Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND AND HYPOTHESIS: IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. RESULTS: The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

School attendance and sport participation amongst children with chronic kidney disease: a cross-sectional analysis from the Kids with CKD (KCAD) study.

BACKGROUND: School attendance and life participation, particularly sport, is a high priority for children with chronic kidney disease (CKD). This study is aimed at assessing the association between CKD stage, sports participation, and school absences in children with CKD. METHODS: Using data from the binational Kids with CKD study (ages 6-18 years, n = 377), we performed multivariable regression to evaluate the association between CKD stage, school absences, and sports participation. RESULTS: Overall, 62% of participants played sport with the most frequent sport activities engaged in being swimming (17%) and soccer (17%). Compared to children with CKD 1-2, the incidence rate ratios (IRR) (95% CI) for sports participation amongst children with CKD 3-5, dialysis, or transplant were 0.84 (0.64-1.09), 0.59 (0.39-0.90), and 0.75 (0.58-0.96), respectively. The median (IQR) days of school absences within a four-week period were 1 day (0-1), with children on dialysis reporting the highest number of school absences (9 days (5-15)), followed by transplant recipients (2 days (1-7)), children with CKD 3-5 (1 day (0-3)), and with CKD 1-2 (1 day (0-3)). Duration of CKD modified the association between CKD stage and school absences, with children with a transplant experiencing a higher number of missed school days with increasing duration of CKD, but not in children with CKD 1-5 or on dialysis (p-interaction < 0.01). CONCLUSIONS: Children receiving dialysis and with a kidney transplant had greater school absences and played fewer sports compared to children with CKD stages 1-2. Innovative strategies to improve school attendance and sport participation are needed to improve life participation of children with CKD.

Immunologic response to SARS-CoV-2 mRNA vaccination in pediatric kidney transplant recipients.

BACKGROUND: COVID-19 disease in kidney transplant (KT) recipients is associated with increased morbidity, mortality, and hospitalization rates. Unfortunately, KT recipients also have a reduced response to SARS-CoV-2 immunization. The primary aim of this study was to assess immunologic response to SARS-CoV-2 mRNA vaccines in pediatric kidney transplant recipients 12-18 years of age. Secondary aims were to assess response rates following a third immunization and determine factors that influence immunization response. METHODS: Pediatric KT recipients in a single tertiary center received SARS-CoV-2 mRNA vaccination as per local protocol. SARS-CoV-2 immunoglobulin (IgG) was measured following second and/or third vaccination. Demographics including patient factors (age, gender, and underlying disease), transplant factors (time and type of transplant), and immunosuppression (induction, maintenance, and immunomodulatory therapies such as IVIG) were collected from the medical records. RESULTS: Of 20 participants, 10 (50%) responded following a two-dose vaccine schedule, which increased to 15 (75%) after three doses. Maintenance immunosuppression affected immunologic response, with azathioprine demonstrating a higher rate of response to vaccine compared to mycophenolate (100% vs. 38%, p = 0.04). Increasing prednisolone dose had a negative impact on immunologic response (0.01 mg/kg/day increase: OR 1.60 95% CI 1.01 to 2.57). Tacrolimus dose and trough levels, age, time post-transplant, underlying disease, and other immunosuppression did not impact immunologic response. CONCLUSIONS: Pediatric KT recipients had similar response rates following SARS-CoV-2 immunization as adult KT recipients. Immunologic response improved following a third immunization. Choice of antimetabolite and prednisolone dosing influenced the rate of response. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.

Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.

Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.

Kidney biopsy adequacy and complications in children - does technique matter?

Kidney biopsy is part of the diagnostic workup of many children with renal disease. Traditionally, a perpendicular approach to the biopsy has been used, but more recently, some proceduralists have favoured a tangential approach. It is not clear if one technique is superior with regards to tissue adequacy or complication rates. In our centre, interventional radiologists (IR) use general anaesthetic and a tangential approach, whereas paediatric nephrologists (PN) use sedation and a perpendicular approach. We examined consecutive native kidney biopsies performed between January 2008 and December 2017 for adequacy (sufficient tissue for light and electron microscopy and immunofluorescence) and examined the electronic medical records for data regarding technique and complications. IR performed 72 (29%) of the 245 native kidney biopsies, obtaining more total glomeruli (median 39 vs 16, p < 0.001) and more glomeruli per tissue core (median 13 vs 8, p < 0.001) than PN. No differences in specimen adequacy were observed between the two groups (79% IR vs 81% PN, p = 0.75) and a diagnosis could be made in 99% and 94% respectively (p = 0.1). A statistically lower rate of peri-nephric haematoma (28% vs 42%, p = 0.04) was detected in the IR group, but there were no significant differences in other complications. One patient required a blood transfusion (PN) and another required surgical intervention for a perinephric haematoma (IR). CONCLUSION: IR obtained larger samples and number of glomeruli, but the overall adequacy for native kidney biopsies was good using both perpendicular and tangential techniques, with low rates of significant complications. WHAT IS KNOWN: • Kidney biopsy is integral to the diagnostic work-up of many children with kidney disease. • Kidney biopsy is a safe procedure with well-established complications in a minority of children. WHAT IS NEW: • Interventional radiologists had higher biopsy yield than paediatric nephrologists, possibly due to the tangential approach. • Biopsy adequacy rates are high using both techniques and provided a diagnosis in over 95% of cases.

Complications of surgical mesh patches after kidney transplantation in children-A case series.

BACKGROUND: Abdominal compartment syndrome after kidney transplantation in pediatric recipients is a recognized complication relating to size discrepancy requiring abdominal wall closure over a large adult allograft. In order to circumvent this problem, our center implemented use of a surgical mesh, Surgisis® (Cook Surgical, Bloomington, IN), for abdominal wall closure in very small children to increase the surface covering over the organ and prevent compression. In this article, we report on the complications encountered following the use of these mesh patches. METHODS: A retrospective case review was conducted of all pediatric kidney transplants from September 2006 to December 2018 and divided into abdominal wall closure with and without implantation of Surgisis® mesh patch. Review of clinical notes was performed to identify information with respect to clinical course and post-operative outcomes. RESULTS: A surgical mesh patch was used in 7 pediatric recipients, of which 5 (71%) presented with post-operative complications. Three recipients were found to have bowel obstruction related to the surgical patch, necessitating bowel resection in one child. In addition, three children developed large serous fluid collections between the subcutaneous layers and the surgical mesh, requiring surgical drainage in two. CONCLUSIONS: In view of these findings, we recommend close surveillance for potential complications in this cohort. Future research is needed to explore the safety of different approaches to achieve abdominal wall closure in this group.

Incidence and predictors of vascular events following end-stage kidney disease in childhood.

AIM: Cardiovascular death is a leading cause of mortality in paediatric end-stage kidney disease (ESKD). There is however little known about the clinically relevant vascular disease in this population. We aimed to describe the incidence of new onset vascular disease and vascular death in Australian children receiving renal replacement therapy (RRT). We also aimed to identify demographic or childhood risk factors for these endpoints, and whether vascular disease predicts mortality. METHODS: Data on Australian patients who commenced RRT at <18 years of age from 1991 to 2017 were extracted from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Multivariable competing risks regression was used to identify factors associated with vascular events. RESULTS: A cohort of 1268 patients were followed up for a median of 10.31 years. Vascular disease was reported in 5.4%, and vascular death in 4.1%. The cumulative incidence of any vascular event, that is, disease or death, at 10 and 20 years was 5.5% and 12.8%, respectively. Childhood vascular events were associated with non-Caucasian, non-Indigenous ethnicity, and for the 804 patients followed up after 18 years of age, vascular events were associated with lack of childhood transplantation, longer childhood dialysis duration and Indigenous ethnicity. Vascular disease was only reported for 25.49% of patients who had a vascular death, and although a significant risk factor for mortality, it had limited ability to predict mortality. CONCLUSION: Cumulative incidence of vascular events is significant after commencing RRT during childhood and is associated with ethnicity, longer childhood dialysis duration and lack of childhood transplantation.

The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients.

BACKGROUND: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. METHODS: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. RESULTS: The cohort comprised 59 children (aged 0-18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07-1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01-1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99-34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25-115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54-186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64-57.72, p = 0.01). CONCLUSIONS: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA.

Baseline characteristics of patients with atypical haemolytic uraemic syndrome (aHUS): The Australian cohort in a global aHUS registry.

AIMS: To describe the baseline characteristics and treatment of Australian patients diagnosed with atypical haemolytic uraemic syndrome (aHUS) reported to the Global aHUS Registry. METHODS: Descriptive analysis of the Australian cohort with aHUS (n = 106) was undertaken for demographics, disease characteristics and prior treatment with eculizumab; comparing with the global cohort (n = 1688) for certain pre-specified disease characteristics. RESULTS: In Australia, almost two-thirds of patients diagnosed with aHUS were female and over 80% of patients were Caucasians, with similar proportions reported in the global cohort. Less than 6% of patients in the Australia and global cohorts were reported to have a history of autoimmune disease (4% vs 2%, respectively; P = .21) or cancer (5% vs 5%, respectively; P = .93), conditions that have been associated with secondary HUS. In the Australian cohort, 26% had received a kidney transplant and 68% of patients had received eculizumab. Kidneys were the most common organ involvement, followed by gastrointestinal tract (26%) and cardiovascular system (19%), with 35% of patients reported to have had at least two organs involved within 6 months prior to baseline visit or entry into the registry. Complement factor H was the most common pathogenic complement gene variant in the Australian patients. CONCLUSION: Data from the aHUS registry confirms and defines region-specific disease characteristics among a selected group of Australian children and adults with aHUS reported to the registry. Ongoing and more inclusive data will provide further information about temporal trends and treatment outcomes, representing a unique opportunity for clinicians and researchers to further develop knowledge surrounding this rare disease.

Parental understanding of relapsing idiopathic nephrotic syndrome-Where are the knowledge gaps?

AIM: To assess parental understanding of idiopathic nephrotic syndrome (INS) and its management, to enable targeted education in areas of deficit. METHODS: Families of children with at least one relapse of INS were interviewed, following a template covering key domains of (a) disease understanding, (b) management of INS and (c) access to information. Common trends and responses were identified and notable observations recorded. RESULTS: Twenty-one parents were interviewed. The mean duration of INS was 4.4 years (range 0.5-14.5 years), with a mean of two steroid-sparing agents used. Although 90% parents self-reported that they understood INS, only 29% could appropriately define relapse and 24% name potential complications. The management of INS was generally good, with most parents appropriately testing urine (81%) and managing relapses (90%). Unnecessary dietary restrictions were imposed on 57% during remission. The Internet was searched by 90% of parents for disease and drug information. Further information was desired in paper form (71%), hospital website (81%) and face-to-face workshop (90%), plus educational materials for schools. CONCLUSION: Parents overestimated their understanding of INS; however, their management was generally well done. Parents desired more information and support in various forms.

Desensitisation strategies in high-risk children before kidney transplantation.

BACKGROUND: Transplantation is the preferred modality for renal replacement therapy in children. With increasing rates of re-transplantation within the paediatric population, there are more sensitised children on waiting lists. One issue with developing strategies to treat these children is the number of different definitions of sensitisation. and we would therefore recommend an immunological risk stratification approach. METHODS: We discuss methods of sensitisation prevention, assessment and management, including paired exchange programmes and desensitisation protocols. RESULTS: There are limited published evidence-based data for desensitisation in adults and none in children; thus, we present information on the available therapies currently in use. DISCUSSION: Further research is required to investigate strategies which prevent sensitisation in children, including the healthcare utility of incorporating epitope-based matching into organ allocation algorithms. Controlled studies are also needed to establish the most appropriate desensitisation regimen(s).

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

Is laparoscopic donation safe for paediatric recipients?--a study of 85 paediatric recipients comparing open and laparoscopic donor nephrectomy.

INTRODUCTION: The safety of adult laparoscopic donor nephrectomy remains controversial with respect to paediatric recipients with few data existing about its efficacy. Small studies have shown no difference in graft survival when compared with open techniques, but previous data from United Network for Organ Sharing suggests a higher incidence of rejection in laparoscopically procured kidneys. METHODS: We examined the outcome in a total of 85 consecutive paediatric renal recipients, comparing 46 recipients of laparoscopically procured kidneys (performed over a 3-year period, 2004-07) to a historical control of 39 open donor recipients. Thirty-seven laparoscopic donors were by the hand-assisted technique. RESULTS: Mean recipient age was 9.8 (SD 5.04) years in the laparoscopic group and 10.4 (SD 4.67) years in the open group (P = 0.617). Two patients had delayed graft function in the laparoscopic group (4.3%) and one (2.5%) in the open group (P = 0.562). At 1 year follow-up, there was 100% graft survival in the laparoscopic group compared to 92% (P = 0.093) in the open group. Incidence of biopsy-proven acute rejection within 1 year of transplant was 26% (16 episodes in 12 patients) in the laparoscopic group compared to 41% (29 episodes in 16 patients) in the open group (P = 0.219). There were no deaths in the laparoscopic group but there were three deaths (7.6%) in the open group (P = 0.093). CONCLUSIONS: Our experience of laparoscopic kidney donation for paediatric recipients suggests excellent outcome with no difference in rejection rate or graft survival compared to open donation. Laparoscopic donation is the optimal method of kidney procurement for paediatric recipients.

Acute kidney injury post neonatal asphyxia.

Acute kidney injury (AKI) is a common consequence of perinatal asphyxia, occurring in up to 56% of these infants. A major difficulty in diagnosing this condition is the lack of a consensus definition of neonatal AKI, largely because of a dearth of specific measurable variables and biochemical markers. This review will discuss the current evidence regarding the epidemiology, investigation, and treatment of AKI in the asphyxiated neonate. Particular emphasis will be given to the investigation of renal function in the neonate and to potential biomarkers that may aid the clinician in the diagnosis of renal injury in this population.

Thromboxane prostanoid receptor stimulation induces shedding of the transmembrane chemokine CX3CL1 yet enhances CX3CL1-dependent leukocyte adhesion.

In atherosclerosis, chemokines recruit circulating mononuclear leukocytes to the vascular wall. A key factor is CX(3)CL1, a chemokine with soluble and transmembrane species that acts as both a chemoattractant and an adhesion molecule. Thromboxane A(2) and its receptor, TP, are also critical to atherogenesis by promoting vascular inflammation and consequent leukocyte recruitment. We examined the effects of TP stimulation on processing and function of CX(3)CL1, using CX(3)CL1-expressing human ECV-304 cells and primary human vascular endothelial cells. TP agonists promoted rapid shedding of cell surface CX(3)CL1, which was inhibited by pharmacological inhibitors or specific small interfering RNA targeting tumor necrosis factor-alpha-converting enzyme (TACE). Because it reduced cell surface CX(3)CL1, we predicted that TP stimulation would inhibit adhesion of leukocytes expressing the CX(3)CL1 cognate receptor but, paradoxically, saw enhanced adhesion. We questioned whether the enhanced ability of the remaining membrane-associated CX(3)CL1 to bind targets was caused by changes in its lateral mobility. Using fluorescence recovery after photobleaching, we found that plasmalemmal CX(3)CL1 was initially tethered but ultimately mobilized by TP agonists. TP stimulation provoked clustering of transmembrane CX(3)CL1 at sites of contact with adherent leukocytes. These data demonstrate that TP stimulation induces two distinct effects: a rapid cleavage of surface CX(3)CL1, thereby releasing the soluble chemoattractant, plus mobilization of the remaining transmembrane CX(3)CL1 to enhance the avidity of interactions with adherent leukocytes. The dual effect of TP allows CX(3)CL1 to recruit leukocytes to sites of vascular inflammation while enhancing their adhesion once recruited.

Post-renal transplant urolithiasis in children: an increasingly diagnosed complication: a retrospective cohort study.

OBJECTIVE: Urolithiasis in renal transplant (RTx) recipients is a potential cause of allograft loss if obstruction is untreated. It is not clear if paediatric transplant recipients are following the global trend for increased prevalence of urolithiasis over time. DESIGN/SETTING/PATIENTS: A retrospective chart review was undertaken to evaluate the frequency, risk factors and characteristics of post-RTx urolithiasis over two decades (1995-2016), in a tertiary Australian paediatric hospital. RESULTS: Stones were diagnosed in 8 of 142 (5.6%) recipients, 6 of whom were transplanted in the latter decade. All patients were male, with a median age 4.9 years and median weight 11.8 kg. Presentation was with haematuria (n=4), pain (n=2), dysuria (n=2), stone passage (n=1) and asymptomatic (n=1). Time to presentation was bimodal; three stones were identified in the initial 3 months post RTx and the remainder after 31-53 months. Two stones were in association with retained suture material and two patients had recurrent urinary tract infections. The average stone size was 8.4 mm. Five stones were analysed; all contained calcium oxalate, three were mixed, including one with uric acid. Five (83.3%) children had hypercalciuria but none had hypercalcaemia. Cystolithotripsy was the the most common treatment (n=5), in combination with citrate supplementation. No graft was lost due to stones. CONCLUSIONS: Calculi occur with increasing frequency after renal transplantation. Clinicians need a high index of suspicion as symptoms may be atypical in this population. The cause for the increased frequency of stones in transplant recipients is not clear but is in keeping with the increase seen in the general paediatric population.

Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.

Generalized arterial calcification of infancy (GACI) (OMIM no. 208000) is characterized by calcification of the major arteries and soft tissues and associated with mutations in the ENPP1 gene. Most affected patients die within the first 6 months of life although prolonged survival is increasingly recognized. We report on three siblings with GACI and striking phenotypic variability. Two siblings (including the sibling survivor) were compound heterozygotes for mutations in exon 7 (c.783C>G (p.Y261X)) and exon 8 (c. 878_879delAA (p.K293fsX5)) of the ENPP1 gene confirming the diagnosis of GACI. The sibling survivor did not have calcification on X-ray studies or evidence of hypophosphatemic rickets. GACI may be under recognized and we emphasize consideration of this condition in patients with multiple arterial stenosis even in the absence of radiographic calcification. This adds to the expanding phenotype of GACI and supports a potential role for modifying genes.