Eduardo José Tonato

Vimentin Expression and Myofibroblast Infiltration Are Early Markers of Renal Dysfunction in Kidney Transplantation: An Early Stage of Chronic Allograft Dysfunction?

INTRODUCTION The objective of this study was to show the morphologic characteristics of allograft renal biopsies in renal transplant patients with stable renal function, which can potentially be early markers of allograft dysfunction, after 5 years of follow-up. METHODS Forty-nine renal transplant patients with stable renal function were submitted to renal biopsies and simultaneous measurement of serum creatinine (Cr). Histology was evaluated using Banff scores, determination of interstitial fibrosis by Sirius red staining and immunohistochemical study of proximal tubule and interstitial compartment (using cytokeratin, vimentin, and myofibroblasts as markers). Biopsies were evaluated according to the presence or absence of the epitheliomesenchymal transition (EMT). The interstitial presence of myofibroblasts and tubular presence of vimentin was also analyzed simultaneously. Renal function was measured over the follow-up period to estimate the reduction of graft function. RESULTS Median posttransplant time at enrollment was 105 days. Patients were followed for 64.3 ± 8.5 months. The mean Cr at biopsy time was 1.44 ± 0.33 mg/dL, and after the follow-up it was 1.29 ± 0.27 mg/dL. Nine patients (19%) had a reduction of their graft function. Eleven biopsies (22%) had tubulointerstitial alterations according to Banff score. Seventeen biopsies (34%) presented EMT. Fifteen biopsies (32%) had high interstitial expression of myofibroblasts and tubular vimentin. Using Cox multivariate analysis, HLA and high expression of interstitial myofibroblasts and tubular vimentin were associated with reduction of graft function, yielding a risk of 3.3 (P = .033) and 9.8 (P = .015), respectively. CONCLUSION Fibrogenesis mechanisms occur very early after transplantation and are risk factors for long-term renal function deterioration.

Effects of ischemia and reperfusion injury on long-term graft function.

BACKGROUND The clinical manifestation of ischemia/reperfusion injury in renal transplantation is delayed graft function (DGF), which is associated with an increase in acute rejection episodes (ARE), costs, and difficulties in immunosuppressive management. We sought to evaluated the DGF impact after renal transplant. METHODS We evaluated a group of 628 patients undergoing deceased donor renal transplantation between 2002 and 2005 at 3 Brazilians institutions to define the main DGF characteristics. RESULTS DGF incidence was 56.8%, being associated with elderly donors (P = .02), longer time on dialysis (P = .001), and greater cold ischemia time (CIT; P = .001). Upon multivariate analysis, time on dialysis >5 years increased DGF risk by 42% (P = .02) and CIT >24 hours increased it by 57% (P = .008). In contrast, DGF was associated with an higher incidence of ARE: 27.7% in DGF versus 18.4% in IGF patients (P = .047). The ARE risk was 46% higher among individuals with DGF (P = .02), 44% among patients >45 years old (P < .001), 50% among those with >5 years of dialysis time (P = .02), and 47% lower among the who were prescribed mycophenolate instead of azathioprine (P < .001). Patients with DGF showed worse 1-year graft function (54.6 ± 20.3 vs 59.6 ± 19.4 mL/min; P = .004), particularly those with ARE (55.5 ± 19.3 vs 60.7 ± 20.4; P = .009). One-year graft survival was 88.5% among DGF versus 94.0% among non-DGF patients. CONCLUSION The high incidence of DGF was mainly associated with a prolonged CIT. There was a relationship between DGF and ARE, as well as with a negative influence on long-term graft function.

Comparison of Long-Term Effect of Thymoglobulin Treatment in Patients With a High Risk of Delayed Graft Function

BACKGROUND T-lymphocyte depletion is a strategy to reverse the impact of ischemia-reperfusion injury (IRI) in progression to chronic allograft dysfunction, especially among patients at high risk for delayed graft function (DGF). METHODS The present work assessed the effect of thymoglobulin among a population with a high incidence of DGF. We analyzed 209 transplanted patients: 97 in the thymoglobulin and 112 in the control group. RESULTS The main complication was DGF (59.3%), with a similar incidence in both groups (63.9% vs. 55.3%; P = .36). Acute rejection episodes (ARE) were decreased with thymoglobulin (8.2% vs. 28.5%; P < .001), but cytomegalovirus viremia was 3.4-fold more frequent (58.3% vs. 17.1%; P < .001). One-year graft function was significantly better in the thymoglobulin group (59.2 ± 17.2 vs. 51.8 ± 15.3 mL/min; P = .004), even when censored by ARE (59.7 ± 17.5 vs. 53.3 ± 14.4; P = .023). The same difference was observed at the 2-year follow-up (P = .024), even when censored for ARE (P = .045). A multivariate analysis showed thymoglobulin to be a factor strongly associated with protection of graft function (P = .039). CONCLUSION Despite not reducing the incidence of DGF, thymoglobulin induction significantly reduced the incidence of ARE and showed a long-term profile of protection of renal graft function, independent of the reduction in ARE.

Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year

The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (≥3 months after transplantation and ≥16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36–58) years, median of 12.5 (IQR, 3–35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77–44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61–12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04–42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge.

Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction

ABSTRACT Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

The role of post‐reperfusion biopsy findings as a predictor of early and long‐term graft function and survival is still a target of research.

Deficient of Megalin in Stable Renal Transplanted Patients with Proximal Tubular Dysfunction

Introduction: Renal-transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for IF/TA. The morphological features associated with this dysfunction are unknown. Material and methods: 54 renal transplant patients with normal and stable renal function were submitted to a biopsy and had urinary retinol binding protein (uRBP) and renal function assessment. Patients were divided according to uRBP levels: 1, these findings had no association with uRBP levels. Megalin expression was observed at BB of PTC, 13.7% of bxs presented its expression in less than 50% of tubules, 56.8% had in more than 50% of tubules but with discontinuity over the BB and in 29.5% megalin expressed in more than 50% of tubules continuouslly over the BB. Patients who presented uRBP > 0.6 mg/L had lower amount of megalin expression in their biopsies, p=0.007. Cellular RBP expression was observed diffusely over the cytoplasma of PTC, with different intensities. No correlation was found between tubular megalin expression and uRBP values with CRBP expression. Conclusions: Half of renal transplant patients with normal renal function had PTD. The deficiency of megalin expression could be the subjacent functional alteration found in patients with PTD.

Indução imunológica com timoglobulina: redução no número de doses em transplante de rim com doador falecido

RESUMO Objetivo: Comparar tres regimes diferentes de inducao com timoglobulina. Metodos: Cento e setenta e dois pacientes submetidos a transplante de rim com doador falecido foram divididos em tres grupos, de acordo com o numero total de doses de timoglobulina utilizada no pos-operatorio: Grupo 1, ate 14 doses – Maio de 2002 a Junho de 2004 (n = 48); Grupo 2, ate 7 doses – Julho de 2004 a Dezembro de 2006 (n = 57); Grupo 3, ate 4 doses [...]

Immunological induction with thymoglobulin: reduction in the number of doses in renal transplant from deceased donor

OBJECTIVE To compare three different regimens of thymoglobulin induction. METHODS One hundred seventy two patients submitted to renal transplantation from a dead donor were divided into three groups according to the total number of thymoglobulin doses used in the post-transplantation surgery: Group 1, until 14 doses - May 2002 to June 2004 (n = 48); Group 2, until 7 doses - July 2004 to December 2006 (n = 57); Group 3, until 4 doses - January 2007 to July 2009 (n = 67). The three groups were compared according to the main outcomes. RESULTS The main demographic differences among the groups were: greater dialysis time in Group 3 (p < 0.001 for Group 1; and p = 0.04 for Group 2); donor age, greater in Groups 2 and 3 (p = 0.02; p = 0.01, respectively); and cold ischemia time progressively greater from Group 1 to 3: 19.5 ± 5.1 to 24.6 ± 5.7 hours (p < 0.001). In relation to the inhibitor of calcineurin, the relation Tac/Csa was 14.6/66.7% in Group 1, 78.9/12.3% in Group 2 and 100/0% in Group 3. Reflecting the increase in cold ischemia time, the incidence of delayed graft function was 64.6%, 68.4% e 82.1% in Groups 1, 2 and 3, respectively (p = ns). The incidence of acute rejection was similar in the three groups: 16.7% (1); 16.3% (2) and 16.4 (3) - p = ns. The prevalence of viremia for cytomegalovirus was 61.7% in Group 1, 66.1% in Group 2 and 83.3% in Group 3 (p = ns). There were no difference related to the number of infected cells with cytomegalovirus in antigenemia, according to the groups, however, patients in Group 3 had an earlier diagnosis: from 64.3 ± 28.5 days in Grup 2, to 47.1 ± 22.5 days, in Group 3, p < 0.001. Survival of the graft in one year was 89.6%, 92.9% and 91.0%, in Groups 1, 2 and 3, respectively (p = ns). The graft function was much better with the lower doses of thymoglobulin: Group 1: 57.0 ± 20.0 mL/min; Group 2: 67.0 ± 18.4 mL/min (p = 0.008); Group 3: 71.2 ± 18.4 mL/min (p < 0.001, Group 1 versus Group 3; p = 0.06, Group 1 versus Group 2). There was a significant reduction in the costs of induction protocol from U

Effect of Thymoglobulin in Graft Survival and Function 1 Year After Kidney Transplantation Using Deceased Donors

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