Glomerulonephropathies are disorders that primarily affect the structure and function of the renal glomerular apparatus. Frequently encountered in clinical practice, glomerulopathies are usually suspected from the history and the urinary findings of hematuria, red cell casts, or proteinuria. The many different causes of glomerular disease can be generally classified into one of three major syndromes: Nephrotic syndrome, nephritic syndrome, and asymptomatic renal disease. However, there may be considerable overlap in their clinical presentation with some diseases presenting with components of both syndromes.
- Proteinuria >3.5 g/1.73 m2/24 hours (40–50 mg/kg/day).
Nephrotic syndrome may appear as a primary (idiopathic) renal disease or occur in association with any of a number of systemic conditions and hereditary diseases. The most common primary glomerular diseases include membranous nephropathy, focal segmental glomerular sclerosis, minimal change, and membranoproliferative glomerulonephritis (MPGN). In the United States, diabetes mellitus is the most common cause of nephrotic syndrome. Approximately one-third of patients with both type 1 and type 2 diabetes mellitus of at least a 25-year duration will develop nephrotic syndrome, predictably leading to renal failure. Other systemic diseases that may lead to the nephrotic syndrome include systemic lupus erythematous (SLE), amyloidosis, and leukemia.
Nephrotic syndrome generally reflects noninflammatory damage to the glomerular capillary wall. The underlying glomerular disease results in proteinuria, which occurs from alterations in the charge or size selectivity of the glomerular capillary wall. This increases glomerular permeability to plasma proteins. Albumin is the principal urinary protein lost, but other plasma proteins lost in the urine include hormone-carrying proteins such as vitamin D-binding protein, transferrin, and clotting inhibitors.
We do not know how to prevent primary nephrotic syndrome. Secondary nephrotic syndromes can often be improved and sometimes completely reversed by treating and controlling the underlying disease.
Nephrotic syndrome can present with a spectrum of findings ranging from asymptomatic proteinuria to the most common presentation of edema. Edema occurs initially in areas of high intravascular hydrostatic pressure such as in the feet and ankles as well as in areas in which tissue hydrostatic pressure is lowest such as the periorbital and scrotal areas. If the edema is severe and generalized it can present as anasarca.
Urine dipstick often demonstrates 3+ to 4+ protein and 24-hour urine collection with >3.5 g protein/1.73 m2. Proteinuria can also be estimated from a single urine specimen by calculating the ratio of total urine protein in mg/dL to urine creatinine in mg/dL. This ratio approximates the actual 24-hour protein excretion in grams per day per 1.73 m2 body surface area. Typically the urine sediment has few cells or casts. Urinary lipid may be present in the sediment. It may be entrapped in casts, free in the urine, or enclosed in the plasma membrane of degenerated epithelial cells known as oval fat bodies. Under polarized light, the lipid in oval fat bodies appears as “Maltese crosses” (Figure 23–1).
Polarized anisotropic fat droplets. Note the “Maltese-cross” formation. (Reproduced with permission from Graff L: A Handbook of Routine Urinalysis. J.B. Lippincott Company, 1983.)
Fundamental laboratory abnormalities in nephrotic syndrome include decreased serum albumin (<3 g/dL), decreased total serum protein (<6 g/dL), and hyperlipidemia. Patients may have elevations in their blood urea nitrogen (BUN) and creatinine, but the glomerular filtration rate (GFR) can be normal. Some patients may also manifest anemia, elevated erythrocyte sedimentation rate (ESR), hypocalcemia, and vitamin D deficiency. Other less common laboratory tests may be indicated depending on the patient's clinical presentation. These may include serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) to evaluate for myeloma or amyloidosis, and antinuclear antibody (ANA) to evaluate for SLE. Other tests might include hepatitis serologies, syphilis serology, HIV, complements, cryoglobulins, and thyroid function tests.
Indications for and benefits of a renal biopsy remain controversial. Nevertheless, it is the standard procedure for determining the cause of proteinuria in adults. Biopsy is often recommended when the etiology of nephrotic-range proteinuria is in doubt, prior to beginning cytotoxic drugs, when the presence of multiple diseases contributing to the clinical picture confounds the diagnosis, or if the patient's clinical course differs from the expected. In general, renal biopsy may be used to aid in management decisions, for example, whether to discontinue therapy because of lack of salvageable renal parenchyma.
The differential diagnosis in nephrotic syndrome can be narrowed significantly based on the patient's age, race, and urine evaluation. For example, minimal change accounts for the majority of cases in children. In adults worldwide, membranous nephropathy and focal glomerulosclerosis are among the commonest causes of primary nephrotic syndrome. In adults over the age of 50 years, membranous nephropathy is the most common cause of idiopathic nephrotic syndrome while focal glomerulosclerosis is the most common cause in African-Americans. Overall, about 50% of patients with nephrotic syndrome have a secondary cause, with the majority of these being secondary to diabetic nephropathy.
Numerous alterations in lipid profiles occur in the nephrotic syndrome as a result of increased synthesis and decreased catabolism of individual lipid fractions. These include hypercholesterolemia, hypertriglyceridemia, and increased low-density protein (LDL) and very low-density protein (VLDL). These abnormalities may possibly contribute to accelerated atherosclerosis.
Several abnormalities of the coagulation system occur in nephrotic syndrome. These abnormalities include urinary losses of antithrombin III, proteins C and S, and factors IX, XI, and XII. In addition, plasma fibrinogen, tissue plasminogen activator, and platelet aggregability are all increased. These aberrations lead to an increased incidence of venous and arterial thromboemboli, especially deep venous thrombosis, pulmonary embolism, and renal vein thrombosis. Renal vein thrombosis is most common in membranous nephropathy, with as many as 20–40% of patients affected.
Vitamin D Deficiency and Hypocalcemia
Vitamin D-binding protein is a relatively small protein (59 kDa) that is readily filtered and hence lost in the urine. ...