Hyperlipidemia Is Associated With Accelerated Chronic Kidney Disease Progression After Lung Transplantation

Hyperlipidemia is associated with faster progression of chronic kidney disease (CKD) in the general public. We sought to investigate this association after lung transplantation. Data was retrospectively collected on 230 lung recipients transplanted between January 1997 and December 2003. Estimated glomerular filtration rates (eGFR) and lipid levels were recorded at regular intervals posttransplant. Independent associations between lipid levels early posttransplant and pertinent renal endpoints were investigated. Baseline LDL was 110 ± 35 mg/dL and remained unchanged at 6 months. A faster decline in eGFR was seen in those with 6 month LDLs > versus < the mean level of 110 mg/dL (p = 0.05). By 6 months posttransplant eGFRs were lower in the 6 month LDL > versus < 110 mg/dL group (53 ± 23 vs. 62 ± 29 mL/min/1.73 m², p = 0.01), a difference that persisted at 60 months (39 ± 24 vs. 73 ± 57 mL/min/1.73 m², p = 0.05). On univariate analysis, a 6 month LDL in the highest quartile, i.e. >140 mg/dL, predicted faster progression to CKD, defined as declining to an eGFR < 30 mL/min/1.73 m² (HR 1.5, p = 0.01). This finding persisted in the multivariate Cox-proportional model (HR 1.4, p = 0.02). Hyperlipidemia predicts faster decline in renal function after lung transplant. Prospective trials are needed to confirm this finding.     

Predictors of Chronic Kidney Disease in Long-Term Survivors of Lung and Heart-Lung Transplantation

Renal insufficiency is common after non-renal organ transplants. The predictors of long-term renal outcomes are not well established. A total of 219 lung and heart-lung transplant recipients surviving more than 6 months after transplantation were studied to determine predictors of time to doubling of serum creatinine and end-stage kidney disease (ESKD) with death as a competing risk. Median follow-up was 79 months (range 9-222 months). Baseline estimated glomerular filtration rate (GFR) was 96.3+/-34.5 mL/min/1.73 m2. One hundred twenty-two recipients (55%) doubled their serum creatinine, 16 (7.3%) progressed to ESKD and 143 (65%) died. The majority of recipients who survived >6 years had a GFR<60 mL/min at both 1 and 7 years. Most of the loss of renal function occurred in the first year post-transplant. Older age at transplant, lower GFR at 1 month and cyclosporine use in the first 6 months predicted shorter time to doubling of serum creatinine when death was handled as a competing risk. Based on this prevalence data and using GFR decay and death as study endpoints, we offer sample size estimates for a prospective, interventional trial that is aimed at slowing or preventing the progression of kidney disease.     

Kidney Transplantation in Previous Heart or Lung Recipients

Outcomes after heart and lung transplants have improved, and many recipients survive long enough to develop secondary renal failure, yet remain healthy enough to undergo kidney transplantation. We used national data reported to United Network for Organ Sharing (UNOS) to evaluate outcomes of 568 kidney after heart (KAH) and 210 kidney after lung (KAL) transplants performed between 1995 and 2008. Median time to kidney transplant was 100.3 months after heart, and 90.2 months after lung transplant. Renal failure was attributed to calcineurin inhibitor toxicity in most patients. Outcomes were compared with primary kidney recipients using matched controls (MC) to account for donor, recipient and graft characteristics. Although 5-year renal graft survival was lower than primary kidney recipients (61% KAH vs. 73.8% MC, p < 0.001; 62.6% KAL vs. 82.9% MC, p < 0.001), death-censored graft survival was comparable (84.9% KAH vs. 88.2% MC, p = 0.1; 87.6% KAL vs. 91.8% MC, p = 0.6). Furthermore, renal transplantation reduced the risk of death compared with dialysis by 43% for KAH and 54% for KAL recipients. Our findings that renal grafts function well and provide survival benefit in KAH and KAL recipients, but are limited in longevity by the general life expectancy of these recipients, might help inform clinical decision-making and allocation in this population.     

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.     

Veno-Occlusive Disease of the Liver After Lung Transplantation

Veno-occlusive disease (VOD) of the liver is mainly described after chemo-irradiation conditioning regimens during haematopoietic stem cell transplantation (SCT) and has been sporadically reported after kidney and liver transplantation. In the latter cases, it is commonly attributed to azathioprine and/or tacrolimus. One case of tacrolimus-induced hepatic VOD developing after lung transplantation (LT) has been recently reported. Here we describe another case of VOD occurring after LT, but in which the causative role was played by azathioprine.     

Predicting Coronary Heart Disease after Kidney Transplantation: Patient Outcomes in Renal Transplantation (PORT) Study

Traditional risk factors do not adequately explain coronary heart disease (CHD) risk after kidney transplantation. We used a large, multicenter database to compare traditional and nontraditional CHD risk factors, and to develop risk‐prediction equations for kidney transplant patients in standard clinical practice. We retrospectively assessed risk factors for CHD (acute myocardial infarction, coronary artery revascularization or sudden death) in 23 575 adult kidney transplant patients from 14 transplant centers worldwide. The CHD cumulative incidence was 3.1%, 5.2% and 7.6%, at 1, 3 and 5 years posttransplant, respectively. In separate Cox proportional hazards analyses of CHD in the first posttransplant year (predicted at time of transplant), and predicted within 3 years after a clinic visit occurring in posttransplant years 1–5, important risk factors included pretransplant diabetes, new onset posttransplant diabetes, prior pre‐ and posttransplant cardiovascular disease events, estimated glomerular filtration rate, delayed graft function, acute rejection, age, sex, race and duration of pretransplant end‐stage kidney disease. The risk‐prediction equations performed well, with the time‐dependent c‐statistic greater than 0.75. Traditional risk factors (e.g. hypertension, dyslipidemia and cigarette smoking) added little additional predictive value. Thus, transplant‐related risk factors, particularly those linked to graft function, explain much of the variation in CHD after kidney transplantation.     

Reversibility of ''Secondary Hypercalcitoninemia'' After Kidney Transplantation

Whether the increase of calcitonin (CT) concentration in patients with chronic kidney disease (CKD) is reversible or not after kidney transplantation is not known. We examined the effect of kidney transplantation on basal and pentagastrin-stimulated CT in CKD patients with elevated screening CT levels. Before transplantation, the median basal CT concentration of 17 patients was 31 pg/mL (13-76), and decreased to 8 pg/mL (4-28) at 23 months (2-34) after kidney transplantation (p < 0.00005). The maximum concentration of pentagastrin-stimulated CT was 63 pg/mL (25-110) before transplantation and decreased to 20 pg/mL (8-91) (p < 0.00005) thereafter. There was a linear association between CT and calcium as well as between phosphorus and parathyroid hormone at the time of screening. After transplantation, CT correlated with serum creatinine. Therefore, the increase of CT concentration in patients with impaired kidney function presumably reflects 'secondary hypercalcitoninemia' due to C-cell hyperactivity.     

心肾联合移植的现状

对同时患有终末期心脏和肾脏疾病的患者 ,心肾联合移植 (CHKT)是一种切实可行的选择 ,术后疗效良好。该手术的适应证为合并由器质性肾脏疾病导致的肾功能衰竭的心脏移植患者 ,合并严重心功能不全的肾移植患者。CHKT术后心脏移植排斥发生率较单纯心脏移植术低 ,但机制尚不确定 ;肾移植排斥发生率较单纯肾移植术显著降低 ,这可能与较短的冷缺血时间和较强的免疫抑制治疗有关。行 CHKT患者的生存率与单纯心脏移植者无明显差别。若严格把握手术适应证 ,CHKT术可在临床上安全、合理地应用 ,但移植物和患者的长期存活率还有待多中心的进一步观察。     

Three-Times-Daily Monotherapy with Tacrolimus (FK 506) in Kidney Transplantation

Background: Tacrolimus (FK 506) was introduced into organ transplantation as a powerful immunosuppressive but with several adverse effects. In fact, an appropriate protocol for using this agent has not yet been established. On the basis of pharmacokinetic studies and the reports of its administration as a continuous intravenous infusion, we designed the regimen of every eight hours in order to reduce the daily dosage.
Methods: Tacrolimus was given to nine patients in the Japanese FK506 study. Although it was discontinued in two patients within two months because of adverse effects and acute rejection, seven other patients tolerated the agent for a long period and received the drug three times a day. Concomitant prednisolone was gradually tapered and finally withdrawn in these patients.
Results: The smaller dosage of tacrolimus led to a higher trough concentration of 14.1 ± 1.6ng/mL in the three-times-a-day regimen compared with 12.7 ± 1.9ng/ml in twice-a-day therapy ( P < 0.01). The daily dosage of tacrolimus proved to be reducible even further. Our target trough concentration was decreased finally to < 5ng/mL. Concomitant prednisolone was withdrawn in all of the seven patients. The course of these patients has been uneventful for a year after withdrawal of prednisolone. Conclusion: Our regimen of three-times-a-day oral administration of tacrolimus is a likely protocol for reduction of its daily dosage, which lowers its adverse effects while maintaining its immunosuppressive action at a lower trough concentration without concomitant prednisolone.     

Combined Heart and Kidney Transplantation in a Patient with Fabry Disease in the Enzyme Replacement Therapy Era

Fabry disease (FD) is an X-linked genetic disease, resulting from the deficiency of alpha-galactosidase A, a lysosomal enzyme responsible for the cleavage of glycosphingolipids. In absence of enzyme replacement therapy (ERT), globotriaosylceramide (Gb3) accumulates in tissue, leading to progressive organ damage with severe renal, cardiac and central nervous system complications.
We herein describe the first case of successful combined and simultaneous heart and kidney transplantation in a young male patient with FD complicated by end-stage renal disease and severe heart failure not responding to late-onset ERT.
Combined heart and kidney transplantation can be recommended for Fabry patients with end-stage renal disease and overt hypertrophic cardiomyopathy, severe ischemic or valvular heart disease.     

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.     

Renal Comorbidity After Solid Organ and Stem Cell Transplantation

After transplantation of solid organs or hematopoietic stem cells, a significant acute decrease in renal function occurs in the majority of patients. Depending on the degree of kidney injury, a large number of patients develop chronic kidney disease (CKD) and some develop end‐stage renal disease requiring renal replacement therapy. The incidence varies depending on the transplanted organ, but important risk factors for the development of CKD are preexisting renal disease, hepatitis C, diabetes, hypertension, age, sex, posttransplant acute kidney injury and thrombotic microangiopathy. This review article focuses on the risk factors of posttransplant chronic kidney disease after organ transplantation, considering the current literature and integrates the incidence and the associated mortality rates of acute and chronic kidney disease. Furthermore, we introduce the RECAST (RE nal C omorbidity A fter S olid organ and hematopoietic stem cell T ransplantation) registry.     

Hypoalbuminemia and Early Mortality After Lung Transplantation: A Cohort Study

Hypoalbuminemia predicts disability and mortality in patients with various illnesses and in the elderly. The association between serum albumin concentration at the time of listing for lung transplantation and the rate of death after lung transplantation is unknown. We examined 6808 adults who underwent lung transplantation in the United States between 2000 and 2008. We used Cox proportional hazard models and generalized additive models to examine multivariable‐adjusted associations between serum albumin and the rate of death after transplantation. The median follow‐up time was 2.7 years. Those with severe (0.5–2.9 g/dL) and mild hypoalbuminemia (3.0–3.6 g/dL) had posttransplant adjusted mortality rate ratios of 1.35 (95% CI: 1.12–1.62) and 1.15 (95% CI: 1.04–1.27), respectively. For each 0.5 g/dL decrease in serum albumin concentration the 1‐year and overall mortality rate ratios were 1.48 (95% CI: 1.21–1.81) and 1.26 (95% CI: 1.11–1.43), respectively. The association between hypoalbuminemia and posttransplant mortality was strongest in recipients with cystic fibrosis and interstitial lung disease. Hypoalbuminemia is an independent risk factor for death after lung transplantation.     

Thrombotic Microangiopathy After Kidney Transplantation

Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation that often causes graft failure. TMA may occur de novo, often triggered by immunosuppressive drugs and acute antibody‐mediated rejection, or recur in patients with previous history of hemolytic uremic syndrome (HUS). Recurrent TMA is very rare in patients who had developed end‐stage renal failure following HUS caused by Shiga‐toxin producing E. scherichia coli, whereas disease recurrence is common in patients with atypical HUS (aHUS). The underlying genetic defect greatly impacts the risk of posttransplant recurrence in aHUS. Indeed recurrence is almost the rule in patients with mutations in genes encoding factor H or factor I, whereas patients with a mutation in membrane‐cofactor‐protein gene have a good transplant outcome. Prophylactic and therapeutic options for posttransplant TMA, including plasma therapy, combined kidney and liver transplantation and targeted complement inhibitors are discussed in this review.     

肾移植术后尿瘘的病因诊断及处理对策

目的：探讨肾移植术后尿瘘的病因诊断及处理对策，以降低肾移植术后患者尿瘘发病率及死亡率。方法：回顾性分析2003年1月～2007年12月以来行340例次肾移植术后出现尿瘘的原因及其积极正确的诊断与治疗经验，以挽救移植肾功能及患者生命。结果：340例次肾移植中，确诊尿瘘15例次，发生率为4．4％，发生时间5～24天，平均15天。根据诊断及临床特征行保守治疗和手术治疗等，恢复功能14例，治愈率为93．3％；死亡1例。死亡率为6．7％。结论：尿瘘是肾移植后主要并发症之一，发生原因各异，排斥反应及血供损伤是主要原因。加强抗排斥反应，防止血供损伤，作抗反流乳头吻合，常规内置双J管，可以减少其发生；早期诊断及个体化治疗方案是其治愈的关键。     

Circulating Endothelial Progenitor Cells After Kidney Transplantation

Circulating endothelial progenitor cells (EPCs) promote vascular repair and maintain integrity of the endothelial monolayer. Reduced EPCs number has been associated with endothelial dysfunction in various cardiovascular diseases. Cardiovascular disease risk is higher in renal transplant patients (RT) than the general population. We studied EPCs number and proliferation in RT, and examined the association with other cardiovascular risk factors such as reduced glomerular filtration rate (GFR) and LDL cholesterol. EPCs concentration was determined in 94 RT and 39 control subjects (C) by flow cytometry. EPCs proliferation was also studied after 7 days in culture. EPCs concentration was significantly reduced in RT versus C (median 33.5 [5-177] vs. 53 [9-257] EPCs/10(5) PMN cells, p=0.006). EPCs proliferation was also reduced in RT versus C (mean+/-SD; 372.7+/-229.3 vs. 539.8+/-291.3 EPCs x field, p=0.003). In multiple regression analysis, GFR, HDL, LDL and body weight were independent predictors of EPCs concentration in RT (r2=0.25, p<0.001). EPCs number is reduced in RT, particularly in patients with reduced GFR. Moreover, EPCs from RT studied in vitro, showed reduced proliferation, which is a sign of functional impairment. These alterations may be involved in increased cardiovascular risk of RT.     

Comparison of Three Tacrolimus-Based Immunosuppressive Regimens in Lung Transplantation

Immunosuppressive therapy for solid organ transplantation has significantly evolved over the past decade. While these therapies have been found to be beneficial in abdominal organ transplantation, the efficacy of these therapies remains unclear in lung transplantation. We retrospectively compared three potent immunosuppressive regimens in our lung transplant population: Group 1 (tacrolimus/azathioprine/prednisone), Group 2 (tacrolimus/azathioprine/prednisone/daclizumab) and Group 3 (tacrolimus/mycophenolate mofetil/prednisone/daclizumab). We compared these three groups with respect to 3-year rates of acute rejection, chronic rejection, infection and survival. A total of 109 patients was followed during the course of this study. There were 32 patients in Group 1, 49 patients in Group 2 and 28 patients in Group 3. Freedom from acute rejection at 1 and 3 years were higher in Group 3 compared with Group 1 (p < 0.05). The overall incidence of infection up to 3 years after transplantation was comparable among all three groups. Freedom from chronic rejection and survival at 1 and 3 years did not differ among the three groups. In conclusion, we determined the safety and efficacy of three potent immunosuppressive regimens in lung transplantation. Addition of daclizumab and MMF to a tacrolimus-based immunosuppressive regimen decreased the incidence of acute rejection episodes without increasing any adverse events in our lung transplantation population.