HIV and kidney transplantation in Romania: The index case.

INTRODUCTION: Human immunodeficiency virus (HIV) is no longer considered a contraindication for kidney transplantation (KT). KT management in HIV patients is a complex process with challenges, such as drug interactions between immunosuppression and antiretroviral (ARV) therapy. In our country, no KT has been performed thus far in this category of patients. CASE PRESENTATION: We present the case of a 29-year-old female patient with HIV and end-stage renal disease (ESRD) who performed a KT from a related living donor in March 2022. KT immediate evolution was favorable. No transplant-related complications were reported. HIV viral load remained undetectable and CD4+ T cells were constantly > 500 cell/ µL, during the 18 months of follow-up. The main challenge in our case was the drug interaction between the protease inhibitor-based regimen and tacrolimus. This led to tacrolimus overdose, and, subsequently, change in ARV therapy. ARV switching was performed on a regimen based on integrase inhibitor and nucleoside reverse transcriptase inhibitors. After the ARV change, the therapeutic level of tacrolimus was easily reached and maintained. Kidney graft function remained normal during follow-up, despite tacrolimus overexposure, and no rejection or anti-HLA antibodies were observed. Another challenge was related to the donor's hepatitis C virus status (positive antibodies, negative nucleic acid test). The recipient did not develop seroconversion or detectable viremia at 3-, 6-, 12- and 18-months post-KT. CONCLUSION: We reported the first case of a successful KT in an ESRD patient with HIV in Romania, in whom the post-transplant evolution was favorable.

Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review.

Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality. We performed an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. We included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and we approached the diagnostic and treatment challenges according to the current guidelines. Prevalence of active TB in KT recipients ranges between 0.3-15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. Understanding the epidemiological risk, risk factors, transmission modalities, diagnosis and treatment challenges is critical for clinicians in providing an appropriate management for KT with TB. Among diagnostic challenges, which are at the same time associated with delay in management, the following should be considered: atypical clinical presentation, association with co-infections, decreased predictive values of screening tests, diverse radiological aspects and particular diagnostic methods. Regarding treatment challenges in KT recipients with TB, drug interactions, drug toxicities and therapeutical adherence must be considered.

Non-HLA Antibodies in Kidney Transplantation: Immunity and Genetic Insights.

The polymorphic human leukocyte antigen (HLA) system has been considered the main target for alloimmunity, but the non-HLA antibodies and autoimmunity have gained importance in kidney transplantation (KT). Apart from the endothelial injury, secondary self-antigen exposure and the presence of polymorphic alloantigens, respectively, auto- and allo- non-HLA antibodies shared common steps in their development, such as: antigen recognition via indirect pathway by recipient antigen presenting cells, autoreactive T cell activation, autoreactive B cell activation, T helper 17 cell differentiation, loss of self-tolerance and epitope spreading phenomena. Both alloimmunity and autoimmunity play a synergic role in the formation of non-HLA antibodies, and the emergence of transcriptomics and genome-wide evaluation techniques has led to important progress in understanding the mechanistic features. Among them, non-HLA mismatches between donors and recipients provide valuable information regarding the role of genetics in non-HLA antibody immunity and development.

Immunosuppression as a Risk Factor for De Novo Angiotensin II Type Receptor Antibodies Development after Kidney Transplantation.

(1) Background: Angiotensin II type I receptor antibodies (AT1R-Ab) represent a topic of interest in kidney transplantation (KT). Data regarding the risk factors associated with de novo AT1R-Ab development are lacking. Our goal was to identify the incidence of de novo AT1R-Ab at 1 year after KT and to evaluate the risk factors associated with their formation. (2) Methods: We conducted a prospective cohort study on 56 adult patients, transplanted between 2018 and 2019. Recipient, donor, transplant, treatment, and complications data were assessed. A threshold of >10 U/mL was used for AT1R-Ab detection. (3) Results: De novo AT1R-Ab were observed in 12 out of 56 KT recipients (21.4%). The median value AT1R-Ab in the study cohort was 8.5 U/mL (inter quartile range: 6.8-10.4) and 15.6 U/mL (10.8-19.8) in the positive group. By multivariate logistic regression analysis, induction immunosuppression with anti-thymocyte globulin (OR = 7.20, 95% CI: 1.30-39.65, p = 0.02), maintenance immunosuppression with immediate-release tacrolimus (OR = 6.20, 95% CI: 1.16-41.51, p = 0.03), and mean tacrolimus trough level (OR = 2.36, 95% CI: 1.14-4.85, p = 0.01) were independent risk factors for de novo AT1R-Ab at 1 year after KT. (4) Conclusions: De novo AT1R-Ab development at 1 year after KT is significantly influenced by the type of induction and maintenance immunosuppression.

The early impact of preformed angiotensin II type 1 receptor antibodies on graft function in a low immunological risk cohort of kidney transplant recipients.

Intruduction and aim: Angiotensin II type 1 receptor antibodies (AT1R-Ab) are associated with graft rejection and poor graft outcomes in kidney transplantation (KT). We aimed to assess the frequency of preformed AT1R-Ab and their impact on graft function and survival at 1 year after KT in a low immunological risk cohort. METHODS: We performed a prospective, observational cohort study in 67 adult KT recipients, transplanted between 2018 and 2019. A cut-off value >10 U/ml was used for AT1R-Ab detection. RESULTS: The frequency of preformed AT1R-Ab was 10.4% and the median value of their level was 8.4 U/ml (IQR: 6.8-10.4). Donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) were absent, no case of biopsy-proven rejection was reported and the incidence of graft failure was 7.5%. Estimated glomerular filtration rate (eGFR) was significantly reduced in the AT1R-Ab group [35 (29.8-55.2) vs 56.1 (41.3-66.5) ml/min, p = 0.02] at 1 year after KT. After multivariate linear regression analysis, preformed AT1R-Ab were found as an independent determinant of eGFR at 1 year after KT (ß: -15.395; 95% CI: -30.49 - -0.30; p = 0.04). By Cox multivariate regression analysis, preformed AT1R-Ab were not associated with graft failure (HR: 1.36; 95% CI:0.10-14.09; p = 0.80). CONCLUSION: Preformed AT1R-Ab are an independent determinant of graft function but do not impact graft survival at 12 months after transplantation in a prospective low immunological risk cohort of KT recipients.

Angiotensin II type 1 receptor antibodies in kidney transplantation: An evidence-based comprehensive review.

Angiotensin II type 1 receptor antibodies (AT1R-Ab) are among the most investigated types of non-HLA antibodies in kidney transplantation. Our aim is to provide an update regarding the clinical relevance of AT1R-Ab by outlining their prevalence, testing methodology, mechanism of graft injury and the association with graft rejection phenotypes, the relationship with HLA-donor specific antibodies (DSA) and some therapeutic aspects. To accomplish these, we performed a literature review between 2005 and 2019, identifying 27 relevant studies for inclusion. The reported prevalence of these antibodies is widely variable in part related to testing variability and lack of a standardized threshold for positivity. Data available suggest that both pre-formed and de novo antibodies are associated with negative graft outcomes. The pathogenesis of AT1R-Ab mediated graft injury seems to be complement-independent. Different phenotypes of antibody-mediated, T-cell-mediated and vascular rejection have been described in patients with AT1R-Ab. The relationship between HLA-DSA and AT1R-Ab is mutual in terms of their development, including a complex process between alloimmunity, autoimmunity, inflammation, endothelial damage and antigen expression. Antibody double positivity had a synergistic negative effect associated with detrimental effects on graft outcomes. Understanding the complexity of AT1R-Ab mediated graft injury and the relationship with HLA-DSA in kidney transplantation could provide a complementary, integrated assessment of immunological risk, help stratify the risk of graft rejection and dysfunction and may guide the treatment approach.

Renal Transplantation in Romania: Where Do We Stand?

INTRODUCTION: According to the Romanian Renal Registry (RRR), only 8% of patients on renal replacement therapy (RRT) in 2012 received a kidney transplant (KTx). As not all transplant centers report to RRR, the outcome of transplanted patients in Romania is not known. Therefore, we aimed to evaluate the outcome in patients grafted in one of the largest transplant center in the country as compared to hemodialysis (HD) and peritoneal dialysis (PD) patients recorded by the RRR. METHOD: In an intention-to-treat analysis using Kaplan-Meier and Cox proportional hazard (CPH) models, survival was compared between 8050 incident HD, 1000 PD and 490 KTx patients treated between 2008 and 2011. The patients were stratified by modality at day 90 of therapy. RESULTS: As compared to HD and PD patients, the KTx recipients were younger, more often of male gender, and had glomerulonephritis as primary renal disease (PRD) more frequently. KTx patients had a higher mean survival time (57.68 [56.95-58.42] months) than HD (45.55 [45.04- 46.06] months) or PD patients (46.33 [45.01-47.65] months). In the multivariate CPH model, higher age (OR=1.03 (1.02-1.03), p<0.01) at RRT initiation, HD (OR=5.60 (3.16-9.94), p<0.01) and PD (OR=5.62 (3.14-10.08), p<0.01) as RRT and diabetic nephropathy (p<0.01) as PRD were associated with a poorer survival. CONCLUSION: The present study is the first to provide representative information about the outcome of the KTx patients in Romania. We found that patient survival after KTx is markedly better than either HD or PD. Urgent implementation of a KTx registry is needed in order to improve the national transplantation program.

Does the KDIGO CKD risk stratification based on GFR and proteinuria predict kidney graft failure?

PURPOSE: The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on chronic kidney disease (CKD) introduced risk classes for adverse outcome based on estimated glomerular filtration rate (eGFR) and albuminuria categories (low-LR, moderately-MR, high-HR, very high risk-VHR). We aimed to investigate if such risk stratification is suitable in kidney transplant (KTx) recipients. METHODS: This single-center prospective study enrolled 231 prevalent KTx recipients [36 (34-48) years, 62 % male, eGFR 53.7 (50.9-56.4) mL/min]. The patients were stratified in risk classes in January 2011; clinical and laboratory data were collected every 6 months till June 2013. Individual slope of linear regression of all eGFR and time-averaged proteinuria (TAP) were computed. The composite endpoint was defined as >30 % decline in eGFR from 6 months after KTx to June 2013, dialysis initiation or death. RESULTS: Fifty-one patients reached the endpoint. They were younger, more often female, donor specific anti-HLA antibodies positive, noncompliant and smokers. TAP was 4 time greater (p < 0.0001) and eGFR abruptly declined [eGFR slope: -3.17 (-4.13 to -2.21) vs. 0.81 (0.45-1.3) mL/min per year, p < 0.0001] in the endpoint group. At baseline: 36 % LR, 23 % MR, 23 % HR and 18 % VHR, without differences between the groups. In the binary logistic regression model, VHR as compared to the other risk classes was an independent risk factor for poorer outcome. The final model also included female gender, cardiovascular events, smoking, GFR slope and BK virus infection. CONCLUSIONS: Risk group stratification according to KDIGO guideline on CKD may prove useful in predicting graft outcome, but this should be confirmed in larger cohorts.

Polyomavirus BK-associated nephropathy after kidney transplantation: a single-center retrospective analysis.

BACKGROUND: Polyomavirus BK-associated nephropathy is a challenging and increasingly recognized cause of kidney transplant morbidity and graft failure. Reported prevalence can vary significantly between centers, averaging 5%. PATIENTS AND METHODS: The paper reports the clinical and pathologic findings in five patients with BK virus-induced nephropathy. We performed a retrospective study including adult patients with graft dysfunction admitted to our department between 2010-2013. Clinical and biological data were obtained every month during the follow-up period. The biopsies were performed in case of graft dysfunction. All biopsy specimens were examined in light microscopy, immunofluorescence and electronic microscopy. RESULTS: We studied 44 graft biopsies, and we found typical histological findings of polyoma BK nephropathy in five (11.4%) cases. All patients received immunosuppressive regimen based on calcineurin inhibitors, Mycophenolate Mofetil and Prednisone. Four of them were on Tacrolimus-based protocol and one patient was on Cyclosporine regimen. Age of transplant at diagnosis varied between 2 and 113 months (patient on Cyclosporine). In all cases, the BK virus nephropathy diagnostic was established taking into account histological findings, all patients presenting intranuclear viral inclusions seen on light microscopy and electronic microscopy. During the follow-up period, the renal dysfunction worsened in two of the five patients, one of them evolving towards ESRD, even though we minimized the immunosuppressive treatment and administered intravenous immunoglobulin. CONCLUSIONS: The prognostic for BK virus nephropathy patients is reserved. Histological picture of BK virus nephropathy is similar to the one of graft rejection, differential diagnosis being difficult in the absence of viral inclusions evidence.

Renal transplantation--substitution therapy in advanced stage uremia.

Advanced stage chronic renal failure (CRF) uremia represents one of the most severe metabolic "catastrophes" of the organism. The current therapeutic possibilities consist in: hemodialysis, peritoneal dialysis and renal transplantation. This paper presents the experience of the Urological Surgery, Dialysis and Renal Transplantation Center of the "Fundcni" Clinical Institute in renal transplantation, the single complete morphological and functional therapeutic option in CRF. During the last 10 years, renal transplantations with kidneys from brain dead donors (multiorgan harvesting) to an adult (1997), a child (1999), a diabetic recipient (1998) and an unephric child due to bilateral Wilms' tumor (2005) were performed at "Fundeni" Renal Transplantation Center as a national première. The immunosuppression protocols are complex, modern and adapted to the immunological risk. A number of 870 renal transplantations with 82% functionality rate of the grati at 10 years were performed and reported. Among these, 152 transplants were performed using kidneys harvested from brain dead donors. Owing to obtained results (60% of all transplanted and functional orgmans in Romania on December 2007) and to its achieved performances, the Fundeni Center represents a reference point on the European map of renal transplant.