Autosomal Dominant Polycystic Kidney Disease Patient Research Articles

A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics.MethodsThe ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population.ResultsA cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles.ConclusionsThe ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.

Generation of an induced pluripotent stem cell line, IBMS-iPSC-014-05, from a female autosomal dominant polycystic kidney disease patient carrying a common mutation of R803X in PKD2

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited forms of polycystic kidney disease, and is characterized by the growth of numerous cysts in both kidneys. Here we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a 63-year-old female ADPKD patient carrying an R803X mutation in the PKD2 gene using the Sendai-virus delivery system. Downstream characterization of these iPSCs showed that they possessed normal karyotyping, were free of genomic integration, retained the disease-causing PKD2 mutation, expressed pluripotency markers and could differentiate into three germ layers.

Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs survey.

Background: Autosomal dominant polycystic kidney disease (ADPKD) affects 12.5 million worldwide. Vasopressin drives cysts growth and in animal models can be suppressed through high water intake. A randomized controlled trial of ‘high’ versus ‘standard’ water intake in ADPKD is essential to determine if this intervention is beneficial. We conducted an ADPKD patient survey to gain an understanding of current fluid intake practices and the design challenges of a randomized water intake trial. Methods: In collaboration with the PKD Charity, we developed and distributed an online survey to ADPKD patients over age 16 years and not on renal replacement therapy. Results: Of the 2377 invited, 89 ADPKD patients completed the Survey of current water Intake practices in autosomal dominant Polycystic kidney disease (SIPs) online questionnaire. Most were female (65, 73%) and white (84, 94%), with a median age group of 45–49 years. The risk of contamination between treatment arms was highlighted by the survey as the majority (70, 79%) routinely discussed ADPKD management with family despite only 17% sharing the same household. More participants reported drinking beyond thirst (65, 73%) than those actually indicating a daily fluid intake of >2 L (54, 61%). This discrepancy emphasizes inaccuracies of fluid intake estimates and the requirement for objective methods of measuring water intake. Overall, only 51% believed high water intake was beneficial, while 91% were willing to participate in research evaluating this. Conclusion: ADPKD poses unique design challenges to a randomized water intake trial. However, the trial is likely to be supported by the ADPKD community and could impact significantly on PKD management and associated healthcare costs.

Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease

Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD). Improvements in screening and diagnosis of ADPKD have allowed earlier diagnosis, later onset of end-stage renal disease, and better survival. However, the main and most effective therapy remains control of hypertension. Hypertension is the most important modifiable risk factor in ADPKD. Therefore, early management of hypertension reduces the incidence of cardiovascular events in ADPKD patients. Stimulation of the renin-angiotensin-aldosterone system (RAAS) plays a central role in the pathogenesis of hypertension in ADPKD. Therapies that block the RAAS have improved patient management, blood pressure control, and ADPKD patient survival. This review highlights the current understanding of the epidemiology, potential pathogenetic mechanisms and proposes a strategy for the treatment and management of hypertension in ADPKD.

Effect of tolvaptan in a patient with autosomal dominant polycystic kidney disease after living donor liver transplantation.

Recently, a large randomized placebo-controlled trial indicated a beneficial effect of tolvaptan on the progression of autosomal dominant polycystic kidney disease (ADPKD) with near-normal kidney function. Meanwhile, the evidence of tolvaptan's efficacy in ADPKD with severe renal insufficiency was limited and higher frequency of liver enzyme elevations were observed in patients taking tolvaptan. Liver transplantation (LT) is the only curative treatment for patients with severe polycystic liver disease associated with ADPKD, but considering that liver injuries should be avoided particularly in patients who underwent LT, we must be careful to start tolvaptan in post-LT ADPKD patients. We describe the case of a patient who had developed severe renal insufficiency after living donor LT, for whom tolvaptan therapy showed marked reduction of total kidney volume and maintenance of renal function without any serious adverse events. This is the first report to show the beneficial effect and safety of tolvaptan, in a post-LT ADPKD patient with severe renal insufficiency, and hopefully will help broaden the spectrum of patients who will benefit from tolvaptan.

LRP5 variants may contribute to ADPKD.

Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c.1680G>T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology.

Inhibition of MiR-199a-5p reduced cell proliferation in autosomal dominant polycystic kidney disease through targeting CDKN1C.

BackgroundWith a prevalence of about 1:500 to 1:1,000, autosomal dominant polycystic kidney disease (ADPKD) often causes renal failure, with many serious complications. However, there is no Food and Drug Administration (FDA) approved therapy available.Material/MethodsMiR-199a-5p level in ADPKD patient samples, rat model, and cell lines were determined with Realtime PCR assay. After miR-199a-5p inhibitor was transfected, we detected the cell proliferation and apoptosis using an MTT assay and an Annexin V-FITC staining kit, respectively. Finally, TargetScan version 5.1 was used to predict the miRNA target and the target gene of miR-199a-5p was proved by a Luciferase assay.ResultsWe identified a dramatically up-regulated microRNA, miR-199a-5p, in ADPKD tissues and cell lines. Our data show that inhibition of miR-199a-5p suppressed cyst cells proliferation and induced cell apoptosis. We found that miR-199a-5p might exert this effect through targeting CDKN1C/p57.ConclusionsUp-regulation of miR-199a-5p in ADPKD tissues might promote cell proliferation through suppressing CDKN1C, suggesting miR-199a-5p as a novel target for ADPKD treatment.

Current management of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD), the most frequent cause of genetic renal disease affecting approximately 4 to 7 million individuals worldwide and accounting for 7%-15% of patients on renal replacement therapy, is a systemic disorder mainly involving the kidney but cysts can also occur in other organs such as the liver, pancreas, arachnoid membrane and seminal vesicles. Though computed tomography and magnetic resonance imaging (MRI) were similar in evaluating 81% of cystic lesions of the kidney, MRI may depict septa, wall thickening or enhancement leading to upgrade in cyst classification that can affect management. A screening strategy for intracranial aneurysms would provide 1.0 additional year of life without neurological disability to a 20-year-old patient with ADPKD and reduce the financial impact on society of the disease. Current treatment strategies include reducing: cyclic adenosine monophosphate levels, cell proliferation and fluid secretion. Several randomised clinical trials (RCT) including mammalian target of rapamycin inhibitors, somatostatin analogues and a vasopressin V2 receptor antagonist have been performed to study the effect of diverse drugs on growth of renal and hepatic cysts, and on deterioration of renal function. Prophylactic native nephrectomy is indicated in patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. The absence of large RCT on various aspects of the disease and its treatment leaves considerable uncertainty and ambiguity in many aspects of ADPKD patient care as it relates to end stage renal disease (ESRD). The outlook of patients with ADPKD is improving and is in fact much better than that for patients in ESRD due to other causes. This review highlights the need for well-structured RCTs as a first step towards trying newer interventions so as to develop updated clinical management guidelines.

Epidemiology of patients in England and Wales with autosomal dominant polycystic kidney disease and end-stage renal failure.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end-stage renal failure (ESRF). The epidemiology of the incident ADPKD patient cohort requiring renal replacement therapy (RRT) in England and Wales has not been described. We used a retrospective cohort design. Incident adult patients commencing RRT between 1 January 2000 and 31 December 2011 in England and Wales were identified from the UK Renal Registry. Patients were stratified into three groups based on primary renal diagnosis (PRD): (i) ADPKD, (ii) diabetes as PRD, (iii) individuals with another PRD ('other'). Baseline demographics, comorbidity, care-related measures and outcomes including patient survival are described. A total of 52,608 individuals started RRT during the study period, 3598 (6.8%) had ADPKD, 12,137 (23.1%) diabetes as PRD and 36,873 had another PRD diagnosis. The median age of commencing RRT was 55 years in the ADPKD group compared with 62 and 66 years in those with diabetes or 'other' PRD, respectively. The median age of starting RRT did not change within the ADPKD group over the 10-year period. Median age at death was similar across all groups. The ADPKD group had a lower hazard for all-cause mortality compared with the 'other' PRD group (adjusted hazard ratio 0.45, 95% CI 0.38-0.53). In all PRD groups, crude mortality rates had improved between 2000-06 and 2007-11. Although engaged in renal services earlier than some other patient groups, individuals with ADPKD start RRT at a younger age and this has remained unchanged over the last decade. Developing a nationwide cohort and an enhanced disease-specific dataset would facilitate a wide range of research and quality improvement initiatives to try to modify progression to ESRF and the course of RRT.

Chronic loin pain in a 65-year old adult polycystic kidney disease patient

Background : Autosomal Dominant Polycystic Kidney Disease (ADPKD) is often characterized clinically by acute/chronic pain, hypertension and variable progression to end-stage renal disease. About 60% of all ADPKD patients are estimated to have chronic pain, and often this is the initially presenting symptom of an ADPKD patient that brings them to medical attention. Aim : This study reports a case of a 65-year old with polycystic kidney disease and chronic loin pain. Findings : Our patient presented with history of chronic loin pain which we believed was due to increased cysts sizes/increase in weight of the kidneys. A good history was taken from him on presentation, and also laboratory investigations were carried out. However, the cause of the pain was believed to be due to increase in cysts sizes/weight of the kidneys. The patient was educated on the possible cause of the pain and various treatment options for the condition. He was placed on intermittent use of paracetamol with good response. Conclusion : A concept that must be employed in patients suffering from chronic loin pain is to educate the patient that the pain may not be relieved permanently by any intervention method adopted, and also to offer them the treatment modalities available to enable them to cope with the pain. Key words : Polycystic kidney disease, chronic loin pain, hypertension, paracetamol

Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2)

Polycystin 2 (Pkd2), which belongs to the transient receptor potential family, plays a critical role in development. Pkd2 is mainly localized in the primary cilia, which also function as mechanoreceptors in many cells that influence multiple biological processes including Ca(2+) influx, chemical activity and signalling pathways. Mutations in many cilia proteins result in craniofacial abnormalities. Orofacial tissues constantly receive mechanical forces and are known to develop and grow through intricate signalling pathways. Here we investigate the role of Pkd2, whose role remains unclear in craniofacial development and growth. In order to determine the role of Pkd2 in craniofacial development, we located expression in craniofacial tissues and analysed mice with conditional deletion of Pkd2 in neural crest-derived cells, using Wnt1Cre mice. Pkd2 mutants showed many signs of mechanical trauma such as fractured molar roots, distorted incisors, alveolar bone loss and compressed temporomandibular joints, in addition to abnormal skull shapes. Significantly, mutants showed no indication of any of these phenotypes at embryonic stages when heads perceive no significant mechanical stress in utero. The results suggest that Pkd2 is likely to play a critical role in craniofacial growth as a mechanoreceptor. Pkd2 is also identified as one of the genes responsible for autosomal dominant polycystic kidney disease (ADPKD). Since facial anomalies have never been identified in ADPKD patients, we carried out three-dimensional photography of patient faces and analysed these using dense surface modelling. This analysis revealed specific characteristics of ADPKD patient faces, some of which correlated with those of the mutant mice.

AA-amyloidosis in Autosomal Dominant Polycystic Kidney Disease Caused by Chronic Cyst Infections Lasting for 30 years

We herein report the case of a 66-year-old Japanese woman who was admitted to our hospital due to diarrhea and malaise. She had been diagnosed with autosomal dominant polycystic kidney disease (ADPKD) at 35 years of age and had suffered from recurrent cyst infections since that time. Antibiotic therapy combined with hepatic cyst drainage and cyst sclerosing therapy led to transient improvements each time. At 66 years of age, watery diarrhea occurred. The patient's serum albumin level declined to 1.8 g/dL, and her C-reactive protein level was 4.5 mg/dL. An endoscopic biopsy of the descending colon revealed amorphous deposits in the small arteries and tissues of the submucosal layer. The deposits were positive for Congo Red staining and amyloid A staining. Therefore, AA-amyloidosis was diagnosed. An endoscopic biopsy of the stomach and duodenum also showed AA-amyloid deposits. If an ADPKD patient with a long history of cyst infection develops diarrhea and malaise, AA-amyloidosis should be considered as a possible complication.

A large coronary aneurysm and its probable precursor lesions in a patient with autosomal dominant polycystic kidney disease: An implication for the process of aneurysmogenesis

Coronary artery aneurysms are rare complications of autosomal dominant polycystic kidney disease (ADPKD), and their pathogenesis remains poorly understood. We report an autopsy case of a 64-year-old ADPKD patient with an asymptomatic, large (4 cm in diameter) saccular aneurysm arising from the left circumflex (LCX) branch of the coronary artery with only mild atherosclerotic changes. Autopsy also revealed small, focal defects of media with or without microaneurysm formation in the LCX, mesenteric and renal arteries, and a fibromuscular dysplasia-like lesion with microaneurysm in the common iliac artery. Since polycystin-1 and -2 are expressed in arterial smooth-muscle cells, these findings imply that abnormal polycystin expression in ADPKD initially causes the focal medial defects, some of which might later progress to microaneurysms and then overt aneurysms. To the best of our knowledge, this is the first description of the pathologic findings of an ADPKD-associated coronary aneurysm and its probable precursor lesions in arteries.

Night blindness in a haemodialysed ADPKD patient receiving octreotide.

A 62-year-old woman on chronic haemodialysis since November 2008 for end-stage renal disease (ESRD) due to autosomal dominant polycystic kidney disease (ADPKD) had developed a massive polycystic liver (10.647 mL), causing severe abdominal discomfort, early satiety, dyspepsia and dyspnoea (Figure 1). On the basis of the demonstrated effectiveness of somatostatin analogues in reducing the liver volume in ADPKD patients [1, 2] and taking into account her reluctance for any liver surgery, we offered her a trial treatment with octreotide. We administered a single-test dose of short-acting subcutaneous 100 μg octreotide and observed the patient over a 24-h period. Diarrhoea, vomiting and abdominal cramps occurred several hours after administration, but disappeared the day after. We then started long-acting octreotide treatment at a monthly dose of 20 mg. A few hours after the injection, the patient suffered from diarrhoea, nausea and vomiting. While nausea and vomiting rapidly resolved, diarrhoea persisted over the whole next month. Thus, the monthly dose of octreotide was reduced to 10 mg. After 3 months of treatment, diarrhoea persisted with fatty and discoloured stools. At the same time, the patient began to report loss of nocturnal peripheral vision. She explained that, in the dark, her visual field was restricted, giving her the feeling of seeing ‘like in a tunnel’.

Successful disease-specific induced pluripotent stem cell generation from patients with kidney transplantation

IntroductionEnd-stage renal disease (ESRD) is a major public health problem. Although kidney transplantation is a viable therapeutic option, this therapy is associated with significant limitations, including a shortage of donor organs. Induced pluripotent stem (iPS) cell technology, which allows derivation of patient-specific pluripotent stem cells, could provide a possible alternative modality for kidney replacement therapy for patients with ESRD.MethodsThe feasibility of iPS cell generation from patients with a history of ESRD was investigated using lentiviral vectors expressing pluripotency-associated factors.ResultsIn the present article we report, for the first time, generation of iPS cells from kidney transplant recipients with a history of autosomal-dominant polycystic kidney disease (ADPKD), systemic lupus erythematosus, or Wilms tumor and ESRD. Lentiviral transduction of OCT4, SOX2, KLF4 and c-MYC, under feeder-free conditions, resulted in reprogramming of skin-derived keratinocytes. Keratinocyte-derived iPS cells exhibited properties of human embryonic stem cells, including morphology, growth properties, expression of pluripotency genes and surface markers, spontaneous differentiation and teratoma formation. All iPS cell clones from the ADPKD patient retained the conserved W3842X mutation in exon 41 of the PKD1 gene.ConclusionsOur results demonstrate successful iPS cell generation from patients with a history of ESRD, PKD1 gene mutation, or chronic immunosuppression. iPS cells from autosomal kidney diseases, such as ADPKD, would provide unique opportunities to study patient-specific disease pathogenesis in vitro.

04 Safety and efficacy of basiliximab vs. anti-thymocyte globulin in living donor high risk renal transplant recipients

04 Safety and efficacy of basiliximab vs. anti-thymocyte globulin in living donor high risk renal transplant recipients

Primary cilia in the pathogenesis of dentigerous cyst: a new hypothesis based on role of primary cilia in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD), an inherited disease, leads to cyst formation in the kidneys. In this condition, the kidneys are grossly enlarged with multiple cysts that result in kidney failure in a majority of individuals. This condition is also associated with cysts in other organs. Recent research has focused on defects in signaling mediated by the primary cilia as the causative factor in ADPKD. Primary cilia are also present in odontogenic epithelium. Dentigerous cyst also is a developmental cyst whose pathogenesis is controversial. Recent studies have shown that loss of Ptch and Shh signaling pathways are involved in the cystogenesis of dentigerous cyst. The Shh signaling pathway is active in the primary cilia. A scanning electron microscopic study of a dentigerous cyst wall in an ADPKD patient showed structures similar to primary cilia. Based on the presentation of a dentigerous cyst in an autosomal dominant polycystic kidney patient and the demonstration of primary cilia like structures on the cyst wall by using a scanning electron microscope, a new hypothesis for the pathogenesis of dentigerous cyst is proposed.

Effects of Specific Genes Activating RAGE on Polycystic Kidney Disease

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and secretion of fluid and is associated with interstitial inflammation and fibrosis, resulting in the loss of renal function. We previously generated mice overexpressing PKD2, causing progressive cyst development with an inflammatory and fibrotic phenotype in the kidneys. Methods: To profile the gene expression related to inflammation and cystogenesis, microarray analysis was performed with kidney tissue from 6-, 12- and 18-month-old mice. Subsequently, levels and related mechanisms of selected genes, s100a8 and s100a9, were evaluated. Results: S100a8 and s100a9 was upregulated more than 2-fold and differently expressed in the cystic region. Receptor of advanced glycation end product (RAGE) is a putative cell surface receptor for s100a8/a9. It was expressed in cyst-lining cells and up-regulated pro-inflammatory transcription factor NF-ĸB in transgenic mice. We also confirmed RAGE expression in ADPKD patient kidneys. It was suggested that the signaling related to proliferative cystogenesis through previous reports; therefore, we confirmed that phosphorylated-ERK and cyst formation was reduced by treatment of RAGE-siRNA. Conclusions: The results may provide important information for the expression of s100a8/a9 and RAGE, linking progressive cystogenesis with inflammation in cystic kidney.

Marginal donor kidney in a marginal recipient: Five year follow-up

The widening gap between demand and supply of organs became apparent as organ shortage became more severe. Organs previously considered unsuitable for transplantation are currently being used. Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by slow progressive cystic changes and deterioration of renal function. We provide our experience with an ADPKD patient who received a kidney from 38-year-old deceased donor ADPKD-affected kidney for renal transplantation.

Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling

Polycystin-1 (PC1), the product of the PKD1 gene mutated in the majority of autosomal dominant polycystic kidney disease (ADPKD) cases, undergoes a cleavage resulting in the intracellular release of its C-terminal tail (CTT). Here, we demonstrate that the PC1 CTT co-localizes with and binds to beta-catenin in the nucleus. This interaction requires a nuclear localization motif present in the PC1 CTT as well as the N-terminal portion of beta-catenin. The PC1 CTT inhibits the ability of both beta-catenin and Wnt ligands to activate T-cell factor (TCF)-dependent gene transcription, a major effector of the canonical Wnt signaling pathway. The PC1 CTT may produce this effect by reducing the apparent affinity of the interaction between beta-catenin and the TCF protein. DNA microarray analysis reveals that the canonical Wnt signaling pathway is activated in ADPKD patient cysts. Our results suggest a novel mechanism through which PC1 cleavage may impact upon Wnt-dependent signaling and thereby modulate both developmental processes and cystogenesis.