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"CYSTIC DISEASES"
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Salt in my soul : an unfinished life
\"Diagnosed with cystic fibrosis at the age of three, Mallory Smith grew into a determined, talented young woman who inspired others even as she raged against her illness. Despite the daily challenges of endless medical treatments and a deep understanding that she'd never lead a normal life, Mallory was determined to 'live happy,' a mantra she followed until her death\"-- Provided by publisher.
Book
Joubert syndrome: congenital cerebellar ataxia with the molar tooth
Joubert syndrome is a congenital cerebellar ataxia with autosomal recessive or X-linked inheritance, the diagnostic hallmark of which is a unique cerebellar and brainstem malformation recognisable on brain imaging—the so-called molar tooth sign. Neurological signs are present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. 21 causative genes have been identified so far, all of which encode for proteins of the primary cilium or its apparatus. The primary cilium is a subcellular organelle that has key roles in development and in many cellular functions, making Joubert syndrome part of the expanding family of ciliopathies. Notable clinical and genetic overlap exists between distinct ciliopathies, which can co-occur even within families. Such variability is probably explained by an oligogenic model of inheritance, in which the interplay of mutations, rare variants, and polymorphisms at distinct loci modulate the expressivity of the ciliary phenotype.
Journal Article
Nephronophthisis
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It is caused by mutations in 11 different genes, denoted nephrocystins (
NPHP1–11
,
NPHP1L
). As an increasing number of these genes are identified, our knowledge of nephronophthisis is changing, thereby improving our understanding of the pathomechanisms in NPHP. Recent publications have described ciliary expression of nephrocystins together with other cystoproteins, such as polycystins 1 and 2 and fibrocystin. These findings have shifted our focus to a pathomechanism involving defects in ciliary function (ciliopathy) and planar cell polarity (PCP). In addition, discoveries of new nephrocystin genes have shown that the disease spectrum of NPHP is much broader than previously anticipated. Different forms of mutations within the same
NPHP
gene can cause different disease severity. In this review, we highlight the different hypotheses on the pathomechanisms for NPHP and underline the clinical variability of this disease. The clinical spectrum has become even more complex with the possibility of oligogenicity in NPHP.
Journal Article
Acquired cystic kidney disease in children with kidney failure
Background
This study aimed to evaluate the incidence, contributing factors, and clinical outcomes of acquired cystic kidney disease (ACKD) in children undergoing kidney replacement therapy (KRT).
Methods
We conducted a cross-sectional, territory-wide study at the designated pediatric nephrology center in Hong Kong. ACKD was defined as the presence of ≥ 3 cysts in the native kidneys, excluding congenital or hereditary cystic diseases. Between June to December 2023, all paediatric patients receiving KRT in Hong Kong underwent ultrasonography, non-contrast magnetic resonance imaging (MRI), or both. Contrast-enhanced computed tomography was performed for patients with complex cysts.
Results
Forty-three children (56% female; median age 14.7 years; IQR, 11.7–18.7) were included in the analysis. ACKD was detected in 18 children (42%). Nine subjects had complex cysts (grade 2,
n
= 5; grade 2F,
n
= 2; grade 3,
n
= 2). Most patients with ACKD (89%) were asymptomatic. One patient (5.5%) developed back pain and gross haematuria 72 months after initiation of KRT. Another patient (5.5%) developed infected cyst with back pain and clinical sepsis 60 months following KRT initiation. A dialysis duration of ≥ 28 months was the only significant factor associated with ACKD development (77.8% vs. 40%;
p
= 0.028; OR
adj
6.09, 95% CI 1.43–25.82,
p
= 0.014). The diagnostic yield of paired ultrasound and MRI was superior to ultrasound alone.
Conclusions
ACKD is prevalent among children and adolescents with kidney failure, with most cases being asymptomatic, however serious complications may arise. Longer duration of dialysis is significantly associated with ACKD development. Therefore, early transplantation and active ACKD surveillance are crucial for children receiving KRT.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Journal Article
Exploring the location patterns and clinical characteristics of isolated simple renal cysts: insights from a multicenter retrospective study
Objective
Surgical decisions for simple renal cysts (SRCs) depend on symptoms and compression of the renal collecting system. This study investigated the relationship between cyst location and patient clinical characteristics, offering insights into personalized management and surgical intervention.
Methods
This study investigated hospitalized isolated SRCs patients, excluding those with renal cancer or unknown cyst sizes. Isolated SRCs were defined as a single large cyst in either kidney, accompanied by less than three additional cysts < 1 cm. Patients with two or more cysts ≥ 1 cm were excluded. Complete clinical data, including cyst location and compression effects, were required for inclusion. Ethical approval was obtained.
Results
This study included 1,093 cases of isolated SRCs: extracalyceal cysts (780 patients), parapelvic cysts (158 patients), cysts above renal pelvis (78 patients), and cysts below renal pelvis (77 patients). Patients with parapelvic cysts had a greater incidence of symptoms (77.85% vs. 57.56%, 61.54%, 53.25%). Parapelvic cysts (72.15%) and cysts below the renal pelvis (88.31%) had a higher risk of collecting system compression risk than extracalyceal cysts (47.69%) and cysts above the renal pelvis (60.26%). The combined risk of hydronephrosis was higher in parapelvic cysts (46.03%) and cysts below the renal pelvis (44.44%) than in extracalyceal cysts (8.96%) and cysts above the renal pelvis (0.00%). Cox regression analysis revealed that cyst size at diagnosis (
p
< 0.001) and the presence of parapelvic cysts (
p
< 0.001) independently contributed to symptomatic risk. Cyst size at diagnosis (
p
< 0.001), parapelvic cysts (
p
< 0.001), and cysts below the renal pelvis (
p
< 0.001) were independent predictors of hydronephrosis in patients with SRCs.
Conclusion
SRCs in different kidney locations have unique features, necessitating tailored management. Cysts size at diagnosis and the presence of parapelvic cysts independently contribute to the symptoms of patients with SRCs. Parapelvic cysts and cysts below the renal pelvis are independent risk factors for hydronephrosis and should be actively managed.
Journal Article
New insights into the role of HNF-1β in kidney (patho)physiology
Hepatocyte nuclear factor-1β (HNF-1β) is an essential transcription factor that regulates the development and function of epithelia in the kidney, liver, pancreas, and genitourinary tract. Humans who carry HNF1B mutations develop heterogeneous renal abnormalities, including multicystic dysplastic kidneys, glomerulocystic kidney disease, renal agenesis, renal hypoplasia, and renal interstitial fibrosis. In the embryonic kidney, HNF-1β is required for ureteric bud branching, initiation of nephrogenesis, and nephron segmentation. Ablation of mouse Hnf1b in nephron progenitors causes defective tubulogenesis, whereas later inactivation in elongating tubules leads to cyst formation due to downregulation of cystic disease genes, including Umod, Pkhd1, and Pkd2. In the adult kidney, HNF-1β controls the expression of genes required for intrarenal metabolism and solute transport by tubular epithelial cells. Tubular abnormalities observed in HNF-1β nephropathy include hyperuricemia with or without gout, hypokalemia, hypomagnesemia, and polyuria. Recent studies have identified novel post-transcriptional and post-translational regulatory mechanisms that control HNF-1β expression and activity, including the miRNA cluster miR17 ∼ 92 and the interacting proteins PCBD1 and zyxin. Further understanding of the molecular mechanisms upstream and downstream of HNF-1β may lead to the development of new therapeutic approaches in cystic kidney disease and other HNF1B-related renal diseases.
Journal Article
Immunofluorescence analyses of respiratory epithelial cells aid the diagnosis of nephronophthisis
Background
Nephronophthisis (NPH) comprises a heterogeneous group of inherited renal ciliopathies clinically characterized by progressive kidney failure. So far, definite diagnosis is based on molecular testing only. Here, we studied the feasibility of NPHP1 and NPHP4 immunostaining of nasal epithelial cells to secure and accelerate the diagnosis of NPH.
Methods
Samples of 86 individuals with genetically determined renal ciliopathies were analyzed for NPHP1 localization using immunofluorescence microscopy (IF). A sub-cohort of 35 individuals was also analyzed for NPHP4 localization. Western blotting was performed to confirm IF results.
Results
NPHP1 and NPHP4 were both absent in all individuals with disease-causing
NPHP1
variants including one with a homozygous missense variant (c.1027G > A; p.Gly343Arg) formerly classified as a “variant of unknown significance.” In individuals with an
NPHP4
genotype, we observed a complete absence of NPHP4 while NPHP1 was severely reduced. IF results were confirmed by immunoblotting. Variants in other genes related to renal ciliopathies did not show any impact on NPHP1/NPHP4 expression. Aberrant immunostaining in two genetically unsolved individuals gave rise for a further genetic workup resulting in a genetic diagnosis for both with disease-causing variants in
NPHP1
and
NPHP4
, respectively.
Conclusions
IF of patient-derived respiratory epithelial cells may help to secure and accelerate the diagnosis of nephronophthisis—both by verifying inconclusive genetic results and by stratifying genetic diagnostic approaches. Furthermore, we provide in vivo evidence for the interaction of NPHP1 and NPHP4 in a functional module.
Graphical abstract
A higher-resolution version of the Graphical abstract is available as
Supplementary information
Journal Article
Renal Tubule-Specific Deletion of Nephrocystin 3 (Nphp3) Causes Infantile Nephronophthisis-like Phenotypes in Mice
Patients with nephronophthisis caused by nephrocystin 3 (NPHP3) variants rapidly progress to end-stage kidney disease. However, existing Nphp3 mouse models fail to fully recapitulate the characteristics of this disease. We generated a renal tubule-specific Nphp3 knockout mouse model that more accurately mirrors the human disease course. The mouse model was first validated by confirming the loss of Nphp3 protein expression in renal tubules. Comprehensive phenotypic analyses were then performed to assess both renal and extrarenal manifestations. The origin of renal cysts was investigated, and the underlying mechanisms were further validated. We successfully generated a renal tubule-specific Nphp3 knockout mouse model (Cdh16-Cre; Nphp3flox/flox). These mice exhibited a markedly shortened lifespan (5–8 weeks) and developed key features of infantile nephronophthisis, including early-onset renal cysts originating from distal tubules and collecting ducts, progressive interstitial fibrosis that was evident by postnatal week 2, a rapid decline in kidney function, and increased urinary protein levels. Importantly, treatment with the vasopressin V2 receptor antagonist tolvaptan or the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040) significantly attenuated cyst growth and improved kidney morphology, confirming shared pathogenic pathways with other Nphp3 models. We established a renal tubule-specific Nphp3 knockout mouse model that accurately recapitulates the aggressive infantile form of nephronophthisis characterized by early cystogenesis, progressive fibrosis, and a shortened lifespan, and is ideal for evaluating novel interventions against this currently untreatable ciliopathy.
Journal Article
Approach to simple kidney cysts in children
The finding of a simple kidney cyst in a child can pose a diagnostic and management challenge for pediatric nephrologists, urologists, and primary care providers. The reported prevalence varies from 0.22 to 1% in large ultrasonography-based series of more than 10,000 children each. The true prevalence, however, may be higher or lower, as factors such as variations in referral patterns, indications for ultrasonography, or technical considerations could impact prevalence rates. For many patients, simple kidney cysts may be found incidentally when imaging is performed for another indication. Although simple cysts can occur in children, they may also represent the first sign of autosomal dominant polycystic kidney disease (ADPKD) or other less common cystic kidney diseases. Definitive guidelines regarding the evaluation and monitoring of children with simple kidney cysts have not been established. The desire on the part of the practitioner and/or parents to establish a definitive diagnosis should be balanced with the cost and inconvenience of repeated imaging and visits with specialists. The goals of this review are to (1) outline the definition, epidemiology, clinical presentation, and natural history of simple kidney cysts in childhood; (2) describe clinical features that could suggest a diagnosis other than a simple kidney cyst; and (3) present a suggested framework for evaluating and monitoring of children with one or more simple kidney cysts.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Journal Article
Matching clinical and genetic data in pediatric patients at risk of developing cystic kidney disease
Background
Cystic kidney disease is a heterogeneous group of hereditary and non-hereditary pathologic conditions, associated with the development of renal cysts. These conditions may be present both in children and adults. Cysts can even be observed already during the prenatal age, and pediatric patients with cysts need to be clinically monitored. An early clinical and genetic diagnosis is therefore mandatory for optimal patient management. The aim of this study was to perform genetic analyses in patients with echographic evidence of kidney cysts to provide an early molecular diagnosis.
Methods
A cohort of 70 pediatric patients was enrolled and clinically studied at the time of first recruitment and at follow-up. Genetic testing by clinical exome sequencing was performed and a panel of genes responsible for “cystic kidneys” was analyzed to identify causative variants. Sanger validation and segregation studies were exploited for the final classification of the variants and accurate genetic counseling.
Results
Data showed that 53/70 of pediatric patients referred with a clinical suspicion of cystic kidney disease presented a causative genetic variant. In a significant proportion of the cohort (24/70), evidence of hyper-echogenic/cystic kidneys was already present in the prenatal period, even in the absence of a positive family history.
Conclusions
This study suggests that cystic kidney disease may develop since the very early stages of life and that screening programs based on ultrasound scans and genetic testing play a critical role in diagnosis, allowing for better clinical management and tailored genetic counseling to the family.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Journal Article