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Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study.
Kurumatani, H, Okada, K, Origasa, H, Fujita, T, Isono, M, Nakamoto, H
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):551-564
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Abstract
We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m2 .
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Prediction of microalbuminuria from proteinuria in chronic kidney disease due to non-diabetic lifestyle-related diseases: comparison with diabetes.
Ogi, M, Seto, T, Wakabayashi, Y
Clinical and experimental nephrology. 2021;(7):727-750
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Abstract
BACKGROUND To suppress increases in kidney failure and cardiovascular disease due to lifestyle-related diseases other than diabetes, early intervention is desirable. We examined whether microalbuminuria could be predicted from proteinuria. METHODS The participants consisted of adults who exhibited a urinary protein-to-creatinine ratio (uPCR) of < 0.5 g/gCr and an eGFR of ≥ 15 ml/min/1.73 m2 in their spot urine at their first examination for lifestyle-related disease. Urine was tested three times for each case, with microalbuminuria defined as a urinary albumin-to-creatinine ratio (uACR) of 30-299 mg/gCr, at least twice on three measurements. Youden's Index was used as an index of the cut-off value (CO) according to the ROC curve. RESULTS A single uPCR was useful for differentiating normoalbuminuria and micro- and macroalbuminuria in patients with non-diabetic lifestyle-related diseases. Regarding the GFR categories, the CO of the second uPCR was 0.09 g/gCr (AUC 0.89, sensitivity 0.76, specificity 0.89) in G1-4 (n = 197) and 0.07 g/gCr (AUC 0.92, sensitivity 0.85, specificity 0.88) in G1-3a (n = 125). Using the sum of two or three uPCR measurements was more useful than a single uPCR for differentiating microalbuminuria in non-diabetic lifestyle disease [CO, 0.16 g/gCr (AUC 0.91, sensitivity 0.85, specificity 0.87) and 0.23 g/gCr (AUC 0.92, sensitivity 0.88, specificity 0.84), respectively]. CONCLUSION Microalbuminuria in Japanese individuals with non-diabetic lifestyle-related diseases can be predicted from the uPCR, wherein the CO of the uPCR that differentiates normoalbuminuria and micro- and macroalbuminuria was 0.07 g/gCr for G1-3a, while that in G3b-4 was 0.09 g/gCr.
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Ferric Citrate Dosing in Iron Deficiency Anemia in Nondialysis-Dependent Chronic Kidney Disease.
Pergola, PE, Belo, D, Crawford, P, Moustafa, M, Luo, W, Goldfarb-Rumyantzev, A, Farag, YMK
American journal of nephrology. 2021;(7):572-581
Abstract
INTRODUCTION Ferric citrate (FC) is indicated as an oral iron replacement for iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis. The recommended starting dose is one 1-g tablet three times daily (TID). This study investigated long-term efficacy and safety of different FC dosing regimens for treating anemia in nondialysis-dependent CKD (NDD-CKD). METHODS In this phase 4, randomized, open-label, multicenter study, patients with anemia with NDD-CKD (estimated glomerular filtration rate, ≥20 mL/min and <60 mL/min) were randomized 1:1 to one FC tablet (1-g equivalent to 210 mg ferric iron) TID (3 g/day) or 2 tablets twice daily (BID; 4 g/day). At week 12, dosage was increased to 2 tablets TID (6 g/day) or 3 tablets BID (6 g/day) in patients whose hemoglobin (Hb) levels increased <0.5 g/dL or were <10 g/dL. Primary endpoint was mean change in Hb from baseline to week 24. RESULTS Of 484 patients screened, 206 were randomized and 205 received FC. Mean (standard deviation) changes from baseline in Hb at week 24 were 0.77 (0.84) g/dL with FC TID 3 g/day and 0.70 (0.98) g/dL with FC BID 4 g/day. DISCUSSION/CONCLUSIONS FC administered BID and TID for 48 weeks was safe and effective for treating anemia in this population, supporting potentially increased dosing flexibility.
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The cost-effectiveness of extended-release calcifediol versus paricalcitol for the treatment of secondary hyperparathyroidism in stage 3-4 CKD.
Kalantar-Zadeh, K, Hollenbeak, CS, Arguello, R, Snyder, S, Ashfaq, A
Journal of medical economics. 2020;(3):308-315
Abstract
Aims: Patients with chronic kidney disease (CKD) not on dialysis frequently have vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT), which are associated with an increased risk of cardiovascular (CV) disease, fracture, CKD progression, and death. This study estimated the cost-effectiveness of extended-release calcifediol (ERC) vs paricalcitol for the treatment of patients with CKD stages 3-4 that have SHPT and VDI.Materials and methods: An economic analysis of SHPT treatments among a hypothetical cohort of 1,000 patients with CKD Stage 3 and 4 with SHPT and VDI was developed to estimate differences in the rates and costs of CV events, fractures, CKD stage progression, and mortality in patients treated with ERC and paricalcitol. A Markov model was developed with 1-year cycles and a 5-year time horizon from a US Medicare payer perspective with costs valued in 2017 US dollars.Results: The outcomes of the model were rates of clinical events, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Across a 1,000-person cohort, ERC was the dominant (less costly, more effective) treatment strategy when compared with paricalcitol. Treatment with ERC resulted in cost savings of $14.8 M (95% CI = -$10.0 M-$45.2 M) and an incremental gain of 340 QALYs (95% CI = 200-496) compared to treatment with paricalcitol.Limitations: Bridging biochemical levels to clinical outcomes may not represent real-world risk of the clinical events modeled. Future real-world outcomes of patients treated with ERC and paricalcitol may be used to evaluate the model results.Conclusions: This model demonstrated favorable short- and long-term clinical benefits associated with the use of ERC in patients with CKD Stage 3 and 4 with SHPT and VDI, suggesting ERC may be cost-effective from the Medicare perspective compared to paricalcitol.
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Mineralocorticoid Receptor Antagonists for Hypertension Management in Advanced Chronic Kidney Disease: BLOCK-CKD Trial.
Bakris, G, Yang, YF, Pitt, B
Hypertension (Dallas, Tex. : 1979). 2020;(1):144-149
Abstract
Spironolactone, a steroidal mineralocorticoid receptor antagonist, is recommended as add-on therapy for treatment-resistant/uncontrolled hypertension. However, caution is advised in patients with advanced chronic kidney disease (CKD) due to an increased risk for hyperkalemia. KBP-5074 is a nonsteroidal mineralocorticoid receptor antagonist under investigation for the treatment of treatment-resistant and uncontrolled hypertension in patients with moderate-to-severe CKD. BLOCK-CKD is a phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of KBP-5074, on top of current therapy, in patients with stage 3B/4 CKD (estimated glomerular filtration rate ≥15 and ≤44 mL/[min·1.73 m2]) and resistant hypertension (trough cuff seated systolic blood pressure ≥140 mm Hg, despite treatment with maximally tolerated doses of 2 or more antihypertensive medicines with complementary mechanisms). Patients (n=240) will be randomized 1:1:1 to once-daily treatment with KBP-5074 0.25 mg, KBP-5074 0.5 mg, or placebo, stratified by estimated glomerular filtration rate (≥30 versus <30 mL/[min·1.73 m2]) and systolic blood pressure (≥160 versus <160 mm Hg). Approximately 30% of enrolled patients should have an estimated glomerular filtration rate of 15 to 29 mL/(min·1.73 m2). The primary efficacy analysis is the change in trough cuff seated systolic blood pressure from baseline to day 84 for the KBP-5074 doses compared with placebo. Changes in urinary albumin-creatinine ratio will be assessed along with changes in serum potassium/incidence of hyperkalemia and changes in estimated glomerular filtration rate and serum creatinine. BLOCK-CKD will determine whether the addition of KBP-5074 will effectively lower blood pressure without an increased risk of hyperkalemia in patients who are not candidates for steroidal mineralocorticoid receptor antagonists due to advanced CKD. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT03574363.
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Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.
Wesson, DE, Mathur, V, Tangri, N, Stasiv, Y, Parsell, D, Li, E, Klaerner, G, Bushinsky, DA
Lancet (London, England). 2019;(10179):1417-1427
Abstract
BACKGROUND Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (≤18 mmol/L vs >18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0·0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING Tricida.
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First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.
Renders, L, Budde, K, Rosenberger, C, van Swelm, R, Swinkels, D, Dellanna, F, Feuerer, W, Wen, M, Erley, C, Bader, B, et al
PloS one. 2019;(3):e0212023
Abstract
In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.
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Effects of the Potassium-Binding Polymer Patiromer on Markers of Mineral Metabolism.
Bushinsky, DA, Spiegel, DM, Yuan, J, Warren, S, Fogli, J, Pergola, PE
Clinical journal of the American Society of Nephrology : CJASN. 2019;(1):103-110
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BACKGROUND AND OBJECTIVES Patiromer is a sodium-free, nonabsorbed, potassium-binding polymer that uses calcium as the counter-exchange ion and is approved for treatment of hyperkalemia. The 4-week TOURMALINE study in patients with hyperkalemia previously demonstrated that patiromer administered once daily reduces serum potassium similarly when given with or without food. We report a prespecified exploratory efficacy analysis as well as a post hoc efficacy and safety analysis of the TOURMALINE study on circulating markers of mineral metabolism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Adults with hyperkalemia (potassium >5.0 mEq/L) were randomized to once-daily patiromer 8.4 g without/with food for 4 weeks, with doses adjusted to achieve and maintain serum potassium 3.8-5.0 mEq/L. Baseline and week 4 serum and 24-hour urine markers of mineral metabolism are reported for all patients combined (evaluable for efficacy, n=112; evaluable for safety, n=113). P values were calculated using a paired t test for change from baseline, unless otherwise specified. RESULTS Mean (SD) baseline eGFR was 41±26 ml/min per 1.73 m2. Mean (SD) changes from baseline to week 4 were 0.0±0.5 mg/dl (P=0.78; n=100) for albumin-corrected serum calcium, -0.2±0.2 mg/dl (P<0.001; n=100) for serum magnesium, and -0.1±0.7 mg/dl (P=0.47; n=100) for serum phosphate. Median (quartile 1, quartile 3) changes in 24-hour creatinine-normalized urine calcium and phosphate from baseline to week 4 were 2.5 (-11.5, 23.7) mg/24 h (P=0.10; n=69) and -43.0 (-162.6, 35.7) mg/24 h (P=0.004; n=95), respectively. Median (quartile 1, quartile 3) changes in intact parathyroid hormone and 1,25-dihydroxyvitamin D from baseline to week 4 were -13 (-31, 4) pg/ml (P<0.001; n=97) and -2 (-9, 3) pg/ml (P=0.05; n=96), respectively. There were no changes in fibroblast growth factor-23 or 25-hydroxyvitamin D. In patients (n=16) with baseline serum phosphate >4.8 mg/dL, the mean (SD) changes in serum and 24-hour creatinine-normalized urine phosphate from baseline to Week 4 were -0.6±0.8 mg/dl (n=13) and -149.1±162.6 mg/24hr (n=9), respectively. CONCLUSIONS Patiromer lowered urine phosphate in all patients, and lowered both serum and urine phosphate in a small subset of patients with hyperphosphatemia. Intact parathyroid hormone and 1,25-dihydroxyvitamin D decreased, with no change in serum calcium.
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Chronic kidney disease in propionic acidemia.
Shchelochkov, OA, Manoli, I, Sloan, JL, Ferry, S, Pass, A, Van Ryzin, C, Myles, J, Schoenfeld, M, McGuire, P, Rosing, DR, et al
Genetics in medicine : official journal of the American College of Medical Genetics. 2019;(12):2830-2835
Abstract
PURPOSE Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.
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Icosapent ethyl reduces atherogenic markers in high-risk statin-treated patients with stage 3 chronic kidney disease and high triglycerides.
Vijayaraghavan, K, Szerlip, HM, Ballantyne, CM, Bays, HE, Philip, S, Doyle, RT, Juliano, RA, Granowitz, C
Postgraduate medicine. 2019;(6):390-396
Abstract
Objective: Patients with chronic kidney disease (CKD) have increased cardiovascular disease (CVD) risk, likely driven by atherogenic and inflammatory markers beyond low-density lipoprotein cholesterol (LDL-C). The objective of this hypothesis-generating post hoc subgroup analysis was to explore the effects of icosapent ethyl at 2 or 4 g/day (prescription pure ethyl ester of the omega-3 fatty acid eicosapentaenoic acid [EPA]) on atherogenic lipid, apolipoprotein, inflammatory parameters (high-sensitivity C-reactive protein [hsCRP], lipoprotein-associated phospholipase A2 [Lp-PLA2]), and oxidative parameters (oxidized-LDL [ox-LDL]) in statin-treated patients from ANCHOR with stage 3 CKD.Methods: The 12-week ANCHOR study evaluated icosapent ethyl in 702 statin-treated patients at increased CVD risk with triglycerides (TG) 200-499 mg/dL despite controlled LDL-C (40-99 mg/dL). This post-hoc analysis included patients from ANCHOR with stage 3 CKD (estimated glomerular filtration rate [eGFR] ≤60 mL/min/1.73 m2 for ≥3 months) randomized to icosapent ethyl 4 g/day (n = 19), 2 g/day (n = 30), or placebo (n = 36).Results: At the prescription dose of 4 g/day, icosapent ethyl significantly reduced TG (-16.9%; P = 0.0074) and other potentially atherogenic lipids/lipoproteins, ox-LDL, hsCRP, and Lp-PLA2, and increased plasma and red blood cell EPA levels (+879% and +579%, respectively; both P < 0.0001) versus placebo. Icosapent ethyl did not significantly alter eGFR or serum creatinine. Safety and tolerability were similar to placebo.Conclusions: In patients with stage 3 CKD at high CVD risk with persistent high TG despite statins, icosapent ethyl 4 g/day reduced potentially atherogenic and other cardiovascular risk factors without raising LDL-C, with safety similar to placebo. These findings suggest prospective investigation may be warranted.