Early Low Urinary CXCL9 and CXCL10 Might Predict Immunological Quiescence in Clinically and Histologically Stable Kidney Recipients.

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.

Dramatic improvement of severe cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient.

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.

Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy.

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.

Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies.

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/m(2)x 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.

Kidney transplantation at Necker Hospital: the most recent 5-year period (2004-2009).

The results of our last 5 years activity in kidney transplantation clearly show that it is possible to perform high-risk transplantations with very acceptable results: ECD kidneys, dual transplantation, recipients with DSAs. In depth statistical analysis of these data should allow a clearer definition of the best strategies to use in these situations.

Donor-estimated GFR as an appropriate criterion for allocation of ECD kidneys into single or dual kidney transplantation.

It has been suggested that dual kidney transplantation (DKT) improves outcomes for expanded criteria donor (ECD) kidneys. However, no criteria for allocation to single or dual transplantation have been assessed prospectively. The strategy of DKT remains underused and potentially eligible kidneys are frequently discarded. We prospectively compared 81 DKT and 70 single kidney transplant (SKT) receiving grafts from ECD donors aged >65 years, allocated according to donor estimated glomerular filtration rate (eGFR): DKT if eGFR between 30 and 60 mL/min, SKT if eGFR greater than 60 mL/min. Patient and graft survival were similar in the two groups. In the DKT group, 13/81 patients lost one of their two kidneys due to hemorrhage, arterial or venous thrombosis. Mean eGFR at month 12 was similar in the DKT and SKT groups (47.8 mL/min and 46.4 mL/min, respectively). Simulated allocation of kidneys according to criteria based on day 0 donor parameters such as those described by Remuzzi et al., Andres et al. and UNOS, did not indicate an improvement in 12-month eGFR compared to our allocation based on donor eGFR.

[Screening biopsies in kidney transplantation: from subclinical acute rejection to chronic allograft lesions]. / Les biopsies de dépistage en transplantation rénale: du rejet aigu infra-clinique aux lésions chroniques de l'allogreffe.

Kidney biopsies for screening purposes have the advantage of revealing the early appearance of lesions having a poor prognosis before kidney function is altered. Early screening of subclinical rejections allows preventive treatment of kidney transplantation in patients taking cyclosporine or azathioprine, thus improving their renal function and reducing the incidence of chronic histological lesions. However, this benefit has yet to be demonstrated in patients taking tacrolimus or mycophenolic acid. As for interstitial fibrosis lesions and tubular atrophy, biopsies can screen subclinical immunological lesions or those related to nephrotoxicity of anticalcineurins, which have a negative prognostic value in terms of graft survival. In addition, detection of these lesions could be a very useful criterion of efficacy in clinical studies. Moreover, they could help decide on modifying immunosuppressor treatment and evaluate the therapeutic strategies in patients at risk for humoral rejection. Finally, given the cost of biopsies and the inconvenience for the patient, the question of the timing and the number of screening biopsies is crucial. However, interventional studies evaluating notably immunosuppressor treatment modifications based on histological data are necessary to justify the daily use of screening biopsies.

Recurrence of HUS due to CD46/MCP mutation after renal transplantation: a role for endothelial microchimerism.

Mutations in the gene of the membrane cofactor protein (MCP/CD46), a complement regulatory protein, were recently described as a cause of hemolytic uremic syndrome (HUS). MCP is a transmembrane glycoprotein expressed in kidneys; therefore, the transplantation of a normal kidney should not be complicated by HUS recurrence. However, we report the case of a 32-year-old woman with an MCP mutation who developed a recurrence of HUS after renal transplantation. We found that she had vascular microchimerism of endothelial cells. We suggest that recurrence may be favored by vascular microchimerism, in which the mutated protein is produced in the in the kidney graft by endothelial cells originating from recipient.

Single-center experience with cyclosporine therapy for kidney transplantation: analysis of a twenty-year period in 1200 patients.

Since the introduction of cyclosporine (CyA) in our center in February 1983, 1267 kidney transplant patients have received an immunosuppressive regimen based on CyA, usually in association with azathioprine and steroids and following an induction therapy in three quarters of patients. The aim of this study was to retrospectively analyze our 20-year experience with CyA and examine the evolution of therapy during this period. Induction treatment has been less commonly used during the past 5 years. Even in the early years of our experience, CyA doses were low (under 6 mg/kg per day at 3 months after transplantation). Acute tubular necrosis was observed in 39.4% of patients. The incidence of acute rejection episodes has dramatically decreased since 1984, but the frequency of steroid-resistant rejection has remained constant (around 20%). The first year of transplantation, 32.7% of patients had arterial hypertension. De novo diabetes mellitus occurred in 2.5% of patients. An incidence of 11.8% of malignancies was observed. Skin cancer and lymphomas accounted for 50% and 12% of neoplasms. Five-year graft and patient survivals were 70% and 87%, respectively. Renal function remained remarkably constant during the first 10 years of follow-up with a mean creatinine of 150 micromol/L. Chronic allograft nephropathy resulted in 43% graft losses. In conclusion, CyA has been well tolerated in our patients. However, the occurrence of chronic allograft nephropathy was a major concern in our cohort.