Dihydropyridine calcium channel blockers in the elderly with diabetic nephropathy: Are they safe?

Dihydropyridine calcium channel blockers (DHP-CCBs) are commonly prescribed antihypertensive medications that have been in use for over 3 decades. Traditional DHP-CCBs exert an action on L-type Ca+2 channels represented in the afferent arteriole. The additional blockade of T-type and N-type Ca+2 channels located in the efferent arteriole by efonidipine or manidipine can mitigate the hyperfiltration induced by afferent arteriolar dilatation.1 Griffin and colleagues2 reported that nifedipine treatment in rats resulted in glomerulosclerosis. Recently, a meta-analysis showed that T-type CCBs are more effective than the L-type CCBs in the protection of renal function.3 The Figure shows findings on kidney biopsy of a 74-year-old patient with diabetes mellitus who had rapid and irreversible decline in renal function following the initiation of a DHP-CCB. Arteriolar hyalinosis, as shown, can result in impaired glomerular perfusion. Even though no data from animal studies are available, there is indirect evidence that arteriolar hyalinosis affects renal function. Hill and colleagues4 suggested that arteriolar hyalinosis supports the presence of afferent arteriolar dilatation and loss of autoregulation resulting in transmission of high blood pressure to the glomerulus. Randomized controlled trials have tested the safety of DHP-CCBs and addressed cardiovascular and renal end points in comparison with different antihypertensive classes but did not adequately study renal outcomes in the elderly (>70 years) with chronic kidney disease and diabetic nephropathy. In ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), 57% of the participants were older than 65 years but 0.01% had diabetes mellitus, received amlodipine, and had an estimated glomerular filtration rate <60.5 Moreover, ALLHAT demonstrated good control of BP, with >65% of all participants achieving BP values <140/90 mm Hg. This effect on systemic BP by DHP-CCBs can counteract the risk from afferent arteriolar vasodilatation.6 IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction in End Points in NIDDM With the Angiotensin II Antagonist Losartan) trial both randomized patients with chronic kidney disease with diabetic nephropathy with >50% of the participants receiving amlodipine, but patients older than 70 years were excluded.7, 8 In AASK (African American Study of Kidney Disease and Hypertension), patients with diabetes mellitus and those older than 70 years were excluded.9 In the ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension) trial, 41% of the patients were older than 70 years, but only 6.1% had kidney disease while proteinuria was not reported.10 It should be noted that amlodipine and benazepril were combined in one arm of the ACCOMPLISH trial and this would be expected to attenuate hyperfiltration. In the Syst-Euro (Systolic Hypertension in Europe) trial where nitrendipine was the main antihypertensive medication used in the active arm, diabetes mellitus and proteinuria were not reported and patients with serum creatinine >180 μmol/L were excluded.11 In a recently published meta-analysis comparing the effect of DHP-CCBs with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists on end-stage renal disease and mortality, end-stage renal disease showed significantly higher frequency with DHP-CCBs although most of the randomized controlled trials included in the analysis were performed in patients without diabetes mellitus and elderly patients (>70 years) were excluded.12 On the other hand, several trials included elderly patients with diabetes mellitus and chronic kidney disease, but DHP-CCBs were not used.13-15 Projected life expectancy in the year 2030 will exceed 80 years in many industrialized countries.16 Attention to kidney disease progression will be more important than ever. Delaying progression of advanced kidney disease in the elderly might be nephrology's most important goal. It is clear that the effect of DHP-CCBs on renal function in elderly patients with chronic kidney disease and diabetic nephropathy needs to be clarified. The answer might exist in some of the already published clinical trials with an additional subgroup analysis.