Erich Pohanka

Adverse effect of low-dose prophylactic human recombinant leukocyte interferon-alpha treatment in renal transplant recipients: cytomegalovirus infection prophylaxis leading to an increased incidence of irreversible rejections

Since infections with Herpetoviridae after kidney transplantation still remain a major clinical problem, we conducted a double-blind, placebo-controlled trial using low-dose recombinant interferon-alpha-2C (rIFNa2C) prophylaxis in 50 renal graft recipients im-munosupressed with cyclosporine and methylpredniso-lone. Ten patients were excluded from further analysis because of graft loss due to surgical complications, side effects of rIFNa2C, and because of lack of compliance. There was a significant difference in graft loss due to irreversible rejections between the verum and the placebo group (6 vs. 0; P< 0.05), whereas no difference was observed with regard to the occurrence of viral infections. We conclude, that low-dose rIFNa2C prophylaxis is harmful in renal allograft recipients treated with cyclosporine in view of the high incidence of irreversible transplant rejections without beneficial effects on the occurrence of viral infections.

Development of Proteinuria After Switch to Sirolimus‐Based Immunosuppression in Long‐Term Cardiac Transplant Patients

Calcineurin‐inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long‐term cardiac transplant patients were switched from cyclosporine to Srl‐based IS. Concomitant IS consisted of mycophenolate mofetil ± steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0–5.7) preswitch to 0.23 g/day (0–9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high‐grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin‐releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high‐grade proteinuria showed decreased renal function at the end of follow‐up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

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.

Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA‐AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA‐AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA‐AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

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 1u2003year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1u2003year, 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; Pu2003<u20030.001). One year glomerular filtration rate (GFR) and GFR‐decline after 1u2003year were similar in DCD and CAD recipients (GFR 56u2003ml/min DCD vs. 59u2003ml/min CAD; GFR‐decline −1.3u2003ml/min DCD vs. −1.4u2003ml/min CAD; Pu2003=u2003not significant). Multifactorial analyses confirmed that GFR at 1u2003year 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 1u2003year.

Relationship of interferon-gamma and neopterin levels during stimulation with alloantigens in vivo and in vitro

We have recently shown that interferon-gamma is capable of activating the key enzyme of pterin biosynthesis in macrophages. This leads to excretion of the stable degradation product neopterin. In this article we present experimental evidence suggesting that stimulation of T cells by alloantigens is associated with release of interferon-gamma--which, in the case of rejection, is locally restricted and not always detectable in the bloodstream. Neopterin induced by this lymphokine, however, readily penetrates tissue barriers and is detectable in the serum. This conclusion is based on two different sets of observations: (1) If supernatants of MLCs are compared with sera from patients with documented acute rejection episodes for their interferon-gamma and neopterin levels, a marked gradient is observed to exist between interferon levels measured in vitro and in vivo; this is not the case for neopterin for which comparable levels were seen. (2) Detection of interferon-gamma in sera of allograft recipients invariably precedes an increase of neopterin; on the other hand, increasing neopterin counts are also seen in the absence of detectable interferon-gamma levels in the serum. It thus appears that although interferon-gamma release during allograft rejection is primarily restricted to the tissue, evaluation of certain metabolites of interferon-dependent metabolic pathways enables definition of its endogenous release. Whereas interferon gamma represents a less reliable marker in the monitoring of rejection episodes, it might offer an additional means to differentiate rejection from systemic infections. Such a discrimination can not be achieved with the neopterin marker.

Metal-on-metal hip implants: do they impair renal function in the long-term? A 10-year follow-up study

IntroductionThe aim of our study was to investigate a potential influence of elevated serumcobalt and serumchromiumlevels on renal function at minimum 10xa0years after implantation of a metal-on-metal hip.Materials and methodsBetween November 1992 and June 1994 98 patients (44xa0m, 54xa0f) with an average age of 56 (22–79) years received a metal-on-metal bearing Metasul™. At the time of the 10-year follow-up, 15 patients had died and 8 were lost to follow-up. The remaining 75 patients had laboratory analysis including serumcreatinine and full blood cell count as well as chromium and cobalt serumlevels.ResultsTen years postoperatively the median serumcreatinine level was 0.86 (0.55–1.51) mg/dl, the serumcreatinine clearance Ccr was in the normal range. The hemogram did not differ from that measured at the time of surgery. The median serumcobalt concentration was 0.75 (0.3–50.10) μg/l and the serumchromium concentration was 0.95 (0.3–58.6) μg/l, 10xa0years postoperatively.ConclusionOur long-term data do not show any influence of serum cobalt or chromium concentrations on renal function following total hip arthroplasty.

Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects

The hyperlipidemic and hypertensive effects of ciclosporin constitute a cardiovascular risk. Cosmetic side‐effects are known to reduce patients’ quality of life. This was a 6‐month, open, prospective, multicentre study in 296 adult kidney transplant patients to evaluate the conversion from ciclosporin to a tacrolimus‐based regimen. Primary indications for conversion were hyperlipidemia (nu2003=77), hypertension (nu2003=u200372), hypertrichosis (nu2003=u200332) and gingival hyperplasia (nu2003=u2003115). At month 6, hyperlipidemia and hypertension were at least moderately improved in 59.1% and 63.5% of patients, and strongly or completely resolved in 29% and 25%. Gingival hyperplasia and hypertrichosis were strongly or completely resolved in 73% and 72% of patients. Mean total cholesterol was reduced from 255 to 218u2003mg/dl. Mean systolic blood pressure (SBP) was reduced from 152.9 to 137.5u2003mmHg and mean diastolic blood pressure (DBP) from 90.7 to 85.8u2003mmHg. Ciclosporin‐related side‐effects resolved or improved after conversion to tacrolimus.

Augmentation index in patients with rheumatoid arthritis and ankylosing spondylitis treated with infliximab

Premature atherosclerosis is linked to inflammation. Arterial stiffness is a marker of vascular dysfunction. We tested the hypothesis that treatment with infliximab, which is effective in reducing inflammation in rheumatoid arthritis (RA) and ankylosing spondylitis (AS), also lowers the augmentation index (AIx) in patients with active disease. We also analyzed the subendocardial viability ratio (SEVR), which is a measure of myocardial perfusion relative to cardiac workload. Included in the study were 30 patients (17 RA, 13 AS). Conventional treatment failed in all patients. The AIx and SEVR were determined by radial applanation tonometry before and after treatment with infliximab, at baseline and at weeku20097. After treatment with infliximab, Disease Activity Score for 28 joints (RA patients), Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (AS patients), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) improved significantly (pu2009<u20090.001). The AIx for all patients increased from 22.0u2009±u200914.0% to 24.6u2009±u200913.0% (pu2009=u20090.03). The increase in the RA sub-group (pu2009=u20090.01) was also significant. The SEVR decreased from 148.6u2009±u200923.7% to 141.2u2009±u200923.7% (pu2009=u20090.04). Infliximab did not reduce the AIx in patients with RA and AS, although there were clinical improvements and CRP and ESR decreased. Instead, the AIx increased. This could negatively influence cardiac workload.

POSTTRANSPLANT HEMOLYTIC UREMIC SYNDROME IN ADULT RETRANSPLANTED KIDNEY GRAFT RECIPIENTS: ADVANTAGE OF FK506 THERAPY?

BACKGROUNDnPosttransplant hemolytic uremic syndrome (pHUS) is a rare but severe disorder that confers a poor prognosis on an allograft due to thrombotic microangiopathy. Immunosuppression with cyclosporine (CsA) is implicated as a significant risk factor for the development of pHUS. In early reports, it was hypothesized that immunosuppression with FK506 (tacrolimus) would avoid the development of pHUS. However, this initially supposed beneficial effect remains controversial, because pHUS associated with tacrolimus therapy has been published in some later case reports. This article aims to further evaluate FK506 with respect to the development and resolution of pHUS.nnnMETHODSnWe describe the course of seven adult kidney graft recipients with pHUS, treated with FK506 either as initial immunosuppression for retransplantation or after discontinuation of CsA for resolution of pHUS. Work-up for pHUS was initiated when certain clinical features, such as hemolytic anemia, thrombocytopenia, and deterioration of graft function, were found. The diagnosis was confirmed by histologic examination of a renal allograft biopsy specimen (thrombotic microangiopathy). With the onset of pHUS, additional plasma exchange was performed in all patients.nnnRESULTSnTwo patients suffered from end-stage renal disease due to primary HUS and had a history of recurrent pHUS in previous renal transplants. In both patients, the attempt to regraft was only made because of the early optimistic reports using FK506. Despite initial FK506 therapy, both recipients developed pHUS again, leading to loss of graft function. Two additional kidney graft recipients with primary renal failure other than HUS also received FK506 as initial immunosuppression. One of them (loss of the first kidney graft due to CsA-induced pHUS) was successfully treated with FK506 for his second renal transplant. The other recipient, a patient in whom de novo pHUS had occurred in the first graft despite initial therapy with FK506, was treated with CsA for his second graft and again developed pHUS. The latter process, however, could be reversed by a switch to steroids and azathioprine. In all three patients regrafted for reasons other than pHUS, development of de novo pHUS was treated by CsA withdrawal and a switch to FK506; this approach was effective in two patients.nnnCONCLUSIONnOur results demonstrate that three of seven renal allograft recipients benefited from FK506 therapy for prevention or resolution of pHUS. Treatment or prophylaxis with FK506 can be considered advantageous in some patients with de novo pHUS, but FK506 fails to prevent recurrent pHUS in patients with primary HUS.