Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis.

INTRODUCTION: Idiopathic focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. In preclinical models and biopsies of human FSGS kidneys, p38 mitogen-activated protein kinase (MAPK) has demonstrated enhanced activity; and p38 MAPK inhibition has improved disease markers. This proof-of-concept trial aimed to assess efficacy, safety, tolerability, and pharmacokinetics of losmapimod, an oral p38 MAPK inhibitor, in humans with FSGS. METHODS: A single-arm, multicenter, open-label, Phase II trial (NCT02000440) was conducted in adults with FSGS; proteinuria ≥2.0 g/d; estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2; blood pressure <140/90 mm Hg. Collapsing and genetic forms of FSGS were excluded. The primary endpoint was number of patients with ≥50% proteinuria reduction and eGFR ≥70% of baseline after receiving losmapimod twice-daily for 16 to 24 weeks. RESULTS: Seventeen patients received ≥1 losmapimod dose. No patients achieved the primary endpoint; therefore, the study was terminated following a prespecified interim analysis. At week 24, proteinuria reductions between 20% and <50% were observed in 4 patients and proteinuria increases >20% in 3 patients. One patient achieved a proteinuria response (≥50% reduction) at week 2 but subsequently relapsed. Losmapimod pharmacokinetics were consistent with prior studies. No serious adverse events (AEs) were reported. CONCLUSION: p38 MAPK inhibition with losmapimod did not result in ≥50% reduction of proteinuria in patients with FSGS. However, study population heterogeneity may have contributed to our negative findings and therefore this does not eliminate the potential to demonstrate benefit in a population more sensitive to p38 MAPK inhibition if identifiable in the future by precision-medicine methods.

Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.

BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.)

Vitamin D insufficiency and treatment with oral vitamin D3 in northern-dwelling patients with chronic kidney disease.

BACKGROUND: Vitamin D insufficiency is common in people living at northern latitudes and those with chronic kidney disease (CKD). We studied persons with both of these risk factors to determine the prevalence of vitamin D insufficiency and whether serum 25-hydroxyvitamin D (25(OH)D) levels were affected by oral vitamin D3 supplementation. METHODS: This was a prospective controlled trial of 128 patients with stage 3-5 non-dialysis dependent CKD. Patients were assigned to the intervention (oral vitamin D3 1,000 IU/day) in a 1:1 ratio at the discretion of the attending dietitian. Serum biochemical markers were measured at baseline (May-July) and after 3 months of follow-up. There were 63 control and 65 intervention subjects. RESULTS: Mean 25(OH)D levels increased significantly higher in the treatment group (mean increase from baseline: 10.3+/-10.4 ng/mL vs. 0.8+/-6.8 ng/mL, p<0.0001). This difference remained significant after adjustment for differing baseline characteristics between groups (p<0.0001). Treatment with oral vitamin D3 reduced vitamin D insufficiency by 37%, as compared with a 2% increase in prevalence among the control group (p<0.0001). Considering the entire study population, 93% of patients had levels less than <30 ng/mL at least once during the study. CONCLUSION: Vitamin D insufficiency is highly prevalent in northern-dwelling patients with stage 3-5 CKD, and is moderated by oral supplementation with 1,000 IU of vitamin D3 daily.

Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study.

BACKGROUND: Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life ( approximately 130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis. METHODS: STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within +/- 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29-36). RESULTS: Most patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (-0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated. CONCLUSIONS: Stable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA.

Evaluation of an anemia algorithm in chronic hemodialysis patients.

Although anemia is a common complication of chronic kidney disease, practice variability in its management continues to exist. In an effort to standardize management, the Northern Alberta Renal Program implemented an anemia algorithm, the "Anemia Protocol." A cohort design was used to evaluate the effectiveness of the "Anemia Protocol" in 98 patients three months pre-implementation and three and six months post- implementation. Clinical outcomes of hemoglobin levels, iron indices, erythropoietin and iron dosages, and its associated costs, were compared pre- and post-implementation of the algorithm. This study did not show significant change in anemia or anemia management pre- versus post-implementation of the "Anemia Protocol" in the Northern Alberta Renal Program. However, this is not to imply that algorithms are not useful in clinical settings. Anemia algorithms are invaluable in standardizing management and limiting practice variability, but to ensure that intended clinical outcomes are achieved, algorithms need to be regularly evaluated and revised as necessary.