Renal Cystic Disease Research Articles

Polycystin 1 is an atypical adhesion GPCR that responds to non‐canonical WNT signals and inhibits GSK3β

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 and PKD2 genes, which encode PC1 and PC2, respectively. PC1 is a 460kD multi‐spanning membrane protein. PC1 undergoes multiple proteolytic cleavages, one of which is an autocatalytic cleavage that produces a large N terminal fragment (NTF) that remains non‐covalently attached to the membrane‐embedded C terminal fragment (CTF). A recent study demonstrates that PC1 serves as a receptor for Wnt ligands through the direct binding of these ligands to the PC1 NTF. We find that PC1 responds to Wnt9b by shedding its 350kD NTF, which bears a striking resemblance to the activation mechanism of an adhesion GPCR. For aGPCRs, NTF removal liberates a short peptide sequence near the GPS cleavage site called stachel, which then interacts with an internal binding site and engages a G protein signalling cascade. We find that Wnt9b induces a PC1‐dependent phosphorylation and inhibition of the GSK3β kinase through the RhoA GTPase‐ROCK kinase pathway. Expression of a “constitutively active” aGPCR form of PC1 that lacks its NTF leads to profound suppression of GSK3β activity that is dependent upon RhoA and ROCK. Interestingly, GSK3β is an important negative regulator of the HIPPO/non‐canonical Wnt signaling target TAZ(WWTR1), lack of which leads to the development severe renal cysts. Furthermore, recent data show that pharmacological inhibition of GSK3β is beneficial in mouse models of ADPKD. We find that exogenous expression of an active form of TAZ in PC1 null cells or in PKD1a/b morphant zebrafish suppresses the development of relevant phenotypes. We also demonstrate that pharmacological inhibition of GSK3β leads to accumulation of the TAZ protein and to reduced cystogenesis in a 3D matrigel assay employing PC1 null cells. TAZ abundance and activity have been shown to be upregulated through the non‐canonical Wnt signalling pathway. We find that HEK293 cells that express PC1 and PC2 respond to Wnt9b treatment by significantly increasing TAZ abundance as compared to the wild type HEK293 cells treated in the same manner. Taken together, our data suggest that PC1 is an aGPCR‐like receptor for non‐canonical Wnt ligands that participates in a novel signalling pathway by linking non‐canonical Wnt ligands to the GSK3β‐dependent regulation of TAZ, a multifaceted signalling molecule whose absence is sufficient to induce renal cystic disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Unilateral renal cystic disease: a case report study

Unilateral renal cystic disease (URCD) of kidney is a non-familial, extremely rare condition, characterized by replacement of the renal parenchyma of one kidney by a cluster of multiple cysts of varying size with a normal contralateral kidney. It is morphologically indistinguishable from autosomal dominant polycystic kidney disease (ADPKD); as such, hepatic and pancreatic cysts is not seen and shows no progressive deterioration in renal function; thus, differentiating ADPKD from URCD becomes important. We report a case of URCD documented by clinical and radiological imaging. A 21 year-old female, presented with history of mild lancinating pain in the left flank for 6 years which aggravated in the past 3 days, with no history of lower urinary tract symptoms. No significant family illnesses reported. Examination showed normal vitals and ballotability present and associated tenderness on deep palpation in left lumbar region. Laboratory findings were within normal limits. Ultrasonography of abdomen and pelvis showed left hydronephrosis with multiple cysts. CECT Abdomen revealed an enlarged left kidney (∼15×16×10 cm) filled with variable sized round, well-marginated multiple cysts. Renal ultrasound was performed on patient’s parents and her siblings and ruled out cystic renal disease. Hence, authors considered the diagnosis of URCD in this patient. In conclusion, treatment and managing guidelines of URCD have not been mentioned in any of the medical literatures. There is little information regarding the progression of URCD. Hence there is a need for further understanding of pathogenesis, progression and management of these patients.

Multifocal renal cell carcinoma associated with multiple simple renal cysts: A rare presentation

Multifocal renal cell carcinoma associated with multiple simple renal cysts: A rare presentation - ACHR- Print ISSN No: - 2581-5725 Online ISSN No:- 2456-9267 Article DOI No:- 10.18231/2456-9267.2019.0016, IP Archives of Cytology and Histopathology Research-IP Arch Cytol Histopathol Res

Increased salt intake does not worsen the progression of renal cystic disease in high water-loaded PCK rats.

The anti-diuretic hormone arginine vasopressin is thought to be a detrimental factor in polycystic kidney disease (PKD). We previously reported that high water intake (HWI) reduced urine osmolality and urinary arginine vasopressin, improved renal function, and reduced the kidney/body weight ratio in PCK rats, an orthologous model of human PKD. In PKD patients, however, it is reported that HWI increases total kidney volume, urine volume, and urine sodium excretion, which could be a consequence of high salt intake. In the current study, we loaded PCK rats with high salt concurrently with HWI to determine whether this human-imitated condition exacerbates disease progression. PCK rats were assigned into 4 groups: control group (CONT: distilled water), HWI group (HWI: 5% glucose in water), HWI with 0.2% NaCl group (HWI+0.2%NaCl), and HWI with 0.45% NaCl group (HWI+0.45%NaCl). Total water intake during the experimental period was increased by 1.86-, 2.02-, and 2.42-fold in HWI, HWI+0.2%NaCl, and HWI+0.45%NaCl, and sodium intake was increased by 2.55- and 5.83-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with CONT. Systolic blood pressure was higher in HWI+0.2%NaCl and HWI+0.45%NaCl than in both CONT and HWI. Serum urea nitrogen, kidney/body weight ratio, cAMP, cystic area, and fibrosis index were significantly lower in HWI compared with CONT, and these ameliorative effects were not abrogated in either HWI+0.2%NaCl or HWI+0.45%NaCl. The amount of sodium excreted into the urine was increased by 2.50- and 8.38-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with HWI. Serum sodium levels were not different between the groups. These findings indicate that the beneficial effect of HWI against the progression of cystic kidney disease was not affected even by high salt-overload in this rodent model of PKD.

Multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney: CT and MRI findings and clinical characteristic.

The aim of this study was to clarify the radiologic and clinical characteristics of multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney. Fourteen patients with unique and characteristic multiple hemorrhagic subcapsular cortical cysts of the kidney, not categorized in any existing renal cystic diseases, were retrospectively reviewed. The clinical information including age, sex, symptom, family history of renal or renal cystic disease, and laboratory data were collected. CT and MRI findings including distribution, number and size of cysts, and CT attenuation and signal intensity on T1- and T2-weighted MRI of cysts were analyzed. All patients except one were young and none had a family history of renal or renal cystic disease. Common clinical symptoms were flank or abdominal pain and hematuria. In all cases, only the left kidney was involved at initial presentation. Cysts were small (median cyst size, 4-15mm), numerous, and distributed mainly along the subcapsular cortex of the kidney. Cysts were hyper-attenuated on unenhanced CT, extremely hypointense on T2-weighted MRI, and mildly hyperintense on T1-weighted MRI. All patients except one had normal renal function. Imaging follow-up revealed stable or mildly progressive disease in seven patients. Two patients developed several hemorrhagic subcapsular cortical cysts in the right kidney at follow-up. Three of five patients with a renal pathology specimen showed concurrent IgA nephropathy. We have identified a unique renal cystic disease with multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney that has a characteristic manifestation both radiologically and clinically. • Multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney is a unique non-familial renal cystic disease with a characteristic manifestation both radiologically and clinically. • Most cases of multiple unilateral subcapsular cortical hemorrhagic cystic disease of the kidney are stable or slowly progressive, and do not require invasive intervention.

Plasma metabolites and lipids associate with kidney function and kidney volume in hypertensive ADPKD patients early in the disease course

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by gradual cyst growth and expansion, increase in kidney volume with an ultimate decline in kidney function leading to end stage renal disease (ESRD). Given the decades long period of stable kidney function while cyst growth occurs, it is important to identify those patients who will progress to ESRD. Recent data from our and other laboratories have demonstrated that metabolic reprogramming may play a key role in cystic epithelial proliferation resulting in cyst growth in ADPKD. Height corrected total kidney volume (ht-TKV) accurately reflects cyst burden and predicts future loss of kidney function. We hypothesize that specific plasma metabolites will correlate with eGFR and ht-TKV early in ADPKD, both predictors of disease progression, potentially indicative of early physiologic derangements of renal disease severity.MethodsTo investigate the predictive role of plasma metabolites on eGFR and/or ht-TKV, we used a non-targeted GC-TOF/MS-based metabolomics approach on hypertensive ADPKD patients in the early course of their disease. Patient data was obtained from the HALT-A randomized clinical trial at baseline including estimated glomerular filtration rate (eGFR) and measured ht-TKV. To identify individual metabolites whose intensities are significantly correlated with eGFR and ht-TKV, association analyses were performed using linear regression with each metabolite signal level as the primary predictor variable and baseline eGFR and ht-TKV as the continuous outcomes of interest, while adjusting for covariates. Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing.ResultsTwelve metabolites significantly correlated with eGFR and two triglycerides significantly correlated with baseline ht-TKV at FDR q-value < 0.05. Specific significant metabolites, including pseudo-uridine, indole-3-lactate, uric acid, isothreonic acid, and creatinine, have been previously shown to accumulate in plasma and/or urine in both diabetic and cystic renal diseases with advanced renal insufficiency.ConclusionsThis study identifies metabolic derangements in early ADPKD which may be prognostic for ADPKD disease progression.Clinical trialHALT Progression of Polycystic Kidney Disease (HALT PKD) Study A; Clinical www.clinicaltrials.gov identifier: NCT00283686; first posted January 30, 2006, last update posted March 19, 2015.

Tulp3 Is a Ciliary Trafficking Gene that Regulates Polycystic Kidney Disease

The primary cilium is an organelle essential for cell signaling pathways. One of the most common human genetic diseases is autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in the PKD1 or PKD2 genes that encode Polycystin 1 and 2 (PC1/2), transmembrane proteins that translocate to the cilium. Mutations in genes that disrupt ciliogenesis also cause kidney cysts as part of a "ciliopathic" disease spectrum. The molecular mechanisms that link cilia function with renal cystic diseases are not well understood, and the mechanistic relationship between ADPKD and ciliopathic PKD is not known. Here we identify the gene Tubby-like protein-3 (Tulp3) as a key regulator of renal cystic disease from a forward genetic screen in the mouse. Mice homozygous for a hypomorphic missense mutation within the conserved Tubby domain of Tulp3 develop cysts at late embryonic stages, leading to severe postnatal loss of kidney function. In contrast to other ciliopathic disease models, Tulp3 mutations do not affect ciliogenesis. Instead, we demonstrate that Tulp3 is essential for the trafficking of the Joubert syndrome-associated small GTPase Arl13b into kidney cilia. We show that reduction of Pkd1 dosage promotes cystogenesis in the Tulp3 conditional ciliopathic PKD model. However, in an adult model of ADPKD utilizing inducible conditional Pkd1 deletion, concomitant removal of Tulp3 surprisingly ameliorates cystic disease. Therefore, Tulp3 controls distinct ciliary pathways that positively or negatively regulate cystogenesis depending on the cellular context.

Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation

Transmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat. Animals with TMEM67 heterozygous mutations manifest slowly progressing hydrocephalus, observed during the postnatal period and continuing into adulthood. These animals have no overt renal phenotype. The TMEM67 homozygous mutant rats have severe ventriculomegaly as well as severe polycystic kidney disease and die during the neonatal period. Protein localization in choroid plexus epithelial cells indicates that aquaporin 1 and claudin-1 both remain normally polarized in all genotypes. The choroid plexus epithelial cells may have selectively enhanced permeability as evidenced by increased Na+, K+ and Cl− in the cerebrospinal fluid of the severely hydrocephalic animals. Collectively, these results suggest that TMEM67 is required for the regulation of choroid plexus epithelial cell fluid and electrolyte homeostasis. The Wpk rat model, orthologous to human MKS3, provides a unique platform to study the development of both severe and mild hydrocephalus.

Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in-depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.

Diagnostic Utility of Exome Sequencing for Kidney Disease

BackgroundExome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.MethodsWe conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.ResultsIn all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.ConclusionsExome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.)

Heterozygous Pkhd1C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney.

Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642* homozygotes. Interestingly, aged female Pkhd1C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.

Increased water intake reduces long-term renal and cardiovascular disease progression in experimental polycystic kidney disease.

Polycystic kidney disease (PKD) is the most common inherited cause of kidney failure and currently has limited treatment options. Increasing water intake reduces renal cyst growth in the pck rat (a genetic ortholog of autosomal recessive PKD) but it is not clear if this beneficial effect is present in other models of PKD. In this study, we tested the hypothesis that high water intake (HWI) reduces the progression of cystic renal disease in Lewis polycystic kidney (LPK) rats (a genetic ortholog of human nephronophthisis-9). Groups of female and male LPK (n = 8–10 per group) and Lewis (n = 4 per group) rats received water ad libitum supplemented with or without 5% glucose [to simulate HWI or normal water intake (NWI) respectively] from postnatal weeks 3 to 16. Water intake increased ~1.3-fold in the LPK+HWI group compared to LPK+NWI rats between weeks 3 to 10 but the differences were not significant at later timepoints. In LPK rats, HWI reduced the increases in the kidney to body weight ratio by 54% at week 10 and by 42% at week 16 compared to NWI (both p<0.01). The reduction in kidney enlargement was accompanied by decreases in the percentage renal cyst area, percentage renal interstitial collagen and proteinuria (all p<0.05). At week 16, HWI reduced systolic blood pressure and the heart to body to weight ratio by 16% and 21% respectively in males LPK rats (both p<0.01). In conclusion, a modest increase in water intake during the early phase of disease was sufficient to attenuate renal cystic disease in LPK rats, with secondary benefits on hypertension and cardiovascular disease. These data provide further preclinical evidence that increased water intake is a potential intervention in cystic renal diseases.

Analysis of primary cilia in renal tissue and cells.

Primary cilia are singular, sensory organelles that extend from the plasma membrane of most quiescent mammalian cells. These slender, microtubule-based organelles receive and transduce extracellular cues and regulate signaling pathways. Primary cilia are critical to the development and function of many tissue types, and mutation of ciliary genes causes multi-system disorders, termed ciliopathies. Notably, renal cystic disease is one of the most common clinical features of ciliopathies, highlighting a central role for primary cilia in the kidney. Additionally, acute kidney injury and chronic kidney disease are associated with altered primary cilia lengths on renal epithelial cells, suggesting ciliary dynamics and renal physiology are linked. Here we describe methods to examine primary cilia in kidney tissue and in cultured renal cells. We include immunofluorescence and scanning electron microscopy to determine ciliary localization of proteins and cilia structure. Further, we detail cellular assays to measure cilia assembly and disassembly, which regulate cilia length.

Seroprevalence of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus among hemodialysis patients in a Tertiary Care Teaching Hospital in a developing country.

Background:Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) prevalence in hemodialysis patients varies geographically, both within and between countries. High prevalence of these infections in dialysis patients reflects the increased presence of common risk factors for their acquisition, including transfusion, transplantation, history of drug abuse, plus susceptibility to nosocomial transmission during dialysis.Objective:The aim of this study is to investigate the seroprevalence and clinical profile of HIV, HBV, and HCV patient's on hemodialysis.Materials and Methods:Clinical and epidemiological data of patients undergoing maintenance hemodialysis in the dialysis unit of a teaching institution were obtained and analyzed over a 5 years' period.Results:A total of 127 males and 69 females were studied. Their mean age was 50.45 years. Out of the total 196 dialysis-dependent patients, 2 (1.02%) were seropositive for HIV antibodies, 6 (3.06%) were hepatitis B surface antigen positive, and 30 (15.30%) were anti-HCV antibody positive. There was no coexistence of HIV, HBV, and HCV markers. The major primary renal diseases in hemodialysis patients included diabetes mellitus (42%), hypertension (22%), chronic nephritis (15%), urologic diseases (6%), cystic renal diseases (4%), and others (11%).Conclusion:Prevalence of transfusion-transmissible viral infections was higher among hemodialysis patients, especially HCV infection which was an alarming situation and therefore strict adherence to infection control strategies, barrier precautions, and preventive measures, including routine hepatitis B vaccination and regular virological follow-up were recommended along with regular education and training programs of technical and nursing personnel's involved with dialysis patients.

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism.

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

Bilateral chromophobe renal cell carcinoma in an end-stage renal disease patient on haemodialysis

There is a well-known association between end-stage renal disease (ESRD) and the development of kidney cancer in the native kidney of patients requiring renal replacement therapy. There is now emerging evidence that lesser degrees of renal insufficiency (chronic kidney disease [CKD]) are also associated with an increased likelihood of cancer in general and kidney cancer in particular. Bilateral renal involvement by primary malignant processes is uncommon, although known to occur with Wilms tumours and in von Hippel–Lindau disease. Our patient is a 65-year-old female CKD, on haemodialysis for 8 years with bilateral renal tumours, underwent laparoscopic bilateral radical nephrectomy with histopathology reported as synchronous chromophobe bilateral renal cell carcinoma (RCC), which is the first case reported in the literature. In a study for 10 years on patients with CKD on haemodialysis, who developed acquired renal cystic disease (ARCD), there was an increase in the prevalence and severity of the ARCD as the dialysis continues over the years. Twenty per cent of patients dialysed for 1–3 years have ARCD, compared with >90% of patients dialysed for 5–10 years. In another study held at the Massachusetts General Hospital. They found that the occurrence of bilateral RCC is rare and found in only 1.8% of 329 patients who were treated RCC in 30 years. In a study published in the European Urology 2011. They also found that there are many favourable clinical, pathological and outcome features in the RCC accompanied with ESRD patients on dialysis which arising in the native kidneys compared with the RCC diagnosed in general population patients.

Pediatric cystic diseases of the kidney.

Pediatric renal cystic diseases include a variety of hereditary or non-hereditary conditions. Numerous classifications exist and new data are continuously published. Ultrasound is the primary technique for evaluating kidneys in children: conventional and high-resolution US allows a detailed visualization of renal parenchyma and of number, size and location of the cysts, hence representing the most important diagnostic imaging technique for the first diagnosis and follow-up of these young patients. The purpose of this pictorial essay is to review the spectrum of renal cystic lesions in children from simple, complex or malignant single cysts to the several poly/multicystic kidney diseases.

A meta-analysis of the incidence and fate of contralateral vesicoureteral reflux in unilateral multicystic dysplastic kidney

Multicystic dysplastic kidney (MCDK) is the most common type of renal cystic disease. It is associated with urinary tract abnormalities in the contralateral kidney in up to 30% of cases, most commonly vesicoureteral reflux (VUR). The objective of this study was to describe the incidence and selected issues in management and evolution for each VUR grade in the contralateral kidney of patients with unilateral MCDK, in order to strengthen the scientific basis regarding the need for voiding cystourethrography (VCUG) screening. A comprehensive search of standard and gray literature was performed. Full-text screening, data abstraction, and quality appraisal were conducted in duplicates. Included studies reported a primary diagnosis of unilateral MCDK with contralateral VUR determined by VCUG. Articles had to include a distribution of VUR grade to meet the eligibility criteria. From 698 retrieved articles, 37 studies enrolling 2057 patients were analyzed. Of the patients, 80% were male; 50% had left unilateral MCDK; and 87% were diagnosed prenatally. A total of 1800 patients had VCUG, of whom 303 had VUR (weighted proportion: 17%; 95% confidence interval [CI]: 14-20%). Weighted proportions of VUR were 9%, 7%, and 17% for grades I-II, III-V, and I-V, respectively. Of the patients, 99% (95% CI: 97-100%) were on continuous antibiotic prophylaxis (CAP) and 18% (95% CI: 8-37%) had urinary tract infections (UTIs), with a higher rate of UTIs (23% vs 10%) in patients with dilating (grades III-V) VUR, over a mean follow-up of 40 months. In patients with dilating VUR, reflux resolved or downgraded to grade I in 52% (95% CI: 37-67%) of patients, and 32% (95% CI: 19-49%) had surgical correction of VUR. Among patients with unilateral MCDK, 17% have VUR in the contralateral kidney, 41% of which is dilating VUR. Of the cases with dilating VUR, half will resolve or downgrade to grade I during follow-up; 23% will develop a UTI despite CAP; and one-third will undergo ureteral re-implantation. While many physicians may thus choose to forego routine VCUG screening of the single functional kidney, shared decision-making with the patient's caregivers is currently recommended, where the risks and benefits of the different approaches can be discussed. The data from this analysis can help inform the discussions.

Renal cystic disease in the Fbn1C1039G/+ Marfan mouse is associated with enhanced aortic aneurysm formation.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.

A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs.

Ciliopathies presenting as inherited hepatorenal fibrocystic disorders are rare in humans and in dogs. We describe here a novel lethal ciliopathy in Norwich Terrier puppies that was diagnosed at necropsy and characterized as diffuse cystic renal disease and hepatic fibrosis. The histopathological findings were typical for cystic renal dysplasia in which the cysts were located in the straight portion of the proximal tubule, and thin descending and ascending limbs of Henle’s loop. The pedigree of the affected puppies was suggestive of an autosomal recessive inheritance and therefore, whole exome sequencing and homozygosity mapping were used for identification of the causative variant. The analyses revealed a case-specific homozygous splice donor site variant in a cilia related gene, INPP5E: c.1572+5G>A. Association of the variant with the defect was validated in a large cohort of Norwich Terriers with 3 cases and 480 controls, the carrier frequency being 6%. We observed that the identified variant introduces a novel splice site in INPP5E causing a frameshift and formation of a premature stop codon. In conclusion, our results suggest that the INPP5E: c.1572+5G>A variant is causal for the ciliopathy in Norwich Terriers. Therefore, genetic testing can be carried out in the future for the eradication of the disease from the breed.