Non-dihydropyridine Calcium Channel Blockers for the Treatment of Proteinuria

Ben Hierlmeier, Pharm.D., Park Nicollet

Background: Proteinuria is a commonly assessed marker for progression of renal disease.  The renoprotective benefits from the use of angiotensin-converting enzyme inhibitors (ACE-Is)  and angiotensin receptor blockers (ARBs) for proteinuria is well-documented and supported by many large, well-designed studies. The question still remains for preferred second line therapy, either for patients with a contraindication to ACE-Is/ARBs or for those who are on maximally tolerated ACE-Is/ARBs and have more room for improvement in proteinuria. There is evidence to support a role for nondihydropyridine calcium channel blockers (non-DHP CCBs) in such situations, although the data is far less robust than for ACE-Is or ARBs.

The mechanism of renoprotection for ACE-Is and ARBs is likely related to lower glomerular capillary bed pressure and protein filtration, however the mechanism for non-DHP CCBs is not well characterized. It is theorized that these medications act through mechanisms not related to known hemodynamic effects, such as reduction in glomerular permeability and prevention of mesangial matrix expansion and glomerulosclerosis. A recent review by Steuber et al. combed the literature to assess the role in therapy for non-DHP CCBs for proteinuria in patients with existing kidney disease.

Evidence: The review article included 13 trials evaluating the use of non-DHP CCBs; nine evaluated the use of verapamil, three evaluated diltiazem, and one included both medications. The trials used a variety of measures to assess progression of kidney disease including urinary evaluation of albumin secretion, albumin-to-creatinine ratio, protein-to-creatinine ratio, serum creatinine, creatinine clearance, and glomerular filtration rate. All of the studies suggested non-DHP CCBs have some beneficial effects on progression of kidney disease, but many had small sample sizes, making it difficult to show significant differences between treatment groups. Only three of 13 studies included more than 100 patients.  Ten of the trails looked at non-DHP CCBs in addition to ACE-Is and three investigated non-DHP CCBs as monotherapy. Whether used as an add-on or monotherapy, the non-DHP CCB groups showed trends toward reduction in proteinuria.

The studies included had many limitations. Many measured surrogate markers rather than clinical outcomes, doses and trial design varied significantly, the majority of the trials were more than 10 years old, none of the trials measured adherence, and there were significant drop out rates in multiple studies. There is a clear need for larger studies that incorporate more patient-oriented renal and cardiovascular outcomes with non-DHP CCBs.

Clinical Impact: The data supports controlling hypertension and diabetes, and using ACE-Is or ARBs as first line treatment for proteinuria. The literature does suggest non-DHP CCBs can also be effective and are a reasonable option for patients who cannot tolerate or have a contraindication to ACE-Is or ARBs. These treatment options would also likely benefit patients on maximally tolerated ACE-Is or ARBs, but continue to have progression of proteinuria. Non-DHP CCBs should be initiated at the lowest dose and titrated up slowly based on tolerability.

References:

  1. Steuber TD, Lee J, Holloway A, Andrus MR. Nondihydropyridine Calcium Channel Blockers for the Treatment of Proteinuria: A Review of the Literature. Ann Pharmacother. 2019 Apr 9.