Iris Fontana

Polyomavirus BK (BKPyV)-associated nephropathy (BKPyV-nephropathy) remains a significant cause of premature kidney allograft failure. In the absence of effective antiviral treatments, current therapeutic approaches rely on immunosuppression (IS) reduction, possibly at the risk of inducing alloimmunity. Therefore, we sought to explore the long-term effects of a tailored viro-immunologic surveillance and treatment program for BKPyV on the development of alloimmunity and kidney graft outcome. Forty-five pediatric kidney transplant recipients were longitudinally monitored for BKPyV replication, virus-specific immunity, and donor-specific HLA antibodies (DSAs). DNAemia developed in 15 patients who were treated with stepwise IS reduction. Among the other 30 patients, 17 developed DNAuria without DNAemia and 13 always resulted as BKPyV-negative. All patients with DNAemia cleared BKPyV after having mounted a virus-specific cellular immune response, and no biopsy-proven BKPyV-nephropathy was observed. The presence of cytotoxic populations directed to the BKPyV Large-T (LT) antigen early after transplantation protected kidney recipients from developing BKPyV replication, and the appearance of LT-specific T cells in viruric patients prevented the development of BKPyV-DNAemia. In our cohort, no significant correlation was observed between BKPyV-DNAemia and the development of DSA and antibody-mediated rejection. However, patients who experienced and cleared BKPyV-DNAemia had a worse allograft survival at a median follow-up of 18.9 years (p = 0.048). These data need to be confirmed in larger cohorts.

The use of tacrolimus (Tac) may be involved in the development of new-onset diabetes after transplantation (NODAT) in a dose-related manner. This study aimed to evaluate the effects of a standard twice-daily formulation of Tac (TacBID) vs. the once-daily slow-release formulation (TacOD) on the basal insulin resistance indexes (Homa and McAuley), and related metabolic parameters, in a cohort of kidney transplant patients. We retrospectively evaluated 20 stable renal transplant recipients who were switched from TacBID to TacOD. Blood levels of Tac were analyzed at one-month intervals from 6 months before to 8 months after conversion. Moreover, Homa and McAuley indexes, C-peptide, insulin, HbA1c, uric acid, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol serum levels and their associations with Tac levels were evaluated. We observed a significant decrease in Tac exposure (8.5 ± 2 ng/mL, CV 0.23 vs. 6.1 ± 1.9 ng/mL, CV 0.31, TacBID vs. TacOD periods, p < 0.001) and no significant changes in Homa (1.42 ± 0.4 vs. 1.8 ± 0.7, p > 0.05) and McAuley indexes (7.12 ± 1 vs. 7.58 ± 1.4, p > 0.05). Similarly, blood levels of glucose, insulin, HbA1c, lipids, and uric acid were unchanged between the two periods, while C-peptide resulted significantly lower after conversion to TacOD. These data suggest that in kidney transplant recipients, reduced Tac exposure has no significant effects on basal insulin sensitivity indexes and metabolic parameters.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m², 95% CI 10.5–40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post‐transplant year. Banff score, CD68⁺ count (score 0‐3) by immunohistochemistry, and 1‐year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68⁺ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow‐up, four patients (11%) suffered from biopsy‐proven T‐cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68⁺ group). Graft survival was lower in KTRs with grade 3 CD68⁺ infiltration (P = 0.0074; log‐rank test). Grade 3 CD68⁺ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74‐16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57‐16; P < 0.001). We conclude that grade 3 CD68⁺ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody‐mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor‐specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis+low‐dose IVIG+Rituximab or high‐dose IVIG+Rituximab. Renal function and DSA properties were assessed before and longitudinally post‐treatment. The eGFR decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (p=0.021) but not on eGFR at treatment (p=0.74). At a median follow‐up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (p<0.001) and presence of C3d‐binding DSAs (p=0.005) at treatment, and failure to remove DSAs (p=0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti‐humoral treatment. In the multivariable analysis, C3d‐binding ability (p<0.05), but not C1q‐binding, and high mean fluorescence intensity (p<0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high‐MFI DSAs.

Background: Carbapenem‐resistant Klebsiella pneumoniae (CR‐KP) infections in solid organ transplant patients are progressively increasing and are associated with worse outcomes, although potential risk factors and therapeutic strategies are still not well defined.Methods: We conducted a retrospective matched‐pair analysis in which we compared 26 recipients CR‐KP‐positive after kidney transplantation (KT) with 52 CR‐KP‐negative patients transplanted in the same period, during a CR‐KP outbreak that occurred in our hospital. Twenty‐one patients (80%) received a combined antibiotic treatment. At the end of the follow‐up, of the 26 CR‐KP infected patients, 11 (42.3%) experienced at least one episode of re‐infection, 9 (34.6%) remained colonized, and 6 (23.0%) had a symptomatic infection. Two of the 11 patients with re‐infection died, while 9 were colonized at the end of the study.Results: A significantly better patient (P = .043) and graft (P < .001) survival was observed in CR‐KP‐negative patients. Univariate analysis identified the following variables as potential risk factors associated with CR‐KP infection after KT: lower body mass index (P = .020); higher creatinine levels at post‐transplant days 7 (P = .009), 15 (P = .026), and 30 (P = .019); longer hospital stay (P = .007); longer cold ischemia time (P = .004); delayed graft function (P = .020); and higher Clavien‐Dindo score (P = .006).Conclusion: The study confirmed that a CR‐KP positivity may affect the outcome of a kidney transplant population. In severe CR‐KP infections with sepsis, a combined antibiotic treatment seems to be advisable.