A case of acute tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine: a case report.

BACKGROUND: More than 4 billion doses of the Coronavirus disease (COVID-19) vaccine have been administered worldwide but the relationship between the different vaccines and the development of renal disease is unknown. We present a case of tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine. CASE PRESENTATION: A previously fit and well 51-year-old female presented on 27th May 2021 with a one-month history of weight loss, fatigue, nausea, and a metallic taste. She had an acute kidney injury with a creatinine of 484 umol/L. She was on no regular medications and denied taking any over-the-counter or alternative medicines. She had received her first dose of the Oxford-AstraZeneca vaccine on 23rd March 2021 and her second dose on 20th May 2021. A renal biopsy was performed the following day. The 19 glomeruli appeared normal to light microscopy but the tubulointerstitial compartment contained a dense inflammatory infiltrate including many eosinophils. There was widespread acute tubular injury with tubulitis, but no established or longstanding atrophy. A diagnosis was made of an acute tubulointerstitial nephritis. She was commenced on oral prednisolone and her renal function improved. She did not require renal replacement therapy at any time. CONCLUSIONS: To our knowledge, this was the first described case of acute tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine, although a number of cases have emerged more recently. In our case the patient was very fit and well, had no previous past medical history and had not taken any recent prescribed, over-the-counter or alternative medications. The absence of these provoking factors in our case makes the vaccine the most likely explanation for the development of tubulointerstitial nephritis although the pathophysiology behind this remains unknown. Given the unprecedented number of vaccinations being delivered around the world, nephrologists should be aware of this possible link although more research into the topic is required.

Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1ß-associated renal disease and can be symptomatic.

BACKGROUND: Heterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. METHODS: Faecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 µg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n = 6) underwent pancreatic imaging. RESULTS: Faecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at <200 µg/g stool; of these, 3 suffered with abdominal pain, loose stools and/or unintentional weight loss. All three experienced symptomatic improvement and weight gain after commencing pancreatic enzyme replacement therapy. Faecal elastase-1 was low in 7/15 (47%) HNF1B patients without diabetes compared with 11/14 (79%) of those with diabetes (P = 0.1). CONCLUSIONS: Faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with known HNF1B-associated disease complaining of chronic abdominal pain, loose stools or unintentional weight loss. The discovery of a low faecal elastase-1 concentration in individuals with developmental kidney disease of uncertain cause should prompt referral for HNF1B genetic testing.

Genome-wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion.

Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 deletion but not in patients with HNF1B coding mutations.Previous investigations have concentrated on identifying a genetic cause for the increase in behavioural problems seen in 17q12 deletion carriers. We have taken the alternative approach of investigating the DNA methylation profile of these two HNF1B genotype groups along with controls matched for age, gender and diabetes status using the Illumina 450K DNA methylation array (total sample n = 60).We identified a number of differentially methylated probes (DMPs) that were associated with HNF1B-associated disease and passed our stringent experiment-wide significance threshold. These associations were largely driven by the deletion patients and the majority of the significant probes mapped to the 17q12 deletion locus. The observed changes in DNA methylation at this locus were not randomly dispersed and occurred in clusters, suggesting a regulatory mechanism reacting to haploinsufficiency across the entire deleted region.Along with these deletion-specific changes in DNA methylation, we also identified a shared DNA methylation signature in both mutation and deletion patient groups indicating that haploinsufficiency of HNF1B impacts on the methylome of a number of genes, giving further insight to the role of HNF1B.

Young adults' perspectives on living with kidney failure: a systematic review and thematic synthesis of qualitative studies.

INTRODUCTION: Young adults fare worse than younger adolescents or older adults on a broad range of health indicators. Those with a chronic illness such as renal failure are a particularly vulnerable group, who experience poor outcomes compared with both children and older adults. Understanding how being in receipt of renal replacement therapy (RRT) affects the lives of young adults might help us to better prepare and support these individuals for and on RRT, and improve outcomes. This study aimed to synthesise research describing young adults' experiences of the psychosocial impact of kidney failure and RRT. DESIGN: A systematic literature review identified qualitative research reporting the perspectives of people aged 16-30 years receiving RRT on the psychosocial impact of renal failure. Electronic databases (including Medline/EMBASE/PsycINFO/ASSIA) were searched to November 2017 for full-text papers. The transparency of reporting of each study was assessed using the Consolidated Criteria for Reporting Qualitative Health Research (COREQ) framework. Quality was assessed using the Critical Appraisal Skills Programme qualitative checklist. An inductive thematic synthesis was undertaken. PARTICIPANTS: Seven studies from five different countries were included, comprising 123 young adults receiving RRT. RESULTS: Comprehensiveness of reporting was variable: studies reported 9-22 of the 32 COREQ-checklist items.Three global themes about the impact of kidney failure on young adults were identified: (1) difference desiring normality, (2) thwarted or moderated dreams and ambitions, and (3) uncertainty and liminality. These reflected five organising themes: (1) physical appearance and body image, (2) activity and participation, (3) educational disruption and underachievement, (4) career ambitions and employment difficulties, and (5) social isolation and intimate relationships. CONCLUSIONS: Across different countries and different healthcare settings, young adults on RRT experience difference and liminality, even after transplantation. Tailored social and psychological support is required to allow young adults to experience wellness while in receipt of RRT, and not have life on hold.

Sociodemographic, Psychologic Health, and Lifestyle Outcomes in Young Adults on Renal Replacement Therapy.

BACKGROUND AND OBJECTIVES: Young adults receiving RRT face additional challenges in life. The effect of established kidney failure on young adulthood is uncertain. We aimed to establish the psychosocial and lifestyle status of young adults receiving RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a systematic review and meta-analysis of 16-30-year olds receiving RRT compared with the general population. We selected randomized, controlled trials; cohort studies; or cross-sectional studies without language restriction and extracted proportions of sociodemographic and lifestyle outcomes or validated psychologic health tests producing quality of life, wellbeing, and self-esteem scores. We undertook random effects meta-analysis. RESULTS: There were 60 studies with a total of 15,575 participants. Studies were largely single-center cross-sectional studies of those transplanted in childhood. Compared with healthy peers, young adults on RRT had lower quality of life, which was worse for patients on dialysis (seven studies: standardized mean difference, -1.01; 95% confidence interval [95% CI], -1.32 to -0.70) compared with patients with transplants (nine studies: standardized mean difference, -0.42; 95% CI, -0.64 to -0.20). They were more likely to be unemployed (seven studies: relative risk, 1.89; 95% CI, 1.47 to 2.44) and live in the family home (two studies: relative risk, 1.84; 95% CI, 1.40 to 2.43). They were less likely to be married or have a partner (four studies: relative risk, 0.71; 95% CI, 0.53 to 0.95). Higher education (three studies: relative risk, 1.05; 95% CI, 0.73 to 1.51), alcohol abstinence (three studies: relative risk, 1.96; 95% CI, 0.84 to 4.67), and smoking status (two studies: relative risk, 0.72; 95% CI, 0.36 to 1.44) did not differ. Results were limited by high heterogeneity and a small evidence base, biased toward surviving patients. CONCLUSIONS: Established kidney failure is associated with lower quality of life in young people and limited employment, independence, and relationships compared with healthy peers. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_10_19_CJASNPodcast_17_12_.mp3.

Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.

BACKGROUND: Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease. CASE PRESENTATION: A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient's renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards. CONCLUSIONS: In an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.

Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services.

HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum.

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1ß (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.