1. Academic Validation
  2. Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial

Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial

  • Am J Kidney Dis. 2019 Sep;74(3):338-350. doi: 10.1053/j.ajkd.2019.01.029.
Barbara Ruggiero 1 Matias Trillini 1 Lida Tartaglione 2 Silverio Rotondi 2 Elena Perticucci 3 Rocco Tripepi 4 Carolina Aparicio 1 Veruska Lecchi 1 Annalisa Perna 1 Francesco Peraro 1 Davide Villa 1 Silvia Ferrari 1 Antonio Cannata 1 Sandro Mazzaferro 2 Francesca Mallamaci 4 Carmine Zoccali 4 Antonio Bellasi 5 Mario Cozzolino 6 Giuseppe Remuzzi 7 Piero Ruggenenti 8 Donald E Kohan 9 ANSWER Study Organization
Affiliations

Affiliations

  • 1 Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
  • 2 Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy.
  • 3 Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
  • 4 Bianchi-Melacrino-Morelli Hospital, Nephrology Unit, Reggio Calabria, Italy.
  • 5 Department of Nephrology and Dialysis, Sant'Anna Hospital, ASST-Lariana, Como, Italy.
  • 6 Renal Division, San Paolo Hospital, Milan, Italy.
  • 7 Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Italy. Electronic address: giuseppe.remuzzi@marionegri.it.
  • 8 Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
  • 9 Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT.
Abstract

Rationale & objective: Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (Ras) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of Ras inhibitors in patients with CKD.

Study design: Phase 2, randomized, controlled, open-label, crossover trial.

Setting & participants: Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy.

Intervention: After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period.

Outcomes: The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness.

Results: Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein Cholesterol levels and increased high-density lipoprotein Cholesterol levels without affecting levels of office BP, measured GFR, Fibroblast Growth Factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer.

Limitations: Short treatment duration, lower pretreatment proteinuria than expected.

Conclusions: 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal Ras blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria.

Funding: Sanofi (Milan, Italy).

Trial registration: Registered at ClinicalTrials.gov with study number NCT01968759.

Keywords

CKD progression; Chronic kidney disease (CKD); FGF-23; Klotho; RAS blockade; clinical trial; inflammation; mineral metabolism; phosphate binder; protein excretion; proteinuria; renin-angiotensin system (RAS); serum phosphate; sevelamer carbonate.

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