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Surgical aortic valve replacement (SAVR) in kidney transplant recipients (KTR) is associated with high morbidity and mortality, and an increased risk of postoperative graft failure potentially leading to graft loss. Transcatheter aortic valve implantation (TAVI) emerged as an alternative in high-risk patients. However, data on TAVI in kidney transplant recipients are limited. We performed a retrospective analysis of 40 KTR in which aortic valve replacement was performed at our center between 2005 and 2015. The outcomes and follow-up of TAVI (n=20; 2010-2015) and SAVR (n=20; 2005-2015) were analyzed with respect to patient and graft survival. Baseline characteristics in both groups were comparable. Hospital stay after TAVI was significantly shorter compared to SAVR (19 [11.5-21.75] days vs. 33 [21-62] days, p=0.001). Acute graft failure occurred more frequently after SAVR (45% vs. 89.5%; p=0.006). Thirty-day mortality was 10% in both groups. However, in-hospital mortality reached 25% in the SAVR group (TAVI 10%), indicating a more complicated course after surgery. Moreover, during a median follow-up time of 1928 days in TAVI patients and 2717 days in patients after SAVR, graft loss occurred only in the surgically treated group (n=7). While one-year survival after TAVR was 90% compared to 69% after SAVR, long-term follow-up showed comparable results (at 5 years: TAVI 58% vs. 52% SAVR; log-rank-test: p=0.86). In KTR, TAVI can be performed with good mid- to long-term results. Compared to SAVR, renal outcomes seem to be improved after TAVI, suggesting better graft survival.

BACKGROUND Varices of the upper gastrointestinal tract are due to portal hypertension and can result from occlusion of the portal venous system. This report is of a 55-year-old man with recurrent gastrointestinal bleeding due to stricture of the portal vein anastomotic site to inferior vena cava (IVC) 12 years after combined pancreas and kidney transplantation. CASE REPORT A 55-year-old man presented bleeding episodes requiring transfusion of more than 70 units of red blood cells (RBCs), complicated by bacterial and viral infection episodes including cytomegalovirus (CMV) reactivation and hepatitis E and transient impairment of function of the renal allograft. Endoscopy, computed tomography (CT) scan, and angiography revealed jejunal varices due to anastomotic stricture at the portal vein to IVC as the cause of the hemorrhage. Neither conservative therapy nor an anastomosis between the splenic vein of the graft and the internal iliac vein as a bypass could stop the life-threatening bleeding. During the recurrent bleeding, CD4 T lymphocytes were low, indicating immunodeficiency despite paused immunosuppressive therapy. After the hemorrhage resolved and immunosuppression was restarted, CD4 T lymphocyte levels normalized. Finally, to stop the hemorrhage and save the transplanted kidney and the patient's life, graft pancreatectomy was performed. Long-term damage to the renal transplant was not found. CONCLUSIONS This report is of a rare case of portal hypertension as a long-term complication of transplant surgery. Although acute venous thrombosis at the anastomotic site is a recognized postoperative complication of pancreatic transplant surgery, this case highlights the importance of post-transplant follow-up and diagnostic imaging.

Background: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4 + T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality., Methods: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4 + T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality., Results: In univariate analyses, high CRP, high neutrophils, CD4 + T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4 + T cells/µL predicted in-hospital mortality, CD4 + T cell lymphopenia remained a risk factor in a Cox regression model., Conclusions: Low CD4 + T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP., (© 2020 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: The second most common infection after kidney transplantation is pneumonia, which has a high complication rate, sometimes even resulting in death. The aim of this study was to identify risk factors associated with mortality in nonopportunistic pneumonia., Methods: We retrospectively studied all kidney transplant recipients with nonopportunistic pneumonia treated at the University Hospital Frankfurt, Germany, between 2004 and 2017. Patient baseline characteristics, laboratory values, and microbiologic tests were analyzed. We focused specifically on acute and chronic graft failure and the immunosuppressive regimen and included a follow-up period of 7.8 years., Results: One hundred seventy-seven patients (12%) collectively had 270 episodes of pneumonia. Although immunosuppressive therapy was reduced in 42% of patients during infection, there was no increase in graft rejection during hospital stay and follow-up. Significant risk factors for mortality were C-reactive protein > 10 mg/dL and serum albumin < 3 g/dL on admittance, congestive heart failure, autosomal dominant polycystic kidney disease as the underlying renal disease, nosocomial pneumonia, septic shock, intensive care unit admittance, mechanical ventilation, and renal replacement therapy., Conclusions: Using these factors, patients at risk for death can be identified and the outcome of those might be improved by close monitoring and modified therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Management of dialysis patients with valvular heart disease waitlisted for kidney transplantation is challenging. Development of severe aortic valve stenosis can lead to the exclusion from the transplant program or even death while on the waiting list. In dialysis patients, surgical aortic valve replacement is associated with a high perioperative risk with increased morbidity and mortality. In contrast, transcatheter aortic valve implantation emerges as a viable option for dialysis patients. Herein, we present the long-term follow-up of successful kidney transplantation after TAVI in a diabetic patient receiving long-term hemodialysis., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Clinical relevance of ELISA- and single-antigen bead assay (SAB)-detected pretransplant HLA antibodies (SAB-HLA-Ab) for kidney graft survival was evaluated retrospectively in 197 patients transplanted between 2002 and 2009 at the University Clinic Frankfurt. Having adjusted for retransplantation and delayed graft function, a significantly increased risk for death-censored graft loss was found in patients with pretransplant SAB-HLA-Ab [HR: 4.46; 95% confidence interval (CI): 1.47-13.48; P = 0.008]. The risk for increased graft loss was also significant in patients with pretransplant SAB-HLA-Ab but without SAB-detected donor-specific Ab (SAB-DSA) (HR: 4.91; 95% CI of 1.43-16.991; P = 0.012). ELISA was not sufficient to identify pretransplant immunized patients with an increased risk for graft loss. In immunized patients, graft loss was predominantly present in patients who received transplants with a mismatch on the HLA-DR locus. In conclusion, even if our study is limited due to small sample size, the results show an increased risk for long-term graft loss in patients with pretransplant SAB-HLA, even in the absence of DSA. SAB-HLA-Ab-positive patients, being negative in ELISA or CDC assay, might profit from a well-HLA-DR-matched graft and intensified immunosuppression., (© 2016 Steunstichting ESOT.)

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 center's 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., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Delayed graft function (DGF) is an important complication in renal transplantation, contributing significantly to decrease in long-term allograft survival. In addition to donor- and recipient-related risk factors such as immunosuppression, altered renal excretion of xenobiotics by membrane transporters may influence DGF. Using DNA samples from recipients and donors, we assessed the impact on DGF of genetic variants in P-glycoprotein (ABCB1), multidrug resistance protein 2 (ABCC2), and the nuclear pregnane X receptor (PXR/NR1I2), which regulates the transcription of enzymes and transporters. In our local cohort of renal transplant recipients (n = 178), DGF occurred in 27.5%. The PXR 8055TT genotype of the donor only (not of the recipient) was significantly associated with an increased risk for DGF. This finding emerged from univariate as well as multivariate logistic regression analysis including 16 nongenetic factors and held true after correction for multiple testing. Our findings provide the first evidence that PXR may be associated with risk of DGF, independent of previously identified risk factors.

Background: Simultaneous pancreas and kidney transplantation (SPK) is associated with great postoperative morbidity, including the need for relaparotomy in up to 40% of cases. Because the pancreatic graft is known to be the major cause of the high morbidity, we examined the incidence and treatment of pancreatic fistula (PF) in this retrospective analysis., Methods: From January 2004 to July 2010, we transplanted 52 pancreas grafts, including 50 SPK, 1 pancreas after kidney, and 1 pancreas transplantation alone. There were 22 female and 30 male patients with an overall mean age of 42.4 ± 7.4 years. The mean duration of diabetes was 27.3 + 8.1 years, mean duration of dialysis was 24.2 ± 28.6 months, and 14 cases were pre-emptive transplantations. All procedures were performed using systemic venous and enteric drainage., Results: The incidence of clinically relevant PF was 16/52 (30.8%), including 11 (68.8%) that were treated conservatively with a drain. Five patients (31.2%) needed relaparotomy: 2 due to enteric leakage, 2 due to acute abdominal pain with graft pancreatitis observed at laparotomy, and 1 due to acute hemorrhage. In 3 cases, graft pancreatectomy was necessary. Comparing the patients with (PF+) versus without (PF-) fistulas, there was no significant difference in cold ischemia time (10.9 ± 2.6 hours vs 10.4 ± 4.4 hours; P = .633), donor age. We found a significantly higher peak C-reactive protein (CRP) level in the patients with pancreatic fistula (3661.4 ± 3474.8 U/L vs 821.8 ± 1293.7 U/L, P = .022). The lipase concentration measured in the drainage fluid postoperatively showed a significant difference between the 2 groups (3661.4 ± 3474.8 U/L vs 821.8 ± 1293.7 U/L; P = 0.006). Also, the amylase concentration was higher in the PF+ group (1747.3 ± 3346.7 U/L vs 265.3 ± 254.9 U/L; P = .097). Graft loss occurred in 4/16 cases (25.0%) of PF+ and 7/36 (19.4%) of PF- (P = .719)., Conclusion: The incidence of PF after pancreas transplantation is high and seems to be associated with ischemia-reperfusion injury reflected by peak-CRP. In most cases a conservative treatment is successful. The occurrence of a PF does not significantly impair graft survival., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Background: Hypertension is a risk factor for the two leading causes of death in renal transplant recipients: cardiovascular disease (CVD) and graft failure. Despite this, the optimum medication for post-transplant hypertension is unclear., Methods: The Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) was an international multicentre, double-blind, randomized investigation of the angiotensin II type 1 receptor blocker (ARB) candesartan cilexetil versus placebo in renal allograft recipients originally designed to study 700 patients for 3 years. The candesartan dose was escalated from 4 to 16 mg daily, followed by addition of co-medication, if needed, with the aim of achieving a diastolic blood pressure (BP) <85 mmHg. The primary efficacy variable was a composite of all-cause mortality, cardiovascular morbidity and graft failure., Results: SECRET was stopped prematurely as the primary event rate was much lower than expected. At that point, 502 patients were enrolled; 255 received candesartan and 247 placebo. Thirteen primary events had occurred in each group. Control of both systolic and diastolic BP was better in the candesartan group. Urinary protein excretion and protein/creatinine ratio decreased on candesartan but increased on placebo. Serum creatinine and potassium were increased in candesartan patients, but these changes were generally small., Conclusions: SECRET provides insights into the design and conduct of studies in this area and evidence for the utility of candesartan, which showed good safety and tolerability, improved BP control and decreased proteinuria in renal transplant recipients.

We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti-hepatitis B surface antigens and anti-hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)-DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV-DNA, anti-HBV antibodies and transaminases for prolonged periods in patients with status post-hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti-HBV antibodies.

Relapse of focal segmental glomerulosclerosis (FSGS) after renal transplantation is 20-40%. Recurrence after a first relapse is 80%. The only current treatment is plasmapheresis and/or cyclophosphamide. We report successful treatment of a second relapse in a 48-year-old patient. At age 33, FSGS was diagnosed. The patient began hemodialysis 1 year later. In her first renal transplant, she developed recurrent FSGS and reached terminal transplant failure 3 years later. Eight years later, a second transplant was performed. Immunosuppressive regimen: steroids, mycophenolate mofetil (MMF), tacrolimus (TAC), and rabbit anti-thymocyte globulin. Proteinuria of 2-6 g/day was detected and a biopsy showed recurrent FSGS. Plasmapheresis was started without success. Another biopsy still showed FSGS. The patient received two doses of rituximab (375 mg/m2 each) i.v. Three weeks later, proteinuria was 350 mg/day (serum-creatinine 1.6 mg/dl). Twelve months later, proteinuria was at 90 mg/day. Rituximab might be an option for recurrent FSGS after renal transplantation.

A 45-year-old man was admitted with fever and elevated pancreas enzymes 6 months after simultaneous pancreas-kidney transplantation (SPKT). Function of the allografts was normal. Bacterial and fungal infections were excluded, while Epstein-Barr virus (EBV)-polymerase chain reaction (PCR) was positive. However, screening for EBV-associated lymphoma was negative. EBV infection did not respond to antiviral therapy. After an 18F-Fluorodeoxyglucose positron emission tomography positive signal and an abnormal computed tomography scan of the pancreas transplant, a biopsy revealed a diffuse large monomorphic B-cell lymphoma, which was confined to the grafted organ. Its origin was assigned to the donor by microsatellite analysis. Reduction of immunosuppression and immunotherapy with rituximab was unsuccessful. After 10 weeks, the patient developed an acute hemolytic uremic syndrome which required explantation of the allografts. Subsequent to the intervention, fever disappeared, EBV DNA became undetectable and lymphoma screening remained negative. In posttransplant lymphoproliferative disorder of donor origin after SPKT, transplantectomy may be a curative therapy.

The main cause of death for diabetic patients and patients on dialysis is coronary artery disease (CAD). The most common cause of graft loss following simultaneous pancreas and kidney transplantation (SPK) is death with a functioning graft due to CAD. Therefore, careful pretransplantation evaluation of CAD is mandatory. In our series, every patient undergoes a noninvasive cardiac function test like dobutamine stress echocardiography (DSE) or myocardial thallium scintigraphy using adenosine to induce medical stress. Thirty patients were evaluated for SPK: 15 patients with myocardial scintigraphy and 8 with DSE. Seven investigations showed pathological findings and we performed coronary angiograms, none of which showed coronary artery stenosis. Seven primary coronary angiograms were performed: four due to a history of CAD and three as a primary diagnostic. Following SPK one patient died at 21 days after transplantation due to myocardial infarction. He had a history of CAD with angioplasty and stent implantation. Noninvasive cardiac function tests like DSE or myocardial scintigraphy are reliable methods to evaluate CAD in patients with diabetic nephropathy awaiting SPK. In case of a suspicious finding or a history of CAD, a coronary angiogram should be performed to assess the need for revascularization. Following this algorithm we may further reduce the mortality of SPK.

Live kidney donation is increasing rapidly. Increases of blood pressure and proteinuria but no accelerated loss of renal function in kidney donors have been described. The credibility of this research is hampered by retrieval rates of only 50-70% of donors. We studied renal function, blood pressure, proteinuria, parathyroid hormone, 1,25(OH)2 cholecalciferol and calcium and phosphate excretion in a live kidney donor cohort with a 93% retrieval rate. A comprehensive physical and laboratory examination including 24-h urine collection was conducted. None of the 152 donors had renal failure. Mean time after uninephrectomy was 11 +/- 7 (range: 1-28) years. GFR had declined by 25%. Blood pressure had increased from 125 +/- 15/79 +/- 11 to 134 +/- 19/81 +/- 9 mmHg (p < 0.01) but remained significantly below normal. Fifty six percent of donors developed proteinuria (>150 mg/day), but only 10% had albuminuria. Nineteen percent had increased PTH, 30% had a decreased tubular reabsorption rate of phosphate. Regarding risk factors for a higher loss of GFR, greater increases in blood pressure or proteinuria no consistent picture emerged. Because of the high incidence of proteinuria and possible changes in bone metabolism inclusion of kidney donors in registries appears worthwhile.

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-gamma (MIG) (CXCL9) and IFN-gamma-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 < 0.0001) different from both nonrejecting allograft patients (NO-AR) (median, 25%, and 75%: 96, 1.0, and 161, n = 54) and healthy controls (median, 25%, and 75%: 144, 19, and 208, n = 13). Urinary MIG predicted AR with a sensitivity of 93% and a specificity of 89%. In AR and NO-AR groups, MIG values correlated well with IP-10 (P < 0.001). MIG values indicated both imminent rejection and response to successful antirejection therapy. MIG was not related to intercurrent infections or other causes for impairment of renal function. In a multivariate analysis, MIG correlated best (P < 0.001) with AR from all AR-associated parameters. In conclusion, urinary MIG serves as a very sensitive and specific predictor for AR, mirrors response to antirejection therapy, and thus may contribute to improved long-term renal allograft survival.

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 donor's 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 donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

Background: The chemokine RANTES is a potent chemoattractant for T cells and monocytes that has been shown to enhance inflammation. The aim of our study was to investigate whether RANTES is upregulated within the early post-transplantation period that may influence short-time allograft function rate., Methods: Serum and urine samples from transplanted renal allograft recipients (n = 17) were obtained from specimens taken for diagnostic reasons. Four patients developed biopsy-proven rejection episodes within the first month. Time course of RANTES was studied within the first 12 days after renal transplantation using ELISA technique. Data were tested for significances between patients with rejection and without rejection, compared to healthy volunteers as controls, and correlated with clinical data., Results: In the control group RANTES concentration was 37.2 +/- 2.7 ng/ml (serum) and 8.1 +/- 1.3 pg/ml (urine), respectively. In transplanted recipients serum RANTES was significantly upregulated up to 132 +/- 28 ng/ml on day 1 after transplantation and remained elevated within the first 12 days (n = 17). Time course of urine RANTES demonstrated elevated concentrations with 754 +/- 115 pg/ml on day 1 followed by an continuous decrease to 22.3 +/- 7 pg/ml on day 12 (n = 17). No significant differences could be detected between patients with rejection and without rejection episodes., Conclusions: In contrast to data of other urinary marker molecules (like IL-6), there are no significant differences between the rejection and non-rejection group. RANTES is therefore not suitable for early detection of rejection. Nevertheless, serum and urine RANTES concentrations were highly elevated in freshly transplanted renal allograft recipients reflecting an activated immune system.

We report on a 42-year-old female patient with glycogen storage disease type 1a (von Gierke disease, GSD 1a) who developed hepatic adenomas and finally a hepatocellular carcinoma 10 years after renal transplantation. The tumor was resected; however, the patient died 6 months later as a result of fulminant carcinoma recurrence. In patients who have GSD 1a with terminal renal failure, combined liver and kidney transplantation may be considered at an early stage of the disease.

Background: The multidrug resistance (MDR) gene product P-glycoprotein (P-gp) is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including the immunosuppressant cyclosporine A (CsA). We have previously shown that CsA increases P-gp expression in proximal tubule and endothelial cells in vitro. The aim of the present study was to investigate the in vivo relevance of these observations in renal allograft biopsies from CsA-treated patients., Methods: P-gp expression was determined by immunohistochemistry of paraffin sections using two different monoclonal antibodies (UIC2 and MRK16). Biopsies were taken from CsA-treated renal transplant patients with different histopathological diagnoses (N = 79) and were compared with biopsies from normal human kidneys (N = 13) or with allograft biopsies from patients under a CsA-free immunosuppression (N = 15). Moreover, biopsies from 10 donor kidneys before implantation and during rejection episodes ("zero biopsies") were investigated., Results: P-gp expression in biopsies with acute tubular necrosis (ATN; N = 10) after CsA treatment was significantly higher in arterial endothelia, proximal tubules, and epithelial cells of Bowman's capsule (BC), whereas P-gp was sparsely induced in CsA nephrotoxicity (N = 19) compared with controls. Acute cellular (N = 30) and vascular rejection (N = 10) or chronic allograft nephropathy (N = 10) after CsA was associated with strong P-gp expression in infiltrating leukocytes and increased P-gp expression in arterial endothelia, proximal tubules, and BC. In contrast, biopsies of patients treated with a CsA-free immunosuppression regimen did not show increases in P-gp expression compared with controls. Zero biopsies showed a weak, homogeneous, nonpolarized expression of P-gp in tubules and an increased expression of P-gp after CsA therapy in the brush border, arterial endothelia, and BC., Conclusions: CsA treatment was associated with increased P-gp expression in parenchymal cells of kidney transplants with ATN, acute or chronic transplant rejection, but P-gp was not increased in patients with CsA nephrotoxicity. This indicates that CsA induces its own detoxification by P-gp and that inadequate up-regulation of P-gp in renal parenchymal cells contributes to CsA nephrotoxicity. Increased expression of P-gp in infiltrating leukocytes correlated with the severity of allograft rejection, suggesting that P-gp may decrease the immunosuppressive efficacy of CsA. Thus, individual differences in the P-gp induction response of CsA-exposed renal parenchymal cells and/or infiltrating leukocytes may predispose to either CsA nephrotoxicity or rejection, respectively.

The incidence of aspergillosis in kidney transplant recipients is low and most commonly occurs in the early posttransplantation period. We report an unusual case of a 52-year-old female patient with Aspergillus endocarditis as a late complication after kidney transplantation, presumably spread from a necrosis in the gut, associated with previous cytomegalovirus colitis. As complications, the patient experienced septic embolization into the coronary and pulmonary arteries, and an infarction of the right parietal cortex and insula. The patient died as a result of global heart failure after a 10-day course of antimycotic therapy with amphotericin B plus 5-flucytosine during surgical valve replacement.

Background: Hypertension is a common concomitant condition in renal transplant recipients. There is accumulating evidence that this disorder is an important risk factor for chronic renal graft failure and other cardiovascular complications in these patients., Subjects and Methods: The current retrospective study in 330 patients treated with cyclosporin or azathioprin covered 5 years and aimed to further characterize the interrelation between hypertension and renal graft failure. Furthermore, the association of hypertension with hyperlipidemia and the prevalence of coronary heart disease was evaluated., Results: Altogether, before transplantation 182 patients were normotensive (no antihypertensive medication except diuretics) and 105 were hypertensive (blood pressure > 160/95 mmHg or patients requiring antihypertensive medication); for the remaining 43 patients no data were available. After transplantation the prevalence of hypertension in the cyclosporin group was 71, 76 and 70% after 1, 3 and 5 years, respectively. The respective numbers for the azathioprin group were 60, 59 and 58%. Hypertension was associated with graft dysfunction both in cyclosporin- and azathioprin-treated patients. Hyperlipidemia (cholesterol, triglycerides) was more severe in hypertensive than in normotensive patients. The prevalence for hypertension was higher in patients with coronary artery disease than in patients without the disease., Conclusion: The results further support the view that hypertension may be a risk factor for the development of chronic renal graft failure and coronary artery disease in this population. Furthermore, the association of hypertension with hyperlipidemia hints to an unfavorable accumulation of renal and cardiovascular risk factors in a large number of renal allograft recipients.

A 30-year-old male patient suffering from membrano-proliferative glomerulonephritis was transplanted a cadaveric kidney 3 years ago. Five days later the transplant was removed because of fresh thrombosis in larger arteries. Three years after first transplantation a second graft was transplanted. Repeated perfusion scintigraphies of persistent anuric patient showed a delayed perfusion of renal parenchyma, no intrarenal bolus was obtained. Urgently, an arterial angiography was performed. It demonstrated that calibers of renal parenchymal vasculature were narrowed. Suggesting ischemic nature of acute renal failure, 50 micrograms human atrial natriuretic peptide (hANP) was injected intrarenally as bolus. Five minutes after hANP injection in a second angiography a significant improvement of renal blood flow was demonstrated but no amelioration of urine production or electrolyte excretion was observed. Histologically an ischemic lesion of transplant was proven. This finding indicates a blunted excretory response of acute renal failure after kidney transplantation despite of significantly ameliorated renal blood flow visualized radiologically.

Sixteen patients with membranoproliferative glomerulonephritis who required kidney transplantation because of renal failure were evaluated for evidence of recurrence of the original disease by serologic and morphologic studies. Of the 12 patients with transplant tissue available for study, seven showed membranoproliferative glomerulonephritis by light morphology. Four of these seven also had hypocomplementemia, and this hypocomplementemia was characterized by decreased serum CH50, C3 beta1A or C3-C9 but norma serum C1, C4 and C2 by hemolytic assay. Immunofluorescent microscopy demonstrated more intense glomerular deposition of C3 and properdin in the hypocomplementemic patients. Ultrastructural studies demonstrated intramembranous deposits typical of dense deposit disease in one patient who also had marked hypocomplementemia. One patient who had two transplant biopsies and persistent hypocomplementemia showed progression from predominantly mesangial glomerular changes to both capillary wall and mesangial abnormalities. This study has shown a high rate of recurrence of membranoproliferative glomerulonephritis in the transplanted kidneys. A high death rate was noted in persistently hypocomplementemic patients. The serum C profile in hypcomplementemic patients who received translants was similar to that seen before transplantation, but the signficance of this finding remains unknown.

Objective: Chronic allograft nephropathy and cardiovascular complications limit the long-term success of renal transplantation. Animal experiments have shown that Angiotensin-R-Blockers (AR-B) can lower the rate of graft failure. Moreover it has been suggested that AR-B might lower cardiovascular mortality as well. Methods: We designed a controlled trial (SECRET-study) in pts. following renal transplantation to evaluate whether the AR-B candesartan cilexetil (CC) (4 - 16 mg/day) vs. placebo (PL) can reduce the amount of graft failure (expected 5%/y) and cardiovascular morbidity (expected 3%/y). 700 pts. were to be included who were to be followed up for three years. During that time we expected to observe the primary endpoints graft failure and cardiovascular morbidity in more than 150 pts. Results: Following an interim analysis after 18 month, the study was discontinued since the observed event rate (26 primary endpoints) was only 25% of what had been expected. At the premature end of the study data of 502 pts. with a median follow-up of 23 month (11-39m) were available (11.500 pts.month). Cardiovascular morbidity and mortality (CC 9 pts., PL 8 pts.), graft failure (CC 1 pts., PL 6 pts.). creatinine doubling (CC 7 pts., PL 4 pts.) did not differ sign. between both groups. Median proteinuria was significantly (p < 0.001) decreased by CC (-27.4%) compared to PL (+15.4%). Although all possible concomitant antihypertensive drugs (except ACE-inhibitors) were allowed in order to lower blood pressure (BP) below 135/80 mmHg (controlled by an automatic device), BP was lowered more markedly (p < 0.001) in the CC group 139.9/84.4 to 130.0/80.3 compared to PL (139.8/84.6 to 133.3/80.8). Early treatment discontinuation was more often observed (p < 0.001) in the PL group esp. due to lack of antihypertensive efficacy (CC 2 pts., PL 17 pts.) and due to consent withdrawal (CC 9 pts., PL 19 pts.). Conclusions: The study failed to show the superiority of the AR-B CC in lowering graft failure and cardiovascular morbidity in renal transplant pts. This may be due to the excellent BP control achieved in both groups: no other intervention trial so far demonstrated mean BP levels of 130/80mmHg at the end of the study. However, treatment with CC was more effective in lowering BP in these pts., and in reducing proteinuria, which can be an early sign of chronic allograft nephropathy. [ABSTRACT FROM AUTHOR]

Objective: Despite major improvements in patient and allograft survival after renal transplantation, acute allograft rejection episodes (AR) are still frequent and decisive for the long-term graft survival. Renal biopsy is still the gold standard for the diagnosis of AR. As recent investigations showed a prominent role of interferon-gamma dependent chemokines in animal models of allograft rejection, the aim of our study was to identify the role of CXCR3 and its ligands MIG/CXCL9 and IP-10/CXCL10 as markers for AR in human renal transplantation. Methods: A total of >1,500 urine samples of 69 patients with de novo renal transplantation in Frankfurt from 2001 through 2003 have been collected in an open-label prospective study on a daily basis for a median time of 29 days following renal transplantation. In pH adjusted fresh morning urine chemokines MIG and IP-10 were determined by modified ELISAs. Additional clinical and laboratory parameters were monitored for the whole study period. AR was confirmed by biopsy and evaluated according to the BANFF classification. In addition biopsies were stained for CXCR3 expression by immunohistochemistry. Results: Biopsy-proven AR occurred in 15/69 recipients. Corresponding to an infiltration of CXCR3-positive cells into the graft urinary MIG elevation was detected in 14/15 AR patients with levels of 6803 ± 2095 pg/ml (mean ± SEM, n = 15) being significantly (P < 0.0001) different from both non-rejecting patients (NR) and healthy controls (135 ± 29, n = 54, and 131 ± 25 pg/ml, n = 13, respectively). Urinary MIG predicted AR with a sensitivity of 93% and a specificity of 89%. In both groups, AR and NR, MIG values were correlated well to IP-10 and CRP (P < 0.001), but not to serum creatinine. MIG values indicated both imminent rejection and response to successful antirejection therapy, while they were not related to delayed graft function or intercurrent bacterial infections. Conclusions: This study identifies urinary MIG/CXCL9 as a very sensitive and specific marker for acute renal allograft rejection. Urinary MIG allows differentiation of AR from other causes of impaired renal function after transplantation and may facilitate clinical decisions for biopsy as well as guide immunosuppressive therapy. Monitoring of urinary MIG will contribute to improve renal long-term allograft survival in the future. [ABSTRACT FROM AUTHOR]