Normally, the kidneys do not excrete appreciable amounts of protein (<150 mg/d) because serum proteins are excluded from the urine by the glomerular filter both by their large size and their net negative charge. Thus, the appearance of significant proteinuria heralds glomerular disease, with disruption of its normal barrier function. Proteinuria in excess of 3-3.5 g of protein per 1.73 m2 body surface area (normal adult male body surface area) per day is considered to be in the nephrotic range. The key feature of nephrotic syndrome is the heavy proteinuria, which leads to loss of albumin and other serum proteins. The hypoalbuminemia and hypoproteinemia result in decreased intravascular oncotic pressure, leading to tissue edema that usually starts in dependent areas such as the feet but may progress to involve the face, hands, and ultimately the whole body (anasarca). The decreased oncotic pressure also triggers the liver to start lipoprotein synthesis, thus leading to hyperlipidemia.
Patients typically present to the doctor complaining of the edema and have the laboratory features described earlier. Urinalysis usually shows few or no cellular elements and may show waxy casts and oval fat bodies (which look similar to Maltese crosses under polarized light) if hyperlipidemia is present.
In adults, one third of patients with nephrotic syndrome have a systemic-disease that involves the kidneys, such as diabetes or lupus; the remainder have a primary renal disease, with one of four pathologic lesions: minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis (FSGS). or membranoproliferative glomerulonephritis (MPGN). Thus, a new diagnosis of nephrotic syndrome warrants further investigation into an underlying systemic disease. Common tests include serum glucose and glycosylated hemoglobin levels to evaluate for diabetes, antinuclear antibody (ANA) to screen for systemic lupus erythematosus, serum and urine protein electrophoresis to look for multiple myeloma or amyloidosis, and viral serologies, because HIV and viral hepatitis can cause nephrosis. Less common causes include various cancers, medications such as nonsteroidal antiinflammatory drugs (NSAIDs). heavy metals such as mercury, and hereditary renal conditions. Of these causes, diabetes mellitus is by far the most common, as in the patient presented in this scenario.
Adults with nephrotic syndrome usually undergo renal biopsy, especially if the underlying diagnosis is unclear, or if there is a possibility of a treatable or reversible condition. Patients with advanced diabetes who have heavy proteinuria and microvascular disease, such as retinopathy, but no active (cellular components) on a urinary sediment are generally presumed to have diabetic nephropathy. These patients typically do not undergo renal biopsy because the nephrotic proteinuria represents irreversible glomerular damage.
Treatment of nephrotic syndrome consists of treatment of the underlying disease, if present, as well as management of the edema and attempts to limit the progression of the renal disease. For edema, all patients require strict salt restriction, but most patients will also need diuretics. Because both thiazide and loop diuretics are highly protein bound, there is reduced delivery to the kidney, and often very large doses are required to manage the edema. Countcrintuitively for a patient with hypoproteinemia, dietary protein restriction usually is recommended. It is thought that high protein intake only causes heavier proteinuria, which can have an adverse effect on renal function. Additionally, use of ACE inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria and slows the progression of renal disease in diabetics with proteinuria.
Besides the edema, patients with nephrotic syndrome have other consequences of renal protein wasting. They have decreased levels of antithrom-bin III and proteins C and S, and often are hypercoagulable, with formation of venous thromboemboli. including renal vein thrombosis. Patients with evidence of thrombus formation require anticoagulation, often for life. Other complications include hypogammaglobulinemia with increased infection risk (especially pneumococcal infection), iron deficiency anemia caused by hypotransferrinemia, and vitamin D deficiency because of loss of vitamin D-binding protein.
In the progression of diabetic nephropathy, initially the glomerular filtration rate (GFR) is elevated and then declines over time. Prior to the decline in GFR, the earliest stages of diabetic nephropathy can be detected as microalbuminuria. This is defined as a urine albumin excretion between 30 and 300 mg/d. It is possible to measure this in a random urine sample rather than a timed collection, because a ratio of albumin (in milligrams) to creatinine (in grams) of 30-300 usually correlates with the total excretion described. When albuminuria exceeds 300 mg/d. it is detectable on ordinary urine dipsticks, and the patient is said to have overt nephropathy.
After the development of microalbuminuria, most patients will remain asymptomatic, but the glomerulopathy will continue to progress over the subsequent 5-10 years until overt nephropathy develops. At this point, many patients have some edema, and nearly all patients have developed hypertension. The presence of hypertension will markedly accelerate the decline of renal function. Untreated, patients then progress to end-stage renal disease (ESRD). requiring dialysis or transplant, within a 5- to 15-year period.
The development of nephropathy and proteinuria is very significant because they are associated with a much higher risk for cardiovascular disease, which is the leading cause of death in patients with diabetes. By the time patients with diabetes develop ESRD and require dialysis, the average life expectancy is less than 2 years.
Thus, the development of microalbuminuria in diabetic patients is extremely important because of the progressive disease it heralds and because it is potentially reversible, or at least its progression to overt proteinuria can be slowed via medications. ACE inhibitors slow the progression of renal disease and should be initiated even when patients are normotensive. Tight glycemic control with a goal hemoglobin A|c <6.5-7.0 has also been shown to slow or prevent the progression of microvascular complications of diabetes, such as retinopathy and nephropathy. If overt nephropathy and hypertension have developed, blood pressure control with a goal <130/80 mniHg (or <125/75 mmHg if heavy proteinuria) is essential to slow progression.
In addition, because cardiovascular disease is the major killer of patients with diabetes, aggressive risk factor reduction should be attempted, including smoking cessation and reduction of hypercholesterolemia. In the newest recommendations regarding management of cholesterol, patients with diabetes now are regarded as the highest risk category, along with patients who already have established coronary artery or other atherosclerotic vascular disease; they should be treated with diet and statins with a goal low-density lipoprotein (LDL) cholesterol <100 mg/dL.
120.11 A 49-year-old woman with type 2 diabetes presents to your office for new onset swelling in her legs and face. She has no other medical problems and says that at her last ophthalmologic appointment she was told that the diabetes had started to affect her eyes. She takes glyburide daily for her diabetes. Physical examination is normal except for pitting edema of bilateral upper and lower extremities, hard exudates and dot hemorrhages on funduscopic exam, and diminished sensation to the mid-shin bilaterally. Urine analysis shows 3+ protein and 2+ glucose (otherwise negative). What is the best treatment for this patient?
A. Have the patient return in 6 weeks and check a repeat urine analysis at that time
B. Start metoprolol
C. Change the glyburide to glipizide and have the patient return for follow-up in 6 weeks
D. Start lisinopril
E. Refer the patient to a cardiologist
[20.2] Which of the following disease states is not known to be a common cause of nephrotic syndrome?
B. Urinary stones
D. Focal segmental glomerulosclerosis
E. Systemic lupus erythematosus
[20.3) What is the best screening test for early diabetic nephropathy?
A. Urine microalbuminuria
B. Dipstick urinalysis
C. Renal biopsy
D. Fasting blood glucose
E. 24-Hour urine collection for creatinine clearance
120.4] A 58-year-old man with type 2 diabetes is normotensive but has a persistent urine albumin/creatinine ratio of KM), but no proteinuria on urine dipstick. What is the best management for this patient?
A. Start ACE inhibitor
B. High-protein diet
C. Switch from oral agent to insulin
D. Refer to ophthalmologist for examination
[20.1 ] D. Beta-blockers are a good first-choice agent for a patient with hypertension and no comorbidities. However, for the patient with diabetes and nephropathy described in the clinical vignette, the benefit of an ACE inhibitor for decreasing proteinuria makes this the best choice for initial treatment. Changing from one sulfonylurea to another is of no benefit because all are equally efficacious. There is no indication for referral to a cardiologist based on the information provided in the vignette.
[20.2] B. Of all of the causes listed, urinary stones are not a common cause of nephrotic syndrome. The six most common causes of nephrotic syndrome are diabetes mellitus. membranous glomerulonephritis, FSGS, MPGN, minimal change disease, and amyloidosis. Other causes include toxins such as lead, gold, and heroin; infections such as HIV, hepatitis, streptococcus, and syphilis; and multisystem disorders such as lupus, Henoch-Schonlein purpura, sarcoidosis, Sjogren syndrome, and rheumatoid arthritis. A new diagnosis of nephrotic syndrome warrants further investigation into its etiology.
[20.3] A. Although a 24-hour urine collection for creatinine may be useful in assessing declining GFR, it is not the best screening test for the diagnosis of early diabetic nephropathy. In the outpatient setting, a dipstick urinalysis is readily available but will detect only patients with overt nephropathy (proteinuria >300 mg/d). Thus, a random urinary albu-min/creatinine ratio of 30-300 is the best test to screen for early diabetic nephropathy. A fasting blood glucose may aid in the diagnosis of diabetes but not nephropathy. Finally, although most patients with nephrotic syndrome require a renal biopsy for diagnosis, a patient with worsening renal function who has had long-standing diabetes is assumed to have renal disease secondary to diabetic nephropathy, and the majority of these patients do not undergo a renal biopsy.
[20.4] A. The albumin/creatinine ratio of 100 is indicative of microalbuminuria. Screening for microalbuminuria is very important because it is the one aspect of the disease that is reversible and to which physicians can target therapy to blunt the progression to overt renal failure. Disease progression is slowed with ACE inhibitors, blood pressure control, limited dietary protein intake, weight loss, and improved glycemic control.
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