In the United States, approximately 37 million people in the United States have chronic kidney disease (CKD), and in 2016, there were more than 720,000 patients with ESRD on various renal replacement therapies (hemodialysis, peritoneal dialysis, or kidney transplantation). Kidney disease was the 9^th leading cause of death in the US in the 2017. Diabetes mellitus (DM), hypertension, and glomerulonephritis are the top three causes of end-stage kidney disease (ESKD) in the US and these diseases often manifest with some degree of proteinuria. In addition to optimal blood pressure control, agents that block the renin-angiotensin system are commonly employed to decrease proteinuria and slow CKD progression in patients with these diseases.

Hyperphosphatemia is an interesting factor with regards to CKD progression. Past studies have shown increased risk of CKD progression in patients with high serum phosphate levels. High phosphate levels have also been associated with overt proteinuria in non-diabetic patients with late stage CKD. Hyperphosphatemia has also been shown to blunt the antiproteinuric and renoprotective effect of RAS blockers. Given all this, can lowering serum phosphate levels with binders decrease proteinuria and CKD progression?

Interestingly, a previously published randomized clinical trial studied the effects of sevelamer carbonate and calcium carbonate in patients with type 2 DM and albuminuria on advanced glycation end products. While overall, there was no differences in the GFR or albuminuria, further subgroup analyses showed that sevelamer reduced albuminuria in non-Caucasian patients and those <65 years of age. However, albuminuria increased in Caucasian patients after both sevelamer and calcium carbonate use. Of note, patients with hyperphosphatemia (>4.5 mg/dL) were excluded in this study.

A recent Italian study (the ANSWER trial) published in AJKD evaluated the effects of sevelamer carbonate in CKD patients with proteinuria. Ruggiero et al conducted a phase 2 randomized controlled, open-label, crossover trial to determine if sevelamar carbonate would enhance the antiproteinuric effects of RAS blockers. This 2-center clinical trial randomized 53 adult patients with CKD (eGFR >15 mL/min/1.73 m²) and 24-hr urine protein of ≥ 0.5 g despite maximal tolerated doses of an angiotensin converting enzyme inhibitor (ACE-I) and/or angiotensin receptor blocker (ARB).

Patients were initially stratified into 2 groups (serum phosphate level ≤4 or >4 mg/dL) and those with serum phosphorus levels <2.5 and >5.5 mg/dL were excluded. Each group was randomized to either one of the following treatments:

• 3 months of sevelamer carbonate (1600 mg three times a day with meals) followed by 1-month washout and 3 months without sevelamer
• 3 months without sevelamer, followed by 1-month washout and 3 months of sevelamer carbonate (1600 mg 3 times daily with meals).

The primary outcome measure of this study was the 24-hr urine protein level at the end of 2 treatments periods (with and without sevelamer compared to each pretreatment period). Several secondary outcomes were studied including measurement of office BP, GFR, urinary electrolytes, serum lipid profiles, inflammation, and bone mineral biomarkers. Patients were advised on low protein diets (approximately 0.8 mg/kg) before enrollment and were monitored by a dietician throughout the entire study period. At the time of randomization, 41 patients were on dual RAS blockade (ramipril and irbesartan), while the remaining 12 were on either ACE-I (n=7: six taking ramipril, one taking benazepril) or ARB therapy (n=5: four taking irbesartan, one taking valsartan). 26% of the patients in this study were diabetic.

While sevelamar was well tolerated, there was no significant difference observed in 24-hr protein levels at the end of the 2 treatment periods. Similarly there were no significant changes in proteinuria seen in the high or low phosphate groups. Adverse events were similar in the treatment periods, although one case of transient hypophosphatemia was seen during sevelamer treatment.

Primary efficacy outcome: Change in 24-hour urine protein excretion (by intention-to-treat analysis) in: (A) entire cohort, (B) high–serum phosphate (P) group, and (C) low–serum P group. Figure 2 from Ruggiero et al, AJKD © National Kidney Foundation.

For secondary outcome measures, sevelamer treatment did not significantly affect office BP readings, measured GFR, serum vitamin D, intact PTH, FGF-23, or klotho levels. Sevelamer, however, significantly decreased C-reactive protein and glycated hemoglobin levels while improving lipid profiles. While sevelamer reduced urinary phosphate excretion, serum phosphate levels were not affected.

Of note, other studies have also reported decreased C-reactive protein and glycated hemoglobin levels with sevelamer use. Similarly, increased HDL and lowering of both total and LDL cholesterol levels are known beneficial effects of sevelamer that have also been described. ANSWER was a randomized trial with small numbers and shorter duration of treatment, but here sevelamer did not further reduce proteinuria in CKD patients on maximally tolerated RAS blockade. While there may be additional benefits of sevelamar treatment (eg lipid lowering, anti-inflammatory effects), it seems that nephrologists cannot justify using these medications as antiproteinurics or to delay progression of CKD, and they remain relegated to management of hyperphosphatemia at this time.

– Post prepared by Hitesh H. Shah, AJKDBlog Contributor

To view Ruggiero et al (subscription required), please visit AJKD.org.

Title: Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial
Authors: B. Ruggiero, M. Trillini, L. Tartaglione, S. Rotondi, E. Perticucci, R. Tripepi, C. Aparicio, V. Lecchi, A. Perna, F. Peraro, D. Villa, S. Ferrari, A. Cannata, S. Mazzaferro, F. Mallamaci, C. Zoccali, A. Bellasi, M. Cozzolino., G. Remuzzi, P. Ruggenenti, D.E. Kohan, on behalf of the ANSWER Study Organization
DOI: 10.1053/j.ajkd.2019.01.029