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers improve the size selectivity of the glomerular barrier and may have long-term renal protective effects. Relapses are common in minimal-change disease despite therapy, and younger patients (<40 years of age) are more likely to have a relapse than older patients. A small case series suggested that up to a quarter of patients have three or more relapses per year.