Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation.

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

[Dual kidney transplantation]. / Duální transplantace ledvin.

Despite the increasing demand for organs for transplantation, the number of cadaveric donors remains stable and waiting time for transplantation is gradually getting longer. In addition to the options of using kidneys from living donors and those of non heart-beating donors (NHBD), an alternative approach is transplantation of both kidneys from adult marginal donors who would otherwise be considered unsuitable for single-kidney donation. Dual kidney transplantation involves the use of both kidneys from a marginal donor for a single recipient without the recipient having to cope with the drawbacks of a limited number of functioning nephrons. Normally. these kidneys would be excluded from the transplantation program and remain unused. The submitted presentation provides information on donor and recipient selection criteria and describes the course of the first dual kidney transplantation in an adult recipient in the Czech Republic.

Efficacy and safety of enteric-coated mycophenolate sodium (myfortic) in de novo renal transplant recipients: results of a 12-month multicenter, open-label, prospective study.

Enteric-coated mycophenolate sodium (EC-MPS) has been developed as an alternative formulation of mycophenolate acid aiming for improved gastrointestinal (GI) tolerability. This 12-month, open-label, multicenter, prospective study investigated the efficacy and tolerability of EC-MPS (720 mg twice a day) given in combination with cyclosporine microemulsion (CsA-ME) in de novo renal transplant recipients (n=140). The efficacy evaluation was the incidence of treatment failure (defined as biopsy-proven acute rejection [BPAR], graft loss, or death) after 6 and 12 months of treatment. The incidences of treatment failure, BPAR, and graft loss were comparable at 6 and 12 months (18.6% vs 22.1%, 15.7% vs 19.3%, and 1.4% vs 2.1%, respectively). Renal function at 6 and 12 months (creatinine clearance) was 60.6+/-19.8 mL/min and 63.2+/-27.1 mL/min, respectively. EC-MPS was generally well tolerated; 95.9% of the reported GI adverse events (AEs) were rated as mild or moderate. The rate of EC-MPS dose reduction was 26.4%; 4.3% were due to GI AEs. The rate of EC-MPS dose interruption was 10%; 2.1% were due to GI AEs. In summary, EC-MPS given in combination with CsA-ME demonstrates good efficacy and tolerability in de novo renal transplant recipients.

Administrative interventions associated with increased initiation on antiretroviral therapy in Irkutsk, Siberia.

A bundle of initiatives to integrate human immunodeficiency virus (HIV) and tuberculosis (TB) services was assessed for the impact on antiretroviral therapy (ART) initiation at a TB referral hospital in Irkutsk, Russian Federation, from February 2014 to December 2015. The ART initiation rates in 166 ART-naïve patients undergoing anti-tuberculosis treatment (34.1% with multidrug or extensively drug-resistant TB) increased significantly from 14 (17%) pre-intervention to 44 (54%) post-intervention (P < 0.001). A survey of TB hospital staff identified administrative prioritisation as the most important initiative for increasing ART initiation.

Un ensemble d'initiatives visant à intégrer les services relatifs au virus de l'immunodéficience humaine (VIH) et à la tuberculose (TB) a été évalué en termes d'impact sur la mise en route du traitement antirétroviral (TAR) dans un hôpital de référence de la TB à Irkoutsk, Fédération de Russie, entre février 2014 et décembre 2015. Les taux de mise en route du TAR chez 166 patients n'en ayant jamais reçu et traités pour TB (34,1% avec une TB multi-résistante ou ultra-résistante) ont significativement augmenté de seulement 14 (17%) avant l'intervention à 44 (54%) après l'intervention (P < 0,001). Une enquête auprès du personnel de la TB a identifié la priorisation administrative comme l'initiative la plus importante dans l'augmentation de l'initiation du TAR.

Se evaluó un conjunto de iniciativas encaminadas a integrar los servicios de atención de la infección por el virus de la inmunodeficiencia humana (VIH) y la tuberculosis (TB), con el objeto de determinar la repercusión de la integración sobre el comienzo del tratamiento antirretrovírico (TAR) en el hospital de referencia de la TB de Irkutsk, en la Federación de Rusia, de febrero del 2014 a diciembre del 2015. La tasa de iniciación del TAR en 166 pacientes que nunca lo habían recibido y que estaban en curso de tratamiento antituberculoso (34,1% con TB multirresistente o extremadamente multirresistente) aumentó de manera significativa de solo 14 pacientes antes de la intervención (17%) a 44 pacientes después de la misma (54%; P < 0,001). Al interrogar al personal encargado de la TB en este hospital de referencia, se puso en evidencia que la priorización administrativa del TAR constituía la iniciativa de más había influido en el incremento de su utilización.

Undertreated HIV and drug-resistant tuberculosis at a referral hospital in Irkutsk, Siberia.

SETTING: A referral hospital for tuberculosis (TB) in Irkutsk, the Russian Federation. OBJECTIVE: To describe disease characteristics, treatment and hospital outcomes of TB-HIV (human immunodeficiency virus). DESIGN: Observational cohort of HIV-infected patients admitted for anti-tuberculosis treatment over 6 months. RESULTS: A total of 98 patients were enrolled with a median CD4 count of 147 cells/mm(3) and viral load of 205 943 copies/ml. Among patients with drug susceptibility testing (DST) results, 29 (64%) were multidrug-resistant (MDR), including 12 without previous anti-tuberculosis treatment. Nineteen patients were on antiretroviral therapy (ART) at admission, and 10 (13% ART-naïve) were started during hospitalization. Barriers to timely ART initiation included death, in-patient treatment interruption, and patient refusal. Of 96 evaluable patients, 21 (22%) died, 14 (15%) interrupted treatment, and 10 (10%) showed no microbiological or radiographic improvement. Patients with a cavitary chest X-ray (aOR 7.4, 95%CI 2.3-23.7, P = 0.001) or central nervous system disease (aOR 6.5, 95%CI 1.2-36.1, P = 0.03) were more likely to have one of these poor outcomes. CONCLUSION: High rates of MDR-TB, treatment interruption and death were found in an HIV-infected population hospitalized in Irkutsk. There are opportunities for integration of HIV and TB services to overcome barriers to timely ART initiation, increase the use of anti-tuberculosis regimens informed by second-line DST, and strengthen out-patient diagnosis and treatment networks.

Lipid metabolism in renal transplant patients receiving tacrolimus/sirolimus combination therapy.

INTRODUCTION: The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR). METHODS: For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions. RESULTS: Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months. CONCLUSION: Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.

Cytokines and chemokine gene expression in human kidney transplantation.

Despite advances in immunosuppression in past decades, allograft rejection remains the main reason for kidney graft failure. Recently, despite great improvements in understanding of molecular basis of allograft rejections, renal histology remains the primary method to monitor the onset of graft rejection. The aim of the present study was to ascertain whether cytokine and chemokine expression profiles in kidney allografts contributed to the diagnosis of graft dysfunction. We analyzed mRNA expression in 174 kidney graft biopsies for the following cytokines: TGF-beta1, TNF-alpha, IL-10, and chemokine RANTES. Based on the expression levels obtained by real-time RT-PCR, we correlated data with the results of morphologic examinations. All tested cytokines and chemokines were upregulated (P < .001) during acute rejection compared to nonrejecting controls. Upregulation was also found in chronic allograft nephropathy (CAN) group for TGF-beta1, IL-10 (P < .001), TNF-alpha, and RANTES (P < .01). Upregulated expression of IL-10 (P < .001), TGF-beta1, (P < .01) and RANTES (P < .05) showed borderline changes. Higher expression levels (P < .001) of TGF-beta1 and IL-10 were also found during ATN. IL-10 was upregulated (P < .01) in specimens with recurrent glomerulonephritis. Weakly increased (P < .05) expressions of TGF-beta1 were found during CsA toxicity. Distinctive expression levels between acute rejection and CAN were only found for IL-10 (P < .01). TNF-alpha showed a different expression profile in acute rejection versus ATN (P < .001). These findings suggest that distinct cytokine and chemokine expression profiles in grafts may contribute to the diagnosis for and elucidation of the immunopathologic process during graft dysfunction.

Effect of cytokines and chemokines (TGF-beta, TNF-alpha, IL-6, IL-10, MCP-1, RANTES) gene polymorphisms in kidney recipients on posttransplantation outcome: influence of donor-recipient match.

Posttransplantation alloantigen-dependent and alloantigen-independent processes are both mediated by cytokines and chemokines. Recently cytokines and chemokines, as well as their receptors, have been shown to be highly polymorphic. The cytokine and chemokine gene polymorphisms are associated with variable production, activity, expression, or ligand-receptor affinity. The aim of our study was to analyze the relation between selected cytokine and chemokine gene polymorphisms in kidney donors and recipients as a function of donor-recipient match and posttransplantation outcome. Polymorphisms transforming growth factor-beta (TGF-beta); tumor necrosis factor-alpha (TNF-alpha); interleukin (IL)-6, and IL-10; monocyte chemoattractant protein-1 (MCP-1); and RANTES (regulated upon activation, normal T-cell expressed and secreted) genes were determined using DNA polymerase chain reaction technology in 268 healthy volunteers, 345 kidney transplant recipients (1997 to 1999), and 298 cadaveric donors. Patients were followed up for 4 to 6 years. The distribution of alleles of selected genes was identical in control subjects, cadaveric donors, and recipients. Low TGF-beta production in both the donor and recipient genotypes was associated with risk for early rejection (6 months) and worse graft function at 4 years. The only tendency for worse graft outcome was observed among donor-recipient combinations mismatched for TGF-beta genotype. Genetic determination of TNF-alpha and IL-10 production was associated with delayed graft function and rejection. IL-6 gene polymorphisms had no effect on the incidence of early acute rejections, but was associated with worse 5-year outcomes. Determinations of MCP-1 overproduction and RANTES-109 TT allele were associated with significant deterioration of graft function. Our data support the hypothesis that the strength of the alloimmune response after transplantation is in part genetically determined. Donor-recipient matching of cytokine gene polymorphisms has a marginal effect.

Graft function, cardiovascular risk factors, and sex hormones in renal transplant recipients on an immunosuppressive regimen of everolimus, reduced dose of cyclosporine, and basiliximab.

A prospective, randomized trial evaluated the combination of everolimus of 1.5 or 3 mg/d with steroids, basiliximab, and low-dose cyclosporine (CsA) adjusted by C2 monitoring in 256 renal transplant recipients. CsA C2 target levels, initially set at 600 ng/mL, were tapered over time posttransplant. The median serum creatinine concentrations were 130 mumol/L in both sirolimus groups (1.5 and 3 mg/d) at 6 months. Biopsy-proven acute rejection (BPAR) occurred in 13.7% and 15.1% of patients in the 1.5 and 3 mg/d groups, respectively. The incidence of BPAR was significantly higher among patients with everolimus trough levels < 3 ng/mL. Posttransplant diabetes mellitus occurred rarely, and blood pressure control appeared favorable; however, serum cholesterol levels were increased by approximately 50%, and serum triglycerides by approximately 100%. Serum testosterone concentrations increased after renal transplantation in both everolimus groups. Concentration-controlled everolimus therapy combined with low-dose CsA provides effective protection against rejection with good renal function and safety profiles.

[Pregnancy and labor after combined pancreas-kidney transplantation in Czech Republic]. / Tehotenství a porod po kombinované transplantaci ledviny a pankreatu v Ceské republice.

OBJECTIVE: To inform about the first own experiences and to present opinion on leading pregnancy and delivery after a combined pancreas and kidney transplantation. DESIGN: Case report and review article. SETTING: Department of Obstetric and Gynecology, 1st Medical Faculty of the Charles University and General Faculty Hospital, Prague. RESULTS AND CONCLUSIONS: Pregnancies and deliveries after the transplantation of solid organs are not common. Mostly there are experiences with women after kidney transplantation, smaller or no experiences are with women after transplantation of other solid organs. About 25 pancreas transplantation per year are performed in the Czech republic. Two women after the combined kidney and pancreas transplantation were the first in Czech republic to get pregnant spontaneously and delivered by using a chronic immunosupressive. therapy (Prograf, Imuran, Prednison) in 2002 and 2003. These single pregnancies were led as a high-risk pregnancy in Regional Perinatology Center in collaboration with Transplant and Diabetic Center. Both pregnancies were termined from the obstetrical indication before the term by cesarean section. Both children were healthy. The pregnancy of both patients has not affected the function of the transplanted organs and development of both children has been normal.

Proportion of glomerulosclerosis in procurement wedge renal biopsy cannot alone discriminate for acceptance of marginal donors.

BACKGROUND: The shortage of available kidneys for renal transplantation could be addressed, to some extent, by expanding the criteria for acceptance of marginal donors. The study of these criteria is limited by the selection of grafts actually retrieved and transplanted, therefore reduced to a study of risk factors. We have evaluated the potential of procurement renal biopies as an instrument for acceptance or refusal of donor kidneys for transplantation. METHODS: This was a prospective study of a consecutive series of 200 donors. Biopsies were performed by wedge technique at the donor operation and were evaluated for proportion of glomerulosclerosis, vascular and tubular changes, and interstitial fibrosis. The study included 387 renal grafts with a representative biopsy, transplanted, and followed-up for survival and functional evaluation; 24 hr creatinine clearance at 1 and 3 weeks, and 3, 6, 12, 18, and 24 months. RESULTS: Factors associated with initial graft function included cold ischemia time, number of DR mismatches, tubular changes, although donor age showed the strongest correlation with short- and long-term level of graft function. DR mismatches and retransplantation appeared to be the only significant risk factors for graft loss. The proportion of glomerulosclerosis (mean 8%, range 0-48%) correlated with graft function in the simple regression analysis. However, when age was taken into account glomerulosclerosis did not correlate significantly with graft function. Furthermore, glomerulosclerosis as high as 25% or more had an acceptable 3-year graft survival rate of 74.7%. CONCLUSION: Procurement biopsy provides only limited information for the decision whether or not to accept a kidney donor.

Serum procalcitonin concentrations in transplant patients with acute rejection and bacterial infections.

Procalcitonin (PCT) represents a new marker of systemic inflammatory reactions of the body to infections. PCT is selectively induced by severe bacterial infections leading to sepsis or multiorgan dysfunction syndrome. The aim of our study was to test PCT as a postoperative infection marker in heart and kidney transplant patients compared with healthy subjects and patients with localized lung-inflammatory processes without a manifest systemic response. PCT concentrations were measured by an immunoluminometric assay (ILMA) in a total of 419 serum samples. Normal serum levels were in the range of 0.08-0.6 ng/ml. Operative trauma associated with heart (not kidney) transplantation induced a transient increase in PCT levels to 7-10 ng/ml with a decline to normal levels within 2-3 days in most patients. Severe bacterial infections dramatically augmented serum PCT concentrations reaching values of 46-297 ng/ml in the most critical periods. Good response to antibiotic therapy was associated with a decline in serum PCT concentrations. Acute rejection or cytomegalovirus infections did not significantly increase the serum PCT levels. Localized pulmonary infections showed either no, or only a limited increase, in the serum PCT levels (max. 7 ng/ml). We conclude from our data that PCT can be used as a sensitive marker to differentiate systemic bacterial infections from other complications in organ transplantation.

Flow cytometry cross-match before kidney transplantation in relation to early postransplant rejection.

The aim of this study was to compare flow cytometry cross match (FCXM) results in patients before first kidney transplantation with the incidence of rejection episodes and kidney graft survival after transplantation. Sera of 51 patients obtained immediately before transplantation were tested on spleen cells of respective kidney donors. We found no correlation between a positive FCXM result before transplantation and the occurrence of immunological complications after transplantation.

ACE gene polymorphism and long-term renal graft function.

OBJECTIVES: The long-term outcome of transplanted kidneys has not changed substantially and only a minority of grafts survives more than 15 yr. The aim of this study was to determine the influence of ACE gene polymorphism on long-term outcome after renal transplantation. DESIGN AND METHODS: Using PCR, we evaluated ACE I/D gene polymorphism in a group of patients with long-term graft function (LTF) over 15 yr and compared it with control groups of transplant recipients and population sample. RESULTS: The distribution of genotypes in the LTF group differed from transplant controls (p < 0.05). Moreover, DD homozygotes in the LTF group had better creatinine clearance (DD: 1.1 +/- 0.3, ID: 0.96 +/- 0.3, II: 0.76 +/- 0.3 mL/s; p < 0.05). There were no differences in genotype distribution between transplant and population samples. CONCLUSIONS: Results of our study have demonstrated a possible connection between the DD variant of ACE I/D gene polymorphism and excellent long-term graft function.

Predicting glomerular function from adjusted serum creatinine in renal transplant patients.

In 22 individuals with a renal graft the correlations between the renal clearance of polyfructosan (CLPF), renal creatinine clearance (CLcr)--established under the same conditions as CLPF--and the value of glomerular function predicted using the equation by Cocroft and Gault (PredCLcr) were followed up, at an interval of 2-3 months, for 8-22 months. A significant linear correlation (r = 0.777, p < 0.001) was found between PredCLcr and CLPF as well as between PredCLcr and CLcr (r = 0.801, p < 0.001). Equally significant correlations, however, were established when relating the serum concentrations of creatinine (Scr) to 1/CLPF (r = 0.784, p < 0.001) and Scr to 1/CLcr (r = 0.744, p < 0.001). The values of the PredCLcr/CLPF and PredCLcr/CLcr ratios during follow-up in one and the same individual may vary significantly. This fluctuation exceeds maximal error of the analytical methods employed in one third of the individuals examined. When considering stabilization or slow changes in graft function on the basis of PredCLcr and CLPF we found significant discrepancies in more than one half of the individuals examined (64%). The findings support the assumption that more accurate methods must be used to assess graft glomerular function on long-term follow-up.

Long-term follow-up of the tubular secretion of creatinine in renal graft recipients.

The differences in glomerular filtration rate (GFR) based on creatinine clearance (Ccr) or obtained by the more exact methods are caused mainly by tubular creatinine secretion. In this study, we monitored creatinine clearance (Ccr), GFR on the basis of polyfructosan renal clearance (C(PF)) and parameters characterizing tubular creatinine secretion (Ccr/C(PF), Ccr - C(PF), Tcr/C(PF) x 100) in 12 individuals with renal grafts (Group A), 12 kidney graft donors for related transplantation (Group B), and in 27 individuals undergoing nephrectomy for a pathological process in one kidney (Group C). In the monitored groups, C(PF) and Ccr values were within the limits consistent with the normal function of a single kidney in a healthy individual. The values characterizing tubular creatinine secretion in Group A did not differ significantly from those obtained in Groups B and C. However, the parameters showed a wide range in all groups. In seven individuals with a renal graft, all the above functional parameters were monitored at three-month intervals for a period of 24 months. Significant differences in the time courses of Ccr and C(PF) due to marked intra-individual fluctuations were found in tubular creatinine secretion. The findings suggest that the rate of tubular creatinine secretion in the renal graft does not differ significantly from that in individuals with a single native (normally functioning) kidney. However, there are large inter-individual differences. The large intra-individual fluctuations in tubular creatinine secretion in the kidney graft result in significant differences in the time courses of Ccr and C(PF) and a possibility of erroneous evaluation of graft function if based exclusively on Ccr.

TGF-beta1 expression and chronic allograft nephropathy in protocol kidney graft biopsy.

Chronic allograft nephropathy (CAN) represents a frequent and irreversible cause of long-term renal graft loss. TGF-beta1 is a key profibrogenic cytokine associated with CAN pathogenesis. Because of clinical diagnostic inaccuracy, protocol biopsy has been suggested to be a beneficial method for early CAN detection. Protocol core biopsy was carried out in 67 consecutive cyclosporine-based immunosuppression-treated kidney transplant recipients with stable renal function 12 months after renal transplantation. Biopsy specimens were analyzed morphologically according to Banff-97' criteria and immunohistologically for TGF-beta1 staining. The data obtained were correlated with plasma TGF-beta1 levels and clinical data. CAN (grade I-III) was found in 51 patients (76 %). CAN grade I was found to be the most frequent one (44 %). A normal finding within the graft was made in only 12 patients (18 %). Clinically silent acute rejection Banff IA was present in 4 patients (6 %). In 8 patients (12 %) with CAN, borderline changes were present. We found a significant correlation between CAN grade and creatinine clearance, as measured by the Cockroft-Gault formula (p<0.01) as well as body mass index (p<0.01). There was a significant correlation between chronic vasculopathy (Banff cv) and creatinine clearance, and between the degree of TGF-beta1 staining and chronic vasculopathy (p<0.01). There were no relations between morphological findings and TGF-beta1 plasma levels, cyclosporine levels, plasma lipids, HLA-mismatches, panel reactive antibodies (PRA), proteinuria, and the donor's age. In conclusion, CAN is a frequent finding in protocol kidney graft biopsies 12 months after transplantation. TGF-beta1 tissue expression is linked with chronic vasculopathy.

Cyclosporine renal dysfunction.

Cyclosporine (CsA), introduced as an immunosuppressive agent in the 1980s, quickly become the first-line treatment in organ transplantation. However, these improvements were associated with an increased incidence of renal dysfunction. CsA causes histopathological changes in renal transplants that are often difficult to distinguish from other processes, especially chronic allograft nephropathy. Enhanced angiotensin II, transforming growth factor-beta, and vascular endothelial growth factor expression together with down-regulation of nitric oxide synthesis may play roles in chronic CsA nephropathy. Efforts have recently focused upon protocols that minimize the risk of CsA nephrotoxicity while preserving low rates of acute rejection. Four types of CsA-sparing studies have emerged from recent clinical experience: (1) conversion studies in which a nonnephrotoxic drug is substituted to allow CsA reduction, (2) minimal CsA exposure studies in which reduced CsA doses are combined with nonnephrotoxic drugs, (3) withdrawal studies in which CsA is completely discontinued at some time after transplantation, and (4) CsA-free studies in which the drug is completely avoided from the time of transplantation. Monitoring of CsA immunosuppression according to C2 blood levels, which better correlate with the area under the time-concentration curve than trough concentrations, should reduce the risk for toxicity; however, the most appropriate target range has not yet been clearly established. Because of interindividual differences in CsA absorption and susceptibility to renal dysfunction, the current therapeutic drug monitoring should be supplemented with pharmacogenetic information on genetic variability of relevant genes for pharmacokinetic parameters and therapeutic targets. This approach may guide choices for immunosuppressants for particular patients, with low toxicity. Thus, despite of 20 years of its history, CsA renal dysfunction remains an important clinical challenge.