Renal graft outcome in combined heart-kidney transplantation compared to kidney transplantation alone: a single-center, matched-control study.

BACKGROUND: Renal allograft outcome in heart-kidney transplantation (HKTx) might be affected by hemodynamic instability and high levels of calcineurin inhibitor-dependent immunosuppression. METHODS: From November 1999 to March 2008, 13 patients who received HKTx were compared with a matched control group of 13 kidney transplantation (KTx) recipients with similar cardiovascular risk factors. Graft function, rejection periods, and patient survival were analyzed. RESULTS: Renal allograft rejection was noted in three patients (23%) after HKTx and in four patients (31%) after KTx. Serum creatinine levels were comparable at 1 week, 1 month, 1, 2, and 3 years after transplantation. Patient survival rates at 1, 2, and 3 years were 100% for HKTx recipients and 100, 92, and 92% for isolated KTx patients. Graft survival was 92% at 1, 2, and 3 years after HKTx and 100% at 1 year and 92% at 2 and 3 years after isolated KTx. CONCLUSIONS: Our results with excellent long-term graft function and survival after combined HKTx indicate that this procedure is a valuable option for a growing number of patients suffering from coexistent cardiac and renal failure.

Relationship of hepatitis B or C virus prevalences, risk factors, and outcomes in renal transplant recipients: analysis of German data.

BACKGROUND: Chronic liver disease resulting from hepatitis B (HBV) and hepatitis C (HCV) virus infections is still a major concern in kidney recipients. Our aim was to evaluate the prevalences, risk factors, and impact of HBV and HCV infections in adult renal transplant recipients in Germany. MATERIALS AND METHODS: Data were collected on 1633 kidney recipients transplanted between 1989 and 2002 at the 21 German renal transplant centers participating in MOST, the prospective Multinational Observational Study in Transplantation. Subgroup analyses compared HBV- and HCV-positive patients vs those with HBV/HCV-negative serology at the time of transplantation. RESULTS: The prevalences of 4.4% (n = 72) for HBV and 5.8% (n = 94) for HCV showed a marked decline over the last 15 years. Retransplantations were significantly more common among HBV+ (29%) and HCV+ (36%) than HBV-/HCV- patients (12%). HCV+ patients experienced significantly longer dialysis times and received significantly more pretransplantation blood transfusions. Between all groups, no significant differences were observed in acute rejection rate at 12 months or in renal graft function up to 5 years posttransplantation (mean glomerular filtration rate: HBV+, 57.3 mL/min; HCV+, 58.5 mL/min; HBV-/HCV-, 59 mL/min). No progressive elevations in liver enzymes and bilirubin were noted during the 5-year observation period. CONCLUSIONS: HBV and HCV infections currently have a low prevalence among German kidney graft recipients. Long dialysis times, blood transfusions, and retransplantations were identified as risk factors for hepatitis infections. At 5 years posttransplantation, kidney and liver functions did not differ significantly between HBV+ and HCV+ vs HBV-/HCV- renal transplant recipients.

Kidney transplantation using donors with history of diabetes and hypertension.

PURPOSE: Due to the persistant organ shortage for kidney transplantation, donor selection has changed in the past years. Although hypertension and diabetes mellitus are known to be risk factors for renal insufficiency, kidneys from donors with these diagnoses in their history have been accepted for kidney transplantation even with an increased risk of poor graft function. Herein we have reported our experience with kidney transplantation using grafts from donors with both, a history of type II diabetes and hypertension. METHODS: Between 2000 and 2005, ten patients were grafted using donors with history of type II diabetes mellitus and hypertension. Mean donor age was 58 +/- 7.5 years and recipient age, 52.2 +/- 15.7 years. Mean HLA mismatch was 0.8 (A); 1.2 (B) and 0.9 (DR). Cold ischemia time was 17.4 +/- 4.1 hours. Immunosuppression was based on CyA (n = 7), tacrolimus (n = 2) or sirolimus (n = 1). RESULTS: Six patients (60%) showed good initial function, and four (40%) had delayed graft function (DGF). One patient died at ten weeks due to multiorgan failure. Two (20%) biopsy-proven rejections were diagnosed, one of which was resistant to therapy. Six months after kidney transplantation, 7 (77%, n = 9) showed good graft function (creatinine 1.3 to 2.4 mg/dL), but one patient displayed long-lasting DGF with poor function. CONCLUSION: Grafts from donors with a history of diabetes mellitus and hypertension are suitable for kidney transplantation. Elevated rate of DGF (40%) would justify allocation of these organs to local transplant centers to shorten ischemia time and thereby reduce DGF and achieve better long-term results. Identification and detailed evaluation of these donors prior to allocation (eg, HbAlc, biopsy) may help transplant centers to accept these kidneys.

Reconstruction of ureteral necrosis in kidney transplantation using an ileum interposition.

PURPOSE: Ureteral necrosis is a serious problem in kidney transplantation. Sometimes re-ureterocystostomy is possible, while other cases require an elaborate reconstruction to maintain kidney function. We report our experience with ileum interposition for ureteral reconstruction. METHODS: After 9 years of dialysis treatment a 58-year-old patient was grafted using the left kidney of a 59-year-old donor with a cold ischemic time of 9.5 hours. The early postoperative course was uneventful apart from delayed graft function. Immunosuppression consisted of an IL-2-receptor antibody, calcineurin inhibitor, mycophenolate mofetil, and corticosteroids. Discharge serum creatinine was 2.3 mg/dL. In month 4 the patient showed a pararenal urinoma; cystoscopy revealed necrosis of the distal ureter. Operative revision showed urine leakage from the renal pelvis through the urinoma into the bladder. As the whole ureter was necrotic, a re-ureterocystostomy was not possible. The patient's own ureter had been extirpated, and the bladder was too small to do a direct anastomosis between it and the kidney. Consequently, an ileum interposition was performed. RESULTS: The postoperative course was uneventful. Kidney function was stable with a nadir creatinine concentration of 2.0 mg/dL 18 months' posttransplantation, and 14 months' post ileal interposition the kidney function was still satisfactory, with a creatinine level of 2.0 mg/dL. CONCLUSION: Ureteral necrosis is a serious complication following kidney transplantation. Whenever a re-ureterocystostomy or an uretero-ureterostomy is not possible, the interposition of the ileal segment represented a safe procedure to deal with this problem.

Living donor kidney transplantation from the elderly donor.

PURPOSE: The organ shortage has led to increasing acceptance of living donation in all transplant centers. Although the risk of impaired long-term outcome seems to be greater using elderly donors, these organs are not generally refused for transplantation. We report our experience with 25 living donor kidney transplantations from donors older than 60 years. METHODS: Between 1995 and 2004, 124 living donor procedures were performed in our center from 83 related and 41 unrelated donors. Twenty-five donors (19 female, 6 male) were 60 years or older (mean, 65.3 +/- 3.9 years). The recipient included (10 females and 15 males) showed a higher degree of variance in age (46.1 +/- 14.6 years). The immunosuppressive protocol was cyclosporine (CyA)-based regimen in related cases and tacrolimus-based in unrelated cases. RESULTS: We transplanted 16 left and 9 right kidneys from older donors. The mean cold ischemia time was 171 +/- 64 minutes with a second warm ischemia time of 24 +/- 6 minutes. Severe arteriosclerosis made vascular reconstruction by graft interposition necessary in two recipients. The acute rejection rate was 20%. Two patients (8%) required dialysis in the early postoperative course, whereas initial function was excellent in 22 patients (88%). The mean serum creatinine concentration after 12 months was 1.6 +/- 0.3 mg/dL (n = 24) and 2.0 +/- 0.7 mg/dL (n = 16) at 4 years. In comparison, the mean creatinine concentration after 4 years in donors under 60 years was 1.6 +/- 0.9 mg/dL. Our analysis showed no significant difference in long-term graft function comparing young versus old donors in the setting of living donor transplants. CONCLUSION: Using living donors older than 60 years for transplantation is a feasible and safe option. The difference in long-term creatinine between young and old donors was not significant.

Conversion to enteric-coated mycophenolate sodium from various doses of mycophenolate mofetil: results of a prospective international multicenter trial in maintenance renal transplant patients receiving cyclosporine.

Conversion from mycophenolate mofetil (MMF, CellCept) to enteric-coated mycophenolate sodium (EC-MPS, myfortic) is safe and effective in renal transplant patients treated with the standard dose of 2 g MMF. In this 6-month, international, multicenter, open-label, single-arm trial, a large cohort of maintenance renal transplant patients receiving different doses of MMF were converted under normal clinical conditions to equimolar doses of EC-MPS. Mean calculated creatinine clearance remained stable from the time of study entry (59.6 +/- 19.7 mL/min) to the end of the study (58.3 +/- 19.8 mL/min). Adverse events were reported by 152 patients (67%), with gastrointestinal complications being observed in 45 patients (20%). Thirty-three patients (15%) experienced adverse events or infections with a suspected relation to EC-MPS, including one case of anemia and two cases of leukopenia. Eleven patients (4.9%) required a reduction in EC-MPS dose and seven patients (3.1%) permanently discontinued EC-MPS owing to adverse events. At month 6 after conversion, five patients (2.2%) experienced biopsy-proven acute rejection. There were no graft losses or deaths. These data support earlier findings that stable maintenance renal transplant patients receiving MMF with cyclosporine with or without corticosteroids can be converted to EC-MPS with no compromise in efficacy and tolerability, and no adverse effect on renal function.

Conversion from cyclosporine to tacrolimus after renal transplantation improves cardiovascular risk factors.

BACKGROUND: It is vital that after, renal transplantation, immunosuppression is efficacious and causes few complications. It is especially important that hyperlipidaemia, hypertension and toxic influences should be avoided because these conditions can reduce patient and transplant survival. Many studies have demonstrated beneficial effects of tacrolimus in comparison with cyclosporine with regard to these conditions. These results have suggested that a conversion to tacrolimus from cyclosporine is advantageous. Our study investigated whether patients with deteriorating renal functions can profit from this conversion. METHODS: Thirty patients with a renal transplant were studied retrospectively, using data recorded from 3 years before to 3 years after conversion from cyclosporine to tacrolimus. RESULTS: While renal function (glomerular filtration rate [GFR]) deteriorated progressively under cyclosporine, it stabilised and even improved under tacrolimus (creatinine: Delta(Cyc)=+1.4 mg/d; Delta(Tac=)-0.7 mg/dl; GFR: Delta(Cyc)=-35 ml/min; Delta(Tac)=14 ml/min). In addition, uric acid level (7.0 vs. 6.4 mg/dl, p<0.05) and cholesterol level (258 vs. 225 mg/dl, p<0.05) were both significantly lower under tacrolimus. CONCLUSION: Conversion from cyclosporine to tacrolimus is recommended for patients with a kidney transplant, in which there has been a progressive fall in renal function. It leads to stabilisation or even improvement of transplant function and a reduction in cardiovascular risk factors.

Switching immunosuppression from cyclosporine to tacrolimus improves long-term kidney function: a 6-year study.

To improve long-term kidney graft function, acute graft rejection, hyperlipidemia, hypertension, and toxic influences must be avoided because they may contribute to chronic allograft nephropathy. Many studies have demonstrated greater efficacy and tolerability of tacrolimus compared with cyclosporine with regard to these conditions. Our study investigated whether 30 patients with deteriorating renal function benefitted from conversion to tacrolimus based upon a retrospective analysis using data recorded from 3 years before to 3 years after conversion. Renal function (GFR) deteriorated progressively under cyclosporine (creatinine: baseline 1.5 mg/dL; delta(Cyc) = +1.4 mg/dL within 3 years; GFR: delta(Cyc) = -35 mL/min within 3 years). After switching to tacrolimus, kidney function stabilized and even improved (creatinine: baseline after switching 2.9 mg/dL; delta(Tac) = -0.7 mg/dL; GFR: delta(Tac) = 14 mL/min). Conversion from cyclosporine to tacrolimus is recommended for patients with a kidney transplant in which there has been a progressive decrease in renal function. It may lead to stabilization of or even improvement in transplant function.

Determination of cyclosporine and its metabolites in blood via HPLC-MS and correlation to clinically important parameters.

The narrow therapeutic window of the immunosuppressive drug cyclosporine (CsA), the interindividual variability of its metabolism, and the immunosuppressive activity/toxicity of some metabolites require investigation to correlate the parent substance and its metabolites and observed clinical parameters. Improved knowledge about these correlations may improve postoperative treatment of transplant patients. To observe such correlation therapeutic drug monitoring was performed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) on 202 blood samples of kidney transplant patients. As CsA and its metabolites are preferably bound to lipoproteins in vivo, sample preparation included protein precipitation, solid phase extraction, and separation on a reversed phase column. Mass-spectrometric detection by an electrospray ionization chamber made the detection and quantification of the sodium adducts of CsA and its metabolites AM1, AM1c, DihydroAM1, AM19, and AM4N possible. With the presented HPLC-MS method, rapid information was achieved about the specific metabolization in a patient. Statistical computations related CsA and its metabolite concentrations to clinically important blood parameters. Significant correlation to the blood level of bilirubin and liver enzymes confirmed the presumed hepatotoxic potential of CsA and some metabolites. Furthermore, a strong correlation of AM19 to CRP and IL6 was observerd. These parameters may influence the prognosis for atherosclerosis, inflammation, and chronic allograft nephropathy.

Differential effects of cyclosporine and tacrolimus on mycophenolate pharmacokinetics in patients with impaired kidney function.

In a single-center prospective randomized controlled study, the impact of calcineurin inhibitor (CNI) reduction or withdrawal on the pharmacokinetics of mycophenolic acid (MPA) was studied in a group of renal transplant recipients with impaired renal function. Mycophenolate mofetil (MMF) was added to a baseline regimen of prednisolone and CNI. Afterwards the patients were randomized into "CNI withdrawal" and "CNI continuation" groups. The dosage of CNIs, cyclosporine or tacrolimus, was gradually reduced and withdrawn within 6 weeks from patients in the withdrawal group. The continuation group was maintained on therapy with CNI, MMF, and steroids. These regimens were maintained until the ninth month. In contrast to the withdrawal of tacrolimus, which has no significant effect on MPA pharmacokinetics, cyclosporine withdrawal was associated with a significant increase in the trough levels and areas under the curve of MPA. Serum creatinine and urine albumine levels stabilized on average after CNI withdrawal in this population. The results are consistent with the hypothesis that cyclosporine attenuates the enterohepatic recirculation of MPA. The withdrawal of CNI has a positive effect on renal function in chronic allograft dysfunction.

Cyclosporine and tacrolimus: influence on cardiovascular risk factors.

After allogenic transplantations, a dramatic increase in the development of arteriosclerotic plaques can be observed, which might be due to metabolic alterations, changes in the transplant organ, or the immunosuppression regimen. Many studies have demonstrated beneficial effects of tacrolimus compared with cyclosporine with regard to these conditions. These results have suggested that conversion to tacrolimus from cyclosporine is advantageous. Our study investigated whether patients with deteriorating renal function profit from this conversion. Thirty renal transplant patients were studied retrospectively, using data recorded from 3 years before to 3 years after conversion from cyclosporine to tacrolimus. While renal function (GFR) deteriorated progressively under cyclosporine, it stabilized and even improved under tacrolimus (creatinine: DeltaCyc = +1.4 mg/d; DeltaTac = -0.7 mg/dL; GFR: DeltaCyc = -35 mL/min; DeltaTac = 14 mL/min). In addition, uric acid levels (7.0 mg/dL vs 6.4 mg/dL, P < .05) and cholesterol levels (258 mg/dL vs 225 mg/dL, P < .05) were both significantly lower under tacrolimus. Conversion from cyclosporine to tacrolimus is recommended for kidney transplant patients in whom there has been a progressive fall in renal function. It leads to stabilization or even improvement of transplant function and a reduction in cardiovascular risk factors.

Cyclosporine-based immunosuppressive strategies for kidney recipients: interim analysis of German data from the Multinational Observational Study (MOST).

INTRODUCTION: We collected data from kidney recipients with a functioning graft at German kidney transplant centers in order to analyze the efficacy of various cyclosporine (CsA)-based immunosuppressive strategies, the effects of different perioperative and maintenance regimens, and the impact of donor source on clinical outcome. METHODS: As part of the ongoing prospective Multinational Observational Study in Transplantation (MOST), data for both prospective and retrospective analysis were collected from kidney recipients over 18 years bearing a functioning graft that was transplanted at 21 German kidney transplant centers between 1987 and 2002. RESULTS: Data from 1223 renal graft recipients, including their CsA-based immunosuppressive regimens, were stratified as: 402 de novo patients (median 6.8 months posttransplant) and 821 patients on maintenance therapy (median 71 months posttransplant). Triple regimens with CsA + mycophenolate mofetil (MMF) + steroids (Ste) currently comprise the major perioperative immunosuppressive strategies in Germany (de novo 65%). IL-2 receptor antagonist (IL-2Ra) use is increasing (de novo 18%, maintenance 4%), while mono and dual regimen use de novo is declining (de novo 4%, maintenance 20%). Among 689 patients transplanted between 1987 and 2002 with outcome data, the mean incidence of acute rejection during the first posttransplant year was 21.6%. Rejection rates on initial therapy with CsA + MMF + Ste +/- antibodies (n = 517) averaged 17.8%. CONCLUSIONS: Between 1987 and 2002, CsA-based immunosuppression combined with MMF and Ste became the most commonly used strategy for both initial and maintenance therapy after kidney transplantation in Germany, yielding the low acute rejection rates particularly when combined with IL-2Ra.

Comparison of quinapril versus atenolol: effects on blood pressure and cardiac mass after renal transplantation.

Based on epidemiologic facts on elevated cardiovascular mortality in renal allograft recipients, an echocardiographic 2-year follow-up in hypertensive renal allograft recipients was conducted. This study provides evidence that, in contrast to atenolol, quinapril, independent of blood pressure reduction, reduces left ventricular hypertrophy and improves left ventricular diastolic function in this population.

Effect of parathyroid hormone levels on carotid intima-media thickness after renal transplantation.

BACKGROUND: The present study aimed to investigate the intact parathyroid hormone (iPTH)-dependent evolution of common carotid intima-media thickness (CC IMT) in renal transplant recipients (RTR) within a 12-month follow-up, ie, before (E0) and 3 months (E3), 6 months (E6), and 12 months after renal transplantation (RTX). METHODS: A total of 55 normotensive patients, aged 47 +/- 1.7 years, underwent a RTX. The graft function was stable (clearanceCockroft >60 mL/min and S-creatinine <2.5 mg/dL) in all patients throughout the follow-up. RESULTS: In 67% of the RTR, the iPTH levels were classified as high at E0 (E6: 63%; E6: 49%; E12: 67%). The plasma iPTH levels decreased after RTX (P < .01). The arterial blood pressure remained stable. The CC IMT was positively and independently correlated with age (P < .01), gender (P < .01), and iPTH levels (P < .01). CONCLUSIONS: Normalization of iPTH levels is associated with a significant intima-media thickness (IMT) reduction. The increased IMT in renal transplant recipients may contribute to the high cardiovascular morbidity and mortality in patients with end-stage renal failure.

Vessel wall alterations in patients with renal failure.

Cardiovascular complications are a major cause of morbidity and mortality in patients with renal failure. Death due to myocardial infarction and to stroke is more frequent in hemodialysis patients than in the total population. These cardiovascular diseases are mainly the consequence of atherosclerosis and cause decreased life expectancy in patients with renal failure. Ultrasound techniques now make it possible to measure atherosclerotic lesions in big and medium-sized arteries. Thickening of the intima-media-complex is an early sign of atherosclerosis in these vessels. It reduces the distensibility of the arteries during systole. The distensibility of big and medium-sized arteries can be determined using ultrasound-doppler-techniques. In our studies, the intima-media-thickness of the carotid artery was significantly (p< 0.01) increased in patients with chronic renal failure (1.32+/-0.49 mm, n=28) as compared with aged-matched healthy control subjects (0.75 +/- 0.20, n= 29). The distensibility coefficient was higher (p< 0.05) in healthy controls (26 +/- 1.8 10(-3)/kPa, n= 12) than in patients with renal insufficiency (19 +/- 1.7 10(-3)/kPa, n = 12). This demonstrates increased stiffness of the vessel wall resulting in loss of Windkessel function and increased work load of the heart.

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant patients: preliminary results from the myfortic prospective multicenter study.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is a new formulation delivering mycophenolic acid developed with the aim of improving upper GI tolerability. A large prospective, open-label, multicenter program (myPROMS: myfortic PROspective Multicenter Study) is underway to determine the efficacy and safety of EC-MPS, in combination with cyclosporine microemulsion (CsA; Neoral) in a large population of de novo and maintenance renal transplant recipients. myPROMS consists of one global protocol with 14 subprotocols. Each subprotocol is designed to address further specific objectives, such as specific patient populations, steroid regimens, and various CsA C2 targets. The preliminary data summarized here are from two subprotocols, which investigated the benefits of converting maintenance renal transplant patients receiving MMF to EC-MPS. The 3-month interim analyses suggest that the conversion from MMF to EC-MPS is well tolerated in maintenance renal transplant recipients.

Antihypertensive treatment in renal transplant patients--is there a role for ACE inhibitors?

During the past two decades great progress was achieved with regards to short-term kidney graft survival. However, long-term graft survival did not improve similarly. Many factors contribute to chronic graft nephropathy eventually resulting in late graft loss, among these arterial hypertension is of major importance. In patients with chronic renal disease of diabetic and non-diabetic origin, angiotensin converting enzyme inhibitors have been convincingly shown to slow the progression of renal failure. The achieved nephroprotection correlates with the reduction of proteinuria by ACE inhibitor treatment. Also in renal transplant patients, ACE inhibitors have been shown unequivocally to reduce urinary protein excretion. The prevention of hyperfiltration, particular in the context of a reduced number of functional nephrons in patients with chronic graft nephropathy, could be important to prolong graft survival after renal transplantation. Moreover, ACE inhibitors may exert beneficial effects on immunologic processes contributing to chronic graft nephropathy. Many studies published in the last decade show convincingly that ACE inhibitors are safe and effective for the treatment of hypertension in renal allograft recipients. However, no data exist so far showing that ACE inhibitors are superior to other antihypertensive drugs in renal transplant patients and that they prolong graft survival. Studies investigating this issue are warranted. Apart from effects on the graft, ACE inhibitors may improve alterations of the cardiovascular system generally observed in renal transplant patients, such as structural alterations of large arteries, left ventricular hypertrophy, disturbed mechanical vessel wall properties and endothelial dysfunction. Therefore, angiotensin converting enzyme inhibitors could reduce cardiovascular morbidity and mortality in kidney transplant patients.

[Therapy of hypertensive crises]. / Therapie der hypertensiven Krise.

Hypertensive crisis is defined as an extreme elevation of arterial blood pressure, with diastolic pressure > 120 mm Hg, and represents an imminent risk to the patient. In such cases, a rapid orientating diagnosis and adequate antihypertensive treatment to avoid sequelae are needed, sometimes even before diagnostic tests are completed. Hypertensive emergencies and hypertensive urgencies can be distinguished. If the critical increase in blood pressure is associated with end-organ damage such as encephalopathy, acute left heart failure and pulmonary edema, angina pectoris, myocardial infarction or dissecting aortic aneurysm, a hypertensive emergency is present, that is an acute threat to the patient's life. A hypertensive emergency requires effective lowering of blood pressure within minutes, but not necessarily to normal range. The choice of suitable antihypertensive agents depends on clinical symptoms, contraindications, duration of pressure elevation and underlying conditions, prior cardiovascular, cerebrovascular and renal disorders. The risk of imminent end-organ damage must be weighed against the risk of rapid blood pressure lowering. In hypertensive urgencies without end-organ complications, blood pressure can be lowered more slowly over several hours, often with oral agents to avoid detrimental fall in blood pressure. The drugs of choice are mainly urapidil i.v. and nitroglycerine.