Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial.

BACKGROUND: We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment. METHODS: NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250-1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders. RESULTS: In the intention-to-treat population (NAMR: n = 539; placebo: n = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P < .001) with a mean difference of -0.39 mg/dl [95% confidence interval (CI) -0.66 to -0.13], but was comparable between the groups at week 52 [mean difference -0.08 (95% CI -0.36-0.20)]. In the completer population (n = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR. CONCLUSIONS: NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation.

Magnesium but not nicotinamide prevents vascular calcification in experimental uraemia.

BACKGROUND: Optimal phosphate control is an unmet need in chronic kidney disease (CKD). High serum phosphate increases calcification burden and is associated with mortality and cardiovascular disease in CKD. Nicotinamide (NA) alone or in combination with calcium-free phosphate binders might be a strategy to reduce phosphate levels and calcification and thus impact cardiovascular disease in CKD. METHODS: We studied the effect of NA alone and in combination with magnesium carbonate (MgCO3) as a potential novel treatment strategy. CKD was induced in dilute brown non-agouti/2 mice by subtotal nephrectomy followed by a high-phosphate diet (HP) and 7 weeks of treatment with NA, MgCO3 or their combination. Control mice underwent subtotal nephrectomy and received an HP or underwent sham surgery and received standard chow plus NA. RESULTS: CKD mice showed increased serum fibroblast growth factor 23 and calcium-phosphate product that was normalized by all treatment regimes. NA alone increased soft tissue and vascular calcification, whereas any treatment with MgCO3 significantly reduced calcification severity in CKD. While MgCO3 supplementation alone resulted in decreased calcification severity, it resulted in increased intestinal expression of the phosphate transporters type II sodium-dependent phosphate transporter 1 (Pit-1). Combined therapy of MgCO3 and NA reduced tissue calcification and normalized expression levels of intestinal phosphate transporter proteins. CONCLUSIONS: In conclusion, the data indicate that NA increases while MgCO3 reduces ectopic calcification severity. Augmented expression of intestinal phosphate transporters by MgCO3 treatment was abolished by the addition of NA. However, the clinical relevance of the latter remains to be explored. Importantly, the data suggest no benefit of NA regarding treatment of calcification in addition to MgCO3.

Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients.

Background: Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. Methods: We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. Results: We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Conclusion: Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.

Efficacy and Safety of a Novel Nicotinamide Modified-Release Formulation in the Treatment of Refractory Hyperphosphatemia in Patients Receiving Hemodialysis-A Randomized Clinical Trial.

INTRODUCTION: Despite widespread use of phosphate binders (PBs), phosphate control is insufficient in many hemodialysis patients. Preliminary clinical observations suggest that nicotinamide may act synergistically with PBs to improve phosphate control. METHODS: This multinational, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of nicotinamide modified release (NAMR) in combination with oral PB in a large cohort of hemodialysis patients with abnormal serum phosphate concentration (>4.5 mg/dl) despite treatment with PB. Patients entered a proof-of-efficacy phase (12 weeks [W12]) in which adjustments of relevant comedication were not permitted, followed by a safety extension phase for up to 52 weeks. Here, we report the results of the first phase. RESULTS: The intention-to-treat (ITT) population consisted of 539 patients in the NAMR and 183 patients in the placebo group. NAMR and placebo were orally administered once daily (250-1500 mg/d). Mean age of patients was 61.8 years, and 63.0% were men. In the confirmatory analysis that estimated the difference in serum phosphate concentration after 12 weeks, NAMR proved superior over placebo with a significant difference of -0.51 mg/dl (95% confidence interval [CI] -0.72, -0.29; P < 0.0001). This effect was associated with significantly lower intact parathyroid hormone (iPTH) values (NAMR: 292.4±300.4 pg/ml vs. placebo: 337.0±302.7 pg/ml; P = 0.04) and an improved calcification propensity (T50 time; NAMR: 23.8±97.1 minutes vs. placebo: 2.3±100.7 minutes; P = 0.02). Diarrhea and pruritus were more frequent in the NAMR group. CONCLUSION: NAMR combined with oral PB significantly improved phosphate control in hemodialysis patients.

Tectal mosaic: organization of the descending tectal projections in comparison to the ascending tectofugal pathway in the pigeon.

The optic tectum of vertebrates is an essential relay station for visuomotor behavior and is characterized by a set of connections that comprises topographically ordered input from the eyes and an output that reaches premotor hindbrain regions. In the avian tectofugal system, different ascending cell classes have recently been identified based on their dendritic and axonal projection patterns, although comparable information about the descending cells is missing. By means of retrograde tracing, the present study describes the detailed morphology of tectal output neurons that constitute the descending tectobulbar and tectopontine pathways in pigeons. Descending cells were more numerous in the dorsal tectum and differed in terms of 1) their relative amount of ipsi- vs. contralateral projections, 2) the location of the efferent cell bodies within different tectal layers, and 3) their differential access to visual input via dendritic ramifications within the outer retinorecipient laminae. Thus, the descending tectal system is constituted by different cell classes presumably processing diverse aspects of the visual environment in a visual field-dependent manner. We demonstrate, based on a careful morphological analysis and on double-labeling experiments, that the descending pathways are largely separated from the ascending projections even when they arise from the same layers. These data support the concept that the tectum is arranged as a mosaic of multiple cell types with diverse input functions at the same location of the tectal map. Such an arrangement would enable the tectal projections onto diverse areas to be both retinotopically organized and functionally specific.

The architecture of an inhibitory sidepath within the avian tectofugal system.

The tectofugal system dominates vision in most avian species. A key component of this pathway is the projection from the optic tectum onto the nucleus rotundus and the nucleus subpretectalis. Since subpretectalis has inhibitory projections onto rotundus, it constitutes a modulatory tectofugal sidepath to the tectorotundal system. We analyzed the connections and the immunocytochemical pattern of the subpretectalis in pigeons and show that it receives afferents from some tectal celltypes and from the nucleus pretectalis. Subpretectalis-neurons project non-topographically onto pretectalis and the rostrolateral rotundus. In addition, our immunocytochemical data make it likely that the cells of the subpretectalis receive glutamatergic and GABAergic input. These data provide evidence that the tectofugal sidepath over the subpretectalis could be involved in two major functions: The first is a modulation of attentional shifts from one eye to the other, while the second is a temporal fine-tuning of rotundal units.

The receptor architecture of the pigeons' nidopallium caudolaterale: an avian analogue to the mammalian prefrontal cortex.

The avian nidopallium caudolaterale is a multimodal area in the caudal telencephalon that is apparently not homologous to the mammalian prefrontal cortex but serves comparable functions. Here we analyzed binding-site densities of glutamatergic AMPA, NMDA and kainate receptors, GABAergic GABA(A), muscarinic M(1), M(2) and nicotinic (nACh) receptors, noradrenergic α(1) and α(2), serotonergic 5-HT(1A) and dopaminergic D(1)-like receptors using quantitative in vitro receptor autoradiography. We compared the receptor architecture of the pigeons' nidopallial structures, in particular the NCL, with cortical areas Fr2 and Cg1 in rats and prefrontal area BA10 in humans. Our results confirmed that the relative ratios of multiple receptor densities across different nidopallial structures (their "receptor fingerprints") were very similar in shape; however, the absolute binding densities (the "size" of the fingerprints) differed significantly. This finding enables a delineation of the avian NCL from surrounding structures and a further parcellation into a medial and a lateral part as revealed by differences in densities of nACh, M(2), kainate, and 5-HT(1A) receptors. Comparisons of the NCL with the rat and human frontal structures showed differences in the receptor distribution, particularly of the glutamate receptors, but also revealed highly conserved features like the identical densities of GABA(A), M(2), nACh and D(1)-like receptors. Assuming a convergent evolution of avian and mammalian prefrontal areas, our results support the hypothesis that specific neurochemical traits provide the molecular background for higher order processes such as executive functions. The differences in glutamate receptor distributions may reflect species-specific adaptations.