Ignacio Revuelta

TGF-β1–Containing Exosomes from Injured Epithelial Cells Activate Fibroblasts to Initiate Tissue Regenerative Responses and Fibrosis

Hypoxia is associated with tissue injury and fibrosis but its functional role in fibroblast activation and tissue repair/regeneration is unknown. Using kidney injury as a model system, we demonstrate that injured epithelial cells produce an increased number of exosomes with defined genetic information to activate fibroblasts. Exosomes released by injured epithelial cells promote proliferation, α-smooth muscle actin expression, F-actin expression, and type I collagen production in fibroblasts. Fibroblast activation is dependent on exosomes delivering TGF-β1 mRNA among other yet to be identified moieties. This study suggests that TGF-β1 mRNA transported by exosomes constitutes a rapid response to initiate tissue repair/regenerative responses and activation of fibroblasts when resident parenchyma is injured. The results also inform potential utility of exosome-targeted therapies to control tissue fibrosis.

A Randomized Study Comparing Parathyroidectomy with Cinacalcet for Treating Hypercalcemia in Kidney Allograft Recipients with Hyperparathyroidism

Tertiary hyperparathyroidism is a common cause of hypercalcemia after kidney transplant. We designed this 12-month, prospective, multicenter, open-label, randomized study to evaluate whether subtotal parathyroidectomy is more effective than cinacalcet for controlling hypercalcemia caused by persistent hyperparathyroidism after kidney transplant. Kidney allograft recipients with hypercalcemia and elevated intact parathyroid hormone (iPTH) concentration were eligible if they had received a transplant ≥6 months before the study and had an eGFR>30 ml/min per 1.73 m(2) The primary end point was the proportion of patients with normocalcemia at 12 months. Secondary end points were serum iPTH concentration, serum phosphate concentration, bone mineral density, vascular calcification, renal function, patient and graft survival, and economic cost. In total, 30 patients were randomized to receive cinacalcet (n=15) or subtotal parathyroidectomy (n=15). At 12 months, ten of 15 patients in the cinacalcet group and 15 of 15 patients in the parathyroidectomy group (P=0.04) achieved normocalcemia. Normalization of serum phosphate concentration occurred in almost all patients. Subtotal parathyroidectomy induced greater reduction of iPTH and associated with a significant increase in femoral neck bone mineral density; vascular calcification remained unchanged in both groups. The most frequent adverse events were digestive intolerance in the cinacalcet group and hypocalcemia in the parathyroidectomy group. Surgery would be more cost effective than cinacalcet if cinacalcet duration reached 14 months. All patients were alive with a functioning graft at the end of follow-up. In conclusion, subtotal parathyroidectomy was superior to cinacalcet in controlling hypercalcemia in these patients with kidney transplants and persistent hyperparathyroidism.

Histopathological evaluation of pretransplant donor biopsies in expanded criteria donors with high kidney donor profile index: a retrospective observational cohort study

There is no consensus on the allocation of renal transplants from expanded criteria donors (ECD). The Kidney Donor Profile Index (KDPI) is used without the need for pretransplant donor biopsies (PTDB). We explored whether PTDB based on Remuzzi Score (RS) allows identification of those marginal kidneys in the highest calculated KDPI risk group (>91%) that appropriate for single transplantation. A retrospective study was conducted of 485 consecutive kidneys procured from a single center and transplanted if the RS was ≤4. We compared 5‐year kidney and patients survival between KDPI groups and between RS <4 or =4 in the highest KDPI group. The median KDPI (interquartile range) was 71 (66–76) for KDPI <80% (n = 77), 86 (81–90) for KDPI 81–90% (n = 82), and 97 (94–100) for KDPI >91% (n = 205). Patient survival at 5 years was 85.7%, 85.3%, and 76.09% (P = 0.058) and death‐censored graft survival was 84.4%, 86.5%, 73.6% (P = 0.015), respectively for each KDPI group. In >91% calculated KDPI group, there were no differences in graft survival depending on the RS (<4 vs. =4) (P = 0.714). The implementation of PTDB based on RS used for allocation of organs with the highest KDPI range could support to the acceptance of suitable organs for single transplantation with good patient and graft survival rate.

Role of HHV‐8 and mTOR pathway in post‐transplant Kaposi sarcoma staging

Kaposis sarcoma (KS) is one of the most frequent transplant related tumors. Several pathways are involved; however, the impact of the molecular phenotype associated to the tumor stage and the behavior‐depending resultant therapy is still unknown. The aim of our study was to analyze the role of HHV‐8 and mTOR pathway in tumor stages of skin KS after renal transplantation. Twelve renal transplant recipients with cutaneous KS from five transplant centers (1980–2007) under reduction of immunosuppression or conversion to mTOR inhibitor were included. The expression of HHV‐8, PTEN, TGFβ, VEGF, phospho‐mTOR, and phospho‐P70S6K in tumoral tissue was analyzed. KS lesions were classified as patch, plaque, and nodule state. HHV‐8 infection was found in all tissue samples. KS lesions showed high activation of VEGF, p‐mTOR and p‐P70S6K, low PTEN, and null TGFβ expression. The only pathway activated in a staging‐dependent manner was mTOR with higher p‐mTOR and p‐P70S6K expression in nodule versus patch stage. KS lesions disappeared after 5.24 months in all converted patients without any recurrence in 14.05 years of mean follow‐up. The activation of mTOR pathway according to KS stages supports the rational of the mTOR inhibitor in post‐transplant Kaposi.

Safety of Induction Immunosuppression in Kidney Transplantation: Focus on 1-Year Hospitalizations for Infection and Development of Post-Transplant Neoplasia

Introduction it is already known that induction therapy favors the development of infection and post-transplant neoplasia. However, few studies have explored so far the differences between different inductive agents, especially anti-CD25 antibodies and polyclonal anti-lymphocytes antibodies. Methods longitudinal analysis of kidney transplant recipients in the Hospital Clínic of Barcelona from 2002 to 2014 (initial n=1753). Recipients of a combined transplant (e.g. kidney-pancreas) or patients with unavailable data were discarded (final n=1448). Patients were divided in three groups according to the administered induction: Group 1) no induction (n=241), Group 2) anti-CD25 antibodies (either basiliximab or daclizumab) (n=593), Group 3) polyclonal anti-lymphocytes antibodies (n=614). Results Group 2 patients were older and more likely received a kidney from a living and an older donor. Group 3 had significantly higher percentage of re-transplantation. About maintenance therapy, there was a higher percentage of patients doing mTOR inhibitors in Group 3. Delayed Graft Function was observed more commonly in Group 3 as well. However, no differences were noted in the incidence of rejection and graft failure. Group 3 patients had higher possibility to be hospitalized during the first year of transplantation for an infection compared to Group 2 patients (p=0.025). Number of hospitalizations was increased as well in Group 3 patients compared to Group 1 (p=0.004) and Group 2 (p=0.027), while no significant difference was found between Group 1 and 2 (p=0.161). There was no difference among groups in the development of post-transplant neoplasia (p=0.44). Conclusions Induction therapy with polyclonal anti-lymphocytes antibodies was associated with a higher likelihood of hospitalization for infection during the first year after kidney transplantation. The number of hospitalizations was increased as well in this group of patients. Figure. No caption available.

Pancreas Graft Outcomes in Living versus Deceased Kidney Donor in Pancreas after Kidney Transplant Recipients

Introduction The advantages presented by pancreas after kidney transplantation (PAK) are often outweighed by conflicting results as to patient and pancreas graft survivals’, when compared to simultaneous kidney-pancreas (SPK). Immunological factors, such as shared mismatches, or kidney transplant donor (living- or deceased-donor) may play a role in these outcomes. Methods We retrospective analyzed all pancreas transplants performed at our center since the beginning of the pancreas after living-donor kidney transplantation (PAldK) program in 2007, and compared patient and grafts survivals’, and acute rejection incidence between PAldK (n=18), SPK (n=139) and pancreas after deceased kidney transplant (PAddK; n=28). Results Overall patient, kidney, and pancreas grafts survivals’ (death-censured) at 12 months was 98%, 99%, and 86%, respectively, and at 5 years 93%, 96%, and 80%. Kaplan-Meier pancreas graft survival estimates were similar between the three groups, but inferior for PAldK when included only those with functioning pancreas at day 90 post-transplant (log-rank p=.004). In a binary logistic regression, both PAK groups presented an increased risk for pancreas graft failure (PAldK HR 3.58 95% CI 1,59-8,08; PAddK HR 2,30 95% CI 1,06-5,00; p<.05). Pancreas acute rejection was significantly increased in PAldK (67%; 1,8±1,4 episodes/graft) when compared to PAddK (25%) and SPK (32%) (p<.05). In a multivariate Cox regression model including known risk factors for pancreas rejection, PAldK was the only factor associated with an increased risk for rejection (HR 6,82 95% CI 1,51-30,70, p<.05). No association was found between pancreas donor-recipient HLA mismatches and graft rejection. In both PAK groups, shared HLA incompatibilities between kidney and pancreas donors (0 vs 1-6) didn’t correlate with pancreas graft rejection or survival (p>.05). Conclusion PAldK transplant was associated with worst pancreas graft outcomes when compared to PAddK and SPK, but with similar patient and kidney survival. It may be advisable to centers to individually evaluate their median waiting-list time before proposing this alternative to patients. Figure. No caption available. Figure. No caption available.

Pancreas outcomes between living and deceased kidney donor in pancreas after kidney transplantation patients

Background Pancreas outcomes in pancreas after kidney transplantation (PAK) patients have been reported as being inferior to those of patients who receive simultaneous pancreas and kidney transplantation (SPK). The influence of the kidney donor (i.e. living versus deceased) has never been previously addressed. Methods We retrospectively analysed all pancreas transplants performed in a single centre since 2007 and compared the outcomes between those patients who had previously received a living-donor kidney transplant (pancreas transplantation after living-donor kidney transplantation, PAldK; n = 18) or a deceased-donor kidney transplant (pancreas transplantation after deceased-donor kidney transplantation, PAddK; n = 28), using SPK (n = 139) recipients as a reference. Results Pancreas survival was similar between all groups, but inferior for PAldK when including only those with a functioning graft at day 90 post-transplantation (P = 0.004). Pancreas acute rejection was significantly increased in PAldK (67%; 1.8 ± 1.4 episodes/graft) when compared with PAddK (25%) and SPK (32%) (P < 0.05) patients. In a multivariate Cox regression model including known risk factors for pancreas rejection, PAldK was the only predictor of acute rejection (hazard ratio 6.82, 95% confidence interval 1.51-30.70, P < 0.05). No association was found between donor-recipient HLA mismatches and graft rejection. Repeated HLA mismatches between kidney and pancreas donors (0 versus 1-6) did not correlate with pancreas graft rejection or survival in either PAK transplantation group (P > 0.05). Conclusion Pancreas graft outcomes are worse for PAldK when compared with PAddK and SPK patients.