Carlo Alfieri

Recent insights into vitamin D and its receptor

The widely differing functions of vitamin D are based both on a wide diffusion of its specific receptor (VDR) and on the ability of many cells, in addition to renal tubular cells, to synthesize calcitriol for autocrine and paracrine functions. In the last few years, many published studies have added new insights into some important points on this topic. Recent data suggest that the control of calcitriol synthesis at tissue levels other than kidneys might differ greatly from the control system working at the renal level. Furthermore, the mechanisms by which the VDR might mediate either the genomic and nongenomic (rapid) vitamin D-mediated effects became much clearer. However, new evidence accumulated suggests that some additional receptor(s), responsive to vitamin D and different from the VDR, could play a role in the rapid response to vitamin D, probably interfering also with the genomic pathway. In this context, there are new possible interpretations of the mechanisms by which different vitamin D metabolites might express variable activities at different levels. In addition, some recent data have challenged the role of the VDR in direct parathyroid hormone (PTH) control, at least in physiological conditions, suggesting that vitamin D-mediated PTH inhibition is mainly secondary to the intestinal effect on calcium absorption. Finally, there is a renewed interest in the field of polymorphic variants in the VDR gene in relation to some clinical conditions, though the mechanisms underlining these associations are far from being clear. The present review briefly addresses all of the above points.

Cinacalcet: pharmacological and clinical aspects

The calcium sensing receptor (CaSR) is expressed in cells secreting calcium-regulating hormones, in cells involved in calcium transport and in many other tissues, with an as yet not completely defined role. In parathyroid cells, the CaSR stimulation inhibits parathyroid hormone (PTH) secretion, synthesis and parathyroid cell proliferation. Cinacalcet belongs to calcimimetic type II compounds that can interact with CaSR, increasing its affinity for calcium. Clinical studies have proved cinacalcet to be effective in reducing calcium and PTH levels in primary hyperparathyroidism and in reducing PTH, calcium and phosphate in patients with secondary hyperparathyroidism owing to chronic renal failure, with a relatively safe profile, the only reported adverse events being hypocalcaemia and gastrointestinal symptoms. However, though calcimimetics do represent a real advancement in the field of the treatment of PTH secretion disturbances, there is a need for clinical trials, which should aim to demonstrate that a better control of biochemical parameters is also matched with better clinical outcomes.

Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease

The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.

Clinical impact of hypercalcemia in kidney transplant.

Hypercalcemia (HC) has been variably reported in kidney transplanted (KTx) recipients (5–15%). Calcium levels peak around the 3rd month after KTx and thereafter slightly reduce and stabilize. Though many factors have been claimed to induce HC after KTx, the persistence of posttransplant hyperparathyroidism (PT-HPT) of moderate-severe degree is universally considered the first causal factor. Though not proven, there are experimental and clinical suggestions that HC can adversely affect either the graft (nephrocalcinosis) and other organs or systems (vascular calcifications, erythrocytosis, pancreatitis, etc.). However, there is no conclusive evidence that correction of serum calcium levels might avoid the occurrence of these claimed clinical effects of HC. The best way to reduce the occurrence of HC after KTx is to treat as best we can the secondary hyperparathyroidism (SHP) during the uraemic stages. The indication to Parathyroidectomy (PTX), either before or after KTx, in order to prevent or to treat, respectively, HC after KTx, is still a matter of debate which has been revived by the availability of the calcimimetic cinacalcet for the treatment of PT-HPT. However, we still need to better clarify many points as regards the potential adverse effects related to either PTX or cinacalcet use in this clinical set, and we are waiting for the results of future randomized controlled trials to achieve some more definite conclusions on this topic.

Calcium and osteoprotegerin levels predict the progression of the abdominal aortic calcifications after kidney transplantation

Background Vascular calcifications (VCs) are a cardiovascular risk factor in patients affected by chronic kidney disease and after kidney transplantation (KTx). We evaluated the prevalence of VCs at the abdominal aortic site in KTx patients at the time of transplantation and 1 year after KTx, exploring the possibly associated factors. Methods In 107 transplanted patients, the following parameters were evaluated at the first and twelfth month after KTx: the aortic calcification index (ACI), fibroblast growth factor 23, osteoprotegerin (OPG), fetuin A, and clinical and biochemical parameters. Patients were followed up for 2 years after KTx. Results At the time of KTx, 60% of patients had some degree of VC (ACI>0), whereas 40% had no VC. One year after KTx, VCs worsened in 26% of patients, whereas in 74%, VCs remained stable or improved. The progression of VC was observed almost exclusively in patients with a positive ACI score at the first month. At the multivariate analysis, serum calcium, OPG, and estimated glomerular filtration rate were the only variables independently associated with the progression of VC. Conclusions VCs at the aortic site are frequent in KTx patients, and in a significant percentage of them, they tend to progress even in the short time. High levels of serum calcium and OPG are significantly associated with the progression of VCs. Whether these associations are based on a cause-effect relationship and their correction might impact on the calcification process could be ascertained by prospective interventional studies.

Calcium and Phosphate Control by Dialysis Treatments

Calcium and phosphate changes, besides their involvement in bone disease, have been claimed to also be involved in the increased vascular morbidity and mortality of dialysis patients. Even after the recent advances of therapeutic options, their control still remains a challenging problem. Dialysis treatment is a basic approach to the control of these two electrolytes. Calcium control by dialysis is mainly dependent on its mass balance, which is variably influenced by the calcium concentration difference between blood and dialysis solutions (either dialysate or infusion fluids) and by the duration of the treatment. There is no full agreement on the ideal calcium concentration in dialysis fluids, since this choice is also mostly influenced by the concomitant medical therapy. However, there is some consensus in suggesting a lower calcium concentration in standard hemodialysis (HD) treatment (1.25–1.50 mmol/l) than in dialysis treatments characterized by high convective transport. In peritoneal dialysis, calcium balance is affected by its blood dialysate concentration difference and dialysate glucose concentration, with ideal calcium concentration probably being >1.25 and <1.75 (which are the most commonly used concentrations). Phosphate dialysis balance is also a critical and challenging problem, since the possibility to reach an always desired null or possibly negative balance relies on this. Even though some increased phosphate removal can be obtained with the highest efficiency techniques, such as hemodiafiltration as compared with traditional HD, the most impacting factor still remains the duration of dialysis treatment. However, some experimental attempts at increasing phosphate removal independently of increasing dialysis duration are mentioned.

Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease.

Chronic kidney disease is a progressive incurable pathology affecting millions of people. Intensive investigations aim to identify targets for therapy. We have previously demonstrated that abnormal expression of the Discoidin Domain Receptor 1 (DDR1) is a key factor of renal disease by promoting inflammation and fibrosis. The present study investigates whether blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology. Severe renal disease was induced by either injecting nephrotoxic serum (NTS) or performing unilateral ureteral obstruction in mice, and the expression of DDR1 was inhibited by administering antisense oligodeoxynucleotides either at 4 or 8 days after NTS (corresponding to early or more established phases of disease, respectively), or at day 2 after ligation. DDR1 antisense administration at day 4 stopped the increase of proteinuria and protected animals against the progression of glomeruloneprhitis, as evidenced by functional, structural and cellular indexes. Antisense administration at day 8 delayed progression –but to a smaller degree- of renal disease. Similar beneficial effects on renal structure and inflammation were observed with the antisense administration of DDR1 after ureteral ligation. Thus, targeting DDR1 can be a promising strategy in the treatment of chronic kidney disease.

Clinical utilization of cinacalcet in hypercalcemic conditions.

Introduction: Cinacalcet has recently been introduced as a treatment for secondary hyperparathyroidism in dialysis patients and for parathyroid carcinoma. However, there has been an increasing interest in finding out whether cinacalcet can be used as a treatment for other parathyroid hormone (PTH)-dependent hypercalcemic conditions also. Areas covered: The article reports the most relevant recent contributions dealing with calcium sensing receptor (CaSR) physiology as well as cinacalcet pharmacokinetics and pharmacodynamics. It also looks at the different hypercalcemic conditions where the use of cinacalcet has been proposed. This article was researched using clinical trials, case reports and outstanding basic research published in the last 3 years (MEDLINE database up to 31 November 2010). It provides the reader with an insight into the many unaddressed issues regarding cinacalcet that need to be resolved before it can be used in newly proposed fields. Expert opinion: Since cinacalcet may not only have an effect on parathyroid CaSR but also on CaSR expressed at bone and renal levels, it can currently only be considered a good alternative to parathyroidectomy in PTH-dependent hypercalcemic conditions when surgical intervention is burdened by a high failure rate or when it can be considered a risky procedure. At present, cinacalcet cannot be considered the first choice treatment in asymptomatic primary hyperparathyroidism or in mild-to-moderate forms of familial hypocalciuric hypocalcemia.

Metabolic acidosis in renal transplantation: neglected but of potential clinical relevance

Chronic metabolic acidosis (CMA) is a common complication of the more advanced stages of chronic kidney diseases (CKD), and is associated with morbidity and mortality of CKD patients and possibly with the progression of renal disease. Nevertheless, there is limited evidence or information on the prevalence, the potential causal factors, the clinical impact and the effects of correction of CMA in kidney transplant recipients. In this review, we briefly look at the more relevant, though scanty, studies which have, over time, addressed the above-mentioned points, with the hope that in the future the interest of transplant nephrologists and surgeons will grow towards this unreasonably neglected issue.

New immunoassays for total, IgA and IgM antibodies against hepatitis E virus: Prevalence in Italian blood donors and patients with chronic liver or kidney diseases

BACKGROUND Hepatitis E virus (HEV) is a zoonotic agent that causes acute hepatitis in humans with sporadic infections and outbreaks in developing countries worldwide. The global spread of HEV remains underestimated because of subclinical infections and lack of sensitive diagnostic assays. AIMS To study the prevalence of HEV antibodies (anti-HEV) in sera of blood-donors and patients with chronic-liver-disease and chronic-renal-disease, using newly developed anti-HEV assays. METHODS 396 sera from 199 blood-donors, 109 chronic-liver-disease patients and 88 chronic-renal-disease patients and three standard reference serum panels were tested in parallel with a sensitive reference anti-HEV assay and newly developed assays for IgA, IgM and total anti-HEV based on HEV-like-particles produced by recombinant baculo-viruses. RESULTS Overall, total anti-HEV was detected in 12.9% (7.0% blood-donors, 9.2% and 30.7% chronic-liver-disease patients and chronic-renal-disease patients, respectively). We observed a higher anti-HEV prevalence in older subjects and in chronic-renal-disease patients in relation with degree on immune-depression (p<0.001). Results from reference serum panels showed an optimal and slightly better performance of the new assay over the commercially available assay. CONCLUSIONS Newly developed anti-HEV assays using recombinant HEV-like-particles showed optimal diagnostic performances assessing that HEV-infection is endemic in Italy with seroprevalence ranging from 7% to 30% in blood donors and immune-compromised hosts, respectively.