Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

INTRODUCTION: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). METHODS: Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). RESULTS: Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0% vs. 85.5%, p < 0.001) and 24 months (61.0% vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4% vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6% vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9% vs. 18.6%, p = 0.003, OR = 0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406 vs. 813 days, p = 0.001) without an increased risk of complications. CONCLUSIONS: CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.

Clinical outcomes and temporal trends of immunological and non-immunological rare diseases in adult kidney transplant.

BACKGROUND: Rare diseases (RDs) encompass many difficult-to-treat conditions with different characteristics often associated with end-stage renal disease (ESRD). However, data about transplant outcomes in adult patients are still lacking and limited to case reports/case series without differentiation between immunological/non-immunological RDs. METHODS: Retrospective analysis among all adult kidney transplanted patients (KTs) with RDs (RDsKT group) performed in our high-volume transplantation center between 2005 and 2016. RDs were classified according to the Orphanet code system differentiating between immunological and non-immunological diseases, also comparing clinical outcomes and temporal trends to a control population without RDs (nRDsKT). RESULTS: Among 1381 KTs, 350 patients (25.3%) were affected by RDs (RDsKTs). During a f/up > 5 years [median 7.9 years (4.8-11.1)], kidney function and graft/patient survival did not differ from nRDsKTs. Considering all post-transplant complications, RDsKTs (including, by definition, patients with primary glomerulopathy except on IgA nephropathy) have more recurrent and de-novo glomerulonephritis (14.6% vs. 9.6% in nRDsKTs; p = 0.05), similar rates of de-novo cancers, post-transplant diabetes, dysmetabolism, hematologic disorders, urologic/vascular problems, and lower infectious episodes than nRDsKTs (63.7% vs 72.7%; p = 0.013). Additional stratification for immunological and non-immunological RDsKTs or transplantation periods (before/after 2010) showed no differences or temporal trends between groups. CONCLUSIONS: Kidney transplant centers are deeply involved in RDs management. Despite their high-complex profile, both immunological and non-immunological RDsKTs experienced favorable patients' and graft survival.

Early effects of first-line treatment with anti-interleukin-6 receptor antibody tocilizumab for chronic active antibody-mediated rejection in kidney transplantation.

INTRODUCTION: Chronic active antibody-mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non-responsive to rituximab/IVIg/PLEX with favorable outcomes. Whether TCZ acts "per se" or requires a priming effect from previous treatments is currently unknown. METHODS: Fifteen patients with cAMR were treated with TCZ as a first-line therapy and followed for a median time of 20.7 months. RESULTS: Despite the majority of patients experiencing advanced transplant glomerulopathy (TG) at diagnosis (60% with cg3), glomerular filtration rate and proteinuria stabilized during the follow-up, with a significant reduction in donor-specific antibodies. Protocol biopsies after 6 months demonstrated significant amelioration of microvascular inflammation and no TG, C4d deposition, or IF/TA progression. Gene-expression and immunofluorescence analysis showed upregulation of three genes (TJP-1, AKR1C3, and CASK) involved in podocyte, mesangial, and tubular restoration. CONCLUSION: Tocilizumab adopted as a first-line approach in cAMR was associated with early serological and histological improvements and functional stabilization even in advanced TG, suggesting a role for the use of TCZ alone with the avoidance of unnecessary previous immunosuppressants.

Case series of six kidney transplanted patients with COVID-19 pneumonia treated with tocilizumab.

Few reports described the outcome of kidney transplanted patients (KTs) affected by COVID-19 treated with interleukin-6 receptor inhibitor tocilizumab (TCZ). We report our case series of 6 KTs with COVID-19 pneumonia who received TCZ: All were of male gender, with a mean age of 55.5 ± 8.4 years, a median time from transplantation of 3611 days (1465-5757); 5/6 had cardiovascular comorbidities, 1/6 had diabetes, and 3/6 have one or more previous KTs. Four out of six patients died, at an average time of 9.75 ± 2.4 days after tocilizumab administration, 3/6 due to a coexistent septic shock. Two patients improved after TCZ and were discharged at 20 and 21 days, respectively; in both patient, a significant increase of total lymphocyte count was observed. In conclusion, KTs, where the role of peculiar factors such as chronic immunosuppression is still undetermined, represent a high-risk group with significant COVID-19-associated mortality. The evaluation of the TCZ effect in COVID-19 pneumonia requires controlled studies (ideally RCTs) in this specific population.

Outsourcing Elderly Care to Migrant Workers: The Impact of Gender and Class on the Experience of Male Employers.

This article, based on semi-structured interviews, addresses masculinity in the international division of reproductive labour through an analysis of the impact of gender and class on the outsourcing of elderly care services to migrant care workers. In the Italian context, characterised by a limited provision of long-term care services and by cash-for-care benefits, the strategies of men as employers of migrant care workers are shaped by class and gender. The outsourcing of care to migrant workers reproduces hegemonic masculinity in so far as male employers are able to withdraw from the 'dirty work'. At the same time, men engage with tasks which are, in principle, kept at a distance. The employers' family status, combined with their class background, are crucial factors in shaping the heterogeneity of men's experiences as employers and managers of care labour, and the ways in which they make sense of their masculinity.

Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies.

Background: Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Methods: Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Results: Differently from TG/DSA+, TG/DSA- showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA- tends to maintain or increase periglomerular/interstitial infiltration. Conclusions: In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.

Different profiles of acute graft pyelonephritis among kidney recipients from standard or elderly donors.

Background: Acute graft pyelonephritis (AGPN) is a relatively common complication in kidney transplants (KTs); however, the effects on allograft function, diagnostic criteria, and risk factors are not well established. Methods: Retrospective analysis of all consecutive adult KTs was performed between 01 January 2011 and 31 December 2018 (follow-up ended on 31 December 2019) to examine the association between the diagnosis of AGPN (confirmed with magnetic resonance imaging [MRI]) during the first post-transplantation year and graft outcomes. Results: Among the 939 consecutive KTs (≈50% with donors ≥60 years), we identified 130 MRI-confirmed AGPN episodes, with a documented association with recurrent and multidrug-resistant bacterial urinary tract infections (UTIs) (p < 0.005). Ureteral stenosis was the only risk factor associated with AGPN (OR 2.9 [95% CI, 1.6 to 5.2]). KTs with AGPN had a decreased allograft function at the first year (ΔeGFR 6 mL/min/1.73 m2 [-2-15] in non-AGPN vs. -0.2 [-6.5-8.5] in AGPN, p < 0.001), with similar and negative profiles in KTs from standard or elderly donors. However, only KTs with AGPN and a donor <60 years showed reduced death-censored graft survival (p = 0.015); most of this subgroup received anti-thymocyte globulin (ATG) induction (40.4% vs. 17.7%), and their MRI presented either a multifocal AGPN pattern (73.9% vs. 56.7%) or abscedation (28.3% vs. 11.7%). No difference was noted in death-censored graft survival between early (<3 months post-KT) or late (3-12 months) AGPN, solitary/recurrent forms, or types of multidrug-resistant pathogens. Linear regression confirmed the independent role of multifocal pattern, abscedation, ATG induction, and donor age on the eGFR at the first year. Conclusion: AGPN, influenced by multifocal presentation, ATG induction, donor age, and abscedation, affects kidney function and significantly impacts allograft survival in KTs with donors <60 years.

Relationship between Cytomegalovirus Viremia and Long-Term Outcomes in Kidney Transplant Recipients with Different Donor Ages.

OBJECTIVES: To explore the Cytomegalovirus (CMV) burden on the long-term post-transplant course in different donor ages, we evaluated the incidence and risk factors for CMV in our kidney-transplanted patients (KTs) with extensive adoption of expanded-criteria donors (ECDs). METHODS: Retrospective evaluation of 929 consecutive first KTs (49.5% receiving an organ from a donor ≥ 60 years) performed between 01-2003 and 12-2013. Overall survival was estimated using Kaplan-Meier curves; cumulative incidence function was additionally analyzed to consider the potential role of death with a functioning graft as a competitive event with graft dysfunction and to avoid overestimation. Apart from regular DNAemia monitoring in all patients, prophylaxis was adopted in high-risk groups (D+/R- or recipients of anti-thymocyte globulin induction), with pre-emptive therapy in the remaining groups. RESULTS: CMV incidence was 19.5% (4-34.9% according to serostatus combination: D-/R-, D-/R+, D+/R+, D+/R-). Donor and recipient age, recipient pre-transplant hypertension, DR antigen compatibility, cold ischemia time, and post-transplant early complications, including rejection, urologic and renal artery stenosis, and lower renal function and proteinuria ≥ 0.5 g/day at one year after KT were associated with CMV. CMV determined lower death-censored graft survival (DCGS) (p < 0.01), with a prominent effect in R+ (p < 0.01) and without impact in R- (p = 0.32 in D-/R- and p = 0.006 in D+/R-). Interestingly, CMV occurrence influenced DCGS only in KTs who received grafts from donors < 50 or 50-69 years old (p < 0.01), while it was not significant with older donors (p = 0.07). The analysis of the cumulative incidence of graft loss accounting for death as a competing risk confirmed all these findings. In multivariate analysis, CMV replication/disease in the first year was an independent predictor for DCGS (HR 1.73 [1.3-2.3]). CONCLUSIONS: In a large population with extensive ECD adoption, CMV viremia in the first year demonstrates its harmful effect with an independent role for graft loss and significant impact among R+ recipients and KTs with donors < 70 years.

[Immunosuppressive treatment after kidney transplant: the frontier of chronic antibody-mediated rejection]. / Terapia immunosoppressiva nel trapianto renale: la frontiera del rigetto cronico anticorpo-mediato.

The recognition of antibody-mediated rejection as an important factor in the reduction of long-term renal graft survival represents a new challenge to the immunosuppressive strategies of recent years, which have been quite successful in reducing the acute rejection rates as well as the side effects of pharmacological immunosuppression. The search for an effective treatment of chronic anti-donor antibody disease has been pursued mostly through limited single-center experiences and therefore in a dispersed fashion, without leading to the definition of a consolidated approach. The most frequently used pharmacological approaches stem from the experience of antibody-mediated acute rejection. In this review we will critically analyze the results reported so far of various intervention strategies and we will discuss future pharmacological novelties targeting the humoral immune response.

Bacterial and Viral Infection and Sepsis in Kidney Transplanted Patients.

Kidney transplanted patients are a unique population with intrinsic susceptibility to viral and bacterial infections, mainly (but not exclusively) due to continuous immunosuppression. In this setting, infectious episodes remain among the most important causes of death, with different risks according to the degree of immunosuppression, time after transplantation, type of infection, and patient conditions. Prevention, early diagnosis, and appropriate therapy are the goals of infective management, taking into account that some specific characteristics of transplanted patients may cause a delay (the absence of fever or inflammatory symptoms, the negativity of serological tests commonly adopted for the general population, or the atypical anatomical presentation depending on the surgical site and graft implantation). This review considers the recent available findings of the most common viral and bacterial infection in kidney transplanted patients and explores risk factors and outcomes in septic evolution.

Monoclonal gammopathy of undetermined significance coexisting in patients undergoing kidney transplantation does not adversely influence post-graft clinical outcome.

BACKGROUND: Management of patients with oncohaematological disorders such as monoclonal gammopathy of undetermined significance (MGUS) is a frequent problem in pre-transplant work-up. Insights on disease progression and long-term functional outcomes are still lacking in this setting. METHODS: This was a retrospective analysis on all patients with MGUS who underwent kidney transplant (KT) at our centre between 1 January 2000 and 31 December 2017 (cases, n = 65). Patients were matched with a control group (KTs with similar characteristics but without history of haematological disease, controls, n = 1079). Primary endpoints were graft and patient survival; secondary endpoints were causes of graft failure, patient death, occurrence of allograft rejection, post-transplant neoplasia (not correlated to previous disorder) and/or infectious episodes. RESULTS: The MGUS and control groups had a similar mean age [60 (29-79) versus 55.2 (19.3-79.5) years, respectively] and percentage of males (69.2% versus 64.6%, respectively). Median follow-up time since KT was 3.5 years (0-14) in cases and 8.3 years (0-14.9) in controls. All MGUS patients underwent KT following extensive multidiscliplinary investigations. No differences were found between cases and controls regarding patient and graft survival or post-transplant complications except for lower incidence of infections (58.7% versus 69.8%, P = 0.019) and increased use of mTOR inhbitors (30.3% versus 14.7%, P = 0.001) in MGUS. MGUS isotype did not influence graft and patient survival. The absence of difference in patients and graft survival was also confirmed in an adjunctive analysis where MGUS were compared with controls (ratio 1:2) matched for recipient age, gender, number of transplantations and transplant period. CONCLUSION: Patients with MGUS may undergo KT without significantly increased risks of complications, provided that appropriate diagnostic procedures are carefully followed. Multidiscipline-based studies are crucial for establishing well designed pre- and post-transplant protocols for the best management of patients with coexisting MGUS and end-stage renal disease.

Renal Allograft Biopsies with Polyomavirus BK Nephropathy: Turin Transplant Center, 2015-19.

BACKGROUND: In kidney transplant patients, polyomavirus-associated nephropathy (PVAN) represents a serious complication; the key factor for the development of PVAN is immunosuppression level and modulation of anti-rejection treatment represents the first line of intervention. Allograft biopsy and histology remain the criterion standard for diagnosing PVAN. METHODS: All consecutive renal biopsies with the diagnosis of PVAN carried out at the University Hospital City of Health and Science of Turin over a five-years period were studied. Renal allograft biopsy was performed due to renal function alterations associated to medium-high polyomavirus BK (BKV)-DNA levels on plasma specimen. RESULTS: A total of 21 patients underwent a first biopsy to diagnose a possible BKV nephropathy, in 18, a second biopsy was made, in eight, a third biopsy, and finally, three underwent the fourth renal biopsy; following the results of each biopsies, immunosuppressant agents dosages were modified in order to reduce the effect of PVAN. CONCLUSIONS: In this study, the clinical and histological features of 21 kidney transplant recipients with BKV reactivation and development of PVAN are described. To date, the only treatment for PVAN consists in the reduction of immunosuppressive agents, constantly monitoring viral load.

Impact of type 2 diabetes mellitus on kidney transplant rates and clinical outcomes among waitlisted candidates in a single center European experience.

Despite type 2 diabetes mellitus (T2D) is commonly considered a detrimental factor in dialysis, its clear effect on morbidity and mortality on waitlisted patients for kidney transplant (KT) has never been completely elucidated. We performed a retrospective analysis on 714 patients admitted to wait-list (WL) for their first kidney transplant from 2005 to 2010. Clinical characteristics at registration in WL (age, body mass index -BMI-, duration and modality of dialysis, underlying nephropathy, coronary artery -CAD- and/or peripheral vascular disease), mortality rates, and effective time on WL were investigated and compared according to T2D status (presence/absence). Data about therapy and management of T2D were also considered. At the time of WL registration T2D patients (n = 86) were older than non-T2D (n = 628) (58.7 ± 8.6 years vs 51.3 ± 12.9) with higher BMI (26.2 ± 3.8 kg/m2 vs 23.8 ± 3.6), more frequent history of CAD (33.3% vs 9.8%) and peripheral vascular disease (25.3% vs 5.8%) (p < 0.001 for all analyses). Considering overall population, T2D patients had reduced survival vs non-T2D (p < 0.001). Transplanted patients showed better survival in both T2D and non-T2D groups despite transplant rate are lower in T2D (75.6% vs 85.8%, p < 0.001). T2D was also associated to similar waiting time but longer periods between dialysis start and registration in WL (1.6 years vs 1.2, p = 0.008), comorbidity-related suspension from WL (571 days vs 257, p = 0.002), and increased mortality rate (33.7% vs 13.9% in the overall population, p < 0.001). In T2D patients admitted to WL, an history of vascular disease was significantly associated to low patient survival (p = 0.019). In conclusion, T2D significantly affects survival also on waitlisted patients. Allocation policies in T2D patients may be adjusted according to increased risk of mortality and WL suspension due to comorbidities.

Prevention of acute rejection after rescue with Belatacept by association of low-dose Tacrolimus maintenance in medically complex kidney transplant recipients with early or late graft dysfunction.

BACKGROUND: Increased acute rejection risk in rescue protocols with Belatacept may limit its use particularly in medically complex patients where preexisting increased risk of rejection couples with CNI toxicity. METHODS: Retrospective analysis was performed in 19 KTs shifted to a Belatacept-based immunosuppression with low-dose Tacrolimus (2-3 ng/mL) after evidence of allograft disfunction, including patients with primary non-function (PNF), chronic-active antibody-mediated rejection (cAMR), history of previous KTs and/or other concomitant transplants (liver, pancreas). Evaluation of CD28+ CD4+ effector memory T cell (TEM) before conversion was performed in 10/19. RESULTS: Kidney function significantly improved (median eGFR 16.5 ml/min/1.73m2 before vs 25 ml/min after; p = 0.001) at a median time after conversion of 12.5 months (9.1-17.8). Overall graft and patient survival were 89.5% and 100% respectively. Definitive weaning from dialysis in 5/5 KTs with PNF was observed, whereas 7/8 patients lost their graft within first year in a control group. eGFR significantly ameliorated in re-trasplants (p = 0.001) and stabilized in KTs with other organ transplants or cAMR. No acute rejection episodes occurred, despite the significant risk suggested by high frequency of CD28+ CD4+ TEM in most patients. Opportunistic infections were limited and most common in early vs late-converted. CONCLUSIONS: Rescue association of Belatacept with low-dose Tacrolimus in medically complex KTs is a feasible option that allows prevention of acute rejection and amelioration of graft function.

Treatment with plasmapheresis, immunoglobulins and rituximab for chronic-active antibody-mediated rejection in kidney transplantation: Clinical, immunological and pathological results.

AIM: To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in chronic-active antibody-mediated rejection (cAMR) settings. METHODS: We compared 21 kidney transplant recipients (KTRs) with a diagnosis of cAMR in a retrospective case-control analysis: nine KTRs treated with plasmapheresis, intravenous immunoglobulins and rituximab (PE-IVIG-RTX group) vs 12 patients (control group) not treated with antibody-targeted therapies. We examined kidney survival and functional outcomes 24 mo after diagnosis. Histological features and donor-specific antibody (DSA) characteristics (MFI and C1q-fixing ability) were also investigated. RESULTS: No difference in graft survival between the two groups was noted: three out of nine patients in the PE-IVIG-RTX group (33.3%) and 4/12 in the control group (33.3%) experienced loss of allograft function at a median time after diagnosis of 14 mo (min 12-max 18) and 15 mo (min 7-max 22), respectively. Kidney functional tests and proteinuria 24 mo after cAMR diagnosis were also similar in both groups. Only microvascular inflammation (glomerulitis + peritubular capillaritis score) was significantly reduced after PE-IVIG-RTX in seven out of eight patients (87.5%) in the PE-IVIG-RTX group (median score 3 in pre-treatment biopsy vs 1.5 in post-treatment biopsy; P = 0.047), without any impact on kidney survival and/or DSA characteristics. No functional or histological parameter at diagnosis was predictive of clinical outcome. CONCLUSION: Our data showed no difference in the two year post-treatment outcome of kidney grafts treated with PE-IVIG-RTX for cAMR diagnosis, however there were notable improvements in microvascular inflammation in post-therapy protocol biopsies. Further studies, especially involving innovative therapeutic approaches, are required to improve the management and long-term results of this severe condition.

Update on the treatment of focal segmental glomerulosclerosis in renal transplantation.

Focal segmental glomerulosclerosis (FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts (30%-50%). Recurrent FSGS portends a negative outcome, with the hazard ratio of graft failure being two-fold higher then that of other glomerulonephritis. Two patterns of clinical presentations are observed: Early recurrence, which is characterized by massive proteinuria within hours to days after implantation of the renal graft, and late recurrence, which occurs several months or years after the transplantation. Many clinical conditions have been recognized as risk factors for recurrence, including younger age, rapid progression of the disease to end-stage renal disease on native kidneys, and loss of previous renal allografts due to recurrence. However, much less is known about the incidence and risk factors of the so-called "de novo" type of FSGS, for which sufferers are transplanted patients without disease on native kidneys; but, rapid development of allograft failure is frequently observed. Management of both forms is challenging, and none of the approaches proposed to date have been demonstrated as consistently beneficial or effective. In the present review we report an update on the available therapeutic strategies for FSGS in renal transplantation within the context of a critical overview of the current literature.