Ernst H. Scheuermann

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C-->T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C-->T and 2677G-->T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (chi2 = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donors ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donors ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

Early diagnosis of acute allograft rejection (AR) is still decisive for long-term renal allograft survival. The aim of this study was to define the role of the chemokine monokine induced by IFN-γ (MIG) (CXCL9) and IFN-γ–inducible protein 10 (IP-10) (CXCL10) as early markers of AR in renal transplantation (NTX). In a prospective study, 69 de novo renal transplant recipients were monitored and urine samples were collected after NTX for a median of 29 d. In pH-adjusted urine, MIG and IP-10 were determined by modified ELISA. AR was clinically diagnosed in 15 of 69 recipients and confirmed by biopsy in 14 of 15 AR patients (Banff classification). Corresponding to CXCR3-positive infiltrates in renal tissue, urinary MIG was elevated in 14 of 15 AR patients with a median of 2809 pg/ml (quartile 25% and 75% = 870 and 13,000; n = 15), being significantly ( P P P

Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors.

Immunosuppression of recipients of renal transplants with azathioprine has been associated with two major side effects: hepatotoxicity and myelotoxicity, mainly in the form of leukopenia. Reports of isolated anemia in these patients have been rare. We now observed the development of severe anemia in 9 out of 11 renal transplant recipients whose immunosuppressive regimen was converted from cyclosporine plus prednisone to azathioprine plus prednisone. A significant (P = 0.001) drop in hematocrit (from 34 +/- 4% to 27 +/- 3%, mean +/- SD) and hemoglobin (from 11.6 +/- 1.3 g/dl to 9.5 +/- 1.0 g/dl) was found. Since a common variable of all these patients was their use of an angiotensin-converting enzyme (ACE) inhibitor as antihypertensive medication, we speculated that the combination of azathioprine and ACE blocker might be the reason for the anemia. We then compared 2 groups of 10 patients each who had been on azathioprine as their regular immunosuppressive agent and who did or did not take an ACE inhibitor. Hematocrit and hemoglobin were significantly (P = 0.01) lower in the group of patients taking ACE inhibitors (33 +/- 6% versus 41 +/- 5% and 11.5 +/- 2.0 g/dl versus 14.0 +/- 1.6 g/dl, respectively). Haptoglobin levels were also significantly (P = 0.05) lower in the ACE inhibitor group (116 +/- 65 mg/dl versus 210 +/- 114 mg/dl). Erythropoietin concentration in the serum and the reticulocyte index were slightly, but not significantly, higher in the ACE inhibitor group but the values were probably too low for their degree of anemia. Comparing hematological parameters of the patients in the ACE inhibitor group before and after beginning of the antihypertensive treatment confirmed a significant reduction of hematocrit and hemoglobin following therapy with an ACE inhibitor. Hematocrit fell from 41 +/- 7% to 36 +/- 6% and hemoglobin from 14.0 +/- 2.3 g/dl to 11.3 +/- 1.5 g/dl (P < 0.05 for both). We conclude that the combination of these two drugs should probably be avoided.

Renal transplantation in the elderly: surgical complications and outcome with special emphasis on the Eurotransplant Senior Programme

BACKGROUND The purpose of this retrospective study was to evaluate the results of the Eurotransplant Senior Programme (ESP) within our centre compared to elderly recipients >or=60 years from the regular Eurotransplant Kidney Allocation System (ETKAS), specifically focusing on surgical aspects. METHODS Data from 73 ESP patients (average donor/recipient age: 71.1/67.1) were compared with those from 51 patients (49.7/63.6) treated within the framework of the ETKAS program between the years 1999 and 2006. The mean follow-up was 39.5 months. RESULTS Cold ischaemic time (ESP versus ETKAS: 10.3 versus 15.0 h), duration of renal replacement therapy (42.2 versus 76.8 months), donor glomerular filtration rate (81.7 versus 109.9 ml/min/1.73 m(2)) and HLA mismatches (4.1 versus 2.4) were significantly different between the two groups (all P < 0.001). Primary graft function was seen in 74% ESP versus 69% of ETKAS patients (P > 0.05). The rate of surgical complications in the ESP versus ETKAS group was 47% versus 28% (P = 0.031) and the revision rate, 33% versus 24% (P = 0.259). Three-year patient and censored graft survival was 84% versus 92% and 85% versus 88% in the ESP and ETKAS group, respectively (all P > 0.05). Ninety-five percent of all deceased patients died with a functioning graft. CONCLUSIONS The donor and recipient pool has been markedly expanded through ESP with similar patient and graft survival compared to elderly recipients grafted according to ETKAS criteria. However, patients and their physicians should be aware of the high surgical complication rate in elderly recipients, particularly when receiving elderly donor kidneys. This might seriously influence postoperative patient management but ultimately does not compromise the transplant outcome.

Transcatheter aortic valve implantation improves outcome compared to open-heart surgery in kidney transplant recipients requiring aortic valve replacement

BACKGROUND Cardiovascular disease is the most frequent cause of mortality for kidney transplant recipients. Open heart surgery has particularly high mortality and morbidity. As an alternative to traditional aortic valve replacement (AVR) for patients with high-grade aortic stenosis, transcatheter aortic valve implantation (TAVI) was developed as an innovative therapy for patients considered at high surgical risk. METHODS We considered all kidney transplant recipients as high-risk patients, which are candidates for TAVI. In 2010 and 2011, eight kidney transplant recipients with severe aortic stenosis underwent TAVI (6 transfemoral; 2 transapical; group I). The outcome of these patients was compared retrospectively to 18 kidney transplant recipients with aortic stenosis, who underwent conventional AVR (group II). RESULTS Both groups had similar baseline characteristics, including estimated perioperative risk (EuroSCORE group I vs. group II: 9.5±5.9 vs. 10.4±10.5; p=0.829). All TAVI procedures were performed successfully with excellent functional results. In the TAVI group (group I), all patients were alive at the 12-month follow-up with one cardiovascular event (stroke). In contrast, the surgical group experienced a 30-day-mortality of 11.1% (n=2) and a 1-year-mortality of 16.7% (n=3). CONCLUSIONS Based on our centers experience, TAVI appears to be an effective and safe alternative to conventional surgery for AVR in patients with prior renal transplantation. Renal transplantation is not currently identified as a risk factor in our traditional scoring system, and may need to be considered independently when weighing alternatives for AVR.

Type III hyperlipoproteinemia acquired by liver transplantation

A case of type III hyperlipoproteinemia (HLP) (dysbetalipoproteinemia) acquired by liver transplantation is reported. The 50-year-old female patient was referred to the Frankfurt University Hospital for orthotopic liver transplantation. She had suffered from ethylic liver cirrhosis. The donor liver showed discrete signs of steatosis. The postoperative course of the patient was satisfactory. Enzyme levels and blood coagulation tests returned to normal within thirty days. However, both cholesterol and triglycerides gradually increased from approximately 2.00 g/L to values ranging from 2.50 to 3.50 g/L within 200 days after transplantation. Cutaneous xanthomas did not develop. The patients lipoprotein pattern met the criteria of type III HLP: the cholesterol to triglyceride ratio in very low-density lipoproteins (VLDL) was 0.64. Intermediate-density lipoprotein (IDL) cholesterol was 0.48 g/L. Lipoprotein elec-trophoresis showed a broad β-band, and β-migrating particles were present in VLDL. Immunoblotting of apolipoprotein (apo) E from the patients plasma revealed an E2/2 phenotype. However, restriction isotyping of an in vitro amplified apoE gene fragment showed the genotype of the patient to be &epsis;3/&epsis;4. These data suggest that the development of type HI HLP in this patient was due to a change in the apoE phenotype from E3/4 to E2/2 after liver transplantation.

Qualität der Leichennierenentnahme in Deutschland

ZusammenfassungHintergrundOrganverletzungen im Rahmen der Organentnahme werden von vielen Transplantationszentren zunehmend als Problem empfunden, wobei publizierte Daten kaum vorliegen. Ziel der vorliegenden Arbeit war es, die Qualität der Leichennierenentnahme in Deutschland zu untersuchen.Material und MethodenAlle an unserer Klinik zwischen 1996 und 2005 durchgeführten allogenen Leichennierentransplantationen mit einem innerhalb Deutschlands entnommenen und von Eurotransplant vermittelten Organ wurden retrospektiv aufgearbeitet.ErgebnisseVon insgesamt 486 entnommenen Leichennieren wurden 103 (21,2%) von den Transplanteuren beanstandet. Keines der Organe musste abgelehnt werden. Bei 18 (3,7%) Transplantationen war die mangelhafte Entnahme mit einer erheblichen Ausweitung des Eingriffs bzw. Komplikationen verbunden.SchlussfolgerungEine mangelhafte Organentnahme geht selten mit klinischen Konsequenzen einher. Trotzdem ist eine intensivere Schulung der entnehmenden Operateure unerlässlich. Ob die von der Bundesärztekammer seit dem 01.01.2006 geforderten 10 Nierenentnahmen unter Anleitung vor selbständiger Entnahme ausreichen, bleibt abzuwarten. Eine zusätzliche klinikübergreifende Fortbildung wäre wünschenswert.AbstractBackgroundOrgan damage during organ procurement is believed to be an increasing problem among transplant centres. However, only very few published data are available. The purpose of our study was to examine the quality of kidney procurement in Germany.MethodsWe retrospectively analyzed all allograft renal transplants performed at our centre from 1996 to 2005. All kidneys were retrieved in Germany and allocated by Eurotransplant.ResultsFrom a total of 486 cadaveric kidneys, 103 (21.2%) were not correctly retrieved. Nevertheless, none of the organs had to be rejected. In 18 (3.7%), a technically insufficient organ retrieval was associated with a considerable extension of the surgical procedure or complications.ConclusionsTechnically insufficient kidney procurement rarely results in clinical consequences. However, surgeons performing organ retrieval should be better trained. Whether adequate technical proficiency is achieved with ten supervised cases, as requested by the German Medical Association, remains to be determined. In our opinion, a further interdisciplinary course that trains surgeons in more refined techniques of organ procurement is desirable.

Quality of kidney procurement in Germany. Ten years experience and 486 renal allografts in a single centre

ZusammenfassungHintergrundOrganverletzungen im Rahmen der Organentnahme werden von vielen Transplantationszentren zunehmend als Problem empfunden, wobei publizierte Daten kaum vorliegen. Ziel der vorliegenden Arbeit war es, die Qualität der Leichennierenentnahme in Deutschland zu untersuchen.Material und MethodenAlle an unserer Klinik zwischen 1996 und 2005 durchgeführten allogenen Leichennierentransplantationen mit einem innerhalb Deutschlands entnommenen und von Eurotransplant vermittelten Organ wurden retrospektiv aufgearbeitet.ErgebnisseVon insgesamt 486 entnommenen Leichennieren wurden 103 (21,2%) von den Transplanteuren beanstandet. Keines der Organe musste abgelehnt werden. Bei 18 (3,7%) Transplantationen war die mangelhafte Entnahme mit einer erheblichen Ausweitung des Eingriffs bzw. Komplikationen verbunden.SchlussfolgerungEine mangelhafte Organentnahme geht selten mit klinischen Konsequenzen einher. Trotzdem ist eine intensivere Schulung der entnehmenden Operateure unerlässlich. Ob die von der Bundesärztekammer seit dem 01.01.2006 geforderten 10 Nierenentnahmen unter Anleitung vor selbständiger Entnahme ausreichen, bleibt abzuwarten. Eine zusätzliche klinikübergreifende Fortbildung wäre wünschenswert.AbstractBackgroundOrgan damage during organ procurement is believed to be an increasing problem among transplant centres. However, only very few published data are available. The purpose of our study was to examine the quality of kidney procurement in Germany.MethodsWe retrospectively analyzed all allograft renal transplants performed at our centre from 1996 to 2005. All kidneys were retrieved in Germany and allocated by Eurotransplant.ResultsFrom a total of 486 cadaveric kidneys, 103 (21.2%) were not correctly retrieved. Nevertheless, none of the organs had to be rejected. In 18 (3.7%), a technically insufficient organ retrieval was associated with a considerable extension of the surgical procedure or complications.ConclusionsTechnically insufficient kidney procurement rarely results in clinical consequences. However, surgeons performing organ retrieval should be better trained. Whether adequate technical proficiency is achieved with ten supervised cases, as requested by the German Medical Association, remains to be determined. In our opinion, a further interdisciplinary course that trains surgeons in more refined techniques of organ procurement is desirable.

Lipoprotein (a) stimulates mitogen activated protein kinase in human mesangial cells.

Evidence suggests an important role of elevated serum lipoproteins in the progression of renal glomerulosclerosis. We report here that lipoprotein (a) (Lp(a)) increased phosphorylation and activity of mitogen activated protein kinase (MAPK) in human mesangial cells. When protein kinase C (PKC) was depleted by long‐term incubation with the phorbol 12‐O‐myristate 13‐acetate the effect of Lp(a) on MAPK activation was completely inhibited. Forskolin, a stimulator of the adenylyl cyclase, and dibutyryl‐cAMP reduced the effect of Lp(a) on MAPK phosphorylation and activation. We conclude that Lp(a) stimulates the MAPK cascade via activation of PKC and that activation of protein kinase A counteracts Lp(a) induced MAPK activation in human mesangial cells.

Effect of procurement‐related organ lesions on renal transplant outcome

Abstract: Background:  The purpose of our study was to examine the nature and incidence of renal injuries during organ procurement, to identify risk factors and to analyse the effects of organ lesions on the following transplantation.