In American adults, the most common cause of nephrotic spectrum glomerular disease is diabetes mellitus. Other causes include minimal change disease, FSGS, membranous nephropathy, and amyloidosis. Any of these entities can present on the less severe end of the nephrotic spectrum with a bland urinalysis and proteinuria or on the most severe end of the full nephrotic syndrome. Serum creatinine may be abnormal at the time of presentation, depending on the severity and chronicity of the disease.
Patients with subnephrotic range proteinuria do not manifest symptoms of kidney disease. In those with the nephrotic syndrome, peripheral edema is present—most likely due both to sodium retention and hypoalbuminemia-induced low plasma oncotic pressure. Edema may develop solely in dependent regions, such as the lower extremities, or it may become generalized and include periorbital edema. Dyspnea due to pulmonary edema, pleural effusions, and diaphragmatic compromise due to ascites can occur.
Proteinuria occurs as a result of podocytopathy and variable alterations of the GBM. The urine dipstick is a good screening test for albuminuria; if positive, urinary protein excretion should be quantified (see earlier Proteinuria section). A spot urine protein to urine creatinine ratio gives a reasonable approximation of grams of protein excreted per day; 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. They appear as “grape clusters” under light microscopy and “Maltese crosses” under polarized light.
The nephrotic syndrome results in hypoalbuminemia (less than 3 g/dL [30 g/L]). Hyperlipidemia, due both falling oncotic pressure triggering increased hepatic production of lipids and to decreased clearance of very low-density lipoproteins causing hypertriglyceridemia, occurs in over 50% of patients with early nephrotic syndrome, and becomes more frequent and worsens in degree as the severity of the nephrotic syndrome increases. An elevated erythrocyte sedimentation rate may be seen as a result of increased levels of fibrinogen. Heavy urinary excretion of binding proteins may result in deficiencies of vitamin D, zinc, and copper.
Laboratory testing to help elucidate the underlying cause of the glomerular disease includes complement levels, serum and urine protein electrophoresis, serum free light chains, antinuclear antibodies, PLA2R antibody titers, HbA1c, and serologic testing for hepatitis B and C, HIV, and syphilis.