A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels (≤11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value<10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p<0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p=0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p<0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

[Calcimimetics, phosphate binders, vitamin D and its analogues for treating secondary hyperparathyroidism in chronic kidney disease: guideline from the Italian Society of Nephrology]. / Utilizzo della vitamina D e analoghi, dei chelanti del fosforo e dei calciomimetici nella terapia dell'iperparatiroidsmo secondario e della patologia ossea nelle nefropatie croniche: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of calcimimetics, phosphate binders, vitamin D and vitamin D analogues for treating secondary hyperparathyroidism in chronic kidney disease (CKD) is presented. METHODS: SR of RCT and RCT on interventions for secondary hyperparathyroidism in CKD were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Three SR and 8 RCT were found addressing this intervention issue. Methodological quality of available RCT was suboptimal according to current methodological standards. Calcimimetics used in patients receiving haemodialysis or peritoneal dialysis are more effective than placebo in controlling secondary hyperparathyroidism (reduced parathyroid hormone levels, calcium levels and phosphorus levels). All phosphate binders are effective in controlling hyperphosphatemia but different doses are to be used with different agents to achieve similar targets. Dosing needs to be adjusted according to phosphorus levels. Vitamin D and its analogues are recommended in CKD patients, although there is no significant evidence of superiority of individual agents in head-to-head comparisons. Dosing should be based on baseline parathyroid hormone levels, but the risk of hypercalcemia should also be considered. CONCLUSION: Available evidence suggests that calcimimetics, phosphate binders and vitamin D or its analogues are effective in the treatment of secondary hyperparathyroidism. Superiority of individual agents or doses is still deeply debated. Further studies are necessary to test these issues.

Recent advances in the management of hepato-renal syndrome (HRS).

Hepato-renal syndrome (HRS) is a functional renal failure complicating end-stage liver disease. HRS is characterized by marked arterial vasodilation (mainly of the splanchnic bed) and severe renal vasoconstriction. HRS is classified into 2 types: type I HRS shows a rapid and progressive decline in renal function with a very poor prognosis (median survival of about 2 weeks); HRS type 2 has a more stable renal failure, with a median survival of about 6 months. The management of HRS is still a big challenge. The definitive therapy for HRS is liver transplantation (LT); however, the survival rate of HRS patients is poor, and important organ shortage exists. Various approaches have been used for HRS treatment including vasoconstrictor therapy. Recent evidence has shown that vasoconstrictor agents are effective and serve as a bridge to LT; the rationale for vasoconstrictors is to counteract the splanchnic arterial vasodilation and increase the effective arterial blood volume. Thus, renal perfusion and glomerular filtration rates improve. Terlipressin, a V1 vasopressin agonist, has been used frequently. A recent meta-analysis of clinical trials showed that the pooled rate of patients who reversed HRS after terlipressin therapy was 0.52 (95% CI, 0.42; 0.61; P = 0.0001, /2 = 24.6%). The pooled Odds Ratio (OR) for mortality rate in HRS patients who were not responders to terlipressin versus responders was 5.746 (95% CI, 1.5; 21.9; P = 0.0005). Prospective, controlled clinical trials are in progress to address the impact of vasoconstrictor use on survival in HRS patients. Alternative therapies such as transjugular intrahepatic portosystemic shunts (TIPS) and extracorporeal albumin dialysis (ECAD) have given encouraging results but experience is extremely limited.

[Bone complications of renal transplantation. How to identify and prevent them]. / Le complicanze ossee del trapianto renale. Come identificarle e prevenirle.

Bone disease is a very frequent complication after renal transplantation (RTx). The main features of transplant bone disease include the osteopenic-osteoporotic syndrome, often complicated by fractures, avascular osteonecrosis of bones, bone pain syndrome and growth retardation in the children. The bone loss is greater during the first 12 months after RTx and can reach the osteoporotic range in above 40% of patients, with a fracture rate of 2-3% per year. The story of bone disease over the long pre-uremic and uremic period is one of the main causal factors. After RTx, glucocorticoid therapy seems to play the major causal role. Much more disputed is the role of the other immunosuppressive drugs, of persistent secondary hyperparathyroidism, and age. Hypophosphatemia and some genetic factors could also affect bone loss after RTx. Diabetic patients are particularly prone to develop bone disease after RTx. The main prophylactic interventions consist in the optimal control of hyperparathyroidism during the pre-transplant period, prescribing parathyroidectomy for autonomous hyperparathyroidism, not-responding to medical therapy. After RTx, both bisphosphonate and vitamin D metabolites, variably associated with calcium supplementation, have been demonstrated to have some beneficial effect on bone loss, at least in the first year after RTx. However, there are no data about the possible efficacy of these treatments on fracture rate.

[Renal osteodystrophy Guidelines]. / Linee Guida osteodistrofia renale.

Renal ostedystrophy (ROD) is a major long-term complication in uremic patients. Bone histomorphometry still remains the gold standard for the diagnosis of ROD. However, the low acceptance grade by patients makes bone biopsy a rarely performed and not easily repeatable investigation. No other instrumental assessment has been proved as yet to have sufficient sensitivity for ROD diagnosis. Many biochemical markers have been proposed for a diagnostic role, but few have a real predictive diagnostic value. Serum intact PTH (i-PTH) levels are thought to represent a good predictor of bone lesions. However, although a i-PTH level greater than 450 pg/mL and lower than 120 pg/mL may well predict high and low bone turnover disease respectively, in the wide range of values defined by the above border levels i-PTH does not have a predictive role for ROD. There is as yet no definite proof that the recently developed PTH assays might increase their diagnostic sensitivity. Bone alkaline phosphatase is a more reliable index of bone turnover than i-PTH levels. With regards to Al overload, given that an iron overburden is excluded, serum Al levels lower than 30 ug/L are seldom associated with increased Al deposition; conversely, levels above 60 mg/L are highly diagnostic for Al overload. In the latter condition, a DFO test is recommended. The main goals of ROD treatment are a) to maintain serum i-PTH levels between 120 and 150 pg/mL; b) to bring the phosphate (Pi) concentration under 5.5 mg/dL, Ca concentration between 9.2 and 10.4 mg/dL, and the Ca x Pi product under 55 mg/dL; c) to bring Al concentration under 20 ug/L; and d) to target serum bicarbonate levels between 20 and 24 mmol/L. The main therapeutic approaches include: Dietary Pi intake control (< 1200 mg/day). Intestinal phosphate binding using calcium salts and sevelamer. Calcium salts must be used at a dosage that avoids Ca overload (< 23 g/day). If Pi control is not reached, Mg and Al salts may be added at a dose lower than 2 g/day and for less than 3 months. Appropriate dialysis dose (KT/V > 1.2) and dialysis time (consider increased dialysis duration or session number for a week). Ca concentration in dialysate and infusion fluids can range between 1.25 and 2.00 mmol/L, according to the dialysis technique and to maintain an appropriate Ca balance. Vitamin D should not be used when i-PTH levels are < 120 pg/mL and/or serum Ca > 11 mg/dL and/or Pi > 6.5 mg/dL. The vitamin D dose should be proportional to PTH levels, with a larger dose given as a bolus (23 ug twice or three times per week). The intravenous route should be preferred in the case of very high i-PTH (> 700 pg/mL) or after 3 months of unsuccessful oral treatment. PTX should be prescribed on the basis of the clinical, biochemical, and instrumental data. A 7/8 PTX, when possible, is the most advisable procedure. Bone transplant disease (BTD) is caused by a combination of previous uremic ROD and bone lesions occurring after renal transplantation, mainly secondary to steroid effect. The main clinical result of BTD is the osteopenicosteoporotic syndrome, which frequently results in bone fractures. The most effective treatment of BTD is a reduction of the cumulative steroid dose. No strong evidence has been produced as yet for a preventive role of either bisphosphonates or vitamin D supplementation on BTD.