Meritxell Ibernon

Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss

Chronic allograft nephropathy (CAN) in protocol biopsies is associated with graft loss while the association between subclinical rejection (SCR) and outcome has yielded contradictory results. We analyze the predictive value of SCR and/or CAN in protocol biopsies on death‐censored graft survival. Since 1988, a protocol biopsy was done during the first 6 months in stable grafts with serum creatinine <300 μmol/L and proteinuria <1 g/day. Biopsies were evaluated according to Banff criteria. Borderline changes and acute rejection were grouped as SCR. CAN was defined as presence of interstitial fibrosis and tubular atrophy. Mean follow‐up was 91 ± 46 months. Sufficient tissue was obtained in 435 transplants. Biopsies were classified as normal (n = 186), SCR (n = 74), CAN (n = 110) and SCR with CAN (n = 65). Presence of SCR with CAN was associated with old donors, percentage of panel reactive antibodies and presence of acute rejection before protocol biopsy. Cox regression analysis showed that SCR with CAN (relative risk [RR]: 1.86, 95% confidence interval [CI]: 1.11–3.12; p = 0.02) and hepatitis C virus (RR: 2.27, 95% CI: 1.38–3.75; p = 0.01) were independent predictors of graft survival. In protocol biopsies, the detrimental effect of interstitial fibrosis/tubular atrophy on long‐term graft survival is modulated by SCR.

Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study.

Background. Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established. Methods. In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria. Results. Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004–1.14), pretransplant body mass index (OR: 1.3, CI: 1.09–1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05–1.9) were independent risk factors for prediabetes. Conclusion. One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Reverse dipper pattern of blood pressure at 3 months is associated with inflammation and outcome after renal transplantation

BACKGROUND Cardiovascular disease is the major cause of morbidity and mortality after renal transplantation. It has been shown that both traditional and transplant-specific risk factors contribute to the high cardiovascular burden after renal transplantation The aim is to evaluate the association among ambulatory blood pressure monitoring (ABPM) at 3 months, inflammation and graft outcome. METHODS ABPM at 3 months was performed in 126 consecutive renal transplants. According to the nocturnal reduction of systolic blood pressure (SBP), dipper (ΔSBP ≥ 10%), non-dipper (0 < ΔSBP < 10%) and reverse dipper (SBP nocturnal rise) pattern were defined. The outcome variable was the combination of any cardiovascular event and graft failure for any reason. RESULTS Circadian blood pressure pattern was dipper (n = 22), non-dipper (n = 65) and reverse dipper (n = 39). Reverse dipper pattern was associated with pre-transplant diabetes (18 versus 2%, P = 0.004), body mass index (26.9 ± 5.0 versus 24.8 ± 3.8 kg/m(2), P = 0.001), calcineurin inhibitor treatment (74 versus 54%, P = 0.001) and serum soluble tumour necrosis factor receptor 2 levels (18 ± 15 versus 11 ± 6 ng/mL, P = 0.010). During 45 ± 11 months of follow-up, 22 patients reached the combined outcome variable. Multivariate Cox regression analysis showed that reverse dipper pattern [relative risk (RR): 3.50 and 95% confidence interval (CI): 1.36-8.93; P = 0.009] and creatinine clearance (RR: 0.94 and 95% CI: 0.91-0.98, P = 0.003) were independently associated with outcome. CONCLUSION The reverse dipper circadian pattern is associated with inflammation and constitutes an independent predictor of graft outcome.

Low serum mannose-binding lectin as a risk factor for new onset diabetes mellitus after renal transplantation.

Introduction. Infections and new onset diabetes mellitus after transplantation (NODAT) are frequent complications after renal transplantation and may be related to innate immunity alterations. We evaluate the relationship among serum mannose-binding lectin (MBL), chronic inflammation, NODAT, and infection. Patients and Methods. Between March 2005 and October 2006, consecutive nondiabetic renal transplant recipients were recruited. MBL, soluble tumor necrosis factor receptor 2, and neutrophil gelatinase-associated lipocalin were determined before transplant and at 1 and 3 months. An oral glucose tolerance test was performed at 3 months. Results. A total of 125 patients were recruited, and 111 patients had a functioning graft at 3 months. MBL levels remained unchanged after transplantation. Subjects with low MBL (lower tertile) had higher pretransplant soluble tumor necrosis factor receptor 2 (40±13 ng/mL vs. 35±11 ng/mL; P=0.05) and neutrophil gelatinase-associated lipocalin (638±114 ng/mL vs. 553±185 ng/mL; P=0.03), an increased incidence of bacterial/fungal infection (P=0.021), and an increased prevalence of NODAT at 3 months (44.4% vs. 22.6%; P=0.01). Multivariate analysis confirmed that MBL was a risk factor for NODAT (relative risk: 3.04, 95% confidence interval: 1.18-7.81; P=0.021) adjusting for age, pretransplant impaired fasting glucose, and body mass index. Conclusion. Low pretransplant MBL is associated with chronic inflammation, NODAT, and infection.

Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation

The survival after renal transplantation of patients with antineutrophil cytoplasmic antibody (ANCA)‐associated to systemic vasculitis is as good as in other diseases, although most of the reports are based on small numbers of patients. Furthermore, it is not known whether comorbidities (cardiovascular [CV] disease and cancer) are more frequent than in general population. We report our experience and the analysis of the published data on this topic. The outcome after transplantation in 49 patients with ANCA‐associated small vessel vasculitis was compared with a control group. The relapse rate of vasculitis was 0.01 per patient per year. Comparison with the control patients revealed no difference in long‐term outcome, CV mortality or incidence of malignancies. In the published literature, patients with ANCA at transplantation and with Wegeners granulomatosis are at greater risk of relapse. Taking our own results together with the review of the literature, we conclude that patient and graft survival rates compare favorably with those in control group that the recurrence rate is very low and that there is no increase in the incidence of cancer or in CV mortality. Patients with ANCA at transplantation and with Wegeners granulomatosis have a higher relapse rate.

Messenger RNA expression of B7-1 and NPHS1 in urinary sediment could be useful to differentiate between minimal change disease and focal segmental glomerulosclerosis in adult patients

BACKGROUND Podocyte proteins are involved in the pathogenesis of glomerular kidney disease (GKD). However, there is little information on messenger RNA (mRNA) expression patterns of B7-1 and NPHS1 in urinary sediment of patients with GKD. The objective of this study was to analyse the gene expression of B7-1 in urinary sediment and correlate it with the expression of podocyte-specific genes in patients with GKD. METHODS Adult patients with proliferative and non-proliferative GKD, proteinuria and stable renal function, were included. A group of healthy subjects was used to determine normal levels of urinary markers and to obtain reference RNA. Biochemical, clinical and experimental procedures included measurement of creatinine level and total urinary protein, renal biopsy, identification of urinary podocytes, gene expression analysis of B7-1, NPHS1, NPHS2 and SyNPO genes and urinary B7-1 protein analysis by enzyme-linked immunosorbent assay. RESULTS Between June 2006 and November 2009, 69 patients with GKD (median age: 46 ± 15 years, 64% men) and 14 healthy subjects (median age: 34 ± 12 years, 43% men) were included. In both groups, urinary mRNA levels of B7-1 and NPHS1 were significantly higher in patients with GKD compared to healthy subjects (P = 0.050 and P = 0.008, respectively). Regarding GKD subtypes, patients with focal segmental glomerulosclerosis (FSGS), but not patients with minimal change disease (MCD), had a significantly higher mRNA expression of B7-1 and NPHS1 than healthy subjects (P = 0.012 and P = 0.030, respectively). Patients with MCD had a significantly lower NPHS1 mRNA expression than patients with FSGS (P = 0.012). The B7-1:NPHS1 urinary mRNA ratio was significantly higher in patients with MCD compared with patients with FSGS (P = 0.027). CONCLUSION mRNA expression analysis of B7-1 and NPHS1 in urinary sediment may be useful to differentiate between different histologic subtypes of GKD, particularly between MCD and FSGS.

Steroids can be safely withdrawn from cyclosporine and mycophenolate mofetil-treated renal allograft recipients : Long-term results

Background. Discontinuation of steroids has long been a goal of transplant teams. However, whether this strategy is associated or not with a higher risk of long-term graft loss has not been resolved. Methods. The authors analyzed a cohort of 91 renal allograft recipients who underwent transplantation between 1993 and 1997. They were treated with cyclosporine and mycophenolate mofetil (MMF) and then had steroids withdrawn. Inclusion criteria were as follows: serum creatinine lower than 133 &mgr;M, first or second renal transplants, no or only one acute rejection episode (borderline or Ia grade), and a peak of panel reactive antibodies under 50%. Prednisone was gradually tapered off and then discontinued over a period of 2 to 4 months. Results. There were no episodes of acute rejection after steroid withdrawal. Whether steroids were withdrawn before (early) or after (late) 6 months of renal transplantation did not influence outcome. By Kaplan-Meier analysis, patient survival was 93.6% and 100% at 5 years and 93.6% and 97.6% at 10 years in the early and late steroid withdrawal groups, respectively. Graft survival was 94.3% and 98.1% at 5 years and 87.6% and 82.4% at 10 years in the early and late steroid-withdrawal groups, respectively. Risk factors for graft loss in multivariate analysis were peak of panel reactive antibodies (relative risk, 1.074; 95% confidence interval, 1.017–1.134; P=0.01) and acute rejection (relative risk, 16.5; 95% confidence interval, 1.8–147; P=0.01). Conclusions. Early and late steroid withdrawal in low-immunologic-risk renal allografts treated with cyclosporine and MMF can be achieved without risk of acute rejection and with excellent long-term results.

Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy

BACKGROUND There is a lack of new therapeutic strategies for IgA nephropathy. Low-dose sirolimus inhibits mesangial cell proliferation and renal fibrosis in animal models. METHODS We performed a pilot, randomized controlled trial to evaluate the efficacy and safety of low-dose sirolimus in patients with a high-risk IgA nephropathy. Twenty-three patients with a glomerular filtration rate (GFR) within 30-60 mL/min and/or proteinuria >1 g/day were randomly assigned to low-dose sirolimus plus enalapril and atorvastatin (SRL group, n = 14) or enalapril plus atorvastatin (CONTROL group, n = 9). Primary composite end point was variation of haematuria, proteinuria and blood pressure. Secondary end points were isotopic GFR, renal histology evaluated by Oxford classification and safety parameters evaluated at 6 and 12 months. RESULTS Primary end point improved significantly in the SRL group at 12 months. Regarding isotopic GFR, patients included in the CONTROL group lost 8 mL/min/1.73 m(2), whereas those in the SRL arm improved 5 mL/min/1.73 m(2) (P = 0.03). Proteinuria decreased similarly in both study groups. At 1 year, SRL treatment was associated with a significant reduction of mesangial and endocapillary proliferation, whereas glomerular sclerosis, tubular atrophy and interstitial fibrosis were similar. Sirolimus was well tolerated; all patients remained on therapy at 12 months. CONCLUSION The addition of low-dose sirolimus to enalapril and statin is safe, stabilizes renal function and reduces glomerular proliferative lesions in patients with poor prognosis IgA nephropathy.

Clinical evolution of post-transplant diabetes mellitus

BACKGROUND The long-term clinical evolution of prediabetes and post-transplant diabetes mellitus (PTDM) is unknown. METHODS We analysed, in this cohort study, the reversibility, stability and progression of PTDM and prediabetes in 672 patients using repeated oral glucose tolerance tests (OGTTs) for ≤5 years. RESULTS Most patients were on tacrolimus, steroids and mycophenolate. About half developed either PTDM or prediabetes. The incidence of PTDM was 32% and bimodal: early PTDM (≤3 months) and late PTDM. Early PTDM reverted in 31%; late PTDM developed in patients with post-transplant prediabetes. The use of OGTTs was necessary to detect around half of PTDM. Pretransplant obesity was a major risk factor for early PTDM, for its persistence and for late PTDM {odds ratio [OR] 1.18 [95% confidence interval (CI) 1.09-1.28]}. At 3 months, higher HbA1c promoted [OR 2.37 (95% CI 1.38-4.06)], while insulin sensitivity protected against [OR 0.64 (95% CI 0.48-0.86)] late PTDM. At 3 months, 28% had prediabetes; of these, 36% remained stable, 43% normalized and 21% developed late PTDM. Pretransplant obesity [OR 1.20 (95% CI 1.04-1.39)] and higher HbA1c [OR 3.80 (95% CI 1.45-9.94)] at 3 months promoted while insulin sensitivity protected against [OR 0.57 (95% CI 0.34-0.95)] evolution from prediabetes to late PTDM. Immunosuppressive levels or acute rejection did not influence PTDM. Most (84%) of the patients with normal tests at 3 months remained stable without evolving into PTDM; 14% developed prediabetes. CONCLUSIONS PTDM and prediabetes are very common in renal transplantation. Classic metabolic factors like obesity, prediabetes and insulin resistance promote the evolution of PTDM and prediabetes. Patients with normal glucose metabolism rarely develop PTDM. OGTT is necessary to detect PTDM and prediabetes and thus should be included in clinical practice.

Anti-factor H antibody affecting factor H cofactor activity in a patient with dense deposit disease

Complement alternative pathway dysregulation seems to be the pathophysiological basis of Dense Deposit Disease (DDD). Here, we describe a monoclonal anti-factor H (FH) autoantibody in a woman diagnosed with DDD with a monoclonal gammapathy. Enzyme-linked immunosorbent assays evidenced the presence of anti-FH antibodies in the patients serum and showed that they were associated with the monoclonal IgG-λ fraction. These autoantibodies recognize the N-terminal region of FH and interfere with its regulatory function. In summary, in the DDD patient described here, the activation of complement alternative pathway was favoured by the presence of anti-FH autoantibodies that recognize the regulatory region of this protein and impede its function and which could ultimately cause the glomerulopathy.