Calcification in Chronic Kidney Disease — What’s New in Phosphate Binders?
Dr. Appel started with the NEJM article from 2010. This article reviewed oral phosphate binders in CKD. Historically, phosphate binders were used to control hyperparathyroidism, but recent data now strongly suggests that phosphate binders should be used to mitigate vascular calcification. Vascular calcification corresponds to increased death and may correspond to the use of calcium-based phosphate binders. Thus far, there are no randomized trials that show that lowering phosphate increases survival — it is simply a correlation.
The DCOR study (n = 2100 patients) is the only study that had sufficient power to detect a difference in mortality based on the type of phosphate binder used. This study compared sevelamer against calcium-based phosphate binders (calcium carbonate or calcium phosphate). Primary analysis revealed no significant difference in mortality. Dr. Appel believes that the secondary analysis showed (rather than suggested, as the article states) that sevelamer is superior in patients over the age of 65. If you received a calcium-based phosphate binder, your survival (at the end of 3 years) was no different than if you received sevelamer. However, in patients over age 65, calcium-based binders had a higher mortality than those taking sevelamer. Unfortunately, the DCOR study can be interpreted in many ways, depending on which end points you choose to believe, especially because conclusions can be based on economics.
In the US, dialysis patients spend about 13 days hospitalized per year (data from the NKF meetings in Orlando in 2009). In a secondary analysis of the DCOR Trial, 10% less hospitalizations per year and 12% less hospital days per year occurred in the sevelamer group. In other words, one would avoid 119 hospital days if 75 dialysis patients were on sevelamer than a calcium-based phosphate binder. Extrapolated to the entire US population on dialysis (n = 360,000), we would avoid 581,000 hospital days and maintain 249,000 in-center dialysis days. Financially, for a dialysis unit, sevelamer would be the better phosphate binder.
The conclusion of the 2010 NEJM article was that a calcium-based phosphate binders are recommended as first line agents because they are the least expensive. Dr. Appel believes that avoiding hospital days and maintaining in-center dialysis days would be more cost-effective. In addition, he believes the litmus test in deciding on which binder to use should be based on what we would choose for a family member.
Dr. Appel turned his attention to binder characteristics. Calcium carbonate and acetate are effective but are absorbed, contribute to the calcium-phosphate product, and have no lipid-lowering effect. Calcium-magnesium combinations are also used, but not widely. Lanthanum is absorbed and is accumulated in the bone (see 2010 NEJM article). Sevelamer is effective, not absorbed, lowers lipids (up to 30% LDL lowering), and does not contribute to the calcium-phosphate product. However, lipid-lowering is not likely to mitigate mortality (see 4D, AURORA, and SHARP Trials).
Phosphate binders have also been studied in in non-dialysis CKD patients. 1000 VA patients were investigated over 3 years — treatment with phosphate binders in CKD III and IV patients was associated with lower mortality. Dr. Appel believes this is the future in phosphate binders: starting early to prevent the long-term vascular calcification damage seen in CKD V and ESRD patients.
Renvela versus Renagel in slowing the progression of CKD: renvela raises the bicarbonate because it is bicarbonate-based. A RCT of 134 patients with CKD and bicarbonate 16–20 mEq/L were given bicarbonate and the rate of decline of creatinine clearance was slower than in the control group. 9% of the renvela group had rapid progression to ESRD versus 45% in the control group. Experimental data in animals suggest that sodium bicarbonate acts on endothelin in interstitial cells and interstitial fibrosis.
In a study by Don Wesson in KI in 2010, patients with hypertensive nephropathy were randomized to receive either, placebo, sodium chloride, or sodium bicarbonate for 5 years. 40 patients in each arm, 66% were African-American. All arms achieved equal BP control. Sodium bicarbonate slowed progression of CKD the most (less albuminuria, lower urinary endothelin levels, lower cystatin C levels, and lower creatinine decline). Simply administering bicarbonate, regardless of whether you raise the serum bicarbonate level, can slow the progression of CKD.
Both PTH and FGF-23 increase in early CKD. FGF-23 is produced by osteocytes and is a phosphaturic hormone. It blocks the reabsorption of phosphate in the proximal tubule and downregulates production of 1,25 vitamin D. Higher FGF-23 levels correlate with vascular calcification, CKD progression, and mortality. In a 6-week study of 40 patients with CKD III or IV using calcium acetate or sevelamer, sevelamer lowers PTH and FGF-23 more than calcium acetate.