A 28-year-old man comes to the clinic for routine follow-up for type 1 diabetes mellitus. The patient was diagnosed 11 years ago and takes insulin as prescribed. He has no new concerns since his last visit. Temperature is 37.1 C (98.8 F), blood pressure is 124/76 mm Hg, and pulse is 72/min. Physical examination shows no evidence of peripheral neuropathy. Serum creatinine is 0.8 mg/dL and hemoglobin A1c is 7.4%. Urine albumin/creatinine ratio is 280 mg/g (increased from 220 mg/g a year ago). Pharmacologic therapy that accomplishes which of the following is most likely to slow the progression of renal disease in this patient?

Question

A 28-year-old man comes to the clinic for routine follow-up for type 1 diabetes mellitus.  The patient was diagnosed 11 years ago and takes insulin as prescribed.  He has no new concerns since his last visit.  Temperature is 37.1 C (98.8 F), blood pressure is 124/76 mm Hg, and pulse is 72/min.  Physical examination shows no evidence of peripheral neuropathy.  Serum creatinine is 0.8 mg/dL and hemoglobin A1c is 7.4%.  Urine albumin/creatinine ratio is 280 mg/g (increased from 220 mg/g a year ago).  Pharmacologic therapy that accomplishes which of the following is most likely to slow the progression of renal disease in this patient?

Quizplus · Accepted Answer

11ec25c8_d2b0_028e_bc81_6de48511ac02_MD0003_00 The early stages of diabetic nephropathy (DN) are characterized by a period of glomerular hyperfiltration involving an increase in the fraction of plasma that is filtered by each glomerulus. This period may be clinically recognized by slightly reduced serum creatinine as well as the onset of moderately increased albuminuria (ie, 30-300 mg/g) (formerly known as microalbuminuria). Glomerular hyperfiltration in early DN is primarily driven by an increase in hormonal mediators that favor afferent arteriole vasodilation (eg, natriuretic peptides, prostaglandins) and efferent arteriole vasoconstriction (eg, angiotensin II). This causes an increase in glomerular hydrostatic pressure, which increases the glomerular filtration rate; however, it also stimulates a sclerotic response in the glomerular capillaries and facilitates the gradual progression of DN. gradual progression Pharmacologic therapy with an ACE inhibitor (eg, lisinopril) or angiotensin II receptor blocker (eg, losartan) slows the progression of DN primarily by blocking angiotensin II-mediated renal efferent arteriole vasoconstriction. This reduces glomerular hydrostatic pressure, decelerating the development of glomerular capillary sclerosis. (Choice A) Renin-angiotensin-aldosterone system activity is already elevated in early DN. A further increase in aldosterone activity would increase blood volume and blood pressure and likely accelerate DN progression. (Choice B) Therapies that increase renal blood flow without reducing glomerular hydrostatic pressure, such as prostaglandin E2 analogs that preferentially dilate afferent arterioles, will likely accelerate the progression of DN. Although ACE inhibitor-induced alleviation of efferent arteriole vasoconstriction may increase renal blood flow, it more importantly reduces glomerular hydrostatic pressure. (Choice C) SGLT-2 inhibitors (eg, canagliflozin) decrease, rather than increase, renal tubular glucose absorption to facilitate glucose loss in the urine and improve blood sugar control. These drugs slow the progression of DN through a poorly understood mechanism. (Choice E) By reducing glomerular hydrostatic pressure, angiotensin II blockade secondarily reduces proteinuria via a reduction in the amount of protein that is filtered by the glomeruli. Alteration in the rate of renal tubular protein secretion or absorption is not a typical target of pharmacologic therapy. Educational objective: The early stages of diabetic nephropathy (DN) involve a period of glomerular hyperfiltration, which is primarily driven by an increase in hormonal mediators that lead to renal afferent arteriole vasodilation and efferent arteriole vasoconstriction. The consequent increase in glomerular hydrostatic pressure stimulates glomerular capillary sclerosis and facilitates the gradual progression of DN. ACE inhibitors and angiotensin II receptor blockers decrease renal efferent arteriole vasoconstriction, reducing glomerular hydrostatic pressure and slowing the rate of DN progression. References: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. (http://www.ncbi.nlm.nih.gov/pubmed/8413456) PGE2, kidney disease, and cardiovascular risk: beyond hypertension and diabetes. (http://www.ncbi.nlm.nih.gov/pubmed/26319242)

A 28-Year-Old Man Comes to the Clinic for Routine Follow-Up