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At least 19 recordsLinked to original sources
PubMed1979

Obstruction of the inferior vena cava complicating hemodialysis in polycystic kidney disease.

Two patients with polycystic kidney disease and renal failure developed profound hypotension within 30 minutes after starting hemodialysis. After ruling out all recognized causes of hypotension during early dialysis, we found that their vena cavas were obstructed by compression of the vessels against the spinal column by the greatly enlarged polycystic kidneys. Immediately after bilateral nephrectomy, the patients had dialysis, with removal of large amounts of fluid without causing hypotension. We speculate that compression of the vena cava by massively enlarged polycystic kidneys may significantly contribute to the renal insufficiency by greatly increasing renal venous pressure.

Humans↗
PubMed2026

PKD1 upstream open reading frames affect Polycystin-1 expression and polycystic kidney disease phenotypes.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5%-10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein's coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5' UTR mouse models with or without single nucleotide edits removing uORF start codons (ΔuORF) to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation, and ΔuORF conveys a 2-4 fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of WT PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.

Animals↗
PubMed1979

[Kidney polycystic disease as the major feature in three adults with congenital hepatic fibrosis. 3 cases (author's transl)].

Congenital hepatic fibrosis is nearly always associated with ectasia of collecting tubules of the kidneys. This abnormality usually remains silent. In this study we report three cases of adult's CHF with associated renal failure treated by hemodialysis. In all three cases, renal injuries were indistinguishable from those found in adult-type of polycystic disease. The kidneys of our third patient, who underwent two nephrectomies at a 14-years interval, showed ectasia of the collecting tubules with only a few cortical cysts. The second one showed numerous large cysts and only a few ectatic tubules. Our data indicate that: renal failure can complicate the CHF course in adults. Uremia can be the pressenting feature; polycystic kidneys in CHF are microscopically different from those found in adult-type, they might be considered as the final stage in ectasia of collecting tubules.

Adult↗
PubMed2026

A Novel Nonsense Variant in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing 6 Promotes Polycystic Kidney Disease in Han:SPRD- Cy Rats and Its Homozygosity Is Prenatally Lethal.

KEY POINTS: A novel nonsense variant ( mcy ) in ankyrin repeat and sterile alpha motif domain-containing 6 ( Anks6 ) promotes rapid disease progression in the Han:SPRD- Cy rat carrying a missense variant in Anks6 . mcy-/- rats exhibit prenatal lethality characterized by laterality and cardiovascular abnormalities. These findings indicate that ANKS6 nonfunction in rats leads to prenatal lethality, whereas misfunction leads to polycystic kidney disease development. BACKGROUND: Polycystic kidney disease (PKD) encompasses a group of genetic disorders characterized by the proliferation of fluid-filled renal cysts, leading to progressive renal failure and death. A key feature of PKD is its variable expressivity across patients, even when caused by the same variant, highlighting the importance of genetic background in PKD expression. METHODS: We identified an ostensibly healthy Sprague Dawley rat line with a variant that modifies PKD expressivity in Han:SPRD- Cy rats (caused by a missense variant [p.Arg717Trp] in the ankyrin repeat and sterile alpha motif domain-containing 6 [ Anks6 ] gene), which we named mcy (modifier of Cy ). We used whole-genome sequencing and segregation analysis to identify the mcy variant, quantitative PCR and mRNA sequencing to evaluate its effects on gene expression, western blotting and immunohistochemistry to assess its protein consequences, and ultrasound and histology to examine its impact on rat embryonic development. RESULTS: We identified a nonsense variant in the Anks6 gene as the genetic basis of the mcy phenotype (c.1126G>T [p.Glu376X]). Although mcy+/- rats are ostensibly healthy and do not develop PKD, mcy-/- rats exhibit laterality defects and die prenatally at E16.5 because of apparent perturbations in cardiovascular development. Notably, mcy+/-Cy+/- rats develop PKD much more rapidly than Cy+/- rats, and in a timeframe consistent with Cy-/-rats . Transcripts with the mcy variant allele seem to undergo nonsense-mediated decay, and no ANKS6 protein is detected. However, gene expression patterns in the kidneys did not differ significantly between age-matched mcy+/+ and mcy+/- rats, indicating that ANKS6 insufficiency does not cause PKD. CONCLUSIONS: We identified a novel nonsense variant in Anks6 . The findings indicate that the absence of wild-type ANKS6 accelerates PKD development in the Han:SPRD- Cy rat and that complete ANKS6 deficiency prevents normal embryonic development in rats.

Animals↗
PubMed1979

Perinephric abscess in patients with polycystic kidney disease undergoing chronic hemodialysis.

5 patients with polycystic kidney disease undergoing chronic hemodialysis who developed perinephric abscesses are described. Gallium-67 scintigraphy was helpful in making a diagnosis in 2 of these patients. All 5 patients initially presented with urinary tract infections. Perinephric abscess became evident over a variable period of time (2--28 days) following completion of antibiotic therapy for their urinary tract infection. Gallium-67 scintigraphy appears useful in detecting this complication, and nephrectomy should be considered once the diagnosis is confirmed.

Abscess↗
PubMed1978

Renal transplantation in polycystic kidney disease.

Thirty-one renal transplantations were performed in 25 patients with end-stage polycystic disease of the kidneys. Of the 14 recipients transplanted with both polycystic kidneys in situ and followed for at least 6 months, 10 had a previous history of urinary tract infection. Four of these 14 recipients had relapsing urinary tract infection after transplantation, the other 10 have been at risk on immunosuppressive therapy for a total of 152 months and have had no trouble that could be attributed to the presence of the polycystic kidneys. Despite the potentiality of polycystic kidneys to be a source of post-transplant infection when left in situ, a good outcome of renal transplatation could be achieved without preparative bilateral nephrectomy. The one-year patient and graft survivals are comparable to those obtained in our total transplantation series and renal transplantation is considered to be an acceptable therapy in polycystic disease.

Adult↗
PubMed1978

Adult polycystic kidney disease: ultrasonographic and computed tomographic appearance.

Sixteen patients with adult polycystic kidney disease (PKD) were studied by gray scale B mode ultrasonography. The nephrosonographic appearance of adult PKD is a spectrum ranging from kidneys of normal size to enlarged kidneys with multiple variable-sized cysts. Strong focal cortical echoes were present in patients with only small cysts in the renal cortex. Hepatic cysts, which appeared as sharply marginated anechoic regions within the liver parenchyma, were detected by ultrasound in 50% of our patients. Hepatic and renal cysts appeared on computed tomograms as sharply defined, ovoid areas of low attenuation. There was good diagnostic correlation between ultrasonography and computed tomograms as sharply defined, ovoid areas of low attenuation. There was good diagnostic correlation between ultrasonography and computed tomography. Ultrasound and computed tomography are accurate methods for diagnosis of adult PKD; however, the ability to diagnose quickly and noninvasively both renal involvement and associated extrarenal involvement makes ultrasound the procedure of choice for diagnosis, screening, and followup.

Adult↗
PubMed1977

The management of polycystic kidney disease with special reference to dialysis and transplantation.

The records of 65 patients with adult type polycystic kidney disease were examined in an attempt to identify the problems and priorities in the management of these patients, with particular reference to ultimate haemodialysis or transplantation. The three main problems of patients presenting before the onset of terminal renal failure were hypertension (72 per cent), pain (36 per cent) and urinary tract infection (32 per cent). Less common complications included haematuria, splenomegaly, gastro-intestinal disturbances and disorders of calcium metabolism. The polycystic kidney patient who is considered for renal transplantation poses questions of the desirability and timing of bilateral nephrectomy, vagotomy and splenectomy. Eight patients died without receiving a transplant, five of them from uraemia. Thirty-one patients received 36 kidney transplants and 46 per cent of these were functioning one year after transplantation. Thirteen patients who had received transplants died. Analysis of the causes of death suggests that in nearly half, major contributing factors might have been anticipated and we therefore feel that regular surveillance from the time of diagnosis is essential for patients with polycystic kidney disease.

Adolescent↗
PubMed1979

Tubular function in adult polycystic kidney disease.

Various tubular functions were assessed in 10 patients with polycystic kidney disease (PKD). Three relatively unique abnormalities were apparent in many of these patients -- an inability to maximally concentrate urine, a decrease in ability to lower urine pH after acute acid challenge, and an inability to excrete adequate amounts of ammonium during persistent acid challenge. The defects in urinary acidification and ammonium excretion in PKD have not been previously described.

Adult↗
PubMed2022

Enhancer and super-enhancer landscape in polycystic kidney disease.

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.

Animals↗
PubMed1978

Transplantation for polycystic kidney disease.

Twenty-four patients with end stage renal failure due to polycystic renal disease have been treated with hemodialysis and transplantation. While on dialysis, the incidence of complications did not differ from a similar group of patients with other causes of renal failure. Bilateral pretransplant nephrectomy is not mandatory except in cases of persistent infection or hemorrhage. A much higher incidence of HLA A3 and HLA B7 was noted in patients with polycystic disease when compared with the general population. Following cadaver renal transplantation, kidney function was significantly better in patients with polycystic disease when compared with those with other forms of renal failure. Patient survival was the same in both groups. We conclude that hemodialysis and transplantation are acceptable forms of treatment for a patient with end stage polycystic renal disease.

Adult↗
PubMed2026

Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease.

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3'UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

Animals↗
PubMed1976

Peritoneoscopy in adult polycystic kidney disease: its diagnostic value.

The value of peritoneoscopy in the diagnosis of renal polycystic disease was tested in nine patients with adult polycystic disease and one with congenital hepatic fibrosis. The right kidney was visualized in all ten cases and the left in seven. Renal cysts were recognized by peritoneoscopy in eight of the ten patients. Factors impeding visualization of the kidneys and the cysts were: a) fixation of the splenic flexure of the colon; b) non-superficial renal cysts. Of six cases in which intravenous pyelography was not diagnostic, peritoneoscopy was positive in four. No correlation was found between the degree of hepatic and renal cystic involvement.

Adolescent↗
PubMed2025

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

PURPOSE: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). METHODS: We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. RESULTS: Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions. CONCLUSION: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

Humans↗
PubMed2026

Pierson syndrome with numerous dilated tubules masquerading as autosomal recessive polycystic kidney disease: a case report.

Pierson syndrome, characterized by congenital nephrotic syndrome, ocular abnormalities, and neurological defects, is caused by biallelic pathogenic variants in LAMB2. LAMB2 encodes laminin β2, a key component of basement membranes that is predominantly expressed in the glomeruli, eyes, and neuromuscular junctions. The renal histopathology of Pierson syndrome typically shows diffuse mesangial sclerosis (DMS), with occasional tubulointerstitial atrophy and fibrosis. We report a case of Pierson syndrome characterized by DMS and prominent tubular dilatation. A fetal ultrasound at 23 weeks of gestation revealed hyperechoic kidneys, which gradually enlarged, accompanied by the onset of anhydramnios from 31 weeks. The patient was delivered at 39 weeks of gestation, weighing 3,132 g, without placentomegaly. Postnatal respiratory failure due to pulmonary hypoplasia required extracorporeal membrane oxygenation, and hemodialysis was initiated for anuria. Left nephrectomy was performed on day 8 of life, revealing replacement of the renal parenchyma by numerous irregularly dilated tubules with eosinophilic casts. The right kidney reached maximal enlargement by 1 month of age and subsequently began to shrink. Ocular findings included bilateral microcoria and cataracts. Whole-exome sequencing identified compound heterozygous truncating variants in LAMB2 (p.Gln1507Ter and p.Gln1622Ter). This case highlights the need to consider Pierson syndrome in the differential diagnosis of prenatally detected hyperechoic and enlarged kidneys, in addition to polycystic kidney disease.

Female↗