Long-term follow-up of renal transplant patients with renal artery stenosis treated by percutaneous angioplasty.

PURPOSE OF THE STUDY: To evaluate if renal angioplasty (PTRA) in patients with transplanted kidney and renal artery stenosis (TRAS) can have long-term effect on hypertension and renal function. MATERIALS AND METHODS: Within a 24-year time period, 58 PTRAs in 55 adults (three times Re-PTRA) with transplanted kidney were performed. The group included 34 males and 21 females, average age 41+/-10.6 (18-72) years. After exclusion of 7 technical failures, 51 PTRAs were followed at 1 week, 6 months and 1-3 years after PTRA. Hypertension improvement was defined as mean arterial pressure (MAP) decrease of at least 15% from the pre-PTRA value. Graft function was evaluated by serum creatinine (Scr) and creatinine clearance (Ccr) levels, and the improvement was defined as a 20% change. Clinical FU was 3 years. RESULTS: PTRA technical success was 88.4%. In 51 kidney recipients at the end of FU, blood pressure improved in 65.2% of patients (MAP decreased from 123+/-13.1 to 107+/-12.1 mmHg), but no patient remained normotensive medication free. Graft function improved in 44.8% of patients and was stabilized in 20.7% of them (average Ccr before PTRA: 0.48+/-0.29, after PTRA: 0.78+/-47 ml/s). PTRA complications were observed in 25.5% of procedures, most often with no clinical sequel. Thirty days mortality was 1.8% (one patient). CONCLUSIONS: PTRA results in kidney recipients are valuable mainly in preserving graft function.

Genetic variability of major inflammatory mediators has no impact on the outcome of kidney transplantation.

BACKGROUND: Functionally relevant polymorphisms in genes of the Th1 and Th2-inflammatory pathway influence the susceptibility to acute rejection (AR), chronic allograft nephropathy (CAN), and subclinical rejection (SR) as well as graft survival after renal transplantation. Because these findings have not been validated, we sought confirmatory evidence of these associations in a larger group of renal transplant recipients. METHODS: A total of 436 kidney transplant recipients were genotyped for 9 single nucleotide polymorphisms (TNF-alpha-308G/A, MCP-1-2518A/G, RANTES-403G/A, -109T/C and -28C/G, CCR2+190G/A, IFN-gamma+874A/T, TGF-beta+869T/C and +915G/C) and for the 32-bp indel polymorphism in CCR5. The effects of these polymorphisms on the incidence of AR, SR, CAN and graft survival were analyzed in single locus and haplotype models. RESULTS: Single locus analysis revealed that there was no significant difference in the distribution of the genotype frequencies between patients with and without AR, and between patients with CAN or SR, and individuals without CAN. Furthermore, no influence of any of the polymorphisms on the long-term graft survival was observed. Haplotype [TGF-beta +869G; TGF-beta +915C] seemed to be associated with the presence of SR (odds ratio: 3.45, 95% confidence interval: 1.19 - 9.99, P=0.023), but the association was nonsignificant due to the insufficient power. CONCLUSION: In contrast to previous allelic association studies, neither of the polymorphisms has been associated with the outcome of kidney transplantation in the single locus analysis nor in the haplotype model. Our findings reinforce the need for more rigorous research compliant with the currently accepted standards for polymorphism-disease association studies.

Intrarenal cytokine and chemokine gene expression and kidney graft outcome.

AIMS: Proinflammatory cytokines are thought to play an important role in various kidney graft diseases resulting in interstitial fibrosis and tubular atrophy frequently found in case biopsies. To explore the role of various cytokines and chemokines in the long-term graft outcome, the transcription patterns of their genes in kidney allograft biopsies were evaluated. METHODS: The real-time RT-PCR was used to identify intragraft mRNA expression of cytokines and chemokines in 74 kidney graft recipients and the results were correlated with histological and clinical parameters and long-term graft outcome. RESULTS: We observed up-regulated IL-10 (p < 0.001), TGF-beta1, IL-6, MCP-1, RANTES (p < 0.01) and TNF-alpha (p < 0.05) mRNA expression in patients with chronic allograft nephropathy (CAN) as compared to controls. There were positive correlations between the mRNA expression of IL-6 (p < 0.001), IL-10 (p < 0.01), TNF-alpha, MCP-1 (p < 0.05) and the proteinuria. The up-regulation of intrarenal MCP-1 in patients with CAN increased the risk for the graft failure within the next 42 months (OR 5.1, p < 0.05). Kaplan-Meier survival analysis revealed that proteinuria and higher intragraft expression of TGF-beta1 and MCP-1 predict a poor kidney graft outcome. CONCLUSION: Expression patterns of intrarenal proinflammatory genes might discriminate patients at a higher risk for the earlier allograft failure.

Soluble CD30 and HLA antibodies as potential risk factors for kidney transplant rejection.

Recent literary data suggest that high pre- and post-transplant serum levels of the soluble CD30 (sCD30) molecule may be a risk factor for acute rejection and worse prognosis of the transplanted kidney. The aim of our study was to correlate the concentrations of sCD30 and the presence of HLA antibodies as defined by flow cytometry and ELISA with the clinical course and graft prognosis after transplantation. One hundred and seventeen kidney transplant patients were included into the study. The incidence of rejection episodes, graft function and graft survival for up to 1 year post-transplant were evaluated. Soluble CD30 levels before transplantation were virtually the same in patients who experienced rejection and in non-rejecting patients. In both patient groups, a significant decrease of sCD30 was detected 2 weeks after transplantation (104.4 U/ml before vs. 37.0 U/ml post-transplant, P < 0.001). However, there was a substantial difference in the level of decrease of sCD30 between rejecting and non-rejecting patients. Patients without rejection had lower sCD30 values (31.2 U/ml post-transplant) compared to patients who experienced rejection episodes (62.9 U/ml), P < 0.04. Multifactorial analysis showed that antibodies to HLA class II antigens and elevated concentrations of sCD30 shortly after transplantation were associated with increased risk for acute rejection in the first post-transplant year. Measurement of soluble CD30 after transplantation, taken into consideration with the presence of HLA class II antibodies, might be helpful for evaluating the potential risk for acute rejection.

Interleukin 18 (IL-18) upregulation in acute rejection of kidney allograft.

Interleukin 18 (IL-18) is a potent proinflammatory cytokine involved in the host defence by upregulating both innate and acquired immune responses and may be of particular importance also in mechanisms of kidney allograft rejection. Immunohistochemical staining of protocol biopsies showed constitutive IL-18 expression in the epithelium of distal tubules with the induction of immunoreactivity in acute rejection patients where also proximal tubules, infiltrating leukocytes, and endothelium were strongly positive. Furthermore, serum levels of IL-18 were significantly elevated in patients with acute rejection of kidney allograft (1247+/-389 pg/l) as compared to patients with uncomplicated outcome of kidney transplantation (444+/-164 pg/l) and subjects with acute tubulointerstitial nephropathy (385+/-155 pg/l, p<0.0001 for both comparisons). Tissue culture model of renal epithelial cells expressed IL-18 mRNA constitutively and released mature IL-18 in response to TNF-alpha and IFN-gamma. We assume that upregulation of epithelial IL-18 plays an important role in immune and immunopathological reactions in renal parenchyma and contributes to rejection mechanisms of kidney allograft.

The Czech registry of renal biopsies. Occurrence of renal diseases in the years 1994-2000.

BACKGROUND: This report describes data collected by the Czech Registry of Renal Biopsies (CRRB). METHODS: Twenty-eight centres provided data on all biopsies of native kidneys performed in the Czech Republic (population 10.3 million) over the period 1994-2000. Data on serum creatinine concentration (sCr), 24 h proteinuria, haematuria, serum albumin level, arterial hypertension, diabetes mellitus, histological diagnosis and complications after renal biopsy were collected. RESULTS: Altogether 4004 biopsies in 3874 patients were performed (males 57.9%, children < or = 15 years 17.7%, elderly >60 years 14.3%). Microhaematuria was present in 65.9%, macrohaematuria in 9.2%, nephrotic proteinuria (> or = 3.5 g/24 h) in 39.3%, and low-grade proteinuria (<3.5 g/24 h) in 41.4%. Among adults, hypertension was present in 45.2%, mild renal insufficiency in 23% (sCr 111-200 micromol/l) and advanced renal insufficiency in 13.7% (sCr 201-400), while 11.5% of patients had sCr >400 micromol/l. The most frequent renal diseases were primary (59.8%) and secondary (25.4%) glomerulonephritis (GN). Tubulointerstitial nephritis (TIN) was observed in 4.4% and hypertensive nephroangiosclerosis in 3.4%. The samples were non-diagnostic in 4.6%. Among primary GNs, the most frequent diagnoses were: IgA nephropathy (IgAN) 34.5%, minimal change disease (MCD) 12.4%, non-IgA mesangioproliferative GN (MesGN) 11.3%, focal segmental glomerulosclerosis (FSGS) 10.8% and membranous GN (MGN) 9.3%. Among secondary GNs, systemic lupus erythematosus (SLE) represented 23.0%, necrotizing vasculitis (NV) 15.5%, Henoch-Schonlein purpura 5.7%, thin basement membrane glomerulopathy (TBN) 19.3%, Alport syndrome 6.9%, renal amyloidosis 9.9% and myeloma kidney 2.9%. Among children, the most common were IgAN (19.2%), MCD (17.6%) and TBM glomerulopathy (12.3%), while among the elderly the most common were MGN (11.0%), NV (10.7%) and amyloidosis (9.6%). The most common in patients with nephrotic proteinuria were MCD (50.5%) among children, but IgAN (24.6%) in adults aged 16-60 years and MGN (16.8%) among the elderly. IgAN (21.3%) and FSGS (8.3%) were the most common diagnoses among patients with mild renal insufficiency, but TIN (11.6%) and NV (11.3%) were the most common in more advanced renal insufficiency. Since 1999, diabetic patients represented 12.2% of adults, with mean proteinuria 8.9 g/24 h; diabetic glomerulosclerosis was found in 42.4% (with microhaematuria present in 66%) and non-diabetic renal diseases in 47.5% (IgAN in 17.5%, MGN and NAS in 11.1% and NV in 9.5%). The mean annual incidence (per million population) was: primary GN 32.4, secondary GN 13.8, IgAN 11.2, MCD 4.0, MesGN 3.7, FSGS 3.5, SLE 3.2, MGN 3.0, TBM 2.7, TIN 2.4 and NV 2.1. Ultrasound needle guidance was used in 56%, preferably in children (79%). The frequency of serious complications (gross haematuria, symptomatic haematoma, blood transfusion) remained at 3%. CONCLUSION: The CRRB provides important data on the epidemiology of GN based on a whole country population.

Renal transplantation in patients with abdominal aortic aneurysm--a new surgical approach.

An increasing number of abdominal aortic aneurysms occurs in renal failure patients because of an accelerated atherosclerosis process associated with uraemia. When technically feasible, endovascular repair of an abdominal aortic lesion should be considered as the treatment of choice. If a surgical repair is suggested, there are several options to select from. Since November 1999, we performed simultaneous aortic reconstruction using fresh arterial allograft and kidney transplantation in five uraemic patients with asymptomatic abdominal aortic aneurysm. The operative and postoperative course of four patients passed without major complications. One patient had ischaemic colitis early after the operation, which required a partial resection of the colon. One patient died 6 weeks after the operation due to non-vascular causes. In conclusion, the advantage of our single-phase procedure is that both diseases are treated simultaneously during a single hospital stay. Moreover, with our procedure, the risk of vascular graft infection in patients with chronic immunosuppression is low.

Antibodies to HLA class II antigens as a risk factor for acute rejection of the allogeneic kindey.

We have investigated the association between the presence of antibodies to HLA class II antigens and the development of acute and chronic rejection after kidney transplantation. Sera from seventy-one patients before, shortly (2 weeks), and in the period between 8 and 22 months after transplantation were analyzed by the standard complement-dependent cytotoxicity (CDC) test, ELISA-LATM, and LAT tests. Absence of antibodies to HLA class II antigens before and shortly after transplantation was associated with a lower incidence of rejection episodes in the first post-transplant year. Donor-specific class II antibodies could not be detected by the ELISA-LAT test and there was no statistically significant difference in serum creatinine levels between the antibody-positive and antibody-negative patient groups two years after transplantation. Our study suggests that anti-HLA class II antibodies represent a risk factor for the development of acute immunological complications during the first year after transplantation.

Clinical relevance of antibodies to HLA antigens undetectable by the standard complement-dependent cytotoxicity test.

Recent literary data suggest that antibodies to HLA antigens undetectable by the standard complement-dependent cytotoxicity test may cause not only chronic, but also acute immunological complications after kidney transplantation. The aim of this study was to investigate the significance of non-cytotoxic antibodies to HLA antigens for the development of immunological complications and a worse graft prognosis after first kidney transplantation. Sera before and early after transplantation from 120 first kidney recipients were analyzed by flow cytometry (FCXM), ELISA and the standard complement-dependent cytotoxicity (CDC) test. Pre-transplant FCXM negativity was related to a lower incidence of rejection episodes in the first post-transplant year ( P<0.01). A significant association between acute rejection and the presence of antibodies to HLA class II antigens before and after transplantation was also found ( P<0.05). Our study supports the findings of other centers of the detrimental role to the kidney graft played by anti-HLA antibodies undetectable by the classical CDC test.

Predicting the grade of Banff 97 classification of chronic allograft nephropathy based on examination of graft dysfunction (a preliminary report).

OBJECTIVES: Progression of chronic allograft nephropathy (CAN) is associated with a progressive decrease in graft function. Prediction of the Banff CAN grade on the basis of correlation between the grade of histological changes and Scr is difficult because of the big spread of individual values. This study sought to predict the Banff CAN grade based on Scr, Ccr and proteinuria using ROC analysis. METHODS: Graft protocol biopsy and functional testing (Scr, Ccr and proteinuria) were performed in 77 subjects (43 men, 34 women, mean age 48.4 +/- 12.8 years) at 33.8 +/- 1.0 months after their first renal transplantation. Immunosuppression was provided with the triple combination of cyclosporin A, prednisone and azathioprine (or mycophenolate mofetil). Statistical evaluation was performed using receiver-operating curve (ROC) analysis. The cut-off value of the Banff CAN score was set at 1. RESULTS: The mean values and SD of the investigated functional parameters in study subjects were as follows: Scr = 201.5 (+/- 100.0) mumol/l Ccr = 48.1 (+/- 21.2) ml/min/1.73 m2, proteinuria = 0.89 (+/- 1.96) g/24 h. ROC analysis showed the highest AUC (+/- SEM) for Scr 0.806 (+/- 0.063). The respective values were 0.790 (+/- 0.053) for Ccr and 0.643 (+/- 0.075) for proteinuria. The AUC (area under the ROC curve) for Scr was significantly higher (P < 0.043) compared with proteinuria. The values for sensitivity (specificity) were as follows: Scr 65.0 (91.2). Ccr 75.0 (82.5), proteinuria 60.0 (68.4). The best fit values (best combination of sensitivity and specificity) were 257.2 umol/l for Scr, 33.6 ml/min/1.73 m2 for Ccr and 0.40 g/24 hr for proteinuria. CONCLUSIONS: Our findings support the assumption that Scr > 275 mumol/l and Ccr < 33.6 ml/min/1.73 m2 suggest a Banff CAN grade higher than 1 (P < 0.001). Proteinuria had the lowest predictive values. Values > 0.40 g/24 hr were probably associated with a Banff CAN grade higher than 1 (p < 0.05).

G-protein beta-3-subunit and eNOS gene polymorphism in transplant recipients with long-term renal graft function.

BACKGROUND: Despite new immunosuppressive drugs, only a minority of graft survive over 15 years. The aim of our study was to determine the influence of gene polymorphisms in the G-protein-beta(3) subunit (Gbeta3) and endothelial nitric oxide synthase (eNOS) on the long-term outcome of kidney grafts. METHODS: Using PCR, corresponding genotypes in Gbeta3 (C825T) and eNOS (G894T) gene polymorphism were evaluated in patients with preserved graft function over 15 years and in a control group of transplant recipients. RESULTS: There were no differences in allele and genotype distributions of both polymorphisms between groups. In Gbeta3 polymorphism, the 825T allele carriers had a significantly lower body mass index while in eNOS polymorphism there were no links between genotypes, renal function and atherosclerosis risk factors. CONCLUSIONS: Our data suggest that these gene polymorphisms have only a minor influence on long-term renal graft function.

Intercellular cell adhesion molecule-1 and selectin ligands in acute cardiac allograft rejection: a study on gene-deficient mouse models.

Cell adhesion molecules and their ligands are essential for regulating lymphocyte recirculation and leucocyte emigration into an inflamed or injured tissue. Vascular endothelial selectins as mediators of leucocyte rolling and intercellular cell adhesion molecule-1 (ICAM-1) have been found to be up-regulated on activated endothelium during acute allograft rejection. This study was designed to investigate whether ICAM-1 or selectin-ligand deficiency, or a combination of both, affected graft survival during acute cardiac allograft rejection. To this goal, we performed cardiac transplantation using mice deficient in genes for ICAM-1 or alpha(1,3)fucosyltransferase Fuc-TVII, representing a model for general absence of selectin-ligand expression, and a newly developed strain with a double mutation in Fuc-TVII and ICAM-1 alleles. Transplantation of a heart from ICAM-1 -/- or Fuc-TVII/ICAM-1 double-mutated mice into allogeneic recipients resulted in limited (2-2.5 days) but nevertheless significant prolongation of the graft survival (P<0.01 and P<0.01 in log-rank test) compared with the survival of unmodified hearts. When ICAM-1 -/- hearts were transplanted into Fuc-TVII -/- recipients, the median survival time was prolonged by 8 days (P<0.01). These data indicate that endothelial ICAM-1 is involved in adhesion events during acute cardiac allograft rejection but reveal that the loss of one type, selectin/leucocyte ligand or selectin/endothelial ligand interaction, does not markedly affect graft survival, thereby suggesting a role for other compensatory adhesion molecule/ligand interactions.