Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study.

ZEUS study was an open-label, 12-month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m(2) with everolimus versus 60.9 mL/min/1.73 m(2) with CsA; the mean difference was 5.3 mL/min/1.73 m(2) in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m(2) (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function.

Reduced residual gene expression of nuclear factor of activated T cells-regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation.

BACKGROUND: Pharmacokinetic monitoring of calcineurin inhibitors (CNIs) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic (PD) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells (NFAT)-regulated genes in liver transplant (LT) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression (RGE) of NFAT-regulated genes and evaluated the association between the RGE of NFAT-regulated genes and the incidence of cytomegalovirus (CMV) infection. PATIENTS AND METHODS: In 20 LT recipients, 10 patients on cyclosporine (CsA) and 10 patients on tacrolimus (Tac) therapy, who presented with CMV infection, the RGEs of interleukin-2, interferon-γ (IFNγ), and granulocyte-monocyte colony-stimulating factor were measured and compared with the RGEs of these cytokines in 40 healthy dose-matched LT controls. RESULTS: CsA-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (30 ± 17 vs. 44 ± 20, P = 0.067). For IFNγ, the level of significance was reached (26 ± 17 vs. 43 ± 17, P = 0.0125). Daily CsA dosage, CsA baseline (C0 ) and 2 h (C2 ) concentrations were comparable (CsA dosage 169 mg/day vs. 165 mg/day; CsA C0 94 µg/L vs. 85 µg/L; CsA C2 389 µg/L vs. 381 µg/L). In addition, Tac-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (68 ± 25 vs. 84 ± 22, P = 0.0769). Analogous to CsA-treated CMV patients, the level of significance was reached for IFNγ (61 ± 24 vs. 88 ± 29, P = 0.0154). Daily Tac dosage and Tac 1.5 h concentrations (C1.5 ) were comparable in both groups (Tac dosage 4 mg/day vs. 4 mg/day; Tac C1.5 8 µg/L vs. 10 µg/L), whereas Tac C0 concentrations were significantly higher in controls (Tac C0 4 µg/L vs. 6 µg/L, P = 0.0276). CONCLUSION: Measuring the RGE of NFAT-regulated genes is appropriate to assess the risk of infections in LT recipients. Measuring the RGE of IFNγ is particularly suitable to assess the risk of CMV infection. PD monitoring of CNIs in LT recipients is an approach to individualize immunosuppression, which may help to reduce infectious complications.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.

The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m(2) , 95%CI 4.3, 11.0 mL/min/1.73 m(2) ; p < 0.001) and month 36 (7.5 mL/min/1.73 m(2) , 95%CI 3.6, 11.4 mL/min/1.73 m(2) ; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients.

BACKGROUND: High-risk human papillomaviruses (HR-HPVs) can be detected in a proportion of non-melanoma skin cancers. Data on prevalence are inconclusive, but are essential to estimate the relevance of HR-HPV, particularly with regard to prophylactic HPV vaccines for skin cancer prevention. METHODS: High-risk human papillomavirus DNA was investigated in 140 non-melanoma skin lesions from 54 immunocompetent patients and 33 immunosuppressed renal allograft recipients. Expression of p16(INK4a), a marker for HR-HPV oncogene expression in the uterine cervix, and of p53 and pRB was evaluated immunohistochemically. RESULTS: The highest prevalence of HR-HPV was found in squamous cell cancer (SCC) (46.2% (6 out of 13) in immunosuppressed and 23.5% (4 out of 17) in immunocompetent patients). High-risk human papillomavirus positivity was accompanied by diffuse p16(INK4a) expression in most SCC (P<0.001) and basal cell cancers (P=0.02), while almost all SCC in situ were p16(INK4a) positive irrespective of HR-HPV presence (P=0.66). Diffuse p16(INK4a) expression was associated with lack of pRB expression (P=0.001). p53 was strongly expressed in 40.0% (56 out of 140) of the lesions irrespective of HR-HPV presence. CONCLUSION: High-risk human papillomavirus can be detected in lesions of keratinised squamous epithelia. The association of HR-HPV with diffuse p16(INK4a) expression might indicate HR-HPV oncogene expression in a proportion of lesions. Overexpression of p53 suggests p53 pathway alterations in HR-HPV-positive and -negative lesions.

Henoch-Schönlein purpura in adults is not uncommon in elderly patients with an adverse prognosis.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a fairly common disease in children and adolescents. There are only limited data available for adults. METHODS: A retrospective analysis was conducted to study renal manifestations in patients with HSP treated in our institution between 1982 and 2007. We divided our adult cohort according to age - under or over 60 years - to examine differences in elderly patients. RESULTS: HSP was identified in 2.2% of patients referred to us for kidney biopsy. Purpuric lesions and renal involvement were found in all patients. An important triggering factor for the development of HSP in our series was chronic alcohol intake. Forty percent of our patients fulfilled the WHO criteria for alcoholics. Renal involvement was particularly prominent in patients over 60 years of age. At disease onset, estimated glomerular filtration rate (eGFR) was 63% lower in the elderly. Within a median follow-up of 8 years, renal function was significantly better in younger adults than in the elderly. 32% of the elderly have shown Modification of Diet in Renal Disease (MDRD) < 20 ml/min/1.73 m2 in contrast to only 7% in patients < 60 years. Furthermore, significantly more elderly patients reached end-stage renal failure. CONCLUSION: The data indicate that renal manifestation of HSP in the elderly is severe and its outcome relatively poor, and worsens when compared to patients < 60 years.

Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients.

BACKGROUND: Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. AIM: Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS: This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. RESULTS: The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8µg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. CONCLUSION: MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.

Mutations in the BC-loop of the BKV VP1 region do not influence viral load in renal transplant patients.

The reactivation and replication of the BK polyomavirus (BKV) leading to BKV-associated nephropathy (BKVAN) is one of the major complications in renal transplantation patients. BKV isolates were classified into four subtypes (I-IV) based on genotype variations within the VP1-coding region. The type-specific amino acid differences cluster within the BC-loop of the major capsid protein VP1. As demonstrated in vitro, mutations in this region also play a role in the infectivity, attachment and stability of viral particles. Therefore, we analyzed the prevalence of BC-loop mutations in isolates of kidney transplant patients and compared their viral load in the urine. The VP1 subtyping regions of BKV isolates obtained from urine samples of 45 renal transplant patients were sequenced. The phylogenetic analysis of these sequences revealed that subtype I (66.67%) is the most prevalent genotype. The remaining isolates belong to subtype IV (33.33%). A high frequency of changes to specific amino acids within the BC-loop was identified among the BKV isolates from renal transplant patients. Patients with BKVAN exhibited a higher viral replication than patients without nephropathy. Although titers of isolates of subtype I were higher than titers of subtype IV isolates, the difference did not reach statistical significance. In addition, amino acid changes in the BC-loop did not influence the viral load and the incidence of BKVAN. These in vivo results demonstrate that high replication rates which serve as a predictive marker for BKVAN are not caused by altered receptor binding or affinity via mutated BC-loops.

Activity of nuclear factor of activated T cells is independent of the number of peripheral lymphocytes in FTY720-treated patients.

UNLABELLED: We studied the inhibition of nuclear factor of activated T-cell (NFAT)-regulated gene expression (interleukin-2 [IL-2], interferon-gamma [IFN-gamma], granulocyte-macrophage colony-stimulating factor [GMCSF]) in cyclosporine (CsA)-treated de novo patients with and without lymphopenia due to FTY720. MATERIALS AND METHODS: Sixteen CsA-treated de novo renal transplant recipients received either FTY720 (n = 8) or mycophenolic acid (MPA; n = 8) in combination with low-dose steroids. Expressions of IL-2, INF-gamma, and GMCSF were measured at 1 (visit 1), 2 (visit 2), and 14 (visit 3) months postoperatively using peripheral lymphocytes obtained at 0 hour versus 2 hours after CsA intake. Gene expression was assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: CsA 0- and 2-hour levels were comparable in both groups. Absolute NFAT-regulated gene expression was significantly lower among FTY720-treated patients at visits 1 and 2. Median residual NFAT-regulated gene expression was 5.9% in the FTY720 group and 4.2% in the MPA-treated group at visit 1, increasing to 7.2% and 7.0%, respectively, at visit 3. One borderline rejection occurred in the MPA group. Median serum creatinine was 1.5 mg/dL among FTY720 and 1.8 mg/dL among MPA patients. CONCLUSIONS: Despite significantly lower expression of NFAT-regulated genes, the relative reduction in NFAT gene expression was comparable in both groups. The absolute number of lymphocytes was not relevant for this immune response. In addition, gene expression increased to comparable levels after FTY720 was switched to MPA. The relative residual gene expression increased with reduction in CsA dose.

Cardiac biomarkers are influenced by dialysis characteristics.

INTRODUCTION: The cardiac biomarkers cardiac Troponin T (cTNT) and NT-proBNP tend to be elevated in nearly all hemodialysis patients. The high percentage and magnitude of these increased molecules is associated with cardiovascular morbidity and mortality in hemodialysis patients. This study investigates the impact of the dialysis procedure itself on cardiac biomarkers. METHODS: Standard chronic hemodialysis lasting 4-5 hs 3 times weekly and using polysulfone dialyzers (high-flux and low-flux) was performed. Blood flow rates varied between 250-350 ml/min. The cTNT levels of 49 chronic hemodialysis patients were measured twice (interval of 6 weeks) before and after a hemodialysis session by a third-generation assay (Elecsys Analyzer, Roche Diagnostics, Mannheim, Germany). NT-proBNP levels were measured with polyclonal antibodies capable of recognizing the N-terminal fragment of BNP. In a follow-up period of 42 months, cardiovascular events and death were assessed. RESULTS: The median concentration of cTNT prior to hemodialysis was 0.024 ng/ml (< 0.001-0.703). All dialysis patients presented high plasma levels of NT-proBNP (median 4,885 pg/ml). Oligoanuric patients had significantly higher cTNT and NT-proBNP levels prior to dialysis compared to patients with normal diuresis (p < 0.0001). cTNT and NT-proBNP levels increased significantly during the hemodialysis sessions in which a low-flux dialyzer was used (p < 0.0001) but remained unchanged when a high-flux dialyzer was utilized. Neither the predialytic nor the interdialytic changes in cTNT and NT-proBNP levels were influenced by blood flow. NT-proBNP levels increased markedly during hemodialysis sessions (p < 0.005) utilizing the low-flux dialyzer. Patients with a non-native fistula had significantly higher predialysis cTNT and NT-proBNP levels (p < 0.05). Patients with cardiovascular events had a significantly higher cTNT and NT-proBNP at the beginning of the study. CONCLUSION: Asymptomatic chronic hemodialysis patients have significantly higher levels of the cardiac biomarkers cTNT and NT-proBNP relative to the general population. The levels are associated with the time of measurement (before and after a hemodialysis session). Dialysis modalities like high-flux dialyzers influence cTNT and NT-proBNP levels and should be taken into account, particularly in patients with acute onset of cardiac ischemia. The elevation of cTNT and NT-proBNP levels after hemodialysis using a low-flux dialyzer are partly due to hemoconcentration. The significant association of cTNT and NT-proBNP with non-native fistulas (catheter or graft) may be due to the chronic inflammation commonly caused by these devices. Both cardiac biomarkers are of prognostic value determining cardiovascular events and death.

Four cases of sirolimus-associated interstitial pneumonitis: identification of risk factors.

Sirolimus-associated interstitial pneumonitis is a severe side effect of sirolimus therapy; fatal outcomes have been described. We report 4 patients with sirolimus-associated interstitial pneumonitis and review the literature for risk factors for the development of disease. Until June 2005, 48 patients received either de novo sirolimus treatment (n = 7) or were switched from a calcineurin inhibitor-containing regimen to a sirolimus-based protocol for various indications (n = 41). Compared with the 44 patients on sirolimus therapy with no evidence of a disorder, the 4 patients (8.3%) who developed suspected sirolimus-associated interstitial pneumonitis showed no difference in gender, immunosuppressive therapy, days posttransplantation, comorbidity, or preexistent lung disease. Several points, however, are of interest. None of the de novo-treated patients except 4 patients (9.8%) with late administration of sirolimus developed interstitial pneumonitis. The 4 patients with interstitial pneumonitis tended to be older (58.7 +/- 5.5 vs 46.9 +/- 1.7 years) and received higher sirolimus doses (3.5 +/- 0.5 vs 1.4 +/- 0.2 mg/d) with greater trough levels (15.4 +/- 2.9 vs 8.0 +/- 1.2 micro g/L) at the onset of symptoms. Most notably, all patients with interstitial pneumonitis had a loading dose at the start of therapy, and an increase in sirolimus dose (or trough level) within 3 weeks prior to the onset of symptoms. Additional potential risk factors identified from the literature include allograft dysfunction, hypervolemia, and male gender. With careful monitoring (or even exclusion from therapy) of patients at risk for the development of disease, we have had no case of sirolimus-associated interstitial pneumonitis since September 2004.

Cardiac biomarkers and survival in haemodialysis patients.

BACKGROUND: In dialysis patients, cardiac troponin T (cTNT) is often elevated despite the absence of acute myocardial ischaemia, and amino-terminal pro-B-natriuretic peptide (NT-proBNP) is markedly higher compared to non-haemodialysis patients. In a longitudinal observation, we evaluated the association of cTNT and NT-proBNP on cardiovascular morbidity and mortality in haemodialysis patients with and without fluid overload. MATERIALS AND METHODS: Plasma cTNT levels of 134 haemodialysis patients were measured before and after a dialysis session by 3rd generation electro-chemoluminiscence immunoassay. NT-proBNP was determined using a polyclonal antibody recognizing the N-terminal fragment of BNP (Elecsys autoanalyzer 2010, Roche Diagnostics, Mannheim, Germany). Volume status was determined by a clinical score system. Cardiovascular morbidity and mortality were assessed over a follow-up period of 36 months. RESULTS: Plasma cTNT > 0.03 ng mL(-1) was found in 39.6% of all patients. Patients with hypervolaemia had significantly higher cTNT levels compared to euvolaemic patients (median 0.054 ng mL(-1), interquartile range 0.019-0.153 vs. 0.005 ng mL(-1), < 0.001-0.034; P < 0.001). All haemodialysis patients had excessively high levels of NT-proBNP (median 4524; interquartile range 2000-10 250 pg mL(-1)), and NT-proBNP was significantly higher in hypervolaemic haemodialysis patients (11 988, 5307-19 242) compared to euvolaemic haemodialysis patients (3247, 1619-5574); P < 0.001. Receiver operator curves showed a threshold of cTNT > 0.026 ng mL(-1) and NT-proBNP > 5300 pg mL(-1) as predictors of hypervolaemia. Asymptomatic chronic haemodialysis patients with cTNT > 0.026 ng mL(-1) and NT-proBNP > 5300 pg mL(-1) were more likely to die due to cardiac events in the follow-up period. Multivariate analysis documented that elevated cTNT and NT-proBNP levels were highly predictive for cardiovascular events. CONCLUSIONS: Plasma levels of cTNT are elevated in approximately 40% and NT-proBNP levels in 100% of asymptomatic chronic haemodialysis patients. Both parameters depend on volume status. Increased NT-proBNP and cTNT are strongly associated with adverse outcome in end-stage renal disease patients undergoing haemodialysis, and are a useful tool for risk stratification in chronic haemodialysis patients.

Color Doppler indices of renal allografts depend on vascular stiffness of the transplant recipients.

A resistance index (RI) of 0.8 or higher was shown to be a strong predictor of kidney allograft and patient survival. Uncertainties persist since the intrarenal RI is closely associated with the vascular stiffness of the allograft recipient. To clarify the diagnostic value of RI further, we analyzed parameters of vascular stiffness of the recipient and intrarenal RI of the renal allograft. In a prospective study laboratory and clinical parameters, pulse wave velocity (PWV), intima media thickness (IMT) and RI were obtained in 76 kidney allograft patients. We found that the RI values significantly correlated with the PWV (p < 0.05) and the recipients age (p < 0.01) but not with the donor age and renal function. Using multiple regression analysis recipient age, PWV, pulse pressure (PP) and IMT were identified as independent factors influencing RI values. For a more correct interpretation of the RI values in renal allografts parameters of vascular stiffness such as IMT, PP or PWV should be included.

Real-time contrast-enhanced sonography of renal transplant recipients predicts chronic allograft nephropathy.

Real-time contrast-enhanced sonography (RT-CES) can assess microvascular tissue perfusion using gas-filled microbubbles. The study was performed to evaluate the feasibility of RT-CES in detecting chronic allograft nephropathy (CAN) in comparison to color Doppler ultrasonography (CDUS). A total of 26 consecutive renal transplant recipients were prospectively studied using RT-CES and conventional CDUS. Transplant tissue perfusion imaging was performed by low-power imaging during i.v. administration of the sonocontrast Optison. Renal tissue perfusion was assessed quantitatively using flash replenishment kinetics of microbubbles to estimate renal blood flow A *beta (A = peak signal intensity, beta= slope of signal intensity rise). In contrast to conventional CDUS resistance and pulsatility indices, renal blood flow estimated by CES was highly significant related to S-creatinine (r =-0.62, p = 0.0004). Determination of renal blood flow by CES reached a higher sensitivity (91% vs. 82%, p < 0.05), specificity (82% vs. 64%, p < 0.05) and accuracy (85% vs. 73%, p < 0.05) for the diagnosis of CAN as compared to conventional CDUS resistance indices. Perfusion parameters derived from RT-CES significantly improve the early detection of CAN compared to conventional CDUS. RT-CES using low-power real-time perfusion imaging is a feasible method to evaluate microvascular perfusion in renal allograft recipients.

[Radiologic diagnosis of the kidneys in dialysis patients]. / Radiologische Diagnostik der Nieren bei Dialysepatienten.

The kidneys of patients with chronic renal failure undergoing maintenance hemodialysis may show different variances or complications. Most common are secondarily acquired renal cysts, which may be found in as many as 92% of patients after 8 years of hemodialysis. Single (in 12.5% of patients) or multiple (8.3%) cysts with bleeding are common; additionally, hematuria or ruptured cysts may be found. Bleeding into cysts is more common in patients with autosomal dominant polycystic kidney disease. Due to the decreasing urinary production development of kidney stones is very uncommon, but calcifications in or around cysts can be found in 71% of patients. Kidney tumors occur 41 times more often in patients with chronic renal failure than in patients without kidney disease. We detected tumors in 4.2% of our patients on long-term dialysis. Diagnostic differentiation of the relatively slow growing and fairly late metastasizing malignant tumors from adenomas is not possible. Nevertheless, we screen our patients every 3-4 years. Computed tomography is superior to ultrasonography for this purpose, because ultrasonography lacks the necessary sensitivity in this group of patients.