Final Stage of Chronic Kidney Disease with Conservative Kidney Management or Renal Replacement Therapy: A Primary-Care Population Study.

BACKGROUND: Studies focus on the incidence and risk factors (RFs) associated with reaching the final stage of chronic kidney disease (CKD-G5) and receiving kidney replacement therapy (KRT). Analysis of those related to reaching CKD-G5 while receiving conservative kidney management (CKM) has been neglected. METHODS: Retrospective cohort study analysing electronic health records of individuals aged ≥ 50 with eGFR < 60 mL/min/m2. Cumulative incidence rates of CKD-G5, with and without KRT, were calculated. Multinomial regression models determined odds ratios (ORs) for CKD-G5 progression with KRT, CKM, or death. RESULTS: Among 332,164 patients, the cumulative incidence of CKD-G5 was 2.79 cases per 100 person-years. The rates were 1.92 for CKD-G5 with KRT and 0.87 for CKD-G5 with CKM. Low eGFR and albuminuria were the primary RFs. Male gender and uncontrolled blood pressure had a greater impact on KRT (OR = 2.63 CI, 1.63) than on CKD-G5 with CKM (OR = 1.45 CI, 1.31). Increasing age and rurality reduced the probability of KRT but increased the probability of CKD-G5 with CKM. Higher incomes decreased the likelihood of developing CKD-G5 with and without KRT (OR = 0.49 CI). CONCLUSION: One-third of CKD-G5 cases receive CKM. Those are typically older, female, rural residents with lower incomes and with lesser proteinuria or cardiovascular RF. The likelihood of receiving KRT is influenced by location and socioeconomic disparities.

Effect of kidney replacement therapy modality after first kidney graft failure on second kidney transplantation outcomes.

Background: There is a lack of information regarding which is the best dialysis technique after kidney transplant (KT) failure. The aim of this study is to compare the effect of kidney replacement therapy modality-peritoneal dialysis (TX-PD-TX), haemodialysis (TX-HD-TX) and preemptive deceased donor retransplantation (TX-TX) on patient survival and second KT outcomes. Methods: A retrospective observational study from the Catalan Renal Registry was carried out. We included adult patients with failing of their first KT from 2000 to 2018. Results: Among 2045 patients, 1829 started on HD (89.4%), 168 on PD (8.2%) and 48 (2.4%) received a preemptive KT. Non-inclusion on the KT waiting list and HD were associated with worse patient survival. For patients included on the waiting list, the probability of human leucocyte antigens (HLA) sensitization and to receive a second KT was similar in HD and PD. A total of 776 patients received a second KT (38%), 656 in TX-HD-TX, 72 in TX-PD-TX and 48 in TX-TX groups. Adjusted mortality after second KT was higher in TX-HD-TX patients compared with TX-TX and TX-PD-TX groups, without differences between TX-TX and TX-PD-TX groups. Death-censored second graft survival was similar in all three groups. Conclusions: Our results suggest that after first KT failure, PD is superior to HD in reducing mortality in candidates for a second KT without options for preemptive retransplantation.

Treatment for severe COVID-19 with a biomimetic sorbent haemoperfusion device in patients on haemodialysis.

Haemodialysis (HD) patients present more morbidity and mortality risk in coronavirus disease 2019 (COVID-19). In patients who may develop severe symptoms, the process called 'viral sepsis' seems to be a crucial mechanism. In those cases, the HD procedure provides an excellent tool to explore the benefit of some extracorporeal therapies. We reported the outcome of four HD patients with severe COVID-19 treated with Seraph®100 haemoperfusion (HP) device. Three of the four cases presented a good clinical response after HP. In conclusion, the treatment with Seraph®100 device may be a simultaneous treatment to improve HD patients with severe acute respiratory syndrome coronavirus 2.

Obesity in Renal Transplantation.

BACKGROUND: Data from the WHO show an increasing rate of overweight and obesity in general population in the last decades. This increase in obesity also affects population with end-stage renal disease (ESRD) and kidney transplant (KT) candidates. SUMMARY: In this review, we focused on how obesity impacts on KT stages: access to KT and outcomes of KT candidates; how to reduce weight and its consequences; short and long-term outcomes in obese recipients and the impact of weight variations; and the implications of obesity in living donor KT. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials until November 30, 2020. We selected systematic reviews and meta-analyses and randomized clinical trials. When no such reports were found for a topic, observational studies were included in the assessment. Key Messages: Although obesity is a risk factor to present worst outcomes after KT, several studies have demonstrated a survival benefit compared to patients who continue on dialysis. There is a need for a public health campaign to raise awareness in KT candidates and to highlight the importance of self-care, increasing exercise, healthy diet, and weight loss.

Impact of Olive Oil Supplement Intake on Dendritic Cell Maturation after Strenuous Physical Exercise: A Preliminary Study.

Physical exercise is known to have a dose-dependent effect on the immune system and can result in an inflammatory process in athletes that is proportional to the intensity and duration of exertion. This inflammatory process can be measured by cell markers such as dendritic cells (DCs), which, in humans, consist of the myeloid DC (mDCs) and plasmacytoid DC (pDCs) subpopulations. The aim of this study was to measure DC differentiation to determine the possible anti-inflammatory effects, after intense aerobic effort, of the intake of a 25 mL extra-virgin olive oil supplement. Three healthy sports-trained subjects went through resistance exercise loads on two days separated by a week: on one day after active supplement intake and on the other day after placebo supplement intake. The results show that the highest increase (77%) in the percentage of mDCs as a proportion of pDCs was immediately after testing. Independently of the supplement taken, mature mDCs showed a decreasing trend between the test one hour after and 24 h after testing ended. Nevertheless, measured in terms of the coefficient of variation, only the decrease (46%) for extra-virgin olive oil supplementation was statistically significant (95% CI: 30-62%; p = 0.05). In conclusion, an extra-virgin olive oil supplement could reduce the inflammatory impact of intense aerobic effort and improve recovery at 24 h.

Impact of obesity on the evolution of outcomes in peritoneal dialysis patients.

BACKGROUND: Some studies reveal that obesity is associated with a decrease in mortality in haemodialysis (HD) patients. However, few studies have addressed the association between body mass index (BMI) and peritoneal dialysis (PD) patients. METHODS: We performed this longitudinal, retrospective study to evaluate the impact of obesity on PD patients, using data from the Catalan Registry of Renal Patients from 2002 to 2015 (n = 1573). Obesity was defined as BMI ≥30; low weight: BMI <18.5; normal range: BMI = 18.5-24.99; and pre-obesity: BMI = 25-29.99 kg/m2. Variations in BMI were calculated during follow-up. The main outcomes evaluated were the technique and patient survival. RESULTS: Obesity was observed in 20% of patients starting PD. We did not find differences in sex or PD modality, with the obesity group being older (65.9% are ≥55 years versus 59% non-obese, P = 0.003) and presenting more diabetes mellitus and cardiovascular disease (CVD) (47.9% obese versus 25.1% non-obese and 41.7% versus 31.5%, respectively). We did not observe differences in haemoglobin, albumin and Kt/V in obese patients. Regarding peritonitis rate, we did not find any difference between groups, presenting more peritonitis patients on continuous ambulatory peritoneal dialysis and aged ≥65 years [sub-hazard ratio (SHR) = 1.75, P = 0.000 and SHR = 1.56, P = 0.009]. In relation to technique survival, we found higher transfer to HD in the obese group of patients in the univariate analysis, which was not confirmed in the multivariate analysis (SHR = 1.12, P = 0.4), and we did not find differences in mortality rate. In relation to being transplanted, the underweight group, elderly and patients with CVD or diabetic nephropathy presented less probability to undergo kidney transplantation (SHR = 0.65, 0.24, 0.5 and 0.54, P < 0.05). Obese patients did not present differences in survival with weight changes but in normal-weight patients, a gain of 7% of the basal weight during the first year had a protective effect on death risk (hazard ratio 0.6, P = 0.034). CONCLUSIONS: Obese and non-obese patients starting on PD had similar outcomes.

Mycophenolic acid interferes the transcriptional regulation and protein trafficking of maturation surface markers in dendritic cells.

BACKGROUND: The ability of dendritic cells (DCs) to regulate adaptive immunity makes them interesting cells to be used as therapeutic targets modulating alloimmune responses. Mycophenolic acid (MPA) is an immunosuppressor commonly used in transplantation, and its effect on DCs has not been fully investigated. METHODS: Monocyte-derived DCs were obtained from healthy volunteers and cultured for 7 days. Cells were treated with MPA on day 2 and matured by lipopolysaccharide (LPS) stimulation. Functionality of mature DC (mDCs) was evaluated by allogeneic mixed lymphocytes reaction. Surface expression of maturation markers (CD40, CD83, CD86, and ICAM-1) was analyzed in both immature DCs (iDCs) and mDCs by flow cytometry. To assess transcriptional regulation and protein subcellular location, RT-PCR and confocal microscopy were used, respectively. RESULTS: MPA decreased surface expression of all maturation markers in mDCs and significantly abrogated DCs-induced allogeneic T-cell proliferation after MPA pre-treatment. In iDCs, the reduced surface protein expression after MPA paralleled with mRNA downregulation of their genes. In mDCs, the mRNA levels of ICAM-1, CD40 and CD83 were enhanced in MPA-treated mDCs with an increase in the expression of CD83 and ICAM-1 near the Golgi compared to non-treated mDCs. In contrast, mRNA levels of CD86 were diminished after MPA treatment. CONCLUSIONS: The reduced surface markers expression in mDCs exerted by MPA produced a decline in their capacity to activate immune responses. Moreover, the inhibition of guanosine-derived nucleotide biosynthesis by MPA treatment leads to DC maturation interference by two mechanisms depending on the marker, transcriptional downregulation or disrupted intracellular protein trafficking.

Effects of body weight variation in obese kidney recipients: a retrospective cohort study.

BACKGROUND: Obese kidney allograft recipients have worse results in kidney transplantation (KT). However, there is lack of information regarding the effect of body mass index (BMI) variation after KT. The objective of the study was to evaluate the effects of body weight changes in obese kidney transplant recipients. METHODS: In this study we used data from the Catalan Renal Registry that included KT recipients from 1990 to 2011 (n = 5607). The annual change in post-transplantation BMI was calculated. The main outcome variables were delayed graft function (DGF), estimated glomerular filtration rate (eGFR) and patient and graft survival. RESULTS: Obesity was observed in 609 patients (10.9%) at the time of transplantation. The incidence of DGF was significantly higher in obese patients (40.4% versus 28.3%; P < 0.001). Baseline obesity was significantly associated with worse short- and long-term graft survival (P < 0.05) and worse graft function during the follow-up (P < 0.005). BMI variations in obese patients did not improve eGFR or graft or patient survival. CONCLUSIONS: Our conclusion is that in obese patients, decreasing body weight after KT does not improve either short-term graft outcomes or long-term renal function.

Clinical features and outcomes in a cohort of patients with immunoglobulin G4-related disease at a university hospital in Spain.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a fibro-inflammatory, immune-mediated disorder, which characteristically affects the glandular tissue but has the potential to affect any organ. METHODS: We retrospectively reviewed clinical, laboratory, histological characteristics and treatment response during 12 months of follow-up of a cohort of patients with IgG4-RD diagnosed at a tertiary public hospital. Disease activity was assessed by means of the IgG4-RD responder index (IgG4-RD RI). RESULTS: In all, 15 patients have been diagnosed at our Institution and herein studied (80% men), with a median age of 60.7 years and a mean affectation of 2.8 organs per patient. We identified six patients with definitive diagnosis and nine with possible IgG4-RD, according to the Japanese diagnostic algorithm. IgG4-RD RI decreased from a median of 11.3 at baseline to 4.0 after 6 months and 6.2 after 12 months. Relapse occurred in five patients and was associated with lower cumulative steroid doses. Five patients (33.3%) required additional immunosuppressive (IS) drugs. Five adverse events were seen during follow-up: three infections, one deep vein thrombosis and one gastrointestinal bleeding. One patient died of pneumonia. CONCLUSIONS: IgG4-RD is an inflammatory disease that can affect any organ. Glucocorticoids were an effective first line of treatment; however, this treatment is associated with important adverse events and relapses occurred in patients with low cumulative doses. As an alternative, IS treatment with rituximab could be an interesting option in those patients.

Frequency of Renal Dysfunction and Frailty in Patients ≥80 Years of Age With Acute Coronary Syndromes.

Although a significant association between renal function and outcomes in patients with acute coronary syndromes (ACS) has been consistently described, little information exists about the magnitude of this association in patients at older ages. No study assessed the prognostic role of renal function according to frailty in patients with ACS. The LONGEVO-SCA registry included unselected ACS patients aged ≥80 years. Frailty was asessesed by the FRAIL scale, and baseline creatinine clearance was calculated by the Cockroff-Gault formula. We evaluated the impact of renal function on mortality or readmission at 6-months according to frailty status by the Cox regression method. A total of 473 patients were assessed, with a mean age of 84.2 years. The distribution of patients across estimated glomerular filtration rate (eGFR) subgroups was as follows: (1) <30 ml/min: n = 76 (16.1%); (2) 30 to 44 ml/min: n = 147 (31.1%); (3) 45 to 60 ml/min: n = 136 (28.8%); and (4) >60 ml/min: n = 114 (24.1%). Patients with lower eGFR values were older, had a higher proportion of comorbidities and other geriatric syndromes (p = 0.001) and underwent less often an invasive management during admission (p < 0.001). The incidence of mortality or readmission at 6 months progressively increased across renal function subgroups (p = 0.001). After adjusting for potential confounders, this association became nonsignificant (p = 0.802). The association between eGFR and outcomes was only significant in patients without frailty (p = 0.001). In conclusion, most patients aged ≥80 years with NSTEACS had renal function impairment at admission. The association between renal function and outcomes was different according to frailty status.

ANRIL as a genetic marker for cardiovascular events in renal transplant patients - an observational follow-up cohort study.

Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients. Several single-nucleotide polymorphisms (SNPs) in the ANRIL gene pathway have been associated with cardiovascular events (CE). The main objective was to ascertain whether ANRIL (rs10757278) and CARD8 (rs2043211) SNPs could mediate susceptibility to CE. This was an observational follow-up cohort study of renal transplant recipients at Bellvitge University Hospital (Barcelona) from 2000 to 2014. A total of 505 recipients were followed up until achievement of a CE. Patients who did not achieve the endpoint were followed up until graft loss, lost to follow-up or death. Survival analysis was used to ascertain association between genetic markers, clinical data, and outcome. Fifty-three patients suffered a CE after renal transplantation. Results showed a significant association between ANRIL SNP and CE. Homozygous GG for the risk allele showed higher risk for CE than A carriers for the protective allele [HR = 2.93(1.69-5.11), P < 0.0001]. This effect was maintained when it was analyzed in combination with CARD8, suggesting that CARD8 SNP could play a role in the ANRIL mechanism. However, our study does not clarify the molecular mechanism for the CARD8 SNP regulation by ANRIL. ANRIL SNP may predispose to the development of CE after successful kidney transplantation.

Online Haemodiafiltration Improves Inflammatory State in Dialysis Patients: A Longitudinal Study.

BACKGROUND: Patients undergoing conventional hemodialysis (C-HD) present a greater immuno-inflammatory state probably related to uremia, sympathetic nervous system (SNS) activation and /or membrane bioincompatibility, which could improve with a technique-switching to online hemodiafiltration (OL-HD). The antigen-independent pathway activation of this modified immunologic state turns dendritic cells (DC) into an accurate cell model to study these patients. The aim of this study is to further evaluate the immune-inflammatory state of patients in C-HD assessed by DC maturation. METHODS: 31 patients were submitted to C-HD and after 4 months switched to the OL-HD technique. Monocytes-derived DCs from HD patients were cultured in the presence of IL-4/GM-CSF. DC-maturation was evaluated by assessing the maturation phenotype by flow cytometry (FACs). DCs-functional capacity to elicit T-cell alloresponse was studied by mixed leucocyte reaction. Cytokine release was assessed by FACs and SNS was evaluated measuring renalase levels by ELISA. RESULTS: An up-regulation of maturation markers was observed in C-HD DCs which induced two fold more T cells proliferation than OL-HD DCs. Also, C-HD-mDCs presented with over-production of pro-inflammatory cytokines (IL-6, IL-1ß, IL-8, IL-10 and TNF-α) compared with OL-HD-mDC (P<0·05). Results were correlated with clinical data. When SNS was evaluated, hypotension events and blood pressure were significantly lower and renalase levels were significantly higher after conversion to OL-HD. Diabetes mellitus type 2 patients also found beneficial reduction of mDC when converted to OL-HD compared to non-diabetics. CONCLUSIONS: OL-HD could interfere with immuno-inflammatory state in HD patients with an improvement of renalase levels as potential key mediators in the mechanistic pathway of down-regulation of DC maturation.

Developments in renal pharmacogenomics and applications in chronic kidney disease.

Chronic kidney disease (CKD) has shown an increasing prevalence in the last century. CKD encompasses a poor prognosis related to a remarkable number of comorbidities, and many patients suffer from this disease progression. Once the factors linked with CKD evolution are distinguished, it will be possible to provide and enhance a more intensive treatment to high-risk patients. In this review, we focus on the emerging markers that might be predictive or related to CKD progression physiopathology as well as those related to a different pattern of response to treatment, such as inhibitors of the renin-angiotensin system (including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers; the vitamin D receptor agonist; salt sensitivity hypertension; and progressive kidney-disease markers with identified genetic polymorphisms). Candidate-gene association studies and genome-wide association studies have analyzed the genetic basis for common renal diseases, including CKD and related factors such as diabetes and hypertension. This review will, in brief, consider genotype-based pharmacotherapy, risk prediction, drug target recognition, and personalized treatments, and will mainly focus on findings in CKD patients. An improved understanding will smooth the progress of switching from classical clinical medicine to gene-based medicine.

Malignancy after renal transplantation: the role of immunosuppression.

Outcomes of kidney transplantation, in terms of graft and patient survival, have improved over the past few decades, partly as a result of the introduction of new immunosuppressive drugs. Many immunosuppressive agents are associated with an increased risk of cardiovascular events and an increased risk of cancer, however, which can compromise patient survival. Cancer is more common among solid-organ transplant recipients than it is in the general population or in patients on dialysis. In fact, malignancy is the third most common cause of death in renal transplant recipients. Immunosuppressive treatments used in renal transplant recipients can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance thereby enabling faster tumor growth. In this Review, we describe the epidemiological and clinical characteristics of common tumor types occurring after kidney transplantation, and the etiopathogenetic factors that lead to their appearance, with a particular focus on the relationship between immunosuppressive treatment and malignancy. Immunosuppressive drugs associated with an increased risk of malignancy after transplantation are also discussed, as are immunosuppressive drugs that seem to have antioncogenic properties.

Different storing and processing conditions of human lymphocytes do not alter P-glycoprotein rhodamine 123 efflux.

P-glycoprotein (Pgp), a protein codified by Multi Drug Resistance (MDR1) gene, has a detoxifying function and might influence the toxicity and pharmacokinetics and pharmacodynamics of drugs. Sampling strategies to improve Pgp studies could be useful to optimize the sensitivity and the reproducibility of efflux assays. This study aimed to compare Pgp expression and efflux activity by measuring Rhodamine123 (Rh123) retention in lymphocytes stored under different conditions, in order to evaluate the potential utility of any of the storing conditions in Pgp functionality. Our results show no change in protein expression of Pgp by confocal studies and Western blotting, nor changes at the mRNA level (qRT-PCR). No differences in Rh123 efflux by Pgp activity assays were found between fresh and frozen lymphocytes after 24 hours of blood extraction, using either of the two Pgp specific inhibitors (VP and PSC833). Different working conditions in the 24 hours post blood extraction do not affect Rh123 efflux. These results allow standardization of Pgp activity measurement in different individuals with different timing of blood sampling and in different geographic areas.

Presence of FoxP3+ regulatory T Cells predicts outcome of subclinical rejection of renal allografts.

Subclinical rejection (SCR) of renal allografts refers to histologic patterns of acute rejection despite stable renal function. The clinical approach to SCR is controversial; it would be helpful to identify biomarkers that could determine whether the identified cellular infiltrates were detrimental. For investigation of whether the presence of FoxP3+ regulatory T cells (Treg) could help determine the functional importance of tubulointerstitial infiltrates observed in 6-mo protocol biopsies, 37 cases of SCR were evaluated. The presence of FoxP3+ Treg discriminated harmless from injurious infiltrates, evidenced by independently predicting better graft function 2 and 3 yr after transplantation. Furthermore, the FoxP3+ Treg/CD3+ T cell ratio positively correlated with graft function at 2 yr after transplantation, suggesting that an increasing proportion of Treg within the global T cell infiltrate may facilitate renal engraftment; therefore, immunostaining for FoxP3+ Treg in patients with SCR on protocol biopsies may ultimately be useful to identify patients who may require alterations in their immunosuppressive regimens.

Different renal toxicity profiles in the association of cyclosporine and tacrolimus with sirolimus in rats.

BACKGROUND: The association of calcineurin inhibitors (CNIs) with mTOR inhibitors (mTORi) is still a problem in clinical practice and there is substantial interest in better understanding the impact of these associations on kidney toxicity. We aimed to analyse the functional and histological profiles of damage and to define the contribution of inflammatory and pro-fibrotic mediators in the association of cyclosporine (CsA) and/or tacrolimus (Tac) with sirolimus (SRL). METHODS: A well-defined model of nephrotoxicity in salt-depleted male rats was used. Monotherapy groups were distributed as a non-treated control group with saline solution (n = 12), the Tac group (n = 16) (tacrolimus 6 mg/kg/day) and the CsA group (n = 13) (CsA 15 mg/kg/day). The groups with different associations were scattered as the Tac + SRL group (n = 14) (tacrolimus 6 mg/kg/day and rapamycin 3 mg/kg/day) and the CsA + SRL group (n = 7) (CsA 15 mg/kg/day and rapamycin 3 mg/kg/day). Groups were divided into 30 and 70 days of follow-up, but the CsA + SRL group was only studied for 30 days because animals became sick. RESULTS: Rats with the CsA + SRL association were the only ones which showed a significant reduction in body weight, impairment of renal function and severe and diffuse tubular vacuolization and tubular atrophy following a striped distribution, and scarce areas of the kidney were still preserved. The Tac + SRL association did not produce renal function impairment, and mild histological damage including enhanced periglomerular tubular atrophy was observed. This local damage affected the distal convoluted tubule involving macula densa and juxtaglomerular apparatus. Pro-inflammatory mediators paralleled functional and structural data. ED-1 and TNF-alpha were noticeably higher in the CsA + SRL than in the Tac + SRL association. Only in the CsA + SRL association an important increase in alpha-SMA+ cells was seen, mainly found in the areas with tubular atrophy. TGF-beta1 was also markedly enhanced in the CsA + SRL association whilst monotherapy or Tac + SRL groups at 30 days TGF-beta1 did not show any changes. However, at 70 days of treatment TGF-beta1 was significantly increased in the Tac + SRL group. Animals receiving SRL showed a decrease in renal vascular endothelial growth factor (VEGF) expression. This growth factor was significantly down-regulated in both CNI associations than in SRL monotherapy. P-glycoprotein (Pgp) was overexpressed in CsA and CsA + SRL therapy whilst Tac and TAC + SRL showed a middle increase Pgp expression but higher than the control and SRL group. CONCLUSION: We conclude that the association of SRL with high doses of CsA or Tac produces a different functional, histological, inflammatory and pro-fibrogenic pattern. Thus, the addition of SRL to high doses of CsA leads to severe renal injury. Combination with high doses of Tac is clearly less deleterious in the short term. However, there is a low grade of pro-fibrotic inflammatory expression when this association is prolonged.

Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates.

Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+ HLADR+ T cells, combined with a sustained enhancement of CD4+ CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+ CD25(+high) T cells, which showed donor-Ag specificity. FOXP3+ CD4+ CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.