The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the management of CKD-MBD are due to be updated in Q2 2017. Literature review is a key component of any guidelines update and the KDIGO committee has highlighted in advance new studies which they believe to be relevant to the treatment of hyperphosphatemia and secondary hyperparathyroidism (SHPT), and so may play a role in updating these chapters. The studies illustrate the growing understanding of the interrelationship between calcium, phosphate and parathyroid hormone (PTH), and a review of each is provided in this article.
Sevelamer vs calcium carbonate in haemodialysis patients: The INDEPENDENT study
- 466 incident haemodialysis patients were randomized to sevelamer or calcium carbonate for 24 months, with follow-up over 36 months
- Patients receiving sevelamer had a 10-fold risk reduction in mortality due to cardiac arrhythmias vs calcium carbonate (HR, 0.06; 95% CI, 0.01-0.25; P<0.001) and all-cause cardiovascular mortality vs calcium carbonate (HR, 0.09; 95% CI, 0.04-0.19; P < 0.001 )
Sevelamer vs calcium carbonate in non-dialysis patients
- 212 consecutive outpatients received either sevelamer or calcium carbonate and were observed for 24 months
- The proportion of patients achieving the target for serum phosphate concentration was similar between groups, while sevelamer resulted in greater PTH control vs calcium carbonate
- Serum calcium concentrations increased in the calcium carbonate group (P<0.01) and decreased for those on sevelamer (P<0.01)
- All-cause mortality was also significantly lower for patients on sevelamer vs calcium carbonate (P<0.01)
Phosphate binders in moderate CKD
- 148 patients with eGFR 20-45 ml/min/1.73msq were randomized to receive either placebo or active treatment (calcium acetate, lanthanum carbonate or sevelamer carbonate)
- Taking the average serum phosphate level at 3,6 and 9 months the results showed a significant reduction in serum phosphorus level with active treatment vs placebo (P=0.03)
- However, patients receiving active treatment also showed significant increases in coronary artery calcification vs placebo (P=0.03), which were most pronounced for patients on calcium acetate
Two further studies considered by KDIGO were meta-analyses, bringing together available data to provide greater insight.
Calcium-based vs non-calcium-based phosphate binders in all stages of CKD
- Inclusion of 11 randomised trials reporting mortality showed a 22% reduction in all-cause mortality for patients on non-calcium-based binders (non-CBBs) vs calcium-based binders (CBBs) (risk ratio 0·78, 95% CI 0·61–0·98)
- Patients on non-CBBs had greater reduction in vascular calcification vs those on CBBs at every time point (significant at longest follow-up, p=0.0003)
- Serum phosphate reductions did not differ between treatment groups
Sevelamer vs CBBs in CKD stages 3-5D
- This more recent meta-analysis included 25 studies published up to March 2015 in patients with CKD stages 3-5D and reported significantly lower all-cause mortality (RR, 0.54; 95% CI, 0.32-0.93) for patients on non-CBB (sevelamer) vs CBBs
- At the end of treatment, intact PTH was significantly higher for sevelamer vs CBBs, while serum phosphate values showed no significant difference
Secondary hyperparathyroidism and vitamin D therapy
Vitamin D is accepted therapy for SHPT; two studies evaluated by KDIGO investigated any effect of active vitamin D on left ventricular (LV) mass and function given the presence of vitamin D receptors in vascular and cardiac tissues.
Paricalcitol 2µg/day: The PRIMO study
- 227 patients with eGFR15 to 60 mL/min/1.73m2, mild to moderate LV hypertrophy and preserved LV ejection fraction were randomized to 2µg paricalcitol or placebo for 48 weeks
- Paricalcitol treatment reduced serum PTH levels within 4 weeks and maintained levels within the normal range for the remainder of the study
- No significant change in LV mass index was found for paricalcitol vs placebo, nor were there any differences in echocardiographic measures of diastolic function
- A slightly higher number of patients treated with paricalcitol withdrew from the study due to adverse events, primarily due to hypercalcemia
Paricalcitol 1µg/day: The OPERA study
- 60 patients with CKD stages 3-5 and LV hypertrophy were randomized to 1µg of paricalcitol or placebo for 52 weeks
- There was no significant difference in change in LV mass between treatment groups, and no difference in other cardiac or echocardiographic parameters, including LV volume
- Serum calcium levels increased in the paricalcitol group vs placebo group (P=0.03) and more paricalcitol patients had hypercalcemia, however, most of these patients were receiving concomitant CBBs
- However, the number of cardiovascular-related hospitalizations was lower in the paricalcitol-treated cohort
The studies highlighted by the KDIGO committee provide important data for consideration in the new guidelines and suggest a more restricted role for calcium-based binders across the CKD disease spectrum after considering the existence and/or the absence of other components of the CKD-MBD syndrome. The evidence for early hyperphosphatemia treatment in pre-dialysis patients suggests a potential risk of increased coronary artery calcification, further supporting the need for careful selection of treatment options in this population. The new data for vitamin D therapy in pre-dialysis patients also highlights the potential for hypercalcemia with paricalcitol treatment, without providing evidence of clear cardioprotective effects.
The studies selected by the KDIGO committee confirm the need for further research into the therapeutic options for CKD-MBD, and the importance of considering all parameters when managing this complex condition.
- KDIGO CKD-MBD Guidelines.
- Public Review | KDIGO 2016 Clinical Practice Guideline Update on Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD.
- Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in incident hemodialysis patients: Results of an open-label 24-month randomized clinical trial. Am J Kidney Dis. 2013;62(4):771-778. doi:10.1053/j.ajkd.2013.03.023.
- Di Iorio B, Bellasi A, Russo D. Mortality in kidney disease patients treated with phosphate binders: A randomized study. Clin J Am Soc Nephrol. 2012;7(3):487-493. doi:10.2215/CJN.03820411.
- Block GA, Wheeler DC, Persky MS, et al. Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-1415. doi:10.1681/ASN.2012030223.
- Jamal S, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382(9900):1268–1277.
- Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016;11(2):232-244. doi:10.2215/CJN.06800615.
- Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial. JAMA. 2012;307(7):674-684. doi:10.1001/jama.2012.120.
- Wang AY-M, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD–the OPERA trial. J Am Soc Nephrol. 2014;25(1):175-86. doi:10.1681/ASN.2013010103.