Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis.

Background: Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death. Methods: In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2). Results: There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed. Conclusions: The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

Deep cutaneous mycoses in kidney transplant recipients: Diagnostic and therapeutic challenges.

Deep cutaneous mycoses (DCMs) are rare infections that extend throughout the dermis and subcutis, often occurring after inoculation with pathogenic fungi. Trends toward a growing incidence have been observed that may be partially related to an increasing population of solid organ transplant patients. The aim of this study is to describe the diagnostics and the outcomes of DCM among kidney transplant recipients so as to optimize their management. We performed a retrospective review of cases of DCM occurring among kidney transplant recipients in our institution over 12 years. Twenty cases were included. Lesions were only located on the limbs and presented mainly as single (10/20, 50%) nodular lesions (15/20, 75%), with a mean size of 3 cm. Direct mycological examination was positive for 17 patients (17/20, 85%) and the cultures were consistently positive. Thirteen different fungal species were observed, including phaehyphomycetes (n = 8), hyalohyphomycetes (n = 3), dermatophytes (n = 1), and mucorale (n = 1). The (1-3) beta-D-glucan antigen (BDG) was also consistently detected in the serum (20/20, 100%). Systematic imaging did not reveal any distant infectious lesions, but locoregional extension was present in 11 patients (11/14, 79%). Nineteen patients received antifungal treatment (19/20, 95%) for a median duration of 3 months, with surgery for 10 (10/20, 50%). There is a great diversity of fungal species responsible for DCMs in kidney transplant recipients. The mycological documentation is necessary to adapt the antifungal treatment according to the sensitivity of the species. Serum BDG positivity is a potentially reliable and useful tool for diagnosis and follow-up.

Efficacy of Prolonged Antibiotic Therapy for Renal Cyst Infections in Polycystic Kidney Disease.

OBJECTIVE: To determine the impact of antibiotic therapy (ATBT) on outcomes of renal cyst infection (CyI) in patients with polycystic kidney disease. PATIENTS AND METHODS: We undertook a single-center retrospective study of CyI in autosomal dominant polycystic kidney disease (January 1, 2000, through December 31, 2018). Cyst infections were classified as definite (microbiologically proven), probable (radiologic signs), or possible (clinical or biologic signs only). We studied the determinants of ATBT failure (persistence of infection beyond 72 hours of microbiologically adequate initial ATBT, with requirement for ATBT change, cyst drainage, or nephrectomy) and recurrences (>14 days after the end of ATBT). RESULTS: Among 90 patients, 139 CyIs (11 definite, 74 probable, 54 possible) were compiled. Cultures were positive in 106 of 139 (76%) episodes, with Escherichia coli found in 89 of 106 (84%). Treatment failures and recurrences within 1 year of follow-up were more frequent in definite/probable CyI (20/85 [34%] and 16/85 [19%]) than in possible CyI (2/54 [4%] and 4/54 [7%]; P<.01 and P=.08, respectively). Male sex (odds ratio [OR], 7.79; 95% CI, 1.72 to 46.68; P<.01), peak C-reactive protein level above 250 mg/L (OR, 7.29; 95% CI, 1.78 to 35.74; P<.01; to convert C-reactive protein values to nmol/L, multiply by 9.524), and cyst wall thickening (OR, 7.70; 95% CI, 1.77 to 43.47; P=.01) but not the modalities of initial ATBT were independently associated with higher risk of failure. In a Cox proportional hazards model, kidney transplant recipients exhibited higher risk of recurrence (hazard ratio, 3.76; 95% CI, 1.06 to 13.37; P=.04), whereas a total duration of ATBT of 28 days or longer was protective (hazard ratio, 0.02; 95% CI, 0.00 to 0.16; P<.001), with an inverse correlation between duration and recurrence (81% for treatment <21 days, 47% for 21 to 27 days, 2% for ≥28 days; P<.0001). CONCLUSION: Initial first-line ATBT had no significant effect on renal CyI treatment failure. Treatment duration of 28 days and longer reduced recurrences.

Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept.

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.

Deciphering the Prognostic and Predictive Value of Urinary CXCL10 in Kidney Recipients With BK Virus Reactivation.

BK virus (BKV) replication increases urinary chemokine C-X-C motif ligand 10 (uCXCL10) levels in kidney transplant recipients (KTRs). Here, we investigated uCXCL10 levels across different stages of BKV replication as a prognostic and predictive marker for functional decline in KTRs after BKV-DNAemia. uCXCL10 was assessed in a cross-sectional study (474 paired urine/blood/biopsy samples and a longitudinal study (1,184 samples from 60 KTRs with BKV-DNAemia). uCXCL10 levels gradually increased with urine (P-value < 0.0001) and blood BKV viral load (P < 0.05) but were similar in the viruria and no BKV groups (P > 0.99). In viremic patients, uCXCL10 at biopsy was associated with graft functional decline [HR = 1.65, 95% CI (1.08-2.51), P = 0.02], irrespective of baseline eGFR, blood viral load, or BKVN diagnosis. uCXL10/cr (threshold: 12.86 ng/mmol) discriminated patients with a low risk of graft function decline from high-risk patients (P = 0.01). In the longitudinal study, the uCXCL10 and BKV-DNAemia trajectories were superimposable. Stratification using the same uCXCL10/cr threshold at first viremia predicted the subsequent inflammatory response, assessed by time-adjusted uCXCL10/cr AUC (P < 0.001), and graft functional decline (P = 0.03). In KTRs, uCXCL10 increases in BKV-DNAemia but not in isolated viruria. uCXCL10/cr is a prognostic biomarker of eGFR decrease, and a 12.86 ng/ml threshold predicts higher inflammatory burdens and poor renal outcomes.

Asymptomatic bacteriuria and urinary tract infections in kidney transplant recipients.

PURPOSE OF REVIEW: Urinary tract infection (UTI) is the most common infection in kidney transplant recipients (KTRs). Several elements increase the risk of UTI and/or modify its clinical presentation among KTRs (e.g. immunosuppressive therapy, kidney allograft denervation, and use of urinary catheters). Also, KTRs may have UTIs because of difficult-to-identify and/or difficult-to-treat organisms. We provide an overview of the current knowledge regarding bacterial UTIs in KTRs, with a focus on recent findings. RECENT FINDINGS: There is accumulating evidence from clinical trials that screening for and treating asymptomatic bacteriuria is not beneficial in most KTRs (i.e. those who are ≥1-2 months posttransplant and do not have a urinary catheter). These patients have a point-prevalence of asymptomatic bacteriuria of only 3% and treating asymptomatic bacteriuria probably does not improve their outcomes. There is no clinical trial evidence to guide the management of symptomatic UTI in KTRs. Several important clinical questions remain unanswered, especially regarding the management of posttransplant pyelonephritis and the prevention of UTI in KTRs. SUMMARY: Despite its frequency and associated morbidity, UTI after kidney transplantation is an understudied infection. In an era of increasing antimicrobial resistance and limited resources, further research is needed to ensure optimal use of antimicrobials in KTRs with UTI.

Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: The French experience.

Organ transplantation is discussed in methylmalonic aciduria (MMA) for renal failure, and poor quality of life and neurological outcome. We retrospectively evaluated 23 French MMA patients after kidney (KT), liver-kidney (LKT), and liver transplantation (LT). Two patients died, one after LKT, one of hepatoblastoma after KT. One graft was lost early after KT. Of 18 evaluable patients, 12 previously on dialysis, 8 underwent KT (mean 12.5 years), 8 LKT (mean 7 years), and 2 LT (7 and 2.5 years). At a median follow-up of 7.3 (KT), 2.3 (LKT), and 1.0 years (LT), no metabolic decompensation occurred except in 1 KT. Plasma and urine MMA levels dramatically decreased, more after LKT. Protein intake was increased more significantly after LKT than KT. Enteral nutrition was stopped in 7/8 LKT, 1/8 KT. Early complications were frequent after LKT. Neurological disorders occurred in four LKT, reversible in one. Five years after KT, four patients had renal failure. The metabolic outcomes were much better after LKT than KT. LKT in MMA is difficult but improves the quality of life. KT will be rarely indicated. We need more long-term data to indicate early LT, in the hope to delay renal failure and prevent neurodevelopmental complications.

Central nervous system complications in adult cystinosis patients.

Little is known about the long-term progression of adult nephropathic cystinosis patients. Our objective was to study central nervous system complications in cystinosis patients in the era of early cysteamine treatment, using advanced neuroimaging techniques. Neurological examination and multimodal brain 3 Tesla MRI were performed in 21 adult cystinosis patients, including 18 infantile cystinosis patients, 20 controls matched for age and renal function, and 12 healthy controls. Differences in gray matter volume and rest cerebral blood flow (CBF) using arterial spin labeling sequence were investigated using whole-brain voxel-based approach. Median age was 33.8 years (18.7-65.8). Seven patients (38.9%) presented with at least one central nervous system clinical abnormality: two (11.1%) with seizures, three (16.7%) with memory defects, five (27.8%) with cognitive defect, and one (5.5%) with stroke-like episode. These patients had a worse compliance to treatment (compliance score 2 vs 1, P = .03) and received a lower median cysteamine dose (0.9 g/day vs 2.1 g/day, P = .02). Among patients with infantile cystinosis, 13 (72.2%) showed cortical atrophy, which was absent in controls, but it was not correlated with symptoms. Cystinosis patients showed a significant gray matter decrease in the middle frontal gyrus compared with healthy controls and a significant negative correlation between the cystine blood level and rest CBF was observed in the right superior frontal gyrus, a region associated with executive function. Compliance to cysteamine treatment is a major concern in these adult patients and could have an impact on the development of neurological and cognitive complications.

[Renal transplantation: Procedure and early follow-up]. / Transplantation rénale : réalisation et suivi précoce.

More than fifty years after the success of the two first renal transplantations in Boston and in Necker hospital in Paris, renal transplantation became the treatment of choice of end stage renal failure, because it improves not only the quality of life of the patients but also their long-term survival. In France, more than 3,700 kidney transplantations are performed every year and more than 40,000 patients are living with a functioning kidney allograft. This treatment of end stage renal disease requires a fine-tuned pre-transplant evaluation and a multidisciplinary post-transplant care in order to prevent, to detect and to treat comorbidities and complications of immunosuppression. The ambition of this manuscript is not to describe in an exhaustive way all the aspects of renal transplantation but starting from the experience of a team, recently published data, and national and international guidelines, to try to provide a synthetic and chronological view of the early post-transplant monitoring.

Conversion From Calcineurin Inhibitors to Belatacept in HLA-sensitized Kidney Transplant Recipients With Low-level Donor-specific Antibodies.

BACKGROUND: Belatacept could be the treatment of choice in renal-transplant recipients with renal dysfunction attributed to calcineurin inhibitor (CNI) nephrotoxicity. Few studies have described its use in patients with donor-specific antibody (DSA). METHODS: We retrospectively evaluated conversion from CNIs to belatacept in 29 human leukocyte antigen-immunized renal-transplant recipients. Data about acute rejection, DSA, and renal function were collected. These patients were compared with 42 nonimmunized patients treated with belatacept. RESULTS: Patients were converted from CNIs to belatacept a median of 444 days (interquartile range, 85-1200) after transplantation and were followed up after belatacept conversion, for a median of 308 days (interquartile range, 125-511). At conversion, 16 patients had DSA. Nineteen DSA were observed in these 16 patients, of which 11/19 were <1000 mean fluorescence intensity (MFI), 7/19 were between 1000 and 3000 MFI, and one was >3000 MFI. At last follow-up, preexisting DSA had decreased or stabilized. Seven patients still had DSA with a mean MFI of 1298 ± 930 at the last follow-up. No patient developed a de novo DSA in the DSA-positive group. In the nonimmunized group, one patient developed de novo DSA (A24-MFI 970; biopsy for cause did not show biopsy-proven acute rejection or microinflammation score). After belatacept conversion, one antibody-mediated rejection was diagnosed. The mean estimated glomerular filtration rate improved from 31.7 ± 14.2 mL/min/1.73 m to 40.7 ± 12.3 mL/min/1.73 m (P < 0.0001) at 12 months after conversion. We did not find any significant difference between groups in terms of renal function, proteinuria, or biopsy-proven acute rejection. CONCLUSIONS: We report on a safe conversion to belatacept in human leukocyte antigen-immunized patients with low DSA levels.

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single-center experience.

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T0 ) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T0 at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV-associated nephropathy (P = 0.033) without impacting 5-year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor-specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium-term clinical outcome but increases the risk of developing dnDSAs.

Severe dermatophytosis in solid organ transplant recipients: A French retrospective series and literature review.

OBJECTIVE: Severe dermatophytosis is described in immunocompromised patients with defective cellular immunity. We report here a large series and a literature review of severe dermatophytosis in solid-organ transplant (SOT) recipients. METHOD: The data main source was a national French retrospective study of severe dermatophytosis in SOT recipients between 2010 and 2016. Inclusion criteria were the presence of dermatophytes in skin culture and 1 severity criteria: dermal invasion by dermatophytes (invasive dermatophytosis) or involvement of at least two body sites or >10% of body surface area (extensive dermatophytosis). RESULTS: A total of 12 patients were included (8 men, median age of 56 years [range: 33-71]). Of the 12 patients, 10 underwent kidney transplantation. The median time from transplantation to severe dermatophytosis diagnosis was 16 months [range: 2-94]. Clinical signs of superficial dermatophytosis were present in 8/12 patients before the emergence of severe dermatophytosis. Nine patients had invasive forms and three extensive ones, and nodules of the lower extremities were found in eight. Trichophyton rubrum was isolated in 11 cases. First-line treatment was terbinafine (7/12), posaconazole (3/12), or topical treatment alone (2/12). Immunosuppressive therapy was reduced in 3 patients because of associated infections. Complete response was obtained for 3/3 and 5/9 patients with extensive or invasive forms, respectively, after a median treatment's duration of 2.5 [range: 1.5-5] months and 7.5 months [range: 4-12]. Unrelated deaths (n = 2) and graft function impairment (n = 3) occurred. CONCLUSION: Severe dermatophytosis is a late complication in SOT recipients presenting with lower limb nodules, which might be prevented by prompt treatment of superficial dermatophytosis.

Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab. METHODS: Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months. RESULTS: Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 ± 40.8 µmol/L. CONCLUSIONS: These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis.

Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis.

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis.

Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection.

Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.

[Current aspects of acute humoral rejection]. / Aspects actuels des rejets aigus humoraux.

Acute clinical antibody-mediated rejection is currently defined by (1), an acute renal failure occurring during the first months following transplantation, (2), at least a microcirculation inflammation (glomerulitis and peritubular capillaritis) on kidney biopsy and (3), the presence in peripheral blood of donor specific antibodies, mostly anti-human leukocyte antigen (HLA) antibodies. The prognosis of this rejection is scored using the severity of vascular lesions and the positivity of C4d on peritubular capillaries. Recently, a subclinical variety of antibody-mediated rejection was recognized as an entity because, as the clinical rejection, it leads to chronic antibody-mediated rejection, currently the most frequent cause of graft loss. The description of these various aspects of antibody-mediated rejection allowed a better understanding of its pathophyiology that may lead in a near future to a more specific treatment.

The kidney as a reservoir for HIV-1 after renal transplantation.

Since the recent publication of data showing favorable outcomes for patients with HIV-1 and ESRD, kidney transplantation has become a therapeutic option in this population. However, reports have documented unexplained reduced allograft survival in these patients. We hypothesized that the unrecognized infection of the transplanted kidney by HIV-1 can compromise long-term allograft function. Using electron microscopy and molecular biology, we examined protocol renal transplant biopsies from 19 recipients with HIV-1 who did not have detectable levels of plasma HIV-1 RNA at transplantation. We found that HIV-1 infected the kidney allograft in 68% of these patients. Notably, HIV-1 infection was detected in either podocytes predominately (38% of recipients) or tubular cells only (62% of recipients). Podocyte infection associated with podocyte apoptosis and loss of differentiation markers as well as a faster decline in allograft function compared with tubular cell infection. In allografts with tubular cell infection, epithelial cells of the proximal convoluted tubules frequently contained abnormal mitochondria, and both patients who developed features of subclinical acute cellular rejection had allografts with tubular cell infection. Finally, we provide a novel noninvasive test for determining HIV-1 infection of the kidney allograft by measuring HIV-1 DNA and RNA levels in patients' urine. In conclusion, HIV-1 can infect kidney allografts after transplantation despite undetectable viremia, and this infection might influence graft outcome.