The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long‐term lesions in renal‐transplant patients who ...received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney‐transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3‐month, 24‐month and 10‐year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten‐year biopsy results showed that 92% of patients in the CsA‐treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.
This comparative 10‐year study of screening biopsies in 141 kidney transplant recipients treated with or without cyclosporine shows that all of the chronic elementary histological lesions, including muscular arteriolar hyalinosis, progressed in frequency and severity in both groups. See editorial by Mengel et al on page 2549.
We monitored the urinary C‐X‐C motif chemokine (CXCL)9 and CXCL10 levels in 1722 urine samples from 300 consecutive kidney recipients collected during the first posttransplantation year and assessed ...their predictive value for subsequent acute rejection (AR). The trajectories of urinary CXCL10 showed an early increase at 1 month (p = 0.0005) and 3 months (p = 0.0009) in patients who subsequently developed AR. At 1 year, the AR‐free allograft survival rates were 90% and 54% in patients with CXCL10:creatinine (CXCL10:Cr) levels <2.79 ng/mmoL and >2.79 ng/mmoL at 1 month, respectively (p < 0.0001), and 88% and 56% in patients with CXCL10:Cr levels <5.32 ng/mmoL and >5.32 ng/mmoL at 3 months (p < 0.0001), respectively. CXCL9:Cr levels also associate, albeit less robustly, with AR‐free allograft survival. Early CXCL10:Cr levels predicted clinical and subclinical rejection and both T cell– and antibody‐mediated rejection. In 222 stable patients, CXCL10:Cr at 3 months predicted AR independent of concomitant protocol biopsy results (p = 0.009). Although its positive predictive value was low, a high negative predictive value suggests that early CXCL10:Cr might predict immunological quiescence on a triple‐drug calcineurin inhibitor–based immunosuppressive regimen in the first posttransplantation year, even in clinically and histologically stable patients. The clinical utility of this test will need to be addressed by dedicated prospective clinical trials.
This observational study of 300 kidney transplant recipients finds that urinary CXCL10 at one month and three months posttransplant may identify patients at risk of acute rejection up to one year posttransplant.
No treatment has consistently induced long‐term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an ...open‐label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18‐month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high‐dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 ± 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05–0.3 g/day) and 0.19 g/day (range 0.05–1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE‐dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.
An open‐label, nonrandomized pilot trial showed that 90% of patients achieved complete and sustained proteinuria remission with a program of steroids, intravenous cyclosporine, and intensive plasmapherisis.
The detection of preformed donor‐specific alloantibodies (DSA) with multiplex‐bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or ...transplantation can have circulating anti‐HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody‐mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause‐unk) at the time of transplantation. Twenty‐one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement‐dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause‐unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m2, the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause‐unk are able to mount AMR but have favorable 1‐year outcomes.
This study analyzes kidney transplants performed in recipients with preformed donor‐specific antibodies but without a history of an HLA‐immunizing event, and shows that although these patients may experience antibodymediated rejection, they have a favorable one‐year outcome.
Persistence of donor‐specific anti‐HLA antibodies (DSA) associated with antibody‐mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and ...reduced graft survival. Targeting plasma cells, the main antibody‐producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m2× 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody‐mediated rejection with persisting DSA (>2000 Mean Fluorescence Intensity MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150‐day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long‐lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well‐controlled studies.
Bortezomib used as the sole desensitization therapy in four renal transplant recipients experiencing sub‐acute antibody‐mediated rejection with persisting DSA did not significantly decrease DSA MFI within the 150‐day post‐treatment period in any patient. See editorial by Kirk on page 447.
Anti‐HLA donor‐specific antibodies (DSAs) cause acute and chronic antibody‐mediated rejection (AMR). However, the clinical relevance of anti‐HLA‐C antibodies remains unclear. We evaluated the ...clinical relevance of the presence of anti‐HLA‐C DSA at day 0 in renal transplant recipients. In this retrospective, case‐controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti‐HLA‐C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530–17 941). The mean fluorescence intensity in the anti‐C group was 4966 (978–17 941) in the AMR group and 981 (530–8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti‐C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti‐HLA‐C DSAs are likely to develop acute AMR during the first year after transplantation.
In this retrospective, case‐controlled study of renal transplant recipients, the authors demonstrate that patients with a high level of pretransplant anti‐HLA‐C donor‐specific antibodies are likely to develop acute antibody‐mediated rejection during the first year after transplantation.
Introduction. Recurrence of nephrotic-range proteinuria in patients with idiopathic nephrotic syndrome (INS) and focal and segmental glomerulosclerosis (FSGS) on native kidneys is associated with ...poor graft survival. Identification of risk factors for recurrence is therefore an important issue. In 2004, Columbia University introduced a histological classification of FSGS that identifies five mutually exclusive variants. In non-transplant patients, the Columbia classification appears to predict the outcome and response to treatment better than clinical characteristics alone. However, the predictive value of this classification to assess the risk of recurrence after transplantation has not been addressed. Methods. We retrospectively studied 77 patients with INS and FSGS on native kidneys who underwent renal transplantation. Of these, 42 recipients experienced recurrence of nephrotic range proteinuria. Results. At time of recurrence, minimal-change disease (MCD) was the main histological feature. On serial biopsies, the incidence of MCD decreased over time, while the incidence of FSGS variants increased. The variant type observed in the native kidneys was not predictive of either recurrence or type of FSGS seen on the allograft. Patients with complete and sustained remission did not developed FSGS. Conclusion. In conclusion, the Columbia classification is of no help in predicting recurrence after renal transplantation or histological lesions in the case of recurrence of proteinuria.
Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of ...sirolimus‐associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20–40 years who received a kidney transplant during 1995–2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post‐transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 ± 31.2 × 106 and 292.2 ± 271.2 × 106, respectively; p = 0.006), and a decreased proportion of motile spermatozoa (22.2 ± 12.3% and 41.0 ± 14.5%, p = 0.01). Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8–42.1) and 92.9 (95% CI, 66.4–130.0) in patients receiving sirolimus‐based and sirolimus‐free regimens, respectively (p = 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.
This study provides evidence of sirolimus‐induced male gonadal toxicity by showing frequent alterations in sperm parameters and a 15‐fold decrease in fathered pregnancy rate in male renal transplant recipients receiving sirolimus.
In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report ...the case of a renal transplant recipient who developed severe cryptococcal meningitis‐associated IRIS 1 week after immunosuppression reduction. High‐dose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor‐α (TNF‐α) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation.
A renal transplant recipient with steroid‐resistant cryptococcal meningitis‐associated immune reconstitution inflammatory syndrome experiences neurological improvement under adalimumab, a human monoclonal tumor necrosis factor‐alpha.
Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. ...The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus‐mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02–1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony‐stimulating factor (G‐CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/μL achieved in a mean of 1.5±0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G‐CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.
Combined tacrolimus‐mycophenolate therapy is associated with the occurrence of neutropenia, which may exert a deleterious effect on the kidney transplant outcome.
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