Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The ...definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively.
These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.
Paediatric kidney failure is a global problem responsible for significant childhood morbidity and mortality. The gold-standard treatment is kidney transplantation. However, the availability of kidney ...transplantation remains limited in some low- and middle-income countries (LMICs). Transplant Links Community (TLC) is a UK-based charity that mentors units in LMICs wishing to start kidney transplantation; the ultimate goal is for these units to become self-sufficient. TLC provides this support through in-person training visits and skill transfer, plus direct mentorship from the UK that is maintained over many years. From such mentoring programmes, it is evident that there are numerous challenges in the initial establishment and long-term maintenance of kidney transplant services, with specific and unique barriers applying to setting up paediatric transplant programmes compared to their adult counterparts. This review summarises TLC’s first-hand experience of developing paediatric kidney transplantation services in LMICs over the past 15 years, the challenges encountered, and the major ongoing barriers that must be addressed to facilitate further progress in delivering transplantation services to children globally.
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a ...combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.
Bardet-Biedl syndrome is a rare autosomal recessive, multisystem disease characterized by retinal dystrophy, renal malformation, obesity, intellectual disability, polydactyly, and hypogonadism. ...Nineteen disease-causing genes (
) have been identified, of which mutations in
are most common in North America and Europe. A hallmark of the disease, renal malformation is heterogeneous and is a cause of morbidity and mortality through the development of CKD. We studied the prevalence and severity of CKD in 350 patients with Bardet-Biedl syndrome-related renal disease attending the United Kingdom national Bardet-Biedl syndrome clinics to further elucidate the phenotype and identify risk indicators of CKD. Overall, 31% of children and 42% of adults had CKD; 6% of children and 8% of adults had stage 4-5 CKD. In children, renal disease was often detected within the first year of life. Analysis of the most commonly mutated disease-associated genes revealed that, compared with two truncating mutations, two missense mutations associated with less severe CKD in adults. Moreover, compared with mutations in
, mutations in
associated with less severe CKD or lack of CKD in adults. Finally, 51% of patients with available ultrasounds had structural renal abnormalities, and 35% of adults were hypertensive. The presence of structural abnormalities or antihypertensive medication also correlated statistically with stage 3b-5 CKD. This study describes the largest reported cohort of patients with renal disease in Bardet-Biedl syndrome and identifies risk factors to be considered in genetic counseling.
Human Hypertension Caused by Mutations in WNK Kinases Wilson, Frederick H.; Disse-Nicodème, Sandra; Choate, Keith A. ...
Science (American Association for the Advancement of Science),
08/2001, Letnik:
293, Številka:
5532
Journal Article
Recenzirano
Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal ...salt reabsorption, and impaired K+and H+excretion. Both genes encode members of the WNK family of serinethreonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
Abstract
Background. Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines ...suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk.
Methods. This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis.
Results. Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = −0.44, P < 0.0001) and alkaline phosphatase (ALP; r = −0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below −2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (β = −0.43 , P < 0.0001), ALP (β = −0.36, P < 0.0001) and Ca (β = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model.
Conclusions. Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4–5D.
Background
Diabetic nephropathy may begin in childhood, but clinical kidney disease ascribable to this is uncommon in children with type 1 (insulin dependent) diabetes mellitus.
Methods
We reviewed ...our experience of kidney biopsies in children with type 1 diabetes mellitus.
Results
Between 1995 and 2022, there were biopsies in 17 children, with various clinical indications for kidney biopsy, making this the largest series of biopsies in diabetic children with clinical kidney abnormalities. Four biopsies showed diabetic nephropathy, three showed the combination of diabetic nephropathy and IgA nephropathy, and ten showed a variety of conditions other than diabetic nephropathy: minimal change disease (2), membranous nephropathy (2), thin glomerular basement membrane lesion (2), non-glomerular chronic damage in Wolcott–Rallison syndrome (2), acute pauciimmune necrotizing crescentic glomerulonephritis (1) and IgA nephropathy (1). Clinical clues of something other than diabetic nephropathy included acute kidney injury, microscopic haematuria or chronic kidney impairment with little or no proteinuria and the nephrotic syndrome after a short duration of diabetes.
Conclusions
We confirm that changes better known in adults with either type 1 or type 2 diabetes mellitus can occur in children with type 1 diabetes mellitus: overt diabetic nephropathy either on its own or combined with other conditions and kidney disorders other than diabetic nephropathy.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative ...glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.
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Background
There is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive ...crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK.
Methods
Questionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups.
Results
Among 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6–14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder.
Conclusion
Longer term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
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