A 21-year-old woman with type 1 diabetes mellitus comes to the office for a follow-up appointment. She has been using daily long-acting and short-acting insulin injections from the time she was diagnosed 6 years ago. The patient was seen by her ophthalmologist 2 weeks ago and had no signs of diabetic retinopathy. She eats a balanced diet and jogs every morning for 40 minutes. On examination, the skin of her extremities is intact and peripheral pulses are palpable. Sensory examination shows normal pinprick, vibration, and temperature sensation in her lower extremities. Laboratory evaluation shows normal renal function and lipid profile. The patient's hemoglobin A1c level is 7%. Screening for early-stage diabetic nephropathy in this patient would best be accomplished by measuring the urinary concentration of which of the following substances?
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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the United States. It occurs in both types 1 and 2 diabetes. The earliest morphological change is glomerular basement membrane thickening with mesangial matrix expansion. Normally, the glomerular basement membrane has negatively charged heparan sulfate moieties that form a charge barrier preventing leakage of negatively charged proteins (eg, albumin) into the Bowman capsule. In diabetes, there is progressive loss of this negative charge due to upregulation of heparanase expression by renal epithelial cells, leading to leakage of albumin and other plasma proteins.
In the initial stages of DN, only small amounts of albumin (30-300 mg/day; ie, moderately increased albuminuria) are lost but can be detected with an albumin-specific urine assay (regular dipstick urinalysis has low sensitivity and is not recommended). Early administration of ACE inhibitors in patients with diabetes and moderately increased albuminuria can reduce urinary albumin excretion and slow progression to overt DN.
(Choice B) Glycosuria is seen at blood glucose levels >200-300 mg/dL due to saturation of renal glucose transporters. Glycosuria reflects poor glycemic control but does not correlate with the degree of renal damage in DN.
(Choice C) Ketonuria occurs in starvation and in conditions that cause ketoacidosis, such as insufficient insulin administration in patients with type 1 diabetes mellitus. It is usually a transient phenomenon that corrects with treatment of the ketoacidosis.
(Choice D) Red blood cell casts are a sign of glomerular bleeding, such as in glomerulonephritis (eg, poststreptococcal glomerulonephritis). Diabetes mellitus usually causes a nephrotic syndrome with proteinuria and a bland urine sediment.
(Choice E) Low-molecular-weight proteins (eg, beta-2 microglobulin, immunoglobulin light chains) are normally filtered by the glomerulus and reabsorbed in the renal tubules. Damage to the tubular cells can cause loss of these tubular proteins in urine. Ischemic tubular damage may be seen in advanced DN.
(Choice F) Waxy casts are shiny, translucent structures formed in the dilated tubules of enlarged nephrons that undergo compensatory hypertrophy in response to reduced renal mass. They indicate advanced renal disease (chronic renal failure).
Educational objective:
Moderately increased albuminuria (urine albumin 30-300 mg/day) is the earliest manifestation of diabetic nephropathy. Screening for diabetic nephropathy is best achieved using an albumin-specific urine assay (regular dipstick urinalysis has low sensitivity).