Favorable Outcome After Single-kidney Transplantation From Small Donors in Children: A Match-controlled CERTAIN Registry Study.

BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 ±â€…6.2 mL/min/1.73 m² compared with a decrease of 6.9 ±â€…5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5 ±â€…25.5 in SDKTx versus 65.7 ±â€…23.1 mL/min/1.73 m² in ADKTx; P = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 ±â€…20.4 versus 104.6 ±â€…35.9; P = 0.043) but superior to ADKTx (68.1 ±â€…23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P = 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

New Insights into Pediatric Kidney Transplant Rejection Biomarkers: Tissue, Plasma and Urine MicroRNAs Compared to Protocol Biopsy Histology.

The early identification of a subclinical rejection (SCR) can improve the long-term outcome of the transplanted kidney through intensified immunosuppression. However, the only approved diagnostic method is the protocol biopsy, which remains an invasive method and not without minor and/or major complications. The protocol biopsy is defined as the sampling of allograft tissue at pre-established times even in the absence of an impaired renal function; however, it does not avoid histological damage. Therefore, the discovery of new possible biomarkers useful in the prevention of SCR has gained great interest. Among all the possible candidates, there are microRNAs (miRNAs), which are short, noncoding RNA sequences, that are involved in mediating numerous post-transcriptional pathways. They can be found not only in tissues, but also in different biological fluids, both as free particles and contained in extracellular vesicles (EVs) released by different cell types. In this study, we firstly performed a retrospective miRNA screening analysis on biopsies and serum EV samples of 20 pediatric transplanted patients, followed by a second screening on another 10 pediatric transplanted patients' urine samples at one year post-transplant. In both cohorts, we divided the patients into two groups: patients with histological SCR and patients without histological SCR at one year post-transplantation. The isolated miRNAs were analyzed in an NGS platform to identify different expressions in the two allograft states. Although no statistical data were found in sera, in the tissue and urinary EVs, we highlighted signatures of miRNAs associated with the histological SCR state.

Pre-Existing Intrarenal Parvovirus B19 Infection May Relate to Antibody-Mediated Rejection in Pediatric Kidney Transplant Patients.

Viral infections can lead to transplant dysfunction, and their possible role in rejection is described. In total, 218 protocol biopsies performed in 106 children at 6, 12 and 24 months after transplantation were analyzed according to Banff '15. RT-PCR for cytomegalovirus, Epstein-Barr virus, BK virus and Parvovirus B19 was performed on blood and bioptic samples at the time of transplant and each protocol biopsy. The prevalence of intrarenal viral infection increases between 6 and 12 months after transplantation (24% vs. 44%, p = 0.007). Intrarenal Parvovirus B19 infection is also associated with antibody-mediated rejection (ABMR) (50% ABMR vs. 19% T-cell-mediated rejection, p = 0.04). Moreover, Parvovirus infection is higher at 12 months of follow-up and it decreases at 48 months (40.4% vs. 14%, p = 0.02), while in 24% of grafts, Parvovirus is already detectable at the moment of transplantation. Intrarenal Parvovirus B19 infection seems to be related to ABMR in pediatric kidney recipients. The graft itself may be the way of transmission for Parvovirus, so performance of a PCR test for Parvovirus B19 should be considered to identify high-risk patients. Intrarenal Parvovirus infection presents mainly during the first-year post-transplantation; thus, we recommend an active surveillance of donor-specific antibodies (DSA) in patients with intrarenal Parvovirus B19 infection during this period. Indeed, it should be considered a treatment with intravenous immunoglobulins in patients with intrarenal Parvovirus B19 infection and DSA positivity, even in the absence of ABMR criteria for kidney biopsy.

Treatment Satisfaction, Efficacy, and Tolerability of Low-Dose Diclofenac Epolamine Soft Capsules in Acute, Mild, or Moderate Musculoskeletal Pain: A Prospective Open-Label, Single-Arm Interventional Study.

INTRODUCTION: The use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) for acute musculoskeletal pain should be at the lowest effective dosage and for the shortest duration to minimize potential adverse effects. This study evaluated treatment satisfaction, effectiveness, and tolerability of a low-dose diclofenac epolamine 12.5-mg soft capsule formulation (DHEP 12.5-mg capsules) using patient-reported outcome measures in a real-life setting over a short period (3 days) in subjects with mild-to-moderate acute musculoskeletal pain. METHODS: A prospective, open-label, phase IV clinical study in adult outpatients at hospital clinic departments/general practitioner's clinics at eight sites in Italy. The primary efficacy variable was the degree of satisfaction with treatment at 72 ± 7 h after initiation of treatment, assessed using the Overall Satisfaction Question of the Pain Treatment Satisfaction Scale (PTSS) and described by classic descriptive statistics. Secondary objectives were to evaluate the analgesic effect after the first administration and over time; the time to and satisfaction with the onset of pain relief, amount of and duration of pain relief; pain intensity differences over time; and safety and tolerability. The investigator's satisfaction with the treatment was also assessed. Subjects initially took 1-2 capsules of the study treatment and then one or two soft capsules every 4-6 h according to their needs. Not more than six soft capsules were to be taken in any 24-h period. RESULTS: A total of 182 subjects (mean age, 56.2 years; 54.4% female) took ≥ 1 dose of DHEP capsule and were included in the full analysis set. The most common musculoskeletal conditions were arthralgia (39.0%) and low back pain (23.1%). All subjects completed the study, and 165/182 (90.7%, 95% CI 0.86, 0.95) were satisfied or very satisfied with the treatment at 72 ± 7 h after the first dose (primary efficacy variable). Similar percentages were recorded for treatment satisfaction concerning other efficacy parameters. The onset of the analgesic effect was rapid, with complete pain relief reached after a mean of 49.45 min. Investigators rated their overall treatment satisfaction as 92.9%. Treatment was well tolerated. CONCLUSIONS: The low-dose (12.5 or 25 mg) oral diclofenac epolamine soft capsules formulation exerted rapid, effective, and safe analgesic activity in patients with mild-to-moderate musculoskeletal pain, with subjects' overall satisfaction with treatment more than 90%. TRIAL REGISTRATION: EudraCT Number: 2018-004886-15 (Study 18I-Fsg08). Registered 04/09/2018.

Hyperparathyroidism Is an Independent Risk Factor for Allograft Dysfunction in Pediatric Kidney Transplantation.

Introduction: Little is known about the consequences of deranged chronic kidney disease-mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. Methods: This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤30 ml/min per 1.73 m2 or a ≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. Results: We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28-2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71-4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87-2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Conclusion: Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.

Timing of reconstruction of the lower urinary tract in pediatric kidney transplant recipients: A CERTAIN multicenter analysis of current practice.

BACKGROUND: Preexistent LUTD are considered a hostile environment, which might negatively impact KTx survival. In such cases, surgical reconstruction of the bladder is required. However, there is still disagreement on the optimal timing of the reconstruction procedure. METHODS: This is a multicenter analysis of data from the CERTAIN Registry. Included were 62 children aged 8.18 ± 4.90 years, with LUTD. Study endpoints were the duration of initial posttransplant hospitalization, febrile UTIs, and a composite failure endpoint comprising decline of eGFR, graft loss, or death up to 5 years posttransplant. Outcome was compared to matched controls without bladder dysfunction. RESULTS: Forty-one patients (66.1%) underwent pretransplant and 14 patients (22.6%) posttransplant reconstruction. Bladder augmentation was performed more frequently in the pretransplant (61%) than in the posttransplant group (21%, p = .013). Outcome in the pre- and posttransplant groups and in the subgroups of patients on pretransplant PD with major bladder surgery either pre- (n = 14) or posttransplant (n = 7) was comparable. Outcomes of the main study cohort and the matched control cohort (n = 119) were comparable during the first 4 years posttransplant; at year 5, there were more events of transplant dysfunction in the study cohort with LUTD than in controls (p = .03). CONCLUSIONS: This multicenter analysis of the current practice of LUTD reconstruction in pediatric KTx recipients shows that pre- or posttransplant surgical reconstruction of the lower urinary tract is associated with a comparable 5-year outcome.

Clinical and laboratory characterization of patients with localized scleroderma and response to UVA-1 phototherapy: In vivo and in vitro skin models.

BACKGROUND/PURPOSE: Localized scleroderma (LS) is a rare disease leading to progressive hardening and induration of the skin and subcutaneous tissues. LS is responsive to UVA-1 phototherapy, though its exact mechanism of action dermal fibrosis is yet to be fully elucidated. We aimed to investigate the molecular changes induced by UVA-1 rays in human primary fibroblasts cultures. METHODS: A total of 16 LS patients were treated with medium-dose UVA-1 phototherapy. At baseline, during and after therapy, Localized Scleroderma Assessment Tool, Dermatology Life Quality Index and lesions' staging and mapping were performed along with high-frequency ultrasound (HFUS) examination for dermal thickness assessment. Gene expression analysis for 23 mRNA transcripts, in vitro UVA-1 irradiation and viability tests were realized on lesional fibroblasts' primary cultures, before and 3 months after therapy. RESULTS: The dermal thickness, the LoSCAT and the DLQI progressively decreased starting from the last phototherapy session up to the 6 and 9 month follow-ups (-57% and -60%, respectively). Molecular gene analysis (rt-PCR) revealed that UVA-1 phototherapy exerts multiple effects: the activation of specific anti-fibrotic pathways (e.g., overexpression of CTHRC1 and metalloproteases 1, 2, 7, 8, 9, 12, suppression of TIMP-1), the downregulation of peculiar pro-fibrotic pathways (e.g., downregulation of TGF-ß, TGF-ßrII, Grb2, SMAD 2/3, TNRSF12A, CTGF) through a significant overexpression of IL-1ß; the stabilization of collagen synthesis acting on genes COL1A1, COL3A1, COL8A1, COL10A1, COL12A1. CONCLUSION: UVA-1 phototherapy adds significant benefits in local tissue remodeling, rebalancing the alteration between pro-fibrotic and anti-fibrotic pathways; these changes can be well monitored by HFUS.

UVA-1 phototherapy as adjuvant treatment for eosinophilic fasciitis: in vitro and in vivo functional characterization.

INTRODUCTION: Eosinophilic fasciitis (EF) is a rare autoimmune disease causing progressive induration of dermal, hypodermal, and muscularis fascia. The exact pathogenesis is yet to be fully understood, and a validated therapy protocol still lacks. We here aimed to realize a clinical-functional characterization of these patients. MATERIALS AND METHODS: A total of eight patients (five males, 45 years average) were treated with adjuvant high-dose UVA-1 phototherapy (90 J/cm), after having received the standard systemic immunosuppressive protocol (oral methylprednisolone switched to methotrexate). Body lesion mapping, Localized Scleroderma Assessment Tool (LoSCAT), Dermatology Life Quality Index (DLQI), High-Resolution Ultrasound (HRUS) (13-17MHz), and ultra HRUS (55-70 MHz) were performed at each examination time taking specific anatomical points. Gene expression analysis at a molecular level and in vitro UVA-1 irradiation was realized on lesional fibroblasts primary cultures. RESULTS: The LoSCAT and the DLQI showed to decrease significantly starting from the last UVA-1 session. A significant reduction in muscularis fascia thickness (-50% on average) was estimated starting from 3 months after the last UVA-1 session and maintained up to 12 months follow-up. Tissues was detected by HRUS. The UVA-1 in vitro irradiation of lesional skin sites cells appeared not to affect their viability. Molecular genes analysis revealed a significant reduction of IL-1ß and of TGF-ß genes after phototherapy, while MMPs 1,2,9 gene expression was enhanced. COMMENT: These preliminary in vivo and in vitro findings suggest that UVA-1 phototherapy is a safe and useful adjuvant therapy able to elicit anti-inflammatory effects and stimulate tissue matrix digestion and remodeling at lesional sites.

Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study.

BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS: We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS: Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. CONCLUSIONS: Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.

Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms?

Nail Patella syndrome (NPS) is a rare autosomal dominant disease characterized by varying degrees of patella, nail, and elbows dysplasia and also ocular and renal congenital abnormalities. The renal involvement, ranging from hematuria and proteinuria to end-stage renal disease, is present in 22-60% of NPS cases. Heterozygous variants in LMX1B are known to be responsible of NPS and it has been hypothesized that the variable expressivity is due to the interaction of LMX1B with other developmental genes. We reported a case of co-presence of LMX1B and PAX2 variants in a child with extrarenal manifestation of NPS and end-stage renal disease but congenital bilateral renal hypodysplasia and vesicoureteral reflux. The LMX1B variant was de novo, whereas the PAX2 variant was inherited from the mother that had bilateral renal hypoplasia although in presence of only a mild chronic kidney disease. The molecular interaction between LMX1B and PAX2 has been already reported in vitro and this finding suggest that the worst renal NPS phenotype of our patient could be due to the defective expression of these two genes during nephrogenesis. In conclusion, our finding suggests that PAX2 may act as modifier gene in Nail Patella phenotype.

Endoscopic iliotibial band release in snapping hip.

Several open surgical techniques have been used to treat recalcitrant cases of snapping iliotibial band with varying results. Recently, endoscopic techniques have become available. The purpose of this study was to investigate the results of a modified endoscopic iliotibial band release using a longitudinal retrospective case series.
 Fifteen patients (three men and 12 women) with symptomatic external snapping hip were treated with an endoscopic release of the iliotibial band. The average age was 25 years (range 16-37 years). The procedure was performed in the lateral decubitus position using two portals; the iliotibial band was transversally released using a radiofrequency hook probe. The mean follow-up period was 33.8 months (range 12-84 months).
 The snapping phenomenon was overcome in all the patients. The mean pre-op pain VAS score was 5.5 mm (range 5-7 mm) and the mean post-op pain VAS score was 0.53 mm (range 0-2 mm) with a statistically significant reduction with respect to the preoperative value (p<0.0001); sixty percent of the patients were pain-free. The mean postoperative Harris Hip Score was 97.5 (range 94-100). No revision procedures were indicated and all the patients returned to their previous level of activity. The mean patient satisfaction score was, on average, 9.3 mm (range 8-10 mm) on the VAS scale. No complications occurred.
 Endoscopic iliotibial band release is a safe and reproducible technique with excellent results in terms of snapping phenomenon resolution, patient satisfaction, and return to previous level of activity. After strenuous sporting activities 40% of patients complained of very slight pain.

Arthroscopic management of primary synovial chondromatosis of the hip.

PURPOSE: We evaluated clinical outcomes after hip arthroscopy in patients with primary synovial chondromatosis (SC). METHODS: We retrospectively assessed 11 patients who underwent hip arthroscopy for primary SC at a mean follow-up of 22 months (range, 12 to 36 months). Clinical preoperative and postoperative evaluation was performed with the Harris hip score. The preoperative evaluation included plain radiographs and magnetic resonance (MR) scanning to detect number and positioning of intra-articular radiopaque loose bodies. The osteochondral damage was graded using the Kellgren-Lawrence classification. The chondral surfaces of both the acetabulum and femoral head were graded according to the Outerbridge scale. RESULTS: The clinical score improved postoperatively. There were statistically significant differences between preoperative and postoperative Harris hip scores (P < .05). Outcomes were rated as very satisfactory and satisfactory in 3 and 5 of 11 patients, respectively. The osteochondral damage ranged between stages 1 and 2. No complications related to surgical procedures were observed. CONCLUSIONS: Hip arthroscopy for the treatment of patients with primary SC showed good clinical results without any complications related to the surgical procedure. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria.

Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) > or =80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1-9.2). Kaplan-Meier curves for the primary end point (decrease of GFR > or = -3.0 ml/min per 1.73 m(2) per year) was two to three times more frequently observed in patients with R/I > or =80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I > or =80. Overt proteinuria did develop in 24% of patients with R/I > or =80 and in 5% of patients with R/I <80 (P < 0.01). In conclusion, intrarenal arterial resistance appears to play a nontrivial role in deteriorating renal function in type 2 diabetic patients. R/I is a noninvasive diagnostic procedure, which strongly predicts the outcome of renal function in type 2 diabetic patients, even when GFR patterns are still normal.