Anna Manonelles

IgA nephropathy recurs early in the graft when assessed by protocol biopsy

BACKGROUND The recurrence of IgA nephropathy (IgAN) in the allograft is common. Factors related to IgA recurrence are unclear. The aims of this study were to determine the incidence of IgAN recurrence as assessed by protocol biopsies and to identify predictive factors for recurrence. METHODS We identified 65 protocol biopsies taken before the second year post-transplantation in patients with IgAN as primary renal disease. Diagnosis of recurrence of IgA was based on the detection of at least 1+ mesangial deposits of IgA. Pathological findings and clinical characteristics were retrospectively compared between recurrent and non-recurrent cases. RESULTS IgAN recurrence rate was 32%. Mesangial C3 was detected in 83% of recurrent cases versus 17% in non-recurrent patients (P < 0.001). Normal urinalysis was observed in 52%. Non-recurrent patients had arteriolar hyalinosis in 31% of the cases versus none in IgAN recurrence (P = 0.006). Seventy-nine per cent of cyclosporine users were free of recurrence, whereas 45% of the patients without cyclosporine experienced recurrence (P = 0.03). The odds ratio (OR) for IgAN recurrence in patients using cyclosporine was 0.3 (confidence interval 0.1-0.9). Zero HLA-DR mismatch was associated with non-recurrence (P < 0.01). The OR for IgA recurrence was 6.7 if any degree of DR mismatch was present. IgAN recurrent patients had better glomerular filtration rate, but after censoring delayed graft function, the differences disappeared. Graft loss due to IgA recurrence was only 3%. CONCLUSIONS IgAN recurrence rate was 32%. The histological diagnosis was not accompanied by abnormalities in the urinalysis in one-half of the patients. Full DR match and cyclosporine were associated with non-recurrence.

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders.

Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients

Background Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response. Methods Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-&ggr; enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months. Results Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients. Conclusions Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.

Changing trends in the aetiology, treatment and outcomes of bloodstream infection occurring in the first year after solid organ transplantation: a single centre prospective cohort study.

To analyse trends in the aetiology, treatment and outcomes of bloodstream infection (BSI) within the first year post‐transplant over the last 10‐year period, we prospectively recorded all episodes of BSI occurring in solid organ transplant (SOT) recipients during the first year post‐transplant from 2007 to 2016. Trends of factors were analysed by 2‐year periods. Of 475 consecutive episodes of BSI, 218 occurred within a year of SOT in 178 SOT recipients. Gram‐positive BSI decreased over time (40.5–2.2%). In contrast, there was a steady increase in Gram‐negative bacilli (GNB) BSI (54.1–93.3%; P < 0.001), mainly due to Pseudomonas aeruginosa (2.4–20.4%) and Klebsiella pneumoniae (7.1–26.5%). Multidrug‐resistant (MDR) GNB (4.8–38.8%; P < 0.001) rose dramatically, especially due to extended‐spectrum β‐lactamase (ESBL) production (7.1–34.7%). There was a sharp rise in the use of carbapenems, both as empirical (11.9–55.3%; P < 0.001) and as targeted antibiotic treatment (11.9–46.9%; P < 0.001). In conclusion, today, GNB are the leading causative agents of BSI in SOT recipients within the first year after SOT. In addition, MDR GNB have emerged mainly due to ESBL‐producing strains. In spite of these changes, length of hospital stay, days of treatment and mortality have remained stable over time.

Residual urinary volume is a risk factor for primary nonfunction in kidney transplantation

Primary nonfunction is a severe complication after kidney transplantation. Residual renal function could be a risk factor for this complication in the current era of kidney transplantation from extended criteria donors (ECD). This is a single‐center case–control study. Between 2000 and 2012, 1112 patients received a kidney transplant from a deceased donor. We identified 56 cases of early graft loss (kidney that never recover renal function and/or graft thrombosis <48 h after kidney transplantation). As controls we used patients receiving the contralateral kidney. Donor age was 55 ± 17 years with 57% fulfilling ECD criteria. Among the 56 cases, 14 were due to vascular rejection and 42 to primary nonfunction. Risk factors for early graft loss due to vascular rejection were previous transplant, time on dialysis, and HLA sensitization. Risk factors for primary nonfunction were first transplant, short period on dialysis, mainly peritoneal dialysis, and a residual urinary volume ≥500 ml/24 h. Conditional logistic regression analysis showed that residual urinary volume (OR = 20.01) rather than the dialysis modality was a major risk factor for primary nonfunction. In conclusion, residual urinary volume seems to be a risk factor for primary nonfunction in the current era of kidney transplantation.

Paricalcitol Versus Calcifediol for Treating Hyperparathyroidism in Kidney Transplant Recipients

Introduction Secondary hyperparathyroidism (SHPT) and vitamin D deficiency are common at kidney transplantation and are associated with some early and late complications. This study was designed to evaluate whether paricalcitol was more effective than nutritional vitamin D for controlling SHPT in de novo kidney allograft recipients. Methods This was a 6-month, investigator-initiated, multicenter, open-label, randomized clinical trial. Patients with pretransplantation iPTH between 250 and 600 pg/ml and calcium <10 mg/dl were randomized to paricalcitol (PAR) or calcifediol (CAL). The intention-to-treat population (PAR: n = 46; CAL: n = 47) was used for the analysis. The primary endpoint was the percentage of patients with serum iPTH >110 pg/ml at 6 months. Secondary endpoints were bone mineral metabolism, renal function, and allograft protocol biopsies. Results The primary outcome occurred in 19.6% of patients in the PAR group and 36.2% of patients in the CAL group (P = 0.07). However, there was a higher percentage of patients with iPTH <70 pg/ml in the PAR group than in the CAL group (63.4% vs. 37.2%; P = 0.03). No differences were observed in bone turnover biomarkers and bone mineral density. The estimated glomerular filtration rate was significantly higher in the CAL group than in the PAR group without differences in albuminuria. In protocol biopsies, interstitial fibrosis and tubular atrophy tended to be higher in the PAR group than in the CAL group (48% vs. 23.8%; P = 0.09). Both medications were well tolerated. Conclusion Both PAR and CAL reduced iPTH, but PAR was associated with a higher proportion of patients with iPTH <70 pg/ml. These results do not support the use of PAR to treat posttransplantation hyperparathyroidism.

Effect of Body Weight Variation in Kidney Transplantation: A Retrospective Cohorts Study.

Introduction Obese kidney allograft recipients have an increased risk of surgical complications, delayed graft function(DGF), prolonged hospital stay and late graft failure. However, there is lack of information regarding the effect of body mass index(BMI) variation after kidney transplantation(KT). Methods and Materials In this longitudinal study, we used data from Catalan Renal Registry including first KT recipients within 1990 and 2011. The annual change on post-transplantation BMI was calculated all patient follow-up (until December 2015). Main outcome variables were DGF, eGFR(CKD-EPI), patient and graft survival. Statistical analysis was adjusted for variables impacting on outcome. Results A total of 5,983 kidney trasnplant recipients were included. Obesity was observed in 609 patients(10.9%) at the time of transplantation. Obese patients were transplanted more recently, were younger and received kidneys from younger donors. Incidence of DGF was significantly higher in obese (40.38% vs 29.5%, P<0.001). Multivariate logistic regression model confirmed that baseline obesity was a risk factor for DGF (class I obesity: OR 1.6; 95%CI 1.3-2.1, P<0.001 and class II OR 2.2; 95%CI 1.5-3.2, P<0.001) whereas under-weight was protective (OR 0.5; 95%CI 0.3-0.8, P=0.005). Moreover, baseline obesity was a detrimental factor concerning long-term graft survival (SHR 1.25; 95%CI 1.03-1.51, P<0.05) without any effect on patient survival (SHR 0.93 95%CI 0.74-1.17, P= 0.53). In obese patients with functioning graft, BMI loss of >7% was associated with better patient survival, and a BMI loss of >7% was associated with worse graft survival. Conclusion Our conclusion is that BMI reduction after KT was not associated with eGFR improvement and only in those with a reduction of >7% patient survival was better with worse long-term graft survival.

Concentric Left Ventricular Hypertrophy Geometry Predicts Cardiovascular Events After Renal Transplantation

Background and Objectives Chronic kidney disease population, even after kidney transplant, is at higher risk of cardiovascular events. The aim of the study is to evaluate the relationship between pre-transplant echocardiographic assessment of left ventricular abnormalities and post-transplant cardiovascular events occurrence. Study Design and Setting, Participants and Measurements: Retrospective cohorts observational study, including 231 consecutive kidney transplant patients from Bellvitge University Hospital between 2010 and 2013 accounting with echocardiographic evaluation up to one year before kidney transplant. Patients were classified depending on its left ventricle morphology and mass into four categories (concentric hypertrophy, eccentric hypertrophy, concentric remodeling and normal geometry). Left ventricle mass was indexed to body surface area. Clinical and analytical data was also gathered. The primary outcome was a composite of cardiovascular events (congestive heart failure, acute coronary syndrome, cardiac sudden death, ictus and aortic aneurism rupture). Renal outcomes, and cardiac and overall mortality was also recorded. Results Using the classical definition of LVH, our study found a prevalence of 71 % for LVH in patients screened for waiting list inclusion, similar to previously described prevalence of LVH in dialysis patients. The mean LVMI in our patients was higher compared to general population, indicating the need for other echocardiographic findings to define cardiovascular risk. Of note mean LVMI was 130,43 ± 42,27 g/m2. 164 (71,6%) patients accomplished the previously described left ventricular hypertrophy criteria. 44 patients (18.2 %) were classified as normal geometry, 22 patients (9.6 %) patients as concentric remodeling, 86 patients (37.6 %) as concentric hypertrophy, and 79 patients (34.6 %) as eccentric hypertrophy. LVMI was higher in concentric group compared to all others groups (p. < 0.001 compared to each other group). Figure 1 shows mean left ventricular mass index among geometry groups. Table 1 shows basal population characteristics according geometric pattern At kaplan mayer analysis, patients with concentric pattern had lower cardiovascular free events survival compared with others group (Log Rank 0.002-see Figure 2) At cox regression logistic analysis concentric hypertrophy increases the risk of cardiovascular events comparing to the rest of geometric patterns (HR 2.753 CI 1.368-5.542 p=0.005). Every g/m2 increase on left ventricular mass (compared to the mean of our population) represents a 1.08 fold risk for cardiovascular events (HR 1.08 1.002-1.014 p value 0.005). Figure. No caption available. Figure. No caption available. Figure. No caption available. Conclusions left ventricular geometry is a simple and useful parameter to stratify patients after kidney transplant by risk of cardiovascular events as earlier as from pre-transplant evaluation.

The Presence of Urinary Renal Progenitor Cells in Stable Kidney Transplant Recipients Anticipates Allograft Deterioration

Long-term kidney transplant outcomes have reached mild improvements recently. Parietal epithelial cells (PECs) are progenitor cells located along the Bowman’s capsule that can be isolated in urine, and display the capability to replace podocytes, but in certain situations cause glomerulosclerosis. In this study, a cohort of stable kidney transplant recipients with 6 months protocol biopsy was divided in two groups depending on the presence (uPEC+; n = 41) or absence (uPEC-; n = 25) of PECs in urine and followed for 2 years. No differences were found between groups at 6 months after transplantation considering clinical variables, alloimmune response, renal function, albuminuria and graft pathology. However, uPEC+ group showed increased podocyturia and a higher rate of proliferating PECs along the Bowman’s capsule, without concomitant enhancement of the CD44 pro-sclerotic activation marker. Accordingly, 2 years follow up evidenced poorer outcomes in the uPEC+ group with worse renal function, increased albuminuria, wider mesangial expansion and more severe IFTA. In summary, chronic allograft damage can progress in certain stable-supposed grafts by podocyte detachment and reactive PECs proliferation, being the uPEC presence a biomarker of this process. This damage-response regenerative process, if sustained in time, might fail in preserve the allograft function and histology. Our study raises new prospects to overcome current limits on long-term allograft results.

Posttransplant Lymphoproliferative Disease and Inhibitors of Mammalian Target of Rapamycin: When a Quick Look Back Can Change the Perspective

Posttransplant lymphoproliferative disease represents a heterogeneous group of diseases characterized by uncontrolled proliferation of lymphocytes, favored by immunosuppression. Several risk factors for its development have been described, with Epstein-Barr virus infection being a main cause of early-onset forms and chronic antigen stimulation of donors and/or accumulated immunosuppression as key factors of later forms of lymphocyte transformation. The present clinical case presents a patient diagnosed with posttransplant lymphoproliferative disease 3 years after renal transplant who had a potentially lethal complication related to conversion to inhibitors of mammalian target of rapamycin. Because clinical studies that establish the most suitable treatment are lacking, it is recommended to identify the strategy, defining possible risks versus benefits of conversion to inhibitors of mammalian target of rapamycin in cases of posttransplant lymphoproliferative disease, and to maintain a high level of surveillance in case of possible secondary effects that can be verified after their introduction.