Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations.

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.

Imaging of Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement.

Kidney cysts can manifest as focal disease (simple and complex kidney cysts), affect a whole kidney (eg, multicystic dysplastic kidney or cystic dysplasia), or manifest as bilateral cystic disease (eg, autosomal recessive polycystic kidney disease [ARPKD] or autosomal dominant polycystic kidney disease [ADPKD]). In children, as opposed to adults, a larger proportion of kidney cysts are due to genetic diseases (eg, HNF1B nephropathy, various ciliopathies, and tuberous sclerosis complex), and fewer patients have simple cysts or acquired cystic kidney disease. The purpose of this consensus statement is to provide clinical guidance on standardization of imaging tests to evaluate kidney cysts in children. A committee of international experts in pediatric nephrology, pediatric radiology, pediatric US, and adult nephrology prepared systematic literature reviews and formulated recommendations at a consensus meeting. The final statement was endorsed by the European Society of Pediatric Radiology, the European Federation of Societies for Ultrasound in Medicine and Biology, the European Society of Pediatric Nephrology, and reviewed by the European Reference Network for Rare Kidney Diseases. Main recommendations are as follows: US is the method of choice when assessing pediatric kidney cysts, with selected indications for MRI and contrast-enhanced US. CT should be avoided whenever possible because of ionizing radiation. Renal US yields essential diagnostic information in many cases. In patients with ARPKD or other ciliopathies, abdominal US is needed for diagnosis and screening of portal hypertension. US is usually sufficient for follow-up kidney imaging, but MRI can be valuable for clinical trials in patients with ADPKD or in older children with tuberous sclerosis complex to evaluate both kidney cysts and angiomyolipomas.

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases.

Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1(nl/nl) mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1(nl/nl) mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3(+) pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1(nl/nl) mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1(cpk/cpk) mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.

Experimental renal progenitor cells: repairing and recreating kidneys?

Strategies to facilitate repair or generate new nephrons are exciting prospects for acute and chronic human renal disease. Repair of kidney injury involves not just local mechanisms but also mobilisation of progenitor/stem cells from intrarenal niches, including papillary, tubular and glomerular locations. Diverse markers characterise these unique cells, often including CD24 and CD133. Extrarenal stem cells may also contribute to repair, with proposed roles in secreting growth factors, transfer of microvesicles and exosomes and immune modulation. Creating new nephrons from stem cells is beginning to look feasible in mice in which kidneys can be dissociated into single cells and will then generate mature renal structures when recombined. The next step is to identify the correct human markers for progenitor cells from the fetus or mature kidney with similar potential to form new kidneys. Intriguingly, development can continue in vivo: whole foetal kidneys and recombined organs engraft, develop a blood supply and grow when xenotransplanted, and there are new advances in decellularised scaffolds to promote differentiation. This is an exciting time for human kidney repair and regeneration. Many of the approaches and techniques are in their infancy and based on animal rather than human work, but there is a rapid pace of discovery, and we predict that therapies based on advances in this field will come into clinical practice in the next decade.

Making your way as an academic paediatric trainee in the UK.

A career path in academic paediatric medicine is an extremely rewarding one, and while not traditionally considered an academic specialty, it offers a wealth of exciting research opportunities. Developing academic paediatrics is becoming increasingly important, as recently reviewed in the Royal College of Paediatrics and Child Health (RCPCH) Turning the Tide report, and developing future leaders in academic paediatrics is a key goal of the academic training pathways. Strategies are being implemented to ensure that the enthusiasm of academic trainees is maintained, and their development into future leaders is secured.

Research priorities for autosomal dominant polycystic kidney disease: a UK priority setting partnership.

OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition, accounting for 7%-10% of patients with kidney failure. Fundamental basic science and clinical research on ADPKD is underway worldwide but no one has yet considered which areas should be prioritised to maximise returns from limited future funding. The Polycystic Kidney Disease Charity began a priority setting partnership with the James Lind Alliance (JLA) in the UK in 2019-2020 to identify areas of uncertainty in the ADPKD care pathway and allow patients, carers and healthcare professionals to rank the 10 most important questions for research. DESIGN: The scope covered ADPKD diagnosis and management, identifying new treatments to prevent/slow disease progression and practical, integrated patient support (https://pkdcharity.org.uk/research/for-researchers/adpkd-research-priorities). We used adapted JLA methodology. Initially, an independent information specialist collated uncertainties in ADPKD care from recent consensus conference proceedings and additional literature. These were refined into indicative questions with Steering Group oversight. Finally, the 10 most important questions were established via a survey and online consensus workshop. SETTING: UK. PARTICIPANTS: 747 survey respondents (76% patients, 13% carers, 11% healthcare professionals); 23 workshop attendees. RESULTS: 117 uncertainties in ADPKD care were identified and refined into 35 indicative questions. A shortlist of 17 questions was established through the survey. Workshop participants reached agreement on the top 10 ranking. The top three questions prioritised by patients, carers and healthcare professionals centred around slowing disease progression, identifying persons for early treatment and organising care to improve outcomes. CONCLUSIONS: Our shortlist reflects the varied physical, psychological and practical challenges of living with and treating ADPKD, and perceived gaps in knowledge that impair optimal care. We propose that future ADPKD research funding takes these priorities into account to focus on the most important areas and to maximise improvements in ADPKD outcomes.

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies.

BACKGROUND: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. OBJECTIVE: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. DESIGN SETTING AND PARTICIPANTS: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. RESULTS AND LIMITATIONS: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. CONCLUSIONS: This study identified CDH12 as a candidate gene for kidney injury in PUV. PATIENT SUMMARY: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people.

These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology, human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at-risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children.

Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system.

Kidney function is directly linked to the number of nephrons which are generated until 32-36 weeks gestation in humans. Failure to make nephrons during development leads to congenital renal malformations, whilst nephron loss in adulthood occurs in progressive renal disease. Therefore, an understanding of the molecular processes which underlie human nephron development may help design new treatments for renal disease. Mesenchyme to epithelial transition (MET) is critical for forming nephrons, and molecular pathways which control rodent MET have been identified. However, we do not know whether they are relevant in human kidney development. In this study, we isolated mesenchymal cell lines derived from human first trimester kidneys in monolayer culture and investigated their differentiation potential. We found that the mesenchymal cells could convert into osteogenic, but not adipogenic or endothelial lineages. Furthermore, addition of lithium chloride led to MET which was accompanied by increases in epithelial (CDH1) and tubular (ENPEP) markers and downregulation of renal progenitor (SIX2, EYA1, CD133) and mesenchymal markers (HGF, CD24). Prior to phenotypic changes, lithium chloride altered Wnt signalling with elevations in AXIN2, GSK3ß phosphorylation and ß-catenin. Collectively, these studies provide the first evidence that lithium-induced Wnt activation causes MET in human kidneys. Therapies targeting Wnts may be critical in the quest to regenerate nephrons for human renal diseases.

Perinatal Diagnosis, Management, and Follow-up of Cystic Renal Diseases: A Clinical Practice Recommendation With Systematic Literature Reviews.

Importance: Prenatal and neonatal cystic kidney diseases are a group of rare disorders manifesting as single, multiple unilateral, or bilateral cysts or with increased echogenicity of the renal cortex without macroscopic cysts. They may be accompanied by grossly enlarged kidneys, renal oligohydramnios, pulmonary hypoplasia, extrarenal abnormalities, and neonatal kidney failure. The prognosis is extremely variable from trivial to very severe or even uniformly fatal, which poses significant challenges to prenatal counseling and management. Objective: To provide a clinical practice recommendation for fetal medicine specialists, obstetricians, neonatologists, pediatric nephrologists, pediatricians, and human geneticists by aggregating current evidence and consensus expert opinion on current management of cystic nephropathies before and after birth. Methods: After 8 systematic literature reviews on clinically relevant questions were prepared (including 90 studies up to mid-2016), recommendations were formulated and formally graded at a consensus meeting that included experts from all relevant specialties. After further discussion, the final version was voted on by all members using the Delphi method. The recommendations were reviewed and endorsed by the working groups on inherited renal disorders of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and European Society for Paediatric Nephrology (ESPN); the German Society of Obstetrics and Gynecology (DGGG), German Society of Perinatal Medicine (DGPM), and German Society of Ultrasound in Medicine (DEGUM); and the alliance of patient organizations, PKD International. Recommendations: The group makes a number of recommendations on prenatal and postnatal imaging by ultrasound and magnetic resonance imaging, genetic testing, prenatal counseling, in utero therapeutic interventions, and postnatal management of prenatal and neonatal cystic kidney diseases, including provision of renal replacement therapy in neonates. In addition to detailed knowledge about possible etiologies and their prognosis, physicians need to be aware of recent improvements and remaining challenges of childhood chronic kidney disease, neonatal renal replacement therapy, and intensive pulmonary care to manage these cases and to empower parents for informed decision making.

Microarray interrogation of human metanephric mesenchymal cells highlights potentially important molecules in vivo.

Many molecules have been implicated in kidney development, often based on experimental animal studies with organ cultures and cell lines. There are very few studies, however, that have directly addressed equivalent living human embryonic tissues. We generated renal mesenchymal cell lines from normal human metanephroi and used a microarray strategy to define changes in gene expression after stimulation with growth factors which enhance nephrogenesis in rodents. Changes were observed in 1) genes modulating diverse general cellular processes, such as matrix metalloproteinase 1 and stanniocalcin 1; 2) genes previously implicated in organogenesis e.g., sprouty 4 and midline 1; and 3) genes involved in blood vessel growth, including angiopoietin 1 and 4. Expression of these same genes was subsequently confirmed in vivo. Our novel data have identified several previously unhighlighted genes that may be implicated in differentiation programs within early human nephrogenesis.

Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis.

CONTEXT: Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder that can cause hypertension during childhood, but the true prevalence of hypertension during childhood is not known. OBJECTIVE: We undertook a systematic review and meta-analysis to determine the prevalence of hypertension in children with ADPKD. DATA SOURCES: Systematic review of articles published between 1980 and 2015 in MEDLINE and EMBASE. STUDY SELECTION: Studies selected by two authors independently if reporting data on prevalence of hypertension in children and young persons aged <21 years with a diagnosis of ADPKD. Observational series were included with study populations of >15 children. Articles were excluded if inadequate diagnostic criteria for hypertension were used. Studies with selection bias were included but analysed separately. DATA EXTRACTION: Data extracted on prevalence of hypertension, proteinuria and reduced renal function using standardised form. Meta-analysis was performed to calculate weighted mean prevalence. RESULTS: 903 articles were retrieved from our search; 14 studies met the inclusion criteria: 1 prospective randomised controlled trial; 8 prospective observational studies; and 5 retrospective cross-sectional studies. From 928 children with clinically confirmed ADPKD, 20% (95% CI 15% to 27%) were hypertensive. The estimated prevalence of proteinuria in children with ADPKD is 20% (8 studies; 95% CI 9% to 40%) while reduced renal function occurred in 8% (5 studies; 95% CI 2% to 26%). LIMITATIONS: Studies showed a high degree of methodological heterogeneity (I2=73.4%, τ2=0.3408, p<0.0001). Most studies did not use ambulatory blood pressure (BP) monitoring to diagnose hypertension. CONCLUSIONS: In this meta-analysis we estimate 20% of children with ADPKD have hypertension. In the population, many children with ADPKD are not under regular follow-up and remain undiagnosed. We recommend that all children at risk of ADPKD have regular BP measurement.

The role of thymosin-ß4 in kidney disease.

Therapies that modulate inflammation and fibrosis have the potential to reduce the morbidity and mortality associated with chronic kidney disease (CKD). A promising avenue may be manipulating thymosin-ß4, a naturally occurring peptide, which is the major G-actin sequestering protein in mammalian cells and a regulator of inflammation and fibrosis. Thymosin-ß4 is already being tested in clinical trials for heart disease and wound healing. This editorial outlines the evidence that thymosin-ß4 may also have therapeutic benefit in CKD.

Mild fetal renal pelvis dilatation: much ado about nothing?

BACKGROUND: Renal pelvis dilatation (RPD) occurs in 1% of fetuses. Severe RPD (>15 mm) is frequently associated with urinary tract pathology. For the majority with mild (5 to 9 mm) to moderate (10 to 15 mm) RPD, however, there is uncertainty about the risk of abnormalities and how much postnatal investigation is required. STUDY DESIGN: Systematic review of cohort studies of fetuses with RPD < or = 15 mm and metaregression to estimate risks of postnatal RPD, obstruction, and VUR. RESULTS: Of 506 potentially relevant papers, 18 met the inclusion criteria. Risk of postnatal RPD increased with fetal RP size and earlier gestation. Odds ratios for postnatal RPD doubled per millimeter increase in fetal RP size: At 20 wk gestation, for example, 18% of fetuses with mean RP of 6 mm were estimated to have persistent postnatal RPD, compared with 95% of fetuses with 12 mm RPD, but risks were decreased by 16% to 18% per week of presentation gestation. Estimated risks of obstruction and VUR were substantially lower, particularly in the mild group such as the 6 mm example above: obstruction 2%, VUR 4%. CONCLUSIONS: Our novel risk estimates are useful for antenatal counseling at presentation. The low frequency of obstruction/VUR in mild RPD raises questions over the most appropriate investigation of these cases but further data are required before establishing definitive postnatal management pathways. We suggest the need for a large prospective multicenter study to collect individual patient parameters/results and search for additional prognostic indicators.

Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development.

Studies of mouse mutants have demonstrated that Sonic hedgehog (SHH) signalling has a functional role in morphogenesis and differentiation at multiple sites within the forming urinary tract, and urinary tract malformations have been reported in humans with mutations that disrupt SHH signalling. However, there is only strikingly sparse and fragmentary information about the expression of SHH and associated signalling genes in normal human urinary tract development. We used immunohistochemistry to demonstrate that SHH protein was localised in distinct urinary tract epithelia in developing normal humans, in the urothelium of the nascent bladder and in kidney medullary collecting ducts. The expression patterns of the SHH-transducing proteins Patched (PTCH) and Smoothened (SMO) were consistent with long-range paracrine signalling associated with detrusor smooth muscle differentiation in the urogenital sinus. In the developing kidney, SHH and PTCH were expressed in epithelia of the collecting system between 16-26 weeks--surprisingly, SMO was not detected. Analysis of cell proliferation and Cyclin B1 immunohistochemistry at 26 weeks, as compared with a 28 week sample in which SHH expression was down-regulated, was consistent with the idea that SHH and PTCH might influence medullary collecting duct growth by regulating the subcellular localisation of Cyclin B1 independently of SMO. Collectively, these descriptive results generate new hypotheses regarding SHH signal transduction in human urinary tract development and help to explain the varied urinary tract malformation phenotypes noted in individuals with mutations in the SHH pathway.

Galectin-3 associates with the primary cilium and modulates cyst growth in congenital polycystic kidney disease.

Several lines of evidence implicate the beta-galactoside-binding lectin galectin-3 in development and pathological processes in renal collecting ducts: galectin-3 is expressed in the ureteric bud/collecting duct lineage during nephrogenesis, modulates collecting duct growth/differentiation in vitro, and is expressed in human autosomal recessive polycystic kidney disease in cyst epithelia, almost all of which arise from collecting ducts. Moreover, exogenous galectin-3 restricts growth of cysts generated by Madin-Darby canine kidney collecting duct-derived cells in three-dimensional culture in collagen. Using the cpk mouse model of recessively inherited polycystic kidney disease, we observed widespread galectin-3 mRNA and protein in cyst epithelia. Exogenous galectin-3 reduced cyst formation in suspension culture, and mice-null mutant for galectin-3 had more extensive renal cysts in vivo. Galectin-3 was also detected for the first time in the centrosome/primary cilium, which has been implicated in diverse polycystic kidney disease. Cilia structure/number appeared normal in galectin-3-null mutants. Finally, paclitaxel, a therapy that retards polycystic kidney disease in cpk mice, increased extracellular galectin-3, in which the lectin could potentially interact with cilia. These data raise the possibility that galectin-3 may act as a natural brake on cystogenesis in cpk mice, perhaps via ciliary roles.

De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.

Molecular mechanisms of human embryogenesis: developmental pathogenesis of renal tract malformations.

The focus of this review is the normal and abnormal development of the kidney and lower urinary tract; for convenience, we will refer to the whole system as the renal tract. The content represents a convergence among the clinical disciplines of histopathology, nephrology, and urology as well the basic sciences of developmental biology and molecular genetics. The story has considerable clinical relevance since diverse renal tract malformations are increasingly detected on fetal ultrasound screening and constitute major causes of chronic renal failure necessitating dialysis and kidney transplantation in children. Evidence is emerging that at least some of these disorders have a defined genetic basis; in others, an abnormal embryonic, or even maternal, environment may contribute to the pathogenesis. This field of study is frequently updated, with new discoveries being made almost every week. Hence this review can not be exhaustive or definitive, but instead highlights some specific areas of interest.

Evolving concepts in human renal dysplasia.

Human renal dysplasia is a collection of disorders in which kidneys begin to form but then fail to differentiate into normal nephrons and collecting ducts. Dysplasia is the principal cause of childhood end-stage renal failure. Two main theories have been considered in its pathogenesis: A primary failure of ureteric bud activity and a disruption produced by fetal urinary flow impairment. Recent studies have documented deregulation of gene expression in human dysplasia, correlating with perturbed cell turnover and maturation. Mutations of nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which renal dysplasia can feature, including Fraser, renal cysts and diabetes, and Kallmann syndromes. Here, it is possible to begin to understand the normal nephrogenic function of the wild-type proteins and understand how mutations might cause aberrant organogenesis.

The P2X7 ATP receptor modulates renal cyst development in vitro.

P2X(7), a purinergic receptor, is expressed in renal collecting ducts as they undergo fulminant cystogenesis in the cpk/cpk mouse model of autosomal recessive polycystic kidney disease (ARPKD). Dissociated cpk/cpk kidneys generate cysts from cell aggregates within 24h of suspension culture and we demonstrate that BzATP, a P2X(7) agonist, reduces cystogenesis. This effect is P2X(7)-specific, because: (i) equimolar concentrations of other purinergic agonists, ATP and UTP, had lesser effects and (ii) the P2X(7) inhibitor, oxidized ATP, abrogated the BzATP-mediated reduction in cystogenesis. BzATP did not significantly affect total cell number, proliferation, LDH release or caspase 3 activity, and zVAD-fmk, a caspase blocker, failed to modulate BzATP effects. In addition, this P2X(7) agonist did not significantly alter cyst size, probably excluding altered vectorial transport. In vivo, ATP was detected in cyst fluid from cpk/cpk kidneys; moreover, P2X(7) protein was also upregulated in human fetal ARPKD epithelia versus normal fetal collecting ducts. Thus, ATP may inhibit pathological renal cyst growth through P2X(7) signaling.