Pharmacokinetics and Pharmacodynamics of Cinacalcet in Patients with Hyperparathyroidism After Renal Transplantation

Cinacalcet is a calcimimetic drug for the treatment of secondary hyperparathyroidism (HPT). In a sequential open-label study, ten patients with persistent HPT after renal transplantation received first 30 and then 60 mg oral cinacalcet once daily over 2 weeks each. Cinacalcet steady state oral clearance was 131.1 ± 20.9 l/h and 92.8 ± 9.5 l/h (mean ± SE) after 30 and 60 mg, respectively. Cinacalcet and parathyroid hormone (PTH) concentrations showed an inverse correlation and were fitted to a simple E_max model (E_max= 80% reduction vs. baseline, EC₅₀= 13 ng/mL). A once daily administration of cinacalcet lowered serum calcium over 24 h without fluctuations. The 8-h fractional urinary excretion of calcium was increased after 60 mg cinacalcet (baseline 0.85 ± 0.17%, 30 mg 1.53 ± 0.35%, 60 mg 1.92 ± 0.37%). Renal function remained stable. Cinacalcet pharmacokinetics and pharmacodynamics showed a pronounced interindividual variability. We conclude that the once daily administration of cinacalcet in patients with secondary HPT after renal transplantation effectively reduced iPTH and serum calcium. The transient calciuria could potentially favor nephrocalcinosis and reduce bone mineral density, suggesting that higher doses of cinacalcet need to be used with caution in renal transplant recipients with severe persistent hyperparathyroidism.     

Paricalcitol for Secondary Hyperparathyroidism in Renal Transplantation

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8–152.0) to 63.3 (52.0–79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.     

Low-Turnover Bone Disease in Hypercalcemic Hyperparathyroidism After Kidney Transplantation

Hypercalcemia in persistent secondary hyperparathyroidism after kidney transplantation is considered to result from increased bone resorption. Bone biopsies' studies, however, have never been performed in these patients. Bone biopsies after double tetracycline labeling were obtained from 17 patients with hypercalcemic hyperparathyroidism and an estimated glomerular filtration rate > 30 mL/min/1.73 m2. Serologic bone markers, calcitriol, intact fibroblast growth factor-23 (iFGF-23), and serum and 24h urine concentration of calcium and phosphate were measured in all patients. Tubular maximum for phosphate corrected for GFR (TmP/GFR), and the fractional excretion of calcium (FeCa) were calculated. High-turnover renal osteodystrophy (ROD) was present in nine and low-turnover ROD in eight patients. The bone formation rate was significantly associated with bone alkaline phosphatase, c-telopeptide and osteocalcin. In patients with high turnover ROD, osteocalcin was also significantly higher than in patients with decreased bone formation. The FeCa was normal or below normal in 14/17 patients. TmP/GFR was below normal in all patients. Neither intact PTH nor iFGF-23 was associated with TmP/GFR, FeCa or any histomorphometric bone parameter. We conclude that hypercalcemia of posttransplant hyperparathyroidism can be associated with high or low turnover bone disease. Decreased calcium excretion suggests an additive tubular effect on hypercalcemia.     

Factors Associated with Hyperhomocysteinemia After Renal Transplantation

Recent studies show that clinically stable renal transplant recipients have an increased prevalence of hyperhomocysteinemia (hyperHcy), but the mechanism of this disorder has not yet been elucidated. The aim of the present study was to evaluate the factors associated with hyperHcy after a successful renal transplantation. In 106 stable renal transplant recipients, total serum Hcy level (tHcy), folate, total protein, serum creatinine concentration, creatinine clearance, lipid status, body weight (BW), body mass index (BMI), and body fat (BF) were determined. The mean doses of cyclosporine, prednisolone, and azathioprine (mg/kg/day) were recorded. The mean serum tHcy level was significantly higher in renal transplant patients than in healthy controls (22.02 ± 8.02 versus 13.0 ± 3.3 μmol/L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 μmol/L and the group of 86 patients with tHcy level >15 μmol/L revealed that the latter was significantly older, heavier, had been longer on dialysis before renal transplantation, and had older donors and poorer renal graft function. Significant correlation was found between tHcy level and recipient age, dialysis duration, BW, creatinine clearance, serum creatinine, and folate concentration. However, multivariate analysis indicated that creatinine clearance (p = 0.025) and BW (p = 0.03) were the only determinants of elevated total Hcy level in renal transplant recipients. HyperHcy persists after successful kidney transplantation in the majority of renal transplant recipients, and its appearance is primarily associated with creatinine clearance and body weight.     

A Case Study with Delayed Renal Graft Function as a Consequence of Severe Secondary Hyperparathyroidism

Abstract: A 36–year-old Arab man had been treated with hemodialysis for 6 years. During that time he received no treatment with phosphate binders or 1,25–dihydroxy-vitamin D₃. He thus developed a severe form of secondary hyperparathyroidism and presented with bone disease, pseudoclubbing of the fingers, and soft-tissue calcification. He was transplanted with a kidney from a living donor, but there was no immediate onset in renal function. A biopsy showed crystal deposition that was thought to be due to his secondary hyperparathyroidism. Four weeks after the renal transplantation with still no evidence of a functioning graft, a parathyroidectomy was performed. A few days later, graft function recovered, and the amount of the crystals in the kidney decreased. There is strong evidence that the severe secondary hyperparathyroidism prevented the onset of renal function. It is concluded that crystal deposition with graft dysfunction should be an absolute indication for parathyroidectomy.     

小剂量钙三醇对慢性肾衰竭继发性甲旁亢早期的疗效研究

目的:研究小剂量口服罗盖全治疗慢性肾衰竭(CRF)继发性甲旁亢(SHPT)早期患者的疗效和副作用.方法:将观察期间(3～12个月)血清全段甲状旁腺激素(iPTH)浓度动态升高且高达正常值3～5倍的180名CRF患者随机分为A、B两组,A组予罗盖全0.125 μg/d, B组予罗盖全0.25 μg/d口服,以血清 iPTH浓度降至正常值2.5倍即160 ng/L为观察终点;另将血清iPTH浓度高达正常值5倍以上的153例患者随机分为C、D两组,C组予罗盖全0.5 μg/d上午口服,D组以相同剂量于晚上10 h口服,以血清iPTH浓度降至正常值3倍即195 ng/L为观察终点.以到达终点的例数和时间为指标判断疗效,分别比较A、B两组及C、D两组疗效和高钙血症等副作用.结果:各组均取得良好疗效.B组有效率90.91%,明显高于A组的57.30%(P<0.01),B组到达终点时间(8.66±3.2)个月,明显早于A组(15.24±3.7)个月(P<0.01).C、D两组疗效相近,有效率分别为86.89%和84.29%(P>0.05),到达终点的时间分别为(9.51±3.1)个月和(9.97±2.9)个月(P>0.05).各组均无发生血清iPTH浓度过低(<130 ng/L).A、B两组极少发生高钙血症,发生率分别为1.11%和2.22%;D组高钙血症发生率为9.72%,明显低于C组的32.88%(P<0.01).各组肝肾功能稳定.结论:根据血清iPTH水平给予小剂量(0.125～0.5 μg/d)罗盖全治疗早期SHPT安全、有效而且经济,0.5 μg/d罗盖全于夜间使用可以减少高钙血症发生率.     

The Burden of Chronic Kidney Disease in Renal Transplant Recipients

The National Kidney Foundation has developed guidelines for the diagnosis and classification of chronic kidney disease (CKD) but it is not known whether these are applicable to renal transplant recipients. This study determined the prevalence of CKD according to the stages defined in the guidelines, the complications related to CKD and whether the prevalence of complications was related to CKD stage in 459 renal transplant recipients. CKD was present in 412 patients (90%) and 60% were in CKD Stage 3 with a glomerular filtration rate (GFR) between 30 and 59 mL/min/1.73 m2. The prevalence of anemia increased from 0% in Stage 1 to 33% in Stage 5 (p<0.001). Hypertension was present in 86% and increased from 60% in Stage 1 to 100% in Stage 5 (p=0.02). The number of anti-hypertensives per patient increased from 0.7 in Stage 1 to 2.3 in Stage 5 (p<0.001). The number of CKD complications per patient increased from 1.1 in Stage 1 to 2.7 in Stage 5 (p<0.001). We conclude that CKD and the complications of CKD are highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians identify patients at increased risk and target appropriate therapy to improve outcomes.     

Kidney Allocation to Liver Transplant Candidates with Renal Failure of Undetermined Etiology: Role of Percutaneous Renal Biopsy

The feasibility, value and risk of percutaneous renal biopsy (PRB) in liver transplant candidates with renal failure are unknown. PRB was performed on 44 liver transplant candidates with renal failure of undetermined etiology and glomerular filtration rate (GFR) <40 mL/min/1.73 m² (n = 37) or on renal replacement therapy (RRT) (n = 7). Patients with ≥30% interstitial fibrosis (IF), ≥40% global glomerulosclerosis (gGS) and/or diffuse glomerulonephritis were approved for simultaneous‐liver‐kidney (SLK) transplantation. Prebiopsy GFR, urinary sodium indices, dependency on RRT and kidney size were comparable between 27 liver‐transplant‐alone (LTA) and 17 SLK candidates and did not relate to the biopsy diagnosis. The interobserver agreement for the degree of IF or gGS was moderate‐to‐excellent. After a mean of 78 ± 67 days, 16 and 8 patients received LTA and SLK transplants. All five LTA recipients on RRT recovered kidney function after transplantation and serum creatinine was comparable between LTA and SLK recipients at last follow‐up. Biopsy complications developed in 13, of these, five required intervention. PRB is feasible in liver transplant candidates with renal failure and provides reproducible histological information that does not relate to the pretransplant clinical data. Randomized studies are needed to determine if PRB can direct kidney allocation in this challenging group of liver transplant candidates.     

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.     

Parathyroidectomy and Cinacalcet Use in Medicare-Insured Kidney Transplant Recipients

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Short-Term Experience with Early Steroid Withdrawal in African-American Renal Transplant Recipients

There are limited data on the results of early steroid withdrawal (ESW) in African-American (AA) renal allograft recipients. We examined short-term transplant outcomes in a retrospective, non-concurrent cohort study of 40 AAs who did not (ESW group), and 33 who did [steroid maintenance (SM) group] receive maintenance steroids after day 4 post-transplant. Patients received thymoglobulin (ATG) induction, mycophenolate mofetil, and tacrolimus or sirolimus. Data were analyzed using survival analysis methods and regression models. Patients in the ESW group were older, had lower current panel reactive antibody and fewer re-transplants, and received fewer doses of ATG. One-year graft survival and acute rejection (AR) rates were 100% and 13% in the ESW group and 97% and 15% in the SM group. After controlling for confounders, at 1 year, ESW was not associated with higher risk of graft loss, AR, or worse graft function, but was associated with less weight gain. The SM group had higher cholesterol levels at 3 months and higher risk of post-transplant diabetes mellitus. We did not observe any cases of subclinical rejection. This study suggests that ESW under modern immunosuppression is safe over the short term in at least a subset of AA recipients with risk profiles similar to those studied herein, and could be associated with improved outcomes.     

Pre-Transplant IFN-γ ELISPOTs Are Associated with Post-Transplant Renal Function in African American Renal Transplant Recipients

Final crossmatch testing is routinely used to assess the risk of antibody-mediated graft injury/rejection post-transplant. Analogously, we postulated that quantitative measurements of anti-donor effector/memory T cells pre-transplant would independently assess post-transplant risk. To address this hypothesis, we determined the frequencies of pre-transplant, donor-specific interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spots (ELISPOTs) and correlated the results with post-transplant outcomes in 37 African American recipients of deceased donor kidney transplants treated with tacrolimus- and sirolimus-based immunosuppression. A positive ELISPOT test (>25 spots/300,000 cells) was detected in 14 (38%) of 37 patients. The incidence of biopsy-proven acute rejection was 50% (7/14) in ELISPOT-positive versus 17% (4/23) in ELISPOT-negative patients (p=0.036). Calculated glomerular filtration rate (MDRD) at 12 months was 37+/-16 mL/min in ELISPOT-positive versus 55+/-20 mL/min in ELISPOT-negative patients (p=0.01). ELISPOT status remained a correlate of allograft function at 12 months by linear regression analysis (p=0.001), independent of rejection and other contributing variables. Pre-transplant donor-directed IFN-gamma ELISPOT assessment of anti-donor cellular immunity may function as a 'cellular crossmatch' and independently correlates with renal allograft function in African Americans receiving tacrolimus- and sirolimus-based immunosuppression.     

Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation

Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 +/- 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61-0.89; p < 0.004). IMPDH activity above the cut-off value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Conclusion: Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.     

Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease

The efficacy and acceptability of cinacalcet for treatment of secondary hyperparathyroidism (SHPT) was assessed in seven pediatric patients suffering from end-stage renal disease (ESRD) presenting with inadequately controlled SHPT despite conventional management. Patients received daily treatment with cinacalcet (dosage 0.25 mg/kg body weight) for a total of 4 weeks. Within 4 h after application of the first dose, median levels of serum parathyroid hormone (PTH) had decreased from 932 pg/ml (range 511-1,938 pg/ml) to 584 pg/ml (88-937 pg/ml), and final pre-dose values after 4 weeks were 199 pg/ml (121-940 pg/ml; each P < 0.05 versus baseline). Median concentrations of serum calcium (Ca) decreased within 4 h of the first administration, from 2.56 mmol/l to 2.38 mmol/l, returning to 2.58 mmol/l at 24 h, and they remained slightly decreased compared to baseline values thereafter (each P < 0.05 versus baseline). Both the median levels of serum phosphorus (P) and the Ca x P ion product decreased significantly during the 4-week period. Cinacalcet was well tolerated and without drug-related adverse effects. Thus, even with approximately half of the dose usually given to adult dialysis patients, PTH and the Ca x P ion product were markedly reduced in pediatric ESRD patients presenting with inadequately controlled SHPT. Therefore, our results support the initiation of a randomized, controlled, long-term trial in children.     

环孢素A血药浓度监测的临床意义

目的：探讨环孢素A(CsA)血药谷值浓度监测的临床意义。方法：对269例同种肾移植受者术后4081次CsA血药谷值浓度进行了分析。结果：随着移植肾存活时间的延长,CsA治疗浓度水平呈逐渐下降趋势。排斥反应发生时及排斥反应前两周内,CsA浓度不仅低下,而且有一持续约2周的显著下降过程,平均降幅达31％。术后一周内急性排斥反应的发生与CsA浓度关系不大。过高的CsA浓度则与肾中毒’反应有关。CsA治疗浓度与发生排斥反应时的浓度及肾中毒浓度均有一定程度的重叠。结论：认为术后CsA理想的治疗窗浓度应为：术后第1月内为300-450ng／ml,3月内为250～400ng／ml,半年内为200～350ng／ml,以后CsA浓度最好维持在150～250ng／ml。     

Early Withdrawal of Calcineurin Inhibitors and Rescue Immunosuppression with Sirolimus-Based Therapy in Renal Transplant Recipients with Moderate to Severe Renal Dysfunction

Mammalian Target-of-Rapamycin inhibitors (mTOR inhibitors) can be used to replace the calcineurin inhibitors (CNIs) to prevent progression in chronic kidney disease (CKD) following organ transplantation. Discontinuation of tacrolimus in 136 recipients of kidney transplants with progressive renal dysfunction significantly decreased the rate of loss of estimated glomerular filtration rate (eGFR, mL/min/1.73 m(2)) (pre-intervention vs. post-intervention slopes, -0.013 vs. -0.002, p < 0.0001). Discontinuation of tacrolimus was associated with a sustained and significant improvement in graft function (pre-eGFR vs. post-eGFR; 26.0 +/- 1.1 vs. 47.4 +/- 2.1, p < 0.0001) in 74% of patients. This intervention was ineffective if the mean and (median) values of creatinine (mg/dL) and eGFR were 3.8 +/- 0.2 (3.4) and 18.4 +/- 1.9 (22.4), respectively, at the time of conversion therapy. During the follow-up (range, 1.5-34.6, months), a total of 13 patients had their first acute rejection following the conversion therapy, an annual incidence of less than 10% and none of these episodes resulted in graft loss. The salutary effects of sirolimus therapy following discontinuation of tacrolimus in patients with moderate to severe graft dysfunction due to allograft nephropathy even in high-risk patients improves kidney function and prevents acute rejection.     

Persistent Hyperparathyroidism Is a Major Risk Factor for Fractures in the Five Years After Kidney Transplantation

The risk of fractures after kidney transplantation is high. Hyperparathyroidism frequently persists after successful kidney transplantation and contributes to bone loss, but its impact on fracture has not been demonstrated. This longitudinal study was designed to evaluate hyperparathyroidism and its associations with mineral disorders and fractures in the 5 posttransplant years. We retrospectively analyzed 143 consecutive patients who underwent kidney transplantation between August 2004 and April 2006. The biochemical parameters were determined at transplantation and at 3, 12 and 60 months posttransplantation, and fractures were recorded. The median intact parathyroid hormone (PTH) level was 334 ng/L (interquartile 151–642) at the time of transplantation and 123 ng/L (interquartile 75–224) at 3 months. Thirty fractures occurred in 22 patients. The receiver operating characteristic (ROC) curve analysis for PTH at 3 months (area under the ROC curve = 0.711, p = 0.002) showed that a good threshold for predicting fractures was 130 ng/L (sensitivity = 81%, specificity = 57%). In a multivariable analysis, independent risk factors for fracture were PTH >130 ng/L at 3 months (adjusted hazard ratio [AHR] = 7.5, 95% CI 2.18–25.50), and pretransplant osteopenia (AHR = 2.7, 95% CI 1.07–7.26). In summary, this study demonstrates for the first time that persistent hyperparathyroidism is an independent risk factor for fractures after kidney transplantation.     

Hyperparathyroidism, Hypertension and Loop Diuretic Medication in Renal Transplant Recipients

The associations between serum parathyroid hormone (PTH), bloodpressure and hypotensive medication were analysed in 282 renaltransplant recipients. Among patients with a normal concentrationof serum creatinine there was no correlation between serum PTHand blood pressure but in those receiving hypotensive medicationserum PTH was appropriately twofold greater than in those nottaking hypotensive medication. Analysis revealed that the dominantcontribution to this association was a specific associationwith loop diuretic therapy. When all patients were stratifiedaccording to creatinine clearance, serum PTH was always greaterin patients receiving loop diuretics but this difference wasparticularly striking in the patients with the poorest graftfunction. It is postulated that loop diuretics exacerbate thehyperparathyroidism which complicates renal disease.