National study on the risks of COVID-19 infection for paediatric kidney transplant recipients: a retrospective, cross-sectional study.

INTRODUCTION: During the COVID-19 pandemic, evidence emerged that immunosuppressed children were less affected by COVID-19 infections compared with immunosuppressed adults. The aim of our study was to investigate how COVID-19 infections affected paediatric kidney transplant recipients (pKTR) in the UK. METHODS: Questionnaires regarding COVID-19 infection data and care of pKTR during the COVID-19 pandemic were sent to all 13 UK paediatric nephrology centres examining asymptomatic and symptomatic pKTR with positive COVID-19 PCR testing from 1 April 2020 to 1 December 2021. RESULTS: 63 pKTR who were 3.1 (range 0.1-15) years post-transplantation had COVID-19 infection with positive SARS-CoV-2 PCR RNA. Classical COVID-19 symptoms were present in half of the patients; with atypical presentations including diarrhoea (13%) and lethargy (13%) also noted, while a third of patients were asymptomatic. Eighteen patients (28%) were hospitalised including five asymptomatic patients admitted for other reasons. No patients needed ventilation or intensive care admission, and one patient received supplemental oxygen. There was evidence of acute kidney injury (AKI) in 71% of patients, but no patients needed kidney replacement therapy with haemofiltration or dialysis. CONCLUSION: We report 10.4% of the UK paediatric renal transplantation population had documented COVID-19 infections with positive SARS-CoV-2 PCR RNA with 28% of those affected requiring hospitalisation. The increased incidence of AKI, particularly after the first wave of the COVID-19 pandemic, was possibly due to increased testing. There was low morbidity and mortality compared with the adult population.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Combining robust urine biomarkers to assess chronic kidney disease progression.

BACKGROUND: Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. METHODS: 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38 mL/min) from the NephroTest prospective cohort. FINDINGS: Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652-0.795) vs. 0.682 (0.614-0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. INTERPRETATION: This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. FUNDING: This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).

Advanced chronic kidney disease among UK children.

The UK Renal Registry currently collects information on UK children with kidney failure requiring long-term kidney replacement therapy (KRT), which supports disease surveillance and auditing of care and outcomes; however, data are limited on children with chronic kidney disease (CKD) not on KRT. METHODS: In March 2020, all UK Paediatric Nephrology centres submitted data on children aged <16 years with severely reduced kidney function as of December 2019, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m2. RESULTS: In total, 1031 children had severe CKD, the majority of whom (80.7%) were on KRT. The overall prevalence was 81.2 (95% CI 76.3 to 86.3) per million of the age-related population. CONCLUSIONS: The prevalence of severe CKD among UK children is largely due to a high proportion of children on long-term KRT. Expanding data capture to include children with CKD before reaching failure will provide greater understanding of the CKD burden in childhood.

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

UK national study of barriers to renal transplantation in children.

AIMS: To investigate access to paediatric renal transplantation and examine potential barriers within the process. METHODS: Cross-sectional, multicentre, observational study where paediatric nephrology centres in the UK were requested to provide data on transplantation plans for all children (<18 years) with end-stage kidney disease (ESKD). RESULTS: 308 children with ESKD were included in this study from 12 out of 13 UK paediatric nephrology centres. 139 (45%) were being prepared for living donor transplantation and 82 (27%) were listed for deceased donor transplantation. The most common cited factors delaying transplantation from occurring in children were disease factors (36%), donor availability (27%) and size of the child (20%). Psychosocial factors were listed as a barrier in 19% of children. CONCLUSIONS: In this study we have documented the main barriers to renal transplantation in children. Some identified factors may be modifiable through local or national intervention, including donor availability and patient psychosocial factors.

Stat3 Controls Tubulointerstitial Communication during CKD.

In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target.

The kidney as a reservoir for HIV-1 after renal transplantation.

Since the recent publication of data showing favorable outcomes for patients with HIV-1 and ESRD, kidney transplantation has become a therapeutic option in this population. However, reports have documented unexplained reduced allograft survival in these patients. We hypothesized that the unrecognized infection of the transplanted kidney by HIV-1 can compromise long-term allograft function. Using electron microscopy and molecular biology, we examined protocol renal transplant biopsies from 19 recipients with HIV-1 who did not have detectable levels of plasma HIV-1 RNA at transplantation. We found that HIV-1 infected the kidney allograft in 68% of these patients. Notably, HIV-1 infection was detected in either podocytes predominately (38% of recipients) or tubular cells only (62% of recipients). Podocyte infection associated with podocyte apoptosis and loss of differentiation markers as well as a faster decline in allograft function compared with tubular cell infection. In allografts with tubular cell infection, epithelial cells of the proximal convoluted tubules frequently contained abnormal mitochondria, and both patients who developed features of subclinical acute cellular rejection had allografts with tubular cell infection. Finally, we provide a novel noninvasive test for determining HIV-1 infection of the kidney allograft by measuring HIV-1 DNA and RNA levels in patients' urine. In conclusion, HIV-1 can infect kidney allografts after transplantation despite undetectable viremia, and this infection might influence graft outcome.

Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals.

Mutations in PKD1, the gene encoding for the receptor Polycystin-1 (PC-1), cause autosomal dominant polycystic kidney disease (ADPKD). The cytoplasmic C-terminus of PC-1 contains a coiled-coil domain that mediates an interaction with the PKD2 gene product, Polycystin-2 (PC-2). Here we identify a novel domain in the PC-1 C-terminal tail, a polyproline motif mediating an interaction with Src homology domain 3 (SH3). A screen for interactions using the PC-1 C-terminal tail identified the SH3 domain of nephrocystin-1 (NPHP1) as a potential binding partner of PC-1. NPHP1 is the product of a gene that is mutated in a different form of renal cystic disease, nephronophthisis (NPHP). We show that in vitro pull-down assays and NMR structural studies confirmed the interaction between the PC-1 polyproline motif and the NPHP1 SH3 domain. Furthermore, the two full-length proteins interact through these domains; using a recently generated model system allowing us to track endogenous PC-1, we confirm the interaction between the endogenous proteins. Finally, we show that NPHP1 trafficking to cilia does not require PC-1 and that PC-1 may require NPHP1 to regulate resistance to apoptosis, but not to regulate cell cycle progression. In line with this, we find high levels of apoptosis in renal specimens of NPHP patients. Our data uncover a link between two different ciliopathies, ADPKD and NPHP, supporting the notion that common pathogenetic defects, possibly involving de-regulated apoptosis, underlie renal cyst formation.

Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss.

Recent studies have suggested adverse outcome for renal allograft rejection associated with dense CD20 lymphocytic infiltrates in transplant renal biopsies. We investigated further the relationship between renal allograft survival and CD20+ lymphocytic infiltrates in renal transplant biopsies from children with graft dysfunction. Fifty consecutive unselected renal transplant biopsies were performed for investigation of acute, chronic or acute on chronic renal allograft dysfunction in 48 children aged 1-17 (median 13.1) years, at 0-155 (median 22) months post-transplantation with median follow up of 24 months post-biopsy. Seventeen (35%) graft losses occurred at 1-163 (median 49) months post-transplantation. There was increased graft loss in those with dense (>300 cells/hpf) CD20+ lymphocytic infiltrates present on biopsy (p = 0.043). Dense B-cell infiltrates were also associated with increased glucocorticoid requirement in those with acute cellular rejection (p = 0.0015). There were no significant differences in age, sex, HLA-mismatch, type of transplantation, EBV or CMV serology or baseline immunosuppressive regimens between those with or without dense CD20+ infiltrates. Dense CD20+ lymphocytic infiltrates in renal transplant biopsies are associated with adverse clinical outcome, including increased graft loss. This observation raises the possibility of future studies examining the efficacy of B cell depletion therapy in this clinical context.

C1q nephropathy: a true immune complex disease or an immunologic epiphenomenon?

We describe a 16-year-old Caucasian boy who presented with steroid-sensitive nephrotic syndrome aged 2 years. His clinical course was one of frequent relapses and severe steroid dependence. To manage this, he was sequentially treated with levamisole, then oral cyclophosphamide before being started on ciclosporin. A renal biopsy performed prior to commencement of ciclosporin confirmed minimal change disease on light microscopy. The immunohistochemistry and electron microscopy findings were in keeping with this. His complement levels were normal and his lupus serology negative. He remained on ciclosporin therapy for 8 years and had two further renal biopsies to detect ciclosporin-induced renal damage. Both biopsies showed evidence of increasing amounts of C1q deposition on immunohistochemistry and the presence of immune deposits on electron microscopy. As he had continued negative lupus serology, this was compatible with a diagnosis of C1q nephropathy. In addition both biopsies had changes compatible with chronic mild ciclosporin nephrotoxicity. This case is the first report describing in detail a paediatric patient with evolving C1q nephropathy who was treated successfully with rituximab. We discuss the role of C1q in this clinicopathological entity and question its significance.