Pedro Ruiz-Esteban

Decrease in the percentage of peripheral blood CXCR3highCD4+ lymphocytes after renal transplantation.

INTRODUCTION Previous studies suggest that infiltration into the graft of active T cells following kidney transplantation depends on the expression of chemokines and their interaction with their T-cell receptors. However, little is known about the natural history of the expression of these molecules during the early post-transplantation phase. AIM To evaluate the percentage of CXCR3highCD4+ and CCR4highCD4+ cells, as markers of the Th1 and Th2 populations, in peripheral blood from uremic patients before transplantation and six months after maintaining an acceptable kidney graft function. MATERIAL AND METHODS Flow cytometry was used to measure CXCR3highCD4+ and CCR4highCD4+ cells from 44 consecutive patients who received a kidney transplant at our center. Measurements were made at the time of transplantation and six months later. RESULTS There was a significant reduction after transplantation in the CXCR3highCD4+/CCR4highCD4+ balance (10.68±20.28 vs. 2.01±3.15, p=0.001). Separate analysis of each subset showed a significant reduction after transplantation in CXCR3highCD4+ (2.37±2.75 vs. 1.49±2.66, p=0.010) but no difference in CCR4highCD4+ (0.83±1.01 vs. 1.01±1.12, p=0.812). CONCLUSION Prior to kidney transplantation uremic patients have an immunologic activation with Th1 polarization (studied by analyzing the CXCR3highCD4+ and CCR4highCD4+ populations) that falls after transplantation. This can be monitored with the CXCR3highCD4+ lymphocyte subset. This may help understand the pathologic mechanisms intervening in immunologic dysfunction of kidney grafts.

Immune response and histology of humoral rejection in kidney transplantation

The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ.

Impact of immunosuppression treatment on the improvement in graft survival after deceased donor renal transplantation: a long-term cohort study

We analyzed graft half-life and attrition rates in 1045 adult deceased donor kidney transplants from 1986-2001, with follow-up to 2011, grouped in two periods (1986-95 vs. 1996-01) according to immunosuppression. The Kaplan-Meier curve showed a significant increase in graft survival during 1996-2001. The uncensored real graft half-life was 10.25 years in 1986-95 and the actuarial was 14.58 years in 1996-2001 (P<0.001). The attrition rates showed a significantly greater graft loss in 1986-95, even excluding the first year from the analysis. The decline in renal function was significantly less pronounced in 1996-2001, indicating better preservation of renal function, despite the increase in donor age and stroke as the cause of donor death. The parsimonious Cox multivariate model showed donor age, acute rejection, panel reactive antibody, cold ischemia time and delayed graft function were significantly associated with a higher risk of graft loss. In contrast, the risk of graft loss fell by 21% in 1996-2001 compared with 1986-95. A similar reduction (25%) was observed when MMF treatment was entered into the multivariate model instead of study period. Long-term graft survival improved significantly in 1996-2001 compared to 1986-1995 despite older donor age. Modern immunosuppression could have contributed to the improved kidney transplant outcome.

Survival in Southern European patients waitlisted for kidney transplant after graft failure: A competing risk analysis

Background Whether patients waitlisted for a second transplant after failure of a previous kidney graft have higher mortality than transplant-näive waitlisted patients is uncertain. Methods We assessed the relationship between a failed transplant and mortality in 3851 adult KT candidates, listed between 1984–2012, using a competing risk analysis in the total population and in a propensity score-matched cohort. Mortality was also modeled by inverse probability weighting (IPTW) competing risk regression. Results At waitlist entry 225 (5.8%) patients had experienced transplant failure. All-cause mortality was higher in the post-graft failure group (16% vs. 11%; P = 0.033). Most deaths occurred within three years after listing. Cardiovascular disease was the leading cause of death (25.3%), followed by infections (19.3%). Multivariate competing risk regression showed that prior transplant failure was associated with a 1.5-fold increased risk of mortality (95% confidence interval [CI], 1.01–2.2). After propensity score matching (1:5), the competing risk regression model revealed a subhazard ratio (SHR) of 1.6 (95% CI, 1.01–2.5). A similar mortality risk was observed after the IPTW analysis (SHR, 1.7; 95% CI, 1.1–2.6). Conclusions Previous transplant failure is associated with increased mortality among KT candidates after relisting. This information is important in daily clinical practice when assessing relisted patients for a retransplant.

Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk?

The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed.

Increase in CD8+CD158a+ T Cells in Kidney Graft Blood is Associated with Better Renal Function

BACKGROUND Studies of liver and heart transplant patients have shown a gradual reconstruction of the CD8 KIR2D+ T cell subpopulations, measured in peripheral blood (PB), associated with better graft acceptance. The kinetics of these populations in kidney transplants, however, is still poorly understood, especially given the lack of studies of blood samples from the kidney graft. MATERIAL AND METHODS Flow cytometry was used to measure CD8+CD158a/b/e T cells in 69 kidney transplant patients who had stable renal function during follow-up. Measurements were made at 3, 6, and 12 months post-transplantation in graft capillary blood extracted by fine needle aspiration puncture (FNAP) and in PB. RESULTS No progressive increase was found in the PB subpopulations. However, the CD8+CD158a+ subsets increased significantly at 12 months in the graft blood versus the PB samples (3.91±4.59 vs. 2.84±4.71; p=0.021). The ratio of the percentage of CD8+CD158a+ cells in graft blood compared to PB at 12 months was associated with better renal function in those patients with a ratio ≥3 (66.6±14.53 vs. 55.7±21.6; p=0.032). CONCLUSIONS An increased ratio of CD8+CD158a+ cells, measured by flow cytometry, between graft blood and PB was associated with improved renal function.

Kidney Donor Profile Index: The Impact on Graft Survival in Deceased Donor Kidney Transplant Recipients

Introduction The Kidney Donor Profile Index (KDPI) (a scoring system based on 10 donor factors) is usually used in USA as a screening tool for donor quality and has been shown to be predictive of both short and long term graft survival. However, whether this clinical tool has accuracy predictive value in other population is undetermined. Objective To evaluate the association between KDPI and graft survival in Southern European deceased donor kidney transplant recipients (DKT). Methods A longitudinal, retrospective cohort study, where were included 733 DKT performed in our center (Regional University Hospital, Málaga, Spain) during 1999-2012. KDPI was calculated in all deceased donors. Results Recipient´s mean age was 49,9±13,8 ys. and 61,1% were male. Mean dialysis time was 38±35 months. 85% was the first transplant. Donor´s mean age was 49,4±17,3 years, and hypertension and diabetes was present in 31,7% and 12%, respectively. Stroke was the cause of donor death in 61%. There was no deceased after cardiac-death. Cold ischemia time (CIT) was 15,3±4,5 h. and 41% of patients had delayed graft function. The most commonly used immunosuppressive treatment was steroids, MMF and Tacrolimus (88%). Induction therapy (46,4% antiCD25, 14,4% thymoglobuline) was administered in 61% of patients. A total of 150 patients (17.1%) lost the graft during follow-up (96±58 months) and the leading cause of loss was death with functioning graft. Median KDPI was 63 (IQR 34-86). Patients were divided into 2 categories: KDPI ⩽80 (502 patients) and KDPI>80 (231 patients). Donors with KDPI>80 were older (65±7 vs 41±14 years; p<0.001), and had more hypertension (63% vs 16%; p<0.001) and diabetes (26,3% vs 5,4%; p<0.001). The patients who received a kidney with KDPI >80 also were older (60±8 vs 45±13 years; p<0.001) and had a higher proportion of diabetics (14,4% vs 6,9%; p=0.001). There were no differences in CIT (15,6±4,2 vs 15,2±4,6; p=0.3). Overall graft survival at first, 5th and 10th years was significantly lower in patients with KDPI>80 vs ⩽80, ( 88%, 74%, 52% vs 91%, 83%, 70%, respectively; p<0.001), as well as patient death-censored graft survival (91%, 83%, 71% vs 93%, 87%,80%; respectively, p=0.03; Figure). This difference was not significant in the recipients over 60 years. In multivariate cox regression analysis, a KDPI value (⩽ o > 80) was significantly associated with graft failure (HR 1.9; 95% IC 1.1-3.3; p=0.009). Conclusions A KDPI value >80 represents an important risk factor for graft loss in our kidney transplant population, with an increased of risk of 1.7 times. These differences are not significant in patients older than 60 years, so these grafts could be viable for this specific population.

C3 glomerulonephritis associated with monoclonal gammopathy of renal significance: case report

BackgroundMorbidity associated with monoclonal gammopathy of renal significance is high due to the severe renal lesions and the associated systemic alterations. Accordingly, early diagnosis is fundamental, as is stopping the clonal production of immunoglobulins using specific chemotherapy.Case presentationA 75-year-old man with chronic renal disease of unknown origin since 2010 experienced rapid worsening of renal function over a period of 6 mos. Bone marrow biopsy showed monoclonal gammopathy of undetermined significance. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence and a membranoproliferative pattern on light microscopy. Skin biopsy showed endothelial deposition of complement. Given both the renal and cutaneous involvement the patient was considered to have monoclonal gammopathy of renal significance. We considered an underlying pathogenic mechanism for the renal alteration secondary to activation of the alternative complement pathway by the anomalous immunoglobulin. Despite treatment with plasmapheresis, bortezomib and steroids, advanced chronic kidney disease developed.ConclusionsThe possible underlying cause of the monoclonal gammopathy of renal significance suggests that monoclonal gammopathy should be considered in adult patients with membranoproliferative glomerulonephritis.

Peripheral Vascular Disease and Death in Southern European Kidney Transplant Candidates: A Competing Risk Modeling Approach

Background The association between peripheral vascular disease (PVD) and survival among kidney transplant (KT) candidates is uncertain. Methods We assessed 3851 adult KT candidates from the Andalusian Registry between 1984 and 2012. Whereas 1975 patients received a KT and were censored, 1876 were on the waiting list at any time. Overall median waitlist time was 21.2 months (interquartile range, 11-37.4). We assessed the association between PVD and mortality in waitlisted patients using a multivariate Cox regression model, with a competing risk approach as a sensitivity analysis. Results Peripheral vascular disease existed in 308 KT candidates at waitlist entry. The prevalence of PVD among nondiabetic and diabetic patients was 4.5% and 25.3% (P < 0.0001). All-cause mortality was higher in candidates with PVD (45% vs 21%; P < 0.0001). Among patients on the waiting list (n = 1876) who died (n = 446; 24%), 272 (61%) died within 2 years after listing. Cumulative incidence of all-cause mortality at 2 years in patients with and without PVD was 23% and 6.4%, respectively (P < 0.0001); similar differences were observed in patients with and without diabetes. By competing risk models, PVD was associated with a 1.9-fold increased risk of mortality (95% confidence interval [95% CI], 1.4-2.5). This association was stronger in waitlisted patients without cardiac disease (subhazard ratio, 2.2; 95% CI, 1.6-3.1) versus those with cardiac disorders (subhazard ratio, 1.5; 95% CI, 0.9-2.5). No other significant interactions were observed. Similar results were seen after excluding diabetics. Conclusions Peripheral vascular disease is a strong predictor of mortality in KT candidates. Identification of PVD at list entry may contribute to optimize targeted therapeutic interventions and help prioritize high-risk KT candidates.

Vascular Damage and Kidney Transplant Outcomes: An Unfriendly and Harmful Link

Abstract Kidney transplant (KT) is the treatment of choice for most patients with chronic kidney disease, but this has a high cardiovascular mortality due to traditional and nontraditional risk factors, including vascular calcification. Inflammation could precede the appearance of artery wall lesions, leading to arteriosclerosis and clinical and subclinical atherosclerosis in these patients. Additionally, mineral metabolism disorders and activation of the renin‐angiotensin system could contribute to this vascular damage. Thus, understanding the vascular lesions that occur in KT recipients and the pathogenic mechanisms involved in their development could be crucial to optimize the therapeutic management and outcomes in survival of this population. This review focuses on the following issues: (1) epidemiological data framing the problem; (2) atheromatosis in KT patients: subclinical and clinical atheromatosis, involving ischemic heart disease, congestive heart failure, stroke and peripheral vascular disease; (3) arteriosclerosis and vascular calcifications; and (4) potential pathogenic mechanisms and their therapeutic targets.