Marcello Amato

C.E.R.A. Corrects Anemia in Patients with Chronic Kidney Disease not on Dialysis: Results of a Randomized Clinical Trial

BACKGROUND AND OBJECTIVES This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation. RESULTS Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated. CONCLUSIONS Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

Management of hyperphosphataemia in chronic renal disease: lessons from the past and future directions

Sir, We read with great interest the recently published article by Malluche and Mawad [1] reviewing the challenging issue of phosphate control in chronic nephropaties. Usually, to ensure an adequate caloric intake, most patients with endstage renal disease (ESRD) are in positive phosphorus balance. Thus, control of blood phosphate concentrations has become a must in treating ESRD patients, but few issues have been as arguable as phosphate binder use. Aluminiumbased binders were found to cause bone and brain disorders while calcium-based binders were blamed for metastatic calcification and adynamic bone disease. The query for the identification of a safe and effective phosphate binder has been acknowledged in sevelamer hydrochloride, which has been welcome as an ideal binder. The ability of sevelamer to control serum phosphorus is unquestionable, but we would raise the question of its tolerability. The authors describe a low incidence of side effects associated with the use of sevelamer. In our experience, most haemodialysis patients complained of various gastrointestinal discomforts with sevelamer doses ranging from 1.2 to 2.0 guday, far below the mean daily dose of 5.4 guday reported to control blood phosphorus [2], and we were induced to stop therapy when increasing the drug dose in many instances. In the same study [2], 10.4% of the enrolled patients were reported to have discontinued treatment due to an adverse event, not a negligible value at all. We, and our patients too, believe that sevelamer side effects do not satisfy the requirements of an ‘ideal’ therapy. We reckon that it is a valuable add in the treatment of renal bone disease allowing lower doses of calcium-based phosphorus binders and decreasing the risk of hypercalcaemia. However, in our opinion the search for the safe, effective and ideal phosphate binder is still open, at least for the time being.

Association between Vitamin D Receptor Gene Polymorphism and Nephrolithiasis

Aims: To study the distribution of vitamin D receptor (VDR) gene alleles in hypercalciuric and nonhypercalciuric nephrolithiasis patients, hypothesizing that distinct biochemical parameters would be associated with different VDR genotypes. Methods: 12 hypercalciuric, 15 normocalciuric nephrolithiasis patients, and 150 healthy subjects were recruited. The individual genetic pattern for VDR was evaluated by DNA extraction followed by polymerase chain reaction amplification of the VDR gene and digestion with the restriction enzyme BsmI. Results: In the hypercalciuric group, Bb patients represented 50% (6/12); bb patients 33% (4/12), and BB cases were 16% (2/12). The VDR frequency distribution was not statistically different in hypercalciuric patients and controls (Bb 72%; bb 16%; BB 12%). In the nonhypercalciuric group, the prevalence of the bb genotype (7/15; 47%) was thrice the percentage of control subjects, while the percentage of BB patients was similar to that of the control group (2/15; 13%). Patients with the bb haplotype exhibited a higher daily urinary calcium excretion. Among hypercalciuric patients, after a calcium-restricted diet, bb patients showed a 39% reduction in daily urinary calcium excretion in comparison with a nonsignificant 13% reduction observed in BB subjects (p = 0.004). Conclusions: The effects of VDR gene polymorphism on calcium metabolism contribute to the understanding of the pathogenesis of urinary calculi.

Iron Indices and Vitamin D Receptor Polymorphisms in Hemodialysis Patients

Cardiovascular disease caused by accelerated atherosclerosis is the major determinant of morbidity and mortality in chronic kidney disease patients. Vitamin D and its analogs provide survival benefit for hemodialysis (HD) patients. Vitamin D exerts its effects through the vitamin D receptor (VDR) that is coded for by a gene showing several polymorphisms that, in turn, are associated with a variety of diseases and differential responses to vitamin D. In this study, we evaluated the association between 4 VDR polymorphisms (ie, those identified by the restriction enzymes BsmI, ApaI, TaqI, and FokI) and iron indices (serum iron, transferrin, transferrin saturation, and ferritin) in 88 hemodialysis patients routinely treated with vitamin D. The absence or presence of the BsmI, ApaI, TaqI, and FokI restriction sites were denominated B and b, A and a, T and t, F and f, respectively. Our results show that in HD patients with transferrin saturation <20%, the F allele was more frequent than in HD patients with transferrin saturation >20% (P = .03). This relationship may provide a link between VDR alleles and iron and nutritional markers, which are highly predictive variables of cardiovascular morbidity and mortality in hemodialysis patients.

Effects of Vitamin D3 and Paricalcitol on Immature Cardiomyocytes: A Novel Role for Vitamin D Analogs in the Prevention of Cardiovascular Diseases

Cardiovascular diseases are more prevalent in patients with chronic kidney disease than in the general population and they are considered the leading cause of death in patients with end-stage renal disease. The discovery that vitamin D3 plays a considerable role in cardiovascular protection has led, in recent years, to an increase in the administration of therapies based on the use of this molecule; nevertheless, several studies warned that an excess of vitamin D3 may increase the risk of hypercalcemia and vascular calcifications. In this study we evaluated the effects of vitamin D3, and of its selective analog paricalcitol, on immature cardiomyocytes. Results show that vitamin D3 induces cAMP-mediated cell proliferation and significant intracellular calcification. Paricalcitol, however, induces cell differentiation, morphological modifications in cell shape and size, and no intracellular calcification. Furthermore, vitamin D3 and paricalcitol differently affect cardiomyoblasts responses to acetylcholine treatment. In conclusion, our results demonstrate that the effects of vitamin D3 and paricalcitol on cardiomyoblasts are different and, if these in vitro observations could be extrapolated in vivo, they suggest that paricalcitol has the potential for cardiovascular protection without the risk of inducing intracellular calcification.

Vitamin D Receptor Gene Polymorphism and Diabetes mellitus Prevalence in Hemodialysis Patients

Accessible online at: www.karger.com/journals/nef Dear Sir, In a recent report, a significant excess transmission of vitamin D receptor haplotypes containing the b allele has been found in families affected by insulin-dependent diabetes mellitus, suggesting that a polymorphism within or close to the vitamin D receptor gene may influence the susceptibility to insulin-dependent diabetes [1]. Moreover, genetic risk factors in diabetic nephropathy have been identified [2]. The role of vitamin D receptor functional allelic variations in the regulation of different endocrine functions is suggested by studies of hemodialyzed patients with secondary hyperparathyroidism, revealing significantly higher circulating parathyroid hormone levels in bb patients than in BB patients [3]. Furthermore, it has been shown that vitamin D receptor gene alleles are differently associated with prostate cancer and breast cancer [4, 5] and nephrolithiasis [6]. In an effort to clarify the role, if any, of the vitamin D receptor gene alleles, the genotype was studied in 86 hemodialyzed patients treated in our hospital. The individual genetic pattern for the vitamin D receptor was evaluated by leukocyte DNA extraction followed by polymerase chain reaction amplification of the polymorphic site and digestion with the restriction enzyme BsmI, as described [3]. Allelic variants in the gene encoding the vitamin D receptor have been labeled as b, on the basis of the presence of the BsmI endonuclease restriction site, or as B, in case of its absence. The distribution of the three different genotypes among the hemodialyzed patients (BB 17.4%; Bb 60.5%; bb 22.1%) did not differ from what we observed in a Caucasian, nonuremic, control population [7]. The prevalence of diabetic subjects was 17.4%. We observed that no diabetic patient was present in the BB allele group (0/15), while they were found in the b allele sharing groups, either bb homozygous (4/19 or 21%) or Bb heterozygous (11/52 or 21%). The insulin secretion is influenced by vitamin D [8], and reduced vitamin D serum concentrations have been found in subjects at risk of non-insulin-dependent diabetes [9]. With regard to the specific sample of end-stage renal failure patients we investigated, vitamin D receptor gene polymorphism may be related to diabetes mellitus, as suggested by McDermott et al. [1], or, alternatively, to the rate of progression of diabetic nephropathy differently affected by the allelic variations in the vitamin D receptor. However, we believe that further studies are necessary to assess the role, if any, of the vitamin D receptor gene polymorphism in the pathophysiology of disorders such as diabetes mellitus, beyond the conventional boundaries of mineral metabolism. References