Klemens Budde

CC chemokine receptor 5 and renal-transplant survival

BACKGROUNDnAbout 1% of white populations are homozygous carriers of an allele of the gene for the CC chemokine receptor 5 (CCR5) with a 32 bp deletion (CCR5Delta32), which leads to an inactive receptor. During acute and chronic transplant rejection, ligands for CCR5 are upregulated, and the graft is infiltrated by CCR5-positive mononuclear cells. We therefore investigated the influence of CCR5Delta32 on renal-transplant survival.nnnMETHODSnGenomic DNA from peripheral-blood leucocytes of 1227 renal-transplant recipients was screened by PCR for the presence of CCR5Delta32. Demographic and clinical data were extracted from hospital records. Complete follow-up data were available for 576 recipients of first renal transplants. Graft survival was analysed by Fishers exact test and Kaplan-Meier plots compared with a log-rank test.nnnFINDINGSnPCR identified 21 patients homozygous for CCR5Delta32 (frequency 1.7%). One patient died with a functioning graft. Only one of the remaining patients lost transplant function during follow-up (median 7.2 years) compared with 78 of the 555 patients with a homozygous wild-type or heterozygous CCR5Delta32 genotype. Graft survival was significantly longer in the homozygous CCR5Delta32 group than in the control group (log-rank p=0.033; hazard ratio 0.367 [95% CI 0.157-0.859]).nnnINTERPRETATIONnPatients homozygous for CCR5Delta32 show longer survival of renal transplants than those with other genotypes, suggesting a pathophysiological role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss.

MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients.

This retrospective study investigated the impact of MDR1 haplotypes derived from the single‐nucleotide polymorphisms (SNPs) 2677G>T (exon 21) and 3435C>T (exon 26) on the pharmacokinetics of cyclosporine in 98 renal transplant patients. Based on SNPs 2677 and 3435, four different haplotypes and nine different genotypes were identified in the study sample. Frequencies of SNPs, genotypes, and haplotypes were in agreement with previously reported values. Cyclosporine pharmacokinetics were characterized using a 2‐hour AUC (AUC0–12), trough concentrations (C0), and blood concentrations 2 hours after cyclosporine administration (C2). No significant differences in dose‐corrected AUC0–12, C0, or C2 values were observed between carriers of different SNP variants and genotypes (Kruskal‐Wallis test), as well as between carriers and noncarriers of each haplotype (Mann‐Whitney U test). Carriers of haplotype 12 (2677G and 3435T), which has previously been associated with increased digoxin AUC values, had a median AUC0–12 of 18.9 μg•h•L−1 (range: 9.0–35.2) compared to 17.5 μg•h•L−1 (range: 7.5–37.1) in the noncarrier group. It was concluded that MDR1 haplotypes derived from the SNPs 2677G>T (exon 21) and 3435C>T (exon 26) are not associated with cyclosporine pharma‐ cokinetics in renal transplant patients.

De novo hemolytic uremic syndrome postrenal transplant after cytomegalovirus infection

After renal transplantation, hemolytic uremic syndrome (HUS) may occur as recurrent disease or de novo. Here, we describe the de novo occurrence of HUS immediately after the onset of primary cytomegalovirus (CMV) disease in two renal allograft recipients. Patient no. 1 had primary CMV disease with biopsy-proven CMV esophagitis 2 months after transplantation. Patient no. 2 experienced primary CMV disease with fever and leukopenia 8 years after transplantation. Both patients were treated with intravenous ganciclovir. Both patients developed HUS with biopsy-proven thrombotic microangiopathy in the renal allograft only a few days (3 to 5 days) after the onset of CMV disease. The short interval between the onset of CMV disease and HUS, as well as the parallel course of CMV viremia and HUS in both patients, indicate there may be a pathophysiological link between both diseases. However, because antiviral therapy with ganciclovir was started before the onset of HUS in both patients, we cannot definitely rule out that HUS was triggered by ganciclovir.

Interleukin-8 Expression in Patients After Renal Transplantation

Cellular invasion and cytokine release are important steps in the initiation of rejection. We studied the release of interleukin-8 (IL-8), a potent proinflammatory and chemotactic cytokine, and its prognostic significance in predicting rejection after renal transplantation. Serum and urine samples were analyzed with an IL-8-specific sandwich enzyme-linked immunosorbent assay. Biopsy tissue specimens (n = 20) were snap-frozen and examined with immunohistochemistry using two monoclonal antibodies against human IL-8 (4G9 and 2A8). Serum IL-8 measurements were of no value in predicting rejection due to low sensitivity (24%). In 45 biopsy-proven acute rejections (< 2 months after transplantation), urinary IL-8 concentrations were elevated in 62% (298 +/- 54 pg/mL; P < 0.01), preceding clinical diagnosis of rejection. After treatment, the IL-8 concentration in urine decreased back to normal (33 +/- 4 pg/mL; P < 0.01). The highest urinary IL-8 concentrations were seen in patients with biopsy-proven rejection in combination with acute tubular necrosis (610 +/- 150 pg/mL). This finding was independent of renal function and urinary volume. Only three of 15 rejection episodes in patients more than 2 months after transplantation showed an elevated IL-8 concentration in urine (94 +/- 60 pg/mL). In 10 of 23 patients with infection, a significant increase of IL-8 in urine was observed as well (157 +/- 67 pg/mL; P < 0.05). IL-8-positive staining was found within interstitial mononuclear cells of all biopsy specimens showing rejection. Additionally, the antibody 4G9 stained arteriolar smooth muscle and tubular cells. Interestingly, a few IL-8-positive cells were present in two donor kidneys before transplantation was performed; control tissue was negative. Further investigations are necessary to determine the clinical value of urinary IL-8 determinations in the diagnosis of rejection and to evaluate the role of IL-8 in the pathogenesis of acute allograft rejection.

The quality of life in end stage renal disease care

Abstract The improved prognosis and survival statistics of both renal transplantation and dialysis have focused attention on the quality of life offered by these treatments. Using a standardized questionnaire, we assessed the quality of life of 612 patients undergoing renal replacement therapy at our center. Of these patients, 359 had been transplanted and 253 patients were on dialysis. Concerning the sociodemographic data, only the time on specific treatment was longer in dialysis patients than in transplanted patients (49.2 versus 55.6 months, P < 0.05). Most complaints were more common in dialysis patients than in transplanted patients. Only the side effects of medication were seen more in transplanted patients (P < 0.005). Life satisfaction was higher in transplanted patients than in dialysis patients. Dialysis patients were more anxious (P < 0.05) and more depressed (P < 0.001) than transplanted patients. Transplanted patients also felt that they had more social support than did dialysis patients. Overall life quality was almost equal between patients on hemodialysis and patients on peritoneal dialysis, and between patients on the waiting list for transplantation and those not on the waiting list. Despite a significantly better quality of life after renal transplantation, the percentage of patients working remained unchanged. (57.5% versus 57.8%, P= n.s.). We conclude that despite an improved quality of life after renal transplantation, these patients are economically not more productive than patients on dialysis.

FTY 720A mediates reduction of lymphocyte counts in human renal allograft recipients by an apoptosis-independent mechanism

Abstract The novel immunosuppressive compound FTY 720A posseses a mode of action which is different from all other immunosuppressive drugs. The most prominent feature is a reversible decrease in peripheral lymphocyte counts observed in animal experiments. We investigated in the first human trial (phase 1) whether FTY 720A induces apoptosis of peripheral blood mononuclear cells (PBMC) in stable renal allograft recipients. Monitoring of lymphocyte counts revealed a significant and dose‐dependent decrease within 6 h post‐FTY 720A dose: placebo 5.1%; 0.25 mg 36.4%; 0.5 mg 40.8%; 0.75 mg 39.4%; 1 mg 45.8%; 2 mg 67.2%; 3.5 mg 64.9%. PBMC apoptosis rates did not change, as determined before intake of FTY 720A and 2 h, 6 h, 24 h and 96 h post‐FTY 720A dose. We detected no significant difference in apoptosis rates between patients who received placebo or FTY 720A. However, in vitro experiments showed that high concentrations of FTY 720 A induced apoptosis in human PBMC.

Reactivation of tuberculosis after conversion from azathioprine to mycophenolate mofetil 16 years after renal transplantation

The incidence of tuberculosis among transplant recipients is greater than in the general population. Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has become part of most standard immunosuppressive protocols after renal transplantation. We have recently shown that conversion from azathioprine (AZA) to MMF in patients with chronic allograft dysfunction may be beneficial. Here, we report a patient with a history of pulmonary tuberculosis during his childhood. This patient was converted from AZA to MMF therapy 16 years after allogenic renal transplantation because of chronic allograft dysfunction. Two months later, he developed axillary lymph node tuberculosis caused by Mycobacterium tuberculosis. Because he denied contact with infectious persons, we diagnosed reactivation of old dormant tuberculosis. After surgical extirpation, quadruple antituberculous therapy was administered for 3 months (isoniazid, rifampicin, ethambutol, and pyrazinamide), followed by dual therapy for 3 months (isoniazid and rifampicin), and monotherapy for another 3 months (isoniazid). In the follow-up period, he remained asymptomatic with stable graft function. We conclude that MMF therapy in renal allograft recipients may cause reactivation of old dormant tuberculosis, even in the very late posttransplantation period. In these patients, close monitoring and isoniazid prophylaxis may be useful.

The influence of age on outcome after renal transplantation

The influence of donor age and recipient age on outcome after renal transplantation has been investigated in numerous studies. There is some evidence that patient survival in elderly patients who receive a transplant is significantly higher compared with those, who remain on dialysis. In general, patient survival after renal transplantation is mainly dependent on recipient age and on comorbid conditions. Concerning graft survival, most studies conclude that the survival of kidneys taken from older donors (> 50 years) and very young donors (< 5 years) is reduced. Graft survival was also found to be reduced in very young recipients (< 5 years). Functional graft survival proved to be better in older recipients (> 50 years) as compared to younger recipients, due to a reduced immunologic response capability. Actual graft survival however, where cases of death with functioning graft are included, is fairly equal in both populations. The question, whether the age difference between donor and recipient has an influence on graft survival, needs to be further investigated. In conclusion, donor and recipient age are important risk factors, which may influence outcome after renal transplantation and therefore should be considered carefully.

Pharmacodynamic effects of everolimus on anti-CD3 antibody-stimulated T-lymphocyte proliferation and interleukin-10 synthesis in stable kidney-transplant patients

Everolimus (rapamycin derivative, RAD) is a new immunosuppressive drug that prevents allograft rejection. Herein, the pharmacodynamics of everolimus in human renal-allograft recipients is evaluated. Single doses of everolimus (0.75-10mg), combined with a maintenance immunosuppressive therapy based on CyA, decreased lymphocyte proliferation. In addition, the effect of multiple doses of everolimus (0.75-10mg) given daily for 21 days, to stable renal-allograft patients (n=11), was investigated. Everolimus treatment resulted in immediate inhibition (25-55%) of lymphocyte proliferation in renal-allograft recipients; values returning to baseline by 14 days after cessation of everolimus treatment. Placebo-treated patients showed no decrease in lymphocyte proliferation. Interestingly, everolimus reduced IL-10 synthesis by 20-60% in renal-allograft recipients. Phagocytosis rates were not changed by everolimus. In vitro, everolimus inhibited lymphocyte proliferation and IL-10 synthesis dose dependently in anti-CD3 mAb and LPS stimulated peripheral blood mononuclear cell cultures derived from human volunteers.

Five year outcome of tacrolimus rescue therapy in late rejection after renal transplantation.

REFRACTORY rejection episodes are major causes of graft failure after renal transplantation. It is well known that late acute rejections have a poor long-term prognosis. Tacrolimus (FK) is an immunosuppressant agent that acts by inhibition of calcineurin activity, similar to cyclosporine A (CyA). It is used as a therapeutic alternative to CyA and is considered to be more potent than CyA. FK has also demonstrated efficacy as rescue therapy in patients who experience persistent acute rejection with CyA-based therapy. A corticosteroid-sparing effect has been demonstrated in several studies with FK, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of FK and CyA may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, CyA has a higher incidence of significant hypercholesterolaemia, hirsutism, and gingival hyperplasia, while FK has a higher incidence of diabetes mellitus, some types of neurotoxicity (eg, tremor, paraesthesia), diarrhea, and alopecia. Conversion from CyA to FK in ongoing allograft rejection after renal transplantation has been shown to be effective in the early posttransplant period ( 6 months after transplantation). However, tacrolimus rescue therapy was performed in only a small number of patients with late acute rejection or chronic rejection. In our institution, FK was introduced for rescue therapy in 27 renal transplant recipients with late rejection between 1994 and 1996. We analyzed the 5-year outcome of FK rescue therapy in these patients.