Volker Kliem

Improvement in Long-Term Renal Graft Survival due to CMV Prophylaxis with Oral Ganciclovir: Results of a Randomized Clinical Trial

Oral ganciclovir prophylaxis and intravenous preemptive therapy are competitive approaches to prevent cytomegalovirus (CMV) disease after renal transplantation. This trial compared efficacy, safety and long-term graft outcome in 148 renal graft recipients randomized to ganciclovir prophylaxis (N = 74) or preemptive therapy (N = 74). Hierarchical testing revealed (i) patients with CMV infection had more severe periods of impaired graft function (creatinine clearance(max-min) 25.0 +/- 14.2 mL/min vs. 18.1 +/- 12.5 mL/min for patients without CMV infection; p = 0.02),(ii) prophylaxis reduced CMV infection by 65% (13 vs. 33 patients; p < 0.0001) but (iii) creatinine clearance at 12 months was comparable for both regimes (54.0 +/- 24.9 vs. 53.1 +/- 23.7 mL/min; p = 0.92). No major safety issues were observed, and patient survival at 12 months was similar in both groups (5 deaths [6.8%] vs. 4 [5.4%], p = 1.0000). Prophylaxis significantly increased long-term graft survival 4 years posttransplant (92.2% vs. 78.3%; p = 0.0425) with a number needed to treat of 7.19. Patients with donor +/recipient + CMV serostatus had the lowest rate of graft loss following prophylaxis (0.0% vs. 26.8%; p = 0.0035). In conclusion, it appears that routine oral prophylaxis may improve long-term graft survival for most renal transplant patients. Preemptive therapy can be considered in low risk patients in combination with adequate CMV monitoring.

Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody‐associated vasculitis) and invasive bacterial infection

OBJECTIVE To investigate whether the determination of serum procalcitonin (PCT) in systemic autoimmune disease will help to discriminate invasive infection from highly active underlying disease. METHODS Three hundred ninety-seven serum samples, from 18 patients with systemic lupus erythematosus (SLE) and 35 patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis (AAV), were analyzed. Clinical disease activity was assessed by the Systemic Lupus Activity Measure in SLE patients and by the Birmingham Vasculitis Activity Score in AAV patients. Procalcitonin concentrations were determined in parallel with concentrations of neopterin, interleukin-6 (IL-6), and C-reactive protein (CRP). Additionally, serum creatinine values were obtained. RESULTS In 321 of the 324 samples from the 42 patients with autoimmune disease but without systemic infection, serum PCT levels were within the normal range (i.e., <0.5 ng/ml), whereas the values for neopterin, IL-6, and CRP were elevated in patients with active underlying disease. All 16 systemic infections occurred in 11 patients with AAV, and were associated with PCT levels that were markedly elevated, to a mean +/- SD of 1.93 +/- 1.19 ng/ml. No correlation between the degree of renal impairment and PCT concentrations was seen. CONCLUSION PCT may serve as a useful marker for the detection of systemic bacterial infection in patients with systemic autoimmune disease.

Incidence of Pneumocystis carinii pneumonia after renal transplantation : Impact of immunosuppression

The incidence and potential risk factors of Pneumocystis carinii pneumonia (PCP) in our population of renal transplant recipients were analyzed retrospectively. Of 1427 patients who received transplants between January 1986 and June 1994, 1192 were evaluated. Four different immunosuppressive regimens were applied: (1) cyclosporine (CsA) + prednisolone (Pred), (2) CsA + azathioprine (Aza, 2 mg/kg/day) + Pred, (3) CsA + Aza + antithymocyte globulin, and (4) (after December 1, 1993, European multicenter trial) FK506 + Aza (1 mg/kg/day) + Pred. No prophylaxis against PCP was performed. Before December 1, 1993, three PCPs in 494 patients on protocol 2 or 3 occurred (0.6%). Afterward, seven PCPs in 77 patients occurred (9%): three in 38 patients on protocol 2 (7.8%) and four in 28 patients on protocol 4 (14.3%). Comparing patients with PCP on CsA and FK506, the mean Aza dose was 2.40 and 1.32 mg/kg/day, five and two patients received additional steroids, antibody treatment was used in three and no patients, and CMV infections occurred in five and two patients, respectively. The incidence of PCP with a moderate CsA-based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. Despite a general increase of PCP, its incidence was highest in patients on FK506 with fewer immunosuppressive cofactors. Thus, prophylaxis against PCP after renal transplantation should be performed, if not in every renal transplant recipient, at least in case of treatment with additional steroids, antibodies, or FK506.

Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant

Background. Long-term success of renal transplantation depends upon the quality of the donor organ, avoidance of peritransplant and early posttransplant damage (rejection), and optimal maintenance of graft function after the first 6–12 months. Glomerular filtration rate (GFR) at 1 year is a standard way to evaluate short-term success, whereas calculated GFR at 5 years gives a better appreciation of long-term outcomes. The objective of this study was to assess the effect of various demographic and transplant-related parameters on renal function via GFR at 1 year and 5 years post transplantation, using univariate and multivariate data analysis. Methods. Data on 1-year GFR were available from 10,397 patients, whereas 2,889 patients provided data on both 1-year and 5-year GFR. All patients were enrolled in the Neoral Multinational Observational Study in Transplantation (Neoral-MOST), an ongoing, prospective, observational study of adult renal transplant recipients. Results. One-year GFR was the most relevant predictor for 5-year GFR. In a multifactorial analysis (ANCOVA) using 1-year GFR as a continuous variable, the effects of several highly relevant parameters from univariate analysis (such as acute rejection and delayed graft function) on 5-year GFR appeared to be fully mediated by their influence on 1-year GFR, whereas immunological risk factors like HLA match or previous transplantation had an ongoing effect on graft function beyond year 1. Conclusions. The findings of this study corroborate and augment data from previous registry surveys, and confirm the importance of observational studies in investigating the role of peritransplant parameters on long-term graft outcome.

Renal transplantation for patients with autoimmune diseases: single-center experience with 42 patients.

BACKGROUND In patients with autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE), end-stage renal disease develops in a high percentage of patients, and kidney transplantation has become a therapeutic option. However, only limited data about the prognosis and outcome after kidney transplantation are available. METHODS Long-term graft survival and graft function of renal transplant recipients with SLE, Wegeners granulomatosis, microscopic polyangiitis, Goodpastures syndrome, and Henoch-Schonlein purpura were evaluated in a single center. In addition, the incidence of renal and extrarenal relapses and the impact of the immunosuppressive therapy on the course of the autoimmune disease were studied. RESULTS Renal transplant recipients with autoimmune diseases such as vasculitis and SLE had a patient survival rate (94% after 5 years) and a graft survival rate (65% after 5 years) comparable to those of patients with other causes of end-stage renal disease (patient survival 88% and graft survival 71% after 5 years). Graft losses due to the underlying disease were rare. Extrarenal relapses occurred in three patients with Wegeners granulomatosis, one patient with microscopic polyangiitis, and three patients with SLE, but were less frequent compared with the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegeners granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. CONCLUSIONS Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

SDMA is an early marker of change in GFR after living-related kidney donation

BACKGROUND Early detection of changes in the glomerular filtration rate (GFR) is crucial in detecting acute kidney injury. There is burgeoning evidence from preclinical and clinical studies that symmetrical dimethylarginine (SDMA) correlates well with different parameters of renal function. In some studies, SDMA even outperformed creatinine as a marker of GFR. It is however unknown how fast SDMA is increasing after reduction in GFR. The aim of our study was therefore to determine the temporal change of SDMA in comparison with cystatin C after a defined reduction in GFR. METHODS Blood samples from 24 healthy living-related kidney donors (19 F/5 M), mean age 55.2 ± 8.3 years, were collected prior to donation of the kidney as well as 1, 6, 12, 24, 72 and 168 h after unilateral nephrectomy. SDMA levels were measured using a liquid chromatography-mass spectrometry-based method. RESULTS Within 6 h after unilateral nephrectomy, i.e. reduction of GFR by 50%, SDMA rose from 0.571 ± 0.120 to 0.659 ± 0.135 µmol/L (P < 0.001). Baseline cystatin C levels increased from 0.87 ± 0.16 to 1.07 ± 0.15 mg/L (P < 0.001). Also, serum creatinine rose significantly within 6 h after removal of one kidney from 65.4 ± 8.4 to 88.8 ± 10.2 µmol/L (P < 0.001). DISCUSSION SDMA might be a valuable and early marker of change in GFR in the clinical and experimental setting. Future studies will have to clarify whether sensitivity, specificity and temporal resolution of SDMA make it an attractive candidate for the assessment of renal function in both the experimental and clinical setting.

Follow-up after renal transplantation with organs from donors after cardiac death

Kidneys obtained from donors after cardiac death (DCD) are known to have higher rates of primary nonfunction and delayed graft function (DGF) than heart beating cadaveric donor (CAD) kidneys, but little is known about long‐term function of DCD grafts that survive to 1 year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1 year, this study analyzed data collected from 326 DCD graft recipients and 340 CAD‐matched controls enrolled in a prospective, multinational, observational study – Neoral®‐MOST (Multinational Observational Study in Transplantation) (Novartis, Basel, Switzerland). No differences were found in the demographics or immunosuppression between the two groups. All patients received a Neoral®‐based immunosuppressive regimen. Donors after cardiac death graft recipients had a higher incidence of DGF (40% vs. 27% CAD; P < 0.001). One year glomerular filtration rate (GFR) and GFR‐decline after 1 year were similar in DCD and CAD recipients (GFR 56 ml/min DCD vs. 59 ml/min CAD; GFR‐decline −1.3 ml/min DCD vs. −1.4 ml/min CAD; P = not significant). Multifactorial analyses confirmed that GFR at 1 year was significantly influenced by donor age and gender, DGF, and acute rejection; however, DCD status was not an independent risk factor in cyclosporine‐treated patients with grafts that had functioned for at least 1 year.

Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study.

Background. Diabetes mellitus is the leading cause of renal failure worldwide. The question of which treatment modality—hemodialysis versus renal transplantation—is associated with the lowest risk of cardiovascular morbidity and mortality in the diabetic end‐stage renal disease (ESRD) population has not yet been investigated in a controlled trial. Methods. We therefore conducted a case‐control study of patients with ESRD caused by type 1 diabetes mellitus. The case patients were diabetics who received a renal graft between 1978 and 1997, whereas the controls were registered for renal transplantation but stayed on maintenance hemodialysis without ever undergoing transplantation. The groups were matched for age, sex, duration of diabetes, length of hemodialysis (up to the registration), and date of registration for renal transplantation. Results. Kaplan‐Meier life table analysis, based on 46 case patients and 46 controls, demonstrated a highly significant (P=0.0001) poorer survival in the control group compared with the case group. Logistic regression showed that hemodialysis was a significant risk factor for death (P=0.0002) and cardiovascular morbidity (P=0.0023). Patients with cardiovascular complications such as coronary artery and peripheral vascular events were significantly more frequent in the control group. Additionally tested risk factors for cardiovascular complications (serum cholesterol, arterial blood pressure, number of antihypertensive drugs, serum calcium, serum phosphate, and glucose control [hemoglobin A1c]) showed no significant correlation to survival or morbidity in either group by logistic regression. Conclusions. Renal transplantation is associated with a significantly improved survival compared with hemodialysis in patients with ESRD caused by type 1 diabetes mellitus. This seems to be a result of a reduced incidence of cardiovascular complications after renal transplantation.

Circulating angiopoietin-2 levels increase with progress of chronic kidney disease

BACKGROUND Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels. METHODS Glomerular filtration rate (GFR) was assessed by the inulin clearance technique ((i)GFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography-electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1-4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and (c)GFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation. RESULTS The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32-1.08) ng/mL; CKD 1: 0.83 (0.67-1.09) ng/mL; CKD 2: 0.93 (0.74-1.15) ng/mL; CKD 3: 1.13 (0.87-1.49) ng/mL; CKD 4: 1.75 (1.23-2.61) ng/mL; and CKD 5: 4.87 (3.22-7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the (i)GFR (r = -0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = -0.54, P = 0.03). CONCLUSIONS Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.

How best to use tacrolimus (FK506) for treatment of steroid- and OKT3-resistant rejection after renal transplantation.

Nineteen patients with biopsy-confirmed ongoing acute rejection of renal allografts were converted from standard immunosuppression to FK506. Eight grafts showed vascular rejection and 11 had cellular rejection on biopsy. All patients had already received intravenous high-dose steroid treatment. Ten patients also had additional OKT3 rescue therapy. Initial FK506 doses were 0.13 +/- 0.06 mg/kg/day; the FK506 whole blood trough level after 3 days of treatment was 9.3 +/- 4.5 ng/ml. After conversion to FK506 all but four patients also received azathioprine, 1.5-2 mg/kg/day, and all patients received oral prednisolone. Concomitant with initiation of FK506, an anti-infective prophylaxis was prescribed, consisting of ganciclovir and trimethoprim/sulfamethoxazole. Sixteen out of 19 of the grafts (84%) were rescued successfully, including two grafts of patients already on hemodialysis at the time of conversion. Graft function of the responders improved from an average serum creatinine level of 364 +/- 109 mumol/L to 154 +/- 49 mumol/L. Of the patients receiving high-dose steroids alone prior to FK506 initiation, 8/9 responded to FK506 treatment, compared with 8/10 of those who had also received OKT3. During the mean follow-up of 35 weeks after conversion, no clinically apparent cytomegalovirus infection and no pneumonia were seen. Treatment with FK506 may successfully suppress ongoing acute rejection, even if antilymphocyte preparations have failed. FK506 can be used at a lower dose than so far recommended without impairing the antirejection potential. An additional anti-infective prophylaxis seems effective in preventing severe complications in the first months after rejection therapy.