Autosomal Dominant Adult Polycystic Kidney Research Articles

The crucial role of the nephrologist in the management of pregnancy in women with adult autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease characterized by gradual kidney enlargement and progressive renal function loss. Pregnancy is a significant risk factor for adverse maternal and fetal outcomes in chronic kidney disease (CKD), regardless of the nephropathy. Women with ADPKD often face concerns about worsening their renal condition and passing the disease on to their offspring. Recent studies show better outcomes due to improved pregnancy surveillance and prior counseling. Risk factors for poor fetal and maternal outcomes include advanced maternal age, pre-existing hypertension, urinary infections, proteinuria, and renal failure. Collaboration between nephrologists and gynecologists is essential for addressing clinically significant concerns in pregnant women with ADPKD. Nephrologists should play an active role in assisting and supporting pregnant ADPKD patients as part of a multidisciplinary team.

Dehydration Accelerates Cytogenesis and Cyst Growth in Pkd1-/- Mice by Regulating Macrophage M2 Polarization.

Adult autosomal dominant polycystic kidney disease (ADPKD) has been shown to be related as a "third hit" to the occurrence of acute or chronic kidney injury. Here, we examined whether dehydration, as a common kidney risk factor, could cause cystogenesis in chronic-onset Pkd1-/- mice by regulating macrophage activation. First, we confirmed that dehydration accelerated cytogenesis in Pkd1-/- mice and that macrophages infiltrated the kidney tissues even earlier than macroscopic cyst formation. Then, microarray analysis suggested that glycolysis pathway may be involved in macrophage activation in Pkd1-/- kidneys under conditions of dehydration. Further, we confirmed glycolysis pathway was activated and lactic acid (L-LA) was overproduced in the Pkd1-/- kidney under conditions of dehydration. We have already proved that L-LA strongly stimulated M2 macrophage polarization and overproduction of polyamine in macrophage in vitro, and in the present study, we further discovered that M2 polarization-induced polyamine production shortened the primary cilia length by disrupting the PC1/PC2 complex. Finally, the activation of L-LA-arginase 1-polyamine pathway contributed to cystogenesis and progressive cyst growth in Pkd1-/- mice recurrently exposed to dehydration.

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner

Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, we investigate the role of global deletion of an IFT-A gene, Ttc21b, in juvenile and adult mouse models of ADPKD. Both juvenile (postnatal day 21) and adult (six months of age) ADPKD mice exhibited kidney cysts, increased kidney weight/body weight ratios, lengthened kidney cilia, inflammation, and increased levels of the nutrient sensor, O-linked β-N-acetylglucosamine (O-GlcNAc). Deletion of Ttc21b in juvenile ADPKD mice reduced cortical collecting duct cystogenesis and kidney weight/body weight ratios, increased proximal tubular and glomerular dilations, but did not reduce cilia length, inflammation, nor O-GlcNAc levels. In contrast, Ttc21b deletion in adult ADPKD mice markedly attenuated kidney cystogenesis and reduced cilia length, inflammation, and O-GlcNAc levels. Thus, unlike IFT-B, the effect of Ttc21b deletion in mouse models of ADPKD is development-specific. Unlike an IFT-A adaptor, deleting Ttc21b in juvenile ADPKD mice is partially ameliorative. Thus, our studies suggest that different microenvironmental factors, found in distinct nephron segments and in developing versus mature stages, modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a pathological feature of ADPKD.

Study of two pedigrees affected with adult polycystic kidney disease and male infertility resulting from novel mutations of PKD1

To explore the genetic etiology of two Chinese pedigrees affected with autosomal dominant adult polycystic kidney disease and male infertility. The coding regions of the PKD1 and PKD2 genes were subjected to PCR and Sanger sequencing. Suspected pathogenic mutations were analyzed by pedigree analysis and bioinformatics analysis. Mutation screening was performed using Sanger sequencing of blood samples obtained from 50 healthy individuals. Two novel heterozygous mutations, c.6953_6977 del(p.Arg2318Hisfs*15) and c.10937T>G (p.Val3646Gly) of the PKD1 gene were identified in the affected members of the two pedigrees, respectively, but not among to normal family members of the two pedigrees. Pedigree and bioinformatics analysis showed that both mutations were pathogenic. No pathological mutations were found in the cohort of 50 healthy individuals. Two novel mutations, c.6953_6977del(p.Arg2318Hisfs*15) and c.10937T>G (p.Val3646Gly) of the PKD1 gene may be responsible for the disease in the two pedigrees, which have enriched the spectrum of PKD1 gene mutations and provided a basis for genetic counseling and prenatal disgnosis.

The association of serum angiogenic growth factors with renal structure and function in patients with adult autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common congenital chronic kidney disease (CKD). We report here the relationship of serum angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) with total kidney volume (TKV), total cyst volume (TCV), and renal failure in adult ADPKD patients at various stages of CKD. This cross-sectional study was conducted with 50 patients diagnosed with ADPKD and a control group of 45 age-matched healthy volunteers. In patient group, TKV and TCV were determined with upper abdominal magnetic resonance imaging, whereas in controls, TKV was determined with ultrasonography according to ellipsoid formula. Renal function was assessed with serum creatinine, estimated glomerular filtration rate (eGFR), and spot urinary protein/creatinine ratio (UPCR). Ang-1, Ang-2, and VEGF were measured using enzyme-linked immunosorbent assay. Patients with ADPKD had significantly higher TKV (p < 0.001) and UPCR (p < 0.001), and lower eGFR (p ≤ 0.001) compared to the controls. Log10Ang-2 was found to be higher in ADPKD patients at all CKD stages. Multiple linear regression analysis showed that there was no association between log10Ang-1, log10Ang-2, or log10VEGF and creatinine, eGFR, UPCR, log10TKV (p > 0.05). There was no association of serum angiogenic growth factors with TKV or renal failure in ADPKD patients. Increased serum Ang-2 observed in stages 1-2 CKD suggests that angiogenesis plays a role in the progression of early stage ADPKD, but not at later stages of the disease. This may be explained by possible cessation of angiogenesis in advanced stages of CKD due to the increased number of sclerotic glomeruli.

A Successful Kidney Transplant for a Case of LMX1B Gene Mutation with a Positive Family History of Polycystic Kidney Disease

Nail-Patella syndrome is pleiotropic autosomal dominant disorder characterized by skeletal abnormalities and frequently renal disease. In this case report genetic analysis revealed a pathogenic heterozygous missense mutation of the LMX1B gene as c.[737G>A], p.([Arg246Gln)]. This variant is predicted to cause substitution of a basic arginine residue for a polar uncharged glutamine residue at position 246. The nucleotide at position 737 and amino acid at position 246 are both highly conserved across species. Although LMX1B mutation causing hereditary focal segmental glomerulosclerosis (FSGS) without any extra-renal involvement has been described as nail patella like renal disease (NPLRD) where there is partial impairment of transcriptional activity with these mutations leading to absence of other features of nail patella syndrome (NPS). Our case report gets interesting as patient had progressed relatively quickly to end stage renal disease. Some of heterozygous gene mutation FSGS cases are expected to recur after kidney transplantation. Our case has received a successful renal transplant from brother which is working well for the last 3 years without any evidence of recurrence. Another interesting feature of our case was the strong family history of unrelated other renal genetic disorder autosomal dominant adult polycystic kidney disease (ADPKD).

Antihypertensive treatments in adult autosomal dominant polycystic kidney disease: network meta-analysis of the randomized controlled trials.

Blood pressure (BP) control is one of the most important treatments of Autosomal dominant polycystic kidney disease (ADPKD). The comparative efficacy of antihypertensive treatments in ADPKD patients is inconclusive. Network meta-analysis was used to evaluate randomized controlled trials (RCT) which investigated antihypertensive treatments in ADPKD. PubMed, Embase, Ovid, and Cochrane Collaboration were searched. The primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes were serum creatinine (Scr), urinary albumin excretion (UAE), systolic BP (SBP), diastolic BP (DBP), mean artery pressure (MAP) and left ventricular mass index (LVMI). We included 10 RCTs with 1386 patients and six interventions: angiotensin-converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), combination of ACEI and ARB, calcium channel blockers (CCB), β-blockers and dilazep. There was no difference of eGFR in all the treatments in both network and direct comparisons. No significant differences of Scr, SBP, DBP, MAP, and LVMI were found in network comparisons. However, ACEI significantly reduced SBP, DBP, MAP and LVMI when compared to CCB. Significantly increased UAE was observed in CCB compared with ACEI or ARB. Bayesian probability analysis found ARB ranked first in the surrogate measures of eGFR, UAE and SBP. There is little evidence to detect differences of antihypertensive treatments on kidney disease progression in ADPKD patients. More RCTs will be needed in the future. Use of ARB may be an optimal choice in clinical practice.

Autopsy report with clinical and pathophysiologic discussion of autosomal dominant adult polycystic kidney disease.

The average weight of a kidney is approximately 135 gm, measuring on average 10 × 6 × 4 cm. In hereditary conditions, autosomal dominant and autosomal recessive polycystic kidney disease, the shape, size, and the weight can be significantly abnormal, causing progressive renal failure, often necessitating dialysis or renal transplant for survival. We report a case of adult polycystic kidney disease in a 50-year-old female without a family history, who died of complications of the disease which included accelerated hypertension, and renal and cardiac failure.

Detected Renal Cysts Are Tips of the Iceberg in Adults with ADPKD

In autosomal dominant polycystic kidney disease, progressive renal enlargement secondary to expanding cysts is a hallmark. The total cyst load and range of cyst diameters are unknown. The purpose of this study was to quantify the total number and range of diameters of individual cysts in adults with preserved GFR. A retrospective, morphometric analysis of renal cyst number and diameter using magnetic resonance images from eight adult autosomal dominant polycystic kidney disease patients was performed at baseline and after 6.9 years. Cyst number and diameter were measured in microscopic sections of nephrectomy specimens from five different adults. The diameters of 1010 cysts ranged from 0.9 to 77.1 mm in baseline T2 magnetic resonance images, and the mean total number of cysts increased from 682 to 1002 in 6.9 years. However, magnetic resonance imaging detects only cysts above the lower limit of detection. In 405 cysts measured in nephrectomy specimens, 70% had diameters <0.9 mm. Cyst counts by magnetic resonance in eight subjects compared with histology revealed approximately 62 times more cysts below the limit of magnetic resonance imaging detection than above it. This study presents quantitative data indicating that renal cysts develop in a minority of renal tubules. Increased numbers detected by magnetic resonance imaging are caused primarily by cysts below detection at baseline enlarging to a detectable diameter over time. The broad range of diameters, with a heavy concentration of microscopic cysts, may be most appropriately explained by a formation process that operates continuously throughout life.

Recent advances in studies on autosomal dominant adult polycystic kidney disease

Adult polycystic kidney disease (APKD) is a severe autosomal dominant inheritable renal disease with high incidence. Because of the late-onset of the disease, patients might have transferred the disease gene to the next generation when diagnosis is made. Since its pathogenic molecular mechanism is still not completely clear and the shortage of effective medicines, the prevention and treatment of the disease is still not satisfactory. In the present article, the recent advances in the research on the pathogenesis, gene diagnosis and management of APKD are reviewed.

Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.

Acute Aortic Dissection Associated with Adult Autosomal Dominant Polycystic Kidney Disease: Three Case Reports and a Review

Adult autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder responsible for 8% to 10% of cases of end-stage chronic renal failure. The extrarenal complications of ADPKD kidney include cardiovascular disorders (such as mitral valve prolapse syndrome, bicuspid aortic valve, aortic coarctation, aortic aneurysm, and aortic dissection), intracranial aneurysms, diverticulum of colon, hepatic cysts, inguinal hernia, and urinary calculus. Acute aortic dissection (AAD) associated with ADPKD is life-threatening. There are few reports of ADPKD with AAD. To the best of our knowledge, only 9 cases have been found, including at autopsy, in Japan. We have treated 121 patients with AAD in the last 5 years, and 3 of these 121 patients also had ADPKD in the intensive care unit of Nippon Medical School. We report clinical features of cases of ADPKD with AAD on the basis of 12 cases, including 9 previously reported cases and our 3 cases. AAD requires urgent antihypertensive therapy, which often aggravates renal function. Priority should be given to antihypertensive therapy in emergent cases. In fact, 2 of our patients required hemodialysis owing to antihypertensive therapy for AAD. Close cooperation between cardiologists and nephrologists is essential.

Tuberous Sclerosis Complex with an Unruptured Intracranial Aneurysm: Manifestations of Contiguous Gene Syndrome

With the advancement of molecular genetics, the deletion of the TSC2/PKD1 gene at chromosome 16p13.3 has been discovered to be responsible for the tuberous sclerosis complex sharing some of the clinical manifestations of autosomal dominant adult polycystic kidney disease such as multiple renal cysts and intracranial aneurysms. The unruptured aneurysm in tuberous sclerosis complex is far beyond the meaning it has in general population. The risk of aneurysmal hemorrhage in tuberous sclerosis complex may be higher than that in autosomal dominant adult polycystic kidney disease due to the synergistic effect of gene deletion and certainly much higher than that in the general population. For such high-risk patients with intracranial aneurysms doomed to subarachnoid hemorrh age, magnetic resonance angiography plays an important role in screening and follow-up, especially more critically for patients with contiguous gene syndrome. Endovascular coil embolization should be the first choice of treatment for un ruptured intracranial aneurysms.

Fraternal sisters with adult polycystic kidney disease and adenoma of the ampulla of vater

The cases of two fraternal sisters with symptomatic biliary obstruction due to adenomas of the ampulla of Vater are reported. Both sisters had autosomal dominant adult polycystic kidney disease. There are no previous reports of a familial occurrence of ampullary adenomas in the absence of familial adenomatous polyposis, nor has an association between autosomal dominant polycystic kidney disease and ampullary adenoma been described. The coexistence of both disorders in these sisters raises the possibility of a genetic link between autosomal dominant polycystic kidney disease and ampullary adenoma.

Genetic analysis of 20 families with autosomal dominant adult polycystic kidney disease from South West Thames Region

Twenty families with autosomal dominant polycystic kidney disease from S. W. Thames Region were analysed using markers for chromosome 16p13.3, the site of the common mutation (PKD1). Six families gave a negative lod-score for 3'HVR, the most informative distal marker. This could be explained in four cases by recombination events. Of the two families where this was not an explanation, one, of Italian origin, was unequivocally unlinked for all markers, and the other was more likely to be non-PKD1 than linked to 16p13.3. The Italian family was ascertained through the Blood Pressure Unit, and the other via the Genetic Clinic. No members of either family had ever attended a renal clinic. The remaining 18 families either came via renal clinics, or had at least one member attending such a centre.

Spectrum of hereditary renal disease in a kidney transplant population

Re-evaluation of the underlying renal disease in 1000 consecutive kidney transplant patients revealed 129 cases of adult autosomal dominant polycystic kidney disease and 60 clear and seven suspected cases with other hereditary renal disorders. Twenty-four of 60 patients had cystic/dysplastic disease--10 of these classified as nephronophthisis, five as polycystic disease, and nine with the renal affection as part of a congenital malformation syndrome. Thirteen patients had Alport's syndrome, nine were diagnosed with tubulointerstitial nephritis, and six had an adult form of focal segmental glomerular sclerosis (FSGS). Two had changes classified as nephrosclerosis, but with an autosomal dominant mode of inheritance. Finnish type congenital nephrotic syndrome was present in two children and familial amyloidosis in two adults. Two patients had an unclassified disease. During follow-up, five patients with cystic/dysplastic disorders manifested liver disease. None of the patients with FSGS had recurrence and none of the Alport patients had anti-GBM disease. There were no other complications related to the renal condition. In conclusion, hereditary disorders are underestimated in regular registries of patients with end-stage renal failure. An adult form of FSGS and what seems to be a hereditary form of nephrosclerosis are among those that merit further study.

The role of genetic factors in the development of end-stage renal disease.

Three etiologies of renal disease account for more than 80% of Medicare-supported (U.S. Federal Government sponsored) end-stage renal disease (ESRD) cases: diabetes mellitus, hypertension and chronic glomerulonephritis. Surprisingly, despite improvements in medical care, their incidence is increasing rapidly in many parts of the world. With the exception of autosomal dominant adult polycystic kidney disease, the DNA polymorphisms causing progressive renal failure in individuals with common diseases have not yet been identified. Although hypertension and diabetes mellitus are associated with ESRD, the majority of patients with these disorders never develop nephropathy. There is abundant evidence that both inherited factors and the environment affect the development of ESRD. Predisposition to nephropathy may be inherited independently from the environmental and hereditary components that produce the associated systemic disease. This review examines the evidence that ESRD results, in part, from inherited factors. It discusses the racially variable risk of renal disease, the familial clustering of ESRD and molecular genetic data in animals and humans with renal failure.

Autosomal dominant polycystic kidney disease

When the BMJ last published an editorial on adult autosomal dominant polycystic kidney disease1 there was no chromosomal assignment for the disorder. Two have since been recognised. The first, designated PKD-1,2 has been localised to a narrow region of about half a million base pairs on the short arm of chromosome 16, but the specific gene has not yet been discovered. A second locus was postulated in 1988,3 and in the past few months two groups have independently confirmed that a second locus exists on chromosome 4q13-q23.4,5 What proportion of cases that this new locus accounts for and whether other loci exist are unknown. The discovery of this second locus will improve the accuracy of presymptomatic …

Diagnosis of adult polycystic kidney disease by genetic markers and ultrasonographic imaging in a voluntary family register.

Diagnosis of autosomal dominant adult polycystic kidney disease (APKD) is possible by ultrasonographic scanning (USS) or by using DNA markers linked to the PKD1 locus. Ultrasonography is complicated by the age dependent penetrance of the gene and linkage studies are subject to recombination errors owing to meiotic crossing over and locus heterogeneity. This study draws on data collected from a voluntary family register of APKD over 10 years. Records of 150 families were examined, ultrasound reports were obtained from 242 people at 50% prior risk, and 37 families were typed for DNA markers. The fraction of APKD resulting from loci unlinked to PKD1 (designated PKD2 here) was calculated at 2.94% (upper confidence limit 8.62%). Some subjects who were negative on initial scan later gave a positive scan, but there was no example of a definite gene carrier aged over 30 giving a negative scan. In families large enough for linkage analysis, most people who were at 50% prior risk could be given a final risk below 5% or above 95%, by using combined ultrasound and DNA studies.

Probe, VK5B, is located in the same interval as the autosomal dominant adult polycystic kidney disease locus, PKD1

The polymorphic DNA probe VK5B (D16S94) was mapped by genetic linkage in families from the Centre d'Etude de Polymorphisme Humain (CEPH) as being in the same interval as the autosomal dominant adult polycystic kidney disease locus (PKD1). The maximum likelihood estimate of the genetic location of VK5B using multipoint linkage analysis was 9.6 cM proximal to 3'HVR (D16S85) and 5.4 cM distal to CRI-0327 (D16S63), in males. The VK5B probe may be useful in PKD1 families for prenatal and presymptomatic diagnosis of the disease. Additional typing of PKD1 families is required to determine whether the location of VK5B is distal or proximal to (PKD1).