The screening, diagnosis, and management of patients with autosomal dominant polycystic kidney disease: A national consensus statement from Taiwan.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients.

Autosomal Dominant Polycystic Kidney Disease: Extrarenal Involvement.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, but kidneys are not the only organs involved in this systemic disorder. Individuals with the condition may display additional manifestations beyond the renal system, involving the liver, pancreas, and brain in the context of cystic manifestations, while involving the vascular system, gastrointestinal tract, bones, and cardiac valves in the context of non-cystic manifestations. Despite kidney involvement remaining the main feature of the disease, thanks to longer survival, early diagnosis, and better management of kidney-related problems, a new wave of complications must be faced by clinicians who treated patients with ADPKD. Involvement of the liver represents the most prevalent extrarenal manifestation and has growing importance in the symptom burden and quality of life. Vascular abnormalities are a key factor for patients' life expectancy and there is still debate whether to screen or not to screen all patients. Arterial hypertension is often the earliest onset symptom among ADPKD patients, leading to frequent cardiovascular complications. Although cardiac valvular abnormalities are a frequent complication, they rarely lead to relevant problems in the clinical history of polycystic patients. One of the newest relevant aspects concerns bone disorders that can exert a considerable influence on the clinical course of these patients. This review aims to provide the "state of the art" among the extrarenal manifestation of ADPKD.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

Evaluation of the Renal and Cardiovascular Effects of Long-Term Tolvaptan Treatment in Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Cardiovascular diseases constitute a significant cause of morbidity and mortality in individuals with autosomal dominant polycystic kidney disease (ADPKD). This study aimed to assess the long-term effects of tolvaptan on the kidneys and heart in rapidly progressing ADPKD. METHODS: Among 354 patients diagnosed with ADPKD, 58 meeting the eligibility criteria for tolvaptan were included in the study. The study comprised two groups with similar demographic and clinical characteristics: 29 patients receiving tolvaptan treatment and 29 in the control group. Several included genetic analysis, magnetic resonance imaging, and echocardiography. Clinical and cardiac changes were recorded in both groups after a 3-year follow-up. RESULTS: Tolvaptan treatment demonstrated a significant reduction in the rate of eGFR decline compared to the control group. Furthermore, it was observed that tolvaptan could prevent the development of cardiac arrhythmias by inhibiting an increase in QTc interval and heart rate. CONCLUSION: These findings suggest that, in addition to slowing kidney progression in ADPKD management, tolvaptan may potentially benefit in preventing cardiac complications.

Mortality risk in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD). Mortality data specific to patients with ADPKD is currently lacking; thus, the aim of this study was to estimate mortality in patients with ADPKD. METHODS: We analyzed data from the United States Renal Data System (USRDS) for patients with ADPKD available during the study period of 01/01/2014-12/31/2016, which included a cohort of patients with non-ESRD chronic kidney disease (CKD) and a cohort of patients with ESRD. Mortality rates with 95% confidence intervals (CIs) were calculated overall and by age group, sex, and race for the full dataset and for a subset of patients aged ≥ 65 years. Adjusted mortality hazard ratios (HRs) were calculated using Cox regression modeling by age group, sex, race, and CKD stage (i.e., non-ESRD CKD stages 1-5) or ESRD treatment (i.e., dialysis and transplant). RESULTS: A total of 1,936 patients with ADPKD and non-ESRD CKD and 37,461 patients with ADPKD and ESRD were included in the analysis. Age-adjusted mortality was 18.4 deaths per 1,000 patient-years in the non-ESRD CKD cohort and 37.4 deaths per 1,000 patient-years in the ESRD cohort. As expected, among the non-ESRD CKD cohort, patients in CKD stages 4 and 5 had a higher risk of death than patients in stage 3 (HR = 1.59 for stage 4 and HR = 2.71 for stage 5). Among the ESRD cohort, patients receiving dialysis were more likely to experience death than patients who received transplant (HR = 2.36). Age-adjusted mortality among patients aged ≥ 65 years in the non-ESRD CKD cohort was highest for Black patients (82.7 deaths per 1,000 patient-years), whereas age-adjusted mortality among patients aged ≥ 65 years in the ESRD cohort was highest for White patients (136.1 deaths per 1,000 patient-years). CONCLUSIONS: Mortality rates specific to patients aged ≥ 65 years suggest racial differences in mortality among these patients in both non-ESRD CKD and ESRD cohorts. These data fill an important knowledge gap in mortality estimates for patients with ADPKD in the United States.

Autosomal dominant polycystic kidney disease with ectopic unilateral multicystic kidney: a case report.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder and the fourth cause of death of end-stage renal disease. The disease has a prevalence of 1:400-1:1000 accounting for 10% of patients on dialysis. In most ADPKD patients, bilateral kidneys are similarly affected, with numerous fluid-filled cysts arising from different nephron segments. Only a few cases of ADPKD with ectopic unilateral multicystic kidney have been reported. It has been observed that the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings especially when the ectopic kidney is dysplastic. CASE PRESENTATION: We report a case of a 46-year-old Ghanaian male patient who presented with left flank pain and hematuria with high BP and deranged renal function. Abdominal ultrasonography showed both kidneys to be larger than normal and had multiple cysts of varying sizes with the right kidney located in the right iliac fossa. Follow up Abdominopelvic computer tomographic scan (CT-Scan) without contrast showed enlarged kidneys with the renal parenchyma replaced by innumerable cyst of varying sizes. The right kidney was ectopically located in the right aspect of the pelvis. A diagnosis of ADPKD with right pelvic ectopic multicystic kidney was made. He was put on antihypertensives, analgesia for the left flank pain and to have follow up at the urology and nephrology departments. CONCLUSION: In most ADPKD patients, bilateral kidneys are similarly affected. Only a few cases of ADPKD with ectopic unilateral multicystic kidney have been reported. It has been observed that the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings especially when the ectopic kidney is dysplastic.

Metastatic Renal Cell Carcinoma in a Patient With Autosomal Dominant Polycystic Kidney Disease.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) manifests as multiple cysts in the kidneys and liver but can also present with musculoskeletal and cardiovascular abnormalities. ADPKD patients are at increased risk for renal cell carcinoma development. We show the FDG PET/CT findings in a patient with renal cell carcinoma secondary to ADPKD and complicated by worsening pulmonary metastasis. The primary renal tumor shows intense FDG uptake despite no suspicious features with contrast CT.

Fatal acute portal vein thrombosis associated with hepatic cysts in a patient with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) often involves polycystic liver disease (PLD). In severe cases, PLD can develop various complications. However, fatal acute portal vein thrombosis (APVT) associated with PLD has not been reported. A 64-year-old male reported mild consciousness disorder. He had been under maintenance hemodialysis for end-stage renal disease due to ADPKD with PLD. Because of recurring hepatic cyst infections, he had sustained high levels of C-reactive protein. Regarding the mild consciousness disorder, a diagnosis of hepatic encephalopathy was made based on an elevation of serum ammonia without any other abnormal liver function tests. Several days after his admission, hepatobiliary enzymes elevated, and acute liver failure progressed. Enhanced abdominal computed tomography suggested the possibility of complete occlusion of the portal vein by a thrombus. Based on an absence of obvious portosystemic collaterals, a diagnosis of APVT was made. The patient died 19 days after admission. Patients with PLD with repeated cystic infections have been seen to develop liver failure, and APVT formation may be one cause of the rapid progression of fatal liver failure. In conclusion, this is the first paper to report on the involvement of APVT in patients with PLD.

A Case of Autosomal Dominant Polycystic Kidney Disease With Resolution of Massive Pericardial Effusion After Renal Transcatheter Artery Embolization.

A 68-year-old woman being treated with hemodialysis for autosomal dominant polycystic kidney disease was admitted for progressive dyspnea over 6 months. On chest radiography, her cardiothoracic ratio had increased from 52.2% 6 months prior, to 71%, and echocardiography revealed diffuse pericardial effusion and right ventricular diastolic insufficiency. A resultant pericardial tamponade was thought to be the cause of the patient's dyspnea, and therefore a pericardiocentesis was performed, with a total of 2,000mL of fluid removed. However, 21 days later the same amount of pericardial fluid had reaccumulated. The second pericardiocentesis was performed, followed by transcatheter renal artery embolization (TAE). The kidneys, which were hard on palpation before TAE, softened immediately after TAE. After resolution of the pericardial effusion was confirmed, the patient was discharged after 24 days in hospital. Twelve months later, the patient was asymptomatic, the cardiothoracic ratio decreased to 48% on chest radiography and computed tomography revealed no reaccumulation of pericardial effusion. This case illustrates a potential relationship between enlarged kidneys in autosomal dominant polycystic kidney disease and pericardial effusion.

Cardiovascular Involvement in Patients with Autosomal Dominant Polycystic Kidney Disease: A Review.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease with a prevalence of 1:400 to 1:1,000 in Caucasians. It is caused by mutations in the PKD1 gene located on chromosome 16p13.3 (in about 85% cases) as well as in the PKD2 gene on chromosome 4q13-23. In the Polish population, the disease is associated with PKD1 mutations in 84% of the ADPKD-affected families. PKD1 and PKD2 genes encode the proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The presence of kidney cysts is a characteristic feature in the ADPKD patients. But in the ADPKD patients, cardiovascular abnormalities, such as hypertension (HT) with higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) values, higher left ventricular mass (LVM), intracranial (ICAN) and extracranial aneurysms, and cardiac valve defects, are significantly more common than in the general population. SUMMARY: According to the literature data, both higher LVM and vascular dysfunction already occur in children and young adults with normal renal function and without HT. Moreover, biventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and impaired coronary flow velocity reserve are present even in young patients with ADPKD who have normal HT and well-preserved renal function. In patients with ADPKD, hypertension has some specific features; in the youngest age group of children, the prevalence of hypertension is greater if their parents suffer from hypertension; in normotensive young ADPKD-diagnosed individuals, ambulant SBP and DBP values were significantly higher than in age- and gender-matched controls; hypertension appears at least 10 years earlier than spontaneous HT in general population. In adults, HT is often diagnosed before any substantial reduction in the GFR, and a lower nocturnal dip in BP in comparison to hypertensives in the general population. PKD1 and PKD2 gene products (PC1 and PC2 proteins) have been shown to assemble at the plasma membrane and to regulate calcium (Ca2+) entry. A defect in Ca2+ binding mediated by mutations in polycystin proteins is a hypothetical factor contributing to left ventricular mass increase. Altered intracellular Ca2+ handling contributes importantly to impaired contractility associated with heart failure. Impairment of intracellular Ca2+ homeostasis and mitochondrial function has been implicated in the development of LVH. KEY MESSAGES: It can be assumed that the cause of LVH in ADPKD patients is the natural course of this disease with developing HT and deteriorating kidney function, which may be influenced by the presence of PKD1- and PKD2-mutated gene products: PC1 and PC2 proteins.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AIMS: The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. METHODS: One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OUTCOMES: The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. CONCLUSION: This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing. REGISTRATION: This study is registered on Clinicaltrials.gov # NCT03273413.

Deep learning-based automated kidney and cyst segmentation of autosomal dominant polycystic kidney disease using single vs. multi-institutional data.

PURPOSE: This study aimed to investigate if a deep learning model trained with a single institution's data has comparable accuracy to that trained with multi-institutional data for segmenting kidney and cyst regions in magnetic resonance (MR) images of patients affected by autosomal dominant polycystic kidney disease (ADPKD). METHODS: We used TensorFlow with a Keras custom UNet on 2D slices of 756 MRI images of kidneys with ADPKD obtained from four institutions in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study. The ground truth was determined via a manual plus global thresholding method. Five models were trained with 80 % of all institutional data (n = 604) and each institutional data (n = 232, 172, 148, or 52), respectively, and validated with 10 % and tested on an unseen 10 % of the data. The model's performance was evaluated using the Dice Similarity Coefficient (DSC). RESULTS: The DSCs by the model trained with all institutional data ranged from 0.92 to 0.95 for kidney image segmentation, only 1-2 % higher than those by the models trained with single institutional data (0.90-0.93).In cyst segmentation, however, the DSCs by the model trained with all institutional data ranged from 0.83 to 0.89, which were 2-20 % higher than those by the models trained with single institutional data (0.66-0.86). CONCLUSION: The UNet performance, when trained with a single institutional dataset, exhibited similar accuracy to the model trained on a multi-institutional dataset. Segmentation accuracy increases with models trained on larger sample sizes, especially in more complex cyst segmentation.

Assessing the Risk of Progression to Kidney Failure in Patients With Autosomal Dominant Polycystic Kidney Disease.

While autosomal dominant polycystic kidney disease (ADPKD) is a dichotomous diagnosis, substantial variability in disease severity exists. Identification of inherited risk through family history, genetic testing, and environmental risk factors through clinical assessment are important components of risk assessment for optimal management of patients with ADPKD. Genetic testing is especially helpful in cases with diagnostic uncertainty, particularly in cases with no apparent family history, in young cases (age less than 25 years) where a definitive diagnosis is sought, or in atypical presentations with early, severe, or discordant findings. Currently, risk assessment in ADPKD may be performed with the use of age-adjusted estimated glomerular filtration rate thresholds, evidence of rapid estimated glomerular filtration rate decline on serial measurements, age- and height-adjusted total kidney volume by Mayo Clinic Imaging Classification, or evidence of early hypertension and urological complications combined with PKD1 or PKD2 mutation class; however, caveats exist with each of these approaches. Fine-tuning of risk stratification with advanced imaging features and biomarkers is the subject of research but is not yet ready for general clinical practice. While conservative treatment strategies will be advised for all patients, those with the greatest rate of disease progression will have the most benefit from aggressive disease-modifying therapy. In this narrative review, we will summarize the evidence behind the clinical assessment and risk stratification of patients with ADPKD.

Vascular Complications in Autosomal Dominant Polycystic Kidney Disease: Perspectives, Paradigms, and Current State of Play.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading cause of inherited kidney disease with significant contributions to CKD and end-stage kidney disease. The underlying polycystin proteins (PC1 and PC2) have widespread tissue expression and complex functional roles making ADPKD a systemic disease. Vascular complications, particularly intracranial aneurysms (ICA) are the most feared due to their potential for devastating neurological complications and sudden death. Intracranial aneurysms occur in 8-12% of all patients with ADPKD, but the risk is intensified 4-5-fold in those with a positive family history. The basis for this genetic risk is not well understood and could conceivably be due to features of the germline mutation with a significant contribution of other genetic modifiers and/or environmental factors. Here we review what is known about the natural history and genetics of unruptured ICA in ADPKD including the prevalence and risk factors for aneurysm formation and subarachnoid hemorrhage. We discuss two alternative screening strategies and recommend a practical algorithm that targets those at highest risk for ICA with a positive family history for screening.

Dialysis and Transplant Considerations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of kidney replacement therapy. Unfortunately, the need for dialysis or kidney transplantation is a foreseeable outcome for many patients affected by ADPKD. We review some of the unique issues that should be considered in the management of patients with ADPKD who require dialysis or kidney transplantation. The choice of dialysis modality may be influenced by the enlarged kidneys and liver, but peritoneal dialysis should not be excluded as an option, as studies do not consistently show that there is an increased risk for technique failure or peritonitis. The optimal kidney replacement therapy option remains kidney transplantation; however, nephrectomy may be needed if there is insufficient space for the allograft. Living donor candidates from at-risk families need to be excluded from carrying the disease either by diagnostic imaging criteria or genetic testing. Other potential transplant issues, such as malignancy and cardiovascular and metabolic risks, should also be recognized. Despite these issues, patients with ADPKD requiring dialysis or kidney transplantation generally have more favorable outcomes as compared to those with other causes of chronic kidney disease. Further studies are still needed to personalize the therapeutic approach for those receiving kidney replacement therapy and eventually improve clinical outcomes.

Management of Hypertension and Associated Cardiovascular Disease in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease is the most commonly inherited disease of the kidneys affecting an estimated 12,000,000 people in the world. Autosomal dominant polycystic kidney disease is a systemic disease, with a wide range of associated features that includes hypertension, valvular heart diseases, cerebral aneurysms, aortic aneurysms, liver cysts, abdominal hernias, diverticulosis, gross hematuria, urinary tract infections, nephrolithiasis, pancreatic cysts, and seminal vesicle cysts. The cardiovascular anomalies are somewhat different than in the general population and also chronic kidney disease population, with higher morbidity and mortality rates. This review will focus on cardiovascular diseases associated with autosomal dominant polycystic kidney disease and their management.

[The Management of Patients with Adult Autosomal Dominant Polycystic Kidney Disease (ADPKD) Requires a Multidisciplinary Approach].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Its main feature is the progressive enlargement of both kidneys with progressive loss of kidney function. ADPKD is the fourth leading cause of terminal renal failure in the world. Even today there are still uncertainties and poor information. Patients too often have a renunciatory and passive attitude toward the disease. However, there are currently no internationally accepted clinical practice guidelines, and there are significant regional variations in approaches to the diagnosis, clinical evaluation, prevention, and treatment of ADPKD. Therefore, we believe it is important to point out the conduct of our specialist outpatient clinic for ADPKD, which from the beginning has developed a multidisciplinary approach (nephrologists, geneticists, psychologists, radiologists, nutritionists) to face the disease at 360° and therefore not only from a purely nephrological point of view. Such a strategy not only enables patients to receive a timely and accurate diagnosis of the disease, but also ensures that they will receive a thorough and focused follow-up over time, that can prevent or at least slow down the disease in its evolution providing patients with a serene awareness of their condition as much as possible.