Adult Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Liver Manifestations in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and their impact on quality of life

Abstract Background ADPKD is the most prevalent monogenic kidney disease with an estimated incidence of 1:1000. The condition is characterized by the formation of kidney cysts, which can cause kidney function loss and bears a significant risk of advancing to kidney failure. This study examined the prevalence of hepatic cysts in individuals with ADPKD, and the possible influence of these cysts on liver function and quality of life. Furthermore, the relationship between hepatic cysts and genotype was analysed. Methods Clinical data from 880 patients with ADPKD were analysed, including longitudinal patient data, genetic information, and laboratory parameters. Results The prevalence of hepatic cysts in adult ADPKD patients was 81.71%, consistent with previous studies. Prevalence increased with age, particularly in male patients. No clear association was observed between ADPKD genotype and the presence of liver cysts. Among male patients with liver cysts, glutamic-pyruvic transaminase (GPT) levels significantly decreased with age, while female patients showed a significant increase in gamma-glutamyl transferase (γ-GT) levels. Overall, hepatic cysts had minimal impact on liver enzymes. Quality of life assessments using the SF-12 questionnaire revealed no significant influence of hepatic cysts on physical or mental well-being. However, physical quality of life was significantly lower in patients showing polycystic liver disease as a manifestation of ADPKD compared to all other patients, both with and without liver cysts. Conclusions Hepatic cysts are highly prevalent in adult patients with ADPKD, increasing with age. ADPKD genotype does not appear to be associated with the presence of hepatic cysts. Liver function, as indicated by enzyme levels, is minimally affected by hepatic cysts in most ADPKD patients. The quality of life of ADPKD patients is generally unaffected by the presence of hepatic cysts, except in severe cases of polycystic liver disease (PLD). Further research is needed to develop effective treatments for severe PLD and gain a better understanding of the factors influencing hepatic cyst incidence and progression in patients with ADPKD.

Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study

PurposeRenin–angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients.MethodsSixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36–47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV).ResultsA statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05).ConclusionWe suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation(35%). The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association of Longitudinal Urinary Metabolic Biomarkers With ADPKD Severity and Response to Metformin in TAME-PKD Clinical Trial Participants

Dysregulated cellular metabolism contributes to autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. The Trial of Administration of Metformin in Polycystic Kidney Disease (TAME-PKD) tested the effects of metformin treatment over 2 years in adult ADPKD patients with mild-moderate disease severity. Metformin was found to be safe and tolerable with an insignificant trend toward reduced estimated glomerular filtration rate (eGFR) decline compared to placebo. Here we tested whether targeted urinary metabolic biomarkers measured in TAME-PKD participants correlated with disease progression, severity, and metformin treatment in cross-sectional and longitudinal analyses. Concentrations of total protein, targeted metabolites (lactate, pyruvate, and succinate), and glycolytic enzymes (pyruvate kinase-M2, lactate dehydrogenase-A, and pyruvate dehydrogenase kinase-1) were measured and normalized by creatinine or osmolality in urine specimens and compared with height-adjusted total kidney volume (htTKV) and eGFR at the different study timepoints. In cross-sectional analyses utilizing placebo group data, urinary succinate normalized by creatinine negatively correlated with ln (htTKV), whereas protein excretion strongly positively correlated with ln (htTKV), and negatively correlated with eGFR. Significant time-varying negative associations occurred with eGFR and the lactate/pyruvate ratio and with urine protein normalized by osmolality, indicating correlations of these biomarkers with disease progression. In secondary analyses, urinary pyruvate normalized by osmolality was preserved in metformin-treated participants but declined in placebo over the 2-year study period with a significant between-arm difference, suggesting time-dependent urinary pyruvate changes may serve as a discriminator for metformin treatment effects in this study population. Proteinuria with enhanced glycolytic and reduced oxidative metabolic markers generally correlated with disease severity and risk of progression in the TAME-PKD study population.

Echocardiographic Abnormalities in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patients.

Cardiovascular abnormalities, such as left ventricular hypertrophy and valvular disorders, particularly mitral valve prolapse, have been described as highly prevalent among adult patients with autosomal dominant polycystic kidney disease (ADPKD). The present study aimed to assess echocardiographic parameters in a large sample of both normotensive and hypertensive ADPKD patients, regardless of kidney function level, and evaluate their association with clinical and laboratorial parameters. A retrospective study consisted of the analysis of clinical, laboratorial, and transthoracic echocardiograms data retrieved from the medical records of young adult ADPKD outpatients. A total of 294 patients (120 M/174 F, 41.0 ± 13.8 years old, 199 hypertensive and 95 normotensive) with a median estimated glomerular filtration rate (eGFR) of 75.5 mL/min/1.73 m2 were included. The hypertensive group (67.6%) was significantly older and exhibited significantly lower eGFR than the normotensive one. Increased left ventricular mass index (LVMI) was seen in 2.0%, mitral valve prolapse was observed in 3.4%, mitral valve regurgitation in 15.3%, tricuspid valve regurgitation in 16.0%, and aortic valve regurgitation in 4.8% of the whole sample. The present study suggested that the prevalence of mitral valve prolapse was much lower than previously reported, and increased LVMI was not seen in most adult ADPKD patients.

Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.

Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.

Endocan Levels in Children with Polycystic Kidney Disease

Objective: Autosomal dominant polycystic kidney disease (ADPKD) is a common renal disorder that is characterized by hypertension and renal failure. Recently, it has been emphasized that endocan which is an endothelial dysfunction biomarker, could increase in many renal diseases. High endocan levels have also been reported in hypertensive ADPKD adult patients with renal failure. However, studies are limited on children. In this study, we investigated the serum endocan levels in normotensive ADPKD children with normal renal function. Material and Methods: The study consisted of 20 ADPKD children without hypertension and renal failure as a patient group, and 20 healthy age- and sex-matched children as a control group. Serum endocan levels were determined by enzyme-linked immunosorbent assay techniques and compared between the two groups. Results: The mean age of patients was 9.9±4.12 years, and the mean age of the control group was 10.2±3.83 years. There was no significant difference between the two groups in terms of gender, age, and BMI (p=0.751, p=0.813, p=0.781, respectively). The leukocyte (p=0.449), hemoglobin (p=0.337), platelets (p=0.134), serum uric acid (p=0.671) and serum creatinine (p=0.074) levels, eGFR (p=0.459) were not significantly differed between groups. The mean serum endocan level in the PKD group was 345.8±169.5 pg/ml, and in the control group was 448.61±258.2 pg/ml. Serum endocan levels did not change between groups (p=0.159). Conclusion: Unlike the adult ADPKD patients, this study suggested that serum endocan level was normal in children with ADPKD without hypertension and renal failure.

Rationale and study protocol of ACQUIRE, a prospective, observational study measuring quality of life, treatment preference and treatment satisfaction of autosomal dominant polycystic kidney disease (ADPKD) patients in Europe

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is considered the most common inherited renal disease. Patient-Reported Outcomes (PROs) and patient experience in ADPKD are difficult to quantify and have not been well studied, particularly in the early stages of the disease. There is evidence to suggest that early-stage ADPKD patients have a lower Health-Related Quality of Life (HRQoL) than the general population due to the signs and symptoms of early-stage ADPKD. However, no research has been carried out on the HRQoL of early-stage ADPKD patients using validated ADPKD-specific PRO measures. Additionally, a new disease progression delaying treatment option has recently emerged for ADPKD. Patient preference for this treatment and unmet treatment needs have not yet been investigated.MethodsThe ACQUIRE study is a prospective, observational study investigating the influence of early-stage ADPKD-related symptoms and treatments on PROs. It aims to collect real-world data on patient demographics, treatment patterns, clinical outcomes, and PROs such as HRQoL, treatment satisfaction and treatment preference in early-stage ADPKD. Adult ADPKD patients in stages 1–3 of chronic kidney disease (CKD) with evidence of rapidly progressing disease are being recruited from seven European countries. At baseline and every 3 months, for a follow-up period of 18 months, general and disease-specific questionnaires are completed remotely to capture patients’ own assessment of their overall and ADPKD-related HRQoL. A Discrete Choice Experiment (DCE) is also used to investigate the value patients place on different attributes of hypothetical treatment options (e.g. treatment outcomes, side effects) and the role each attribute plays in determining overall patient treatment preference.DiscussionThe results of this study will highlight the real-world effects of ADPKD-related challenges on PROs including HRQoL, treatment experience and satisfaction; and help physicians gain greater insight into likely disease outcomes based on early-stage patient symptoms and patients’ experience with treatment. Data captured by the DCE may inform ADPKD treatment decision-making from a patient perspective. The DCE will also provide insights into which patients are more likely to perceive benefit from treatments based on the value and trade-offs they place on specific treatment attributes.Trial registrationNCT02848521.Protocol Number/Version: 156–303-00096/Final

SO090EVALUATING PAIN IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Chronic pain is prevalent in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and is associated with a substantial quality of life burden. Literature describing ADPKD-related chronic pain (ACP) is limited, and generic pain management strategies are suboptimal with patients often reporting inadequate relief. Furthermore, the absence of a validated and widely accepted pain assessment tool (PAT) in ADPKD has posed a significant barrier to better pain management and research. We established an ADPKD PAT (APAT) and confirmed its feasibility and validity through administration to ADPKD patients participating in a randomised high water intake trial (NCT02933268). Method A collaboration of key stakeholders (patients, ADPKD experts, trialists and pain specialists) constructed an ADPKD pain conceptual framework consisting of eight prioritized pain assessment domains. We constructed an APAT from components of previously validated pain assessment tools covering each of the prioritized pain domains. The finalized APAT was administered to participants in a feasibility trial which randomised adult ADPKD patients with an eGFR≥20mls/min/1.73m2 to prescribed high water intake (HW) or ad libitum water intake (AW group) over eight weeks. Participants were asked to complete the APAT at least twice (baseline and week 8), although more frequent submissions were permitted. Results 93% (39/42) of trial participants with CKD stages 1-4 completed a total of 129 questionnaires. Each participant completed a median of 3 (range 1-10) questionnaires. In terms of baseline characteristics; mean age of respondents was 47±13 years, 90% (35) were White British ethnicity, and 59% (23) were female. Median disease duration was 14.2 (IQR 7.0-25.9) years, 69% had enlarged kidneys, 64% had hypertension and hepatic cysts were present in 59%. Pain (52%) and associated analgesic use (29%) were prevalent. Participants with pain were more likey to report interference with mobility (25% vs 0%), self-care (20% vs 0%) and usual activities (31% vs 1%) compared to those with no pain (p&amp;lt;0.001. Pain was also associated with a higher risk of anxiety and depression (RR 2.97, CI 1.70-5.20, p=0.000). Pain severity was predicted by traditional risk factors of disease progression including increasing age (OR 1.07, p=0.009), eGFR&amp;lt;60mls/min/1.73m2 (OR 5.45, p=0.021), and hypertension (OR 12.11, p=0.007), but not kidney size, consistent with findings of previous studies. Neuropathic descriptors were not commonly used, while continuous and intermittent descriptors were more frequently selected by patients to describe their pain quality (figure). The APAT achieved good internal consistency (Cronbach’s alpha coefficient =0.91) and test-retest reliability was demonstrated with domain intra-class correlation coefficients ranging from 0.62-0.90. Conclusion A bespoke APAT including components of previously validated pain assessment tools was reliable in evaluating pain in patients with ADPKD, and was acceptable to participants. Pain was prevalent among participants and associated with a substantial emotional and physical burden. The APAT represents a viable instrument for standardised evaluation of ADPKD pain in observational and interventional research.

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

Background Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. Aims Assess the feasibility of a definitive randomized high water intake trial in ADPKD. Methods In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. Results We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. Conclusion DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

BackgroundVasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown.AimsAssess the feasibility of a definitive randomized high water intake trial in ADPKD.MethodsIn this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence.ResultsWe enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9–107.2] vs. AW 75.8 [IQR 59.0–111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190–438] vs. AW 350 [IQR 240–452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190–438] vs. 379 [IQR 235–503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270–4295] vs. 1920 [IQR 1670–2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study.ConclusionDRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

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.

Evidence for Bone and Mineral Metabolism Alterations in Children With Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Hypophosphatemia was demonstrated in adult patients with preserved renal function, together with high fibroblast growth factor 23 (FGF23) and low soluble Klotho levels. The latter explained the relative FGF23 hyporesponsiveness in this cohort. Evaluating phosphate and bone mineral metabolism in children with ADPKD compared with what is known in adult ADPKD patients. Observational cross-sectional study. Multicenter study via ambulatory care in tertiary centers. Ninety-two children with ADPKD (52 males; mean ± standard deviation age, 10.2 ± 5.0 years) and 22 healthy controls (HCs, 10 males; mean ± standard deviation age, 10.3 ± 4.1 years). The predictor was early ADPKD stage. Bone mineral metabolism and renal phosphate handling were the main outcome measures. Performed measurements were serum phosphate, tubular maximum phosphorus reabsorption per glomerular filtration rate, FGF23, soluble Klotho, sclerostin, and bone alkaline phosphatase. ADPKD children had significantly lower serum phosphate levels compared with HC. Low tubular maximum phosphorus reabsorption per glomerular filtration rate was observed in 24% of patients, although not significantly different from HC. Serum FGF23 and soluble Klotho levels were comparable between patients and HC. In addition, we showed decreased bone alkaline phosphatase levels in ADPKD children, suggesting suppressed bone formation. This report demonstrates hypophosphatemia and suppressed bone formation in a pediatric ADPKD cohort, with preserved renal function, compared with HC. Although FGF23 levels were not different from controls, they should be considered inappropriate, given the concomitant hypophosphatemia. Further studies are required to elucidate underlying pathophysiology and potential clinical consequences.

Expanding the role of vasopressin antagonism in polycystic kidney diseases: From adults to children?

Polycystic kidney disease (PKD) encompasses a group of genetic disorders that are common causes of renal failure. The two classic forms of PKD are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Despite their clinical differences, ARPKD and ADPKD share many similarities. Altered intracellular Ca2+ and increased cyclic adenosine monophosphate (cAMP) concentrations have repetitively been described as central anomalies that may alter signaling pathways leading to cyst formation. The vasopressin V2 receptor (V2R) antagonist tolvaptan lowers cAMP in cystic tissues and slows renal cystic progression and kidney function decline when given over 3years in adult ADPKD patients. Tolvaptan is currently approved for the treatment of rapidly progressive disease in adult ADPKD patients. On the occasion of the recent initiation of a clinical trial with tolvaptan in pediatric ADPKD patients, we aim to describe the most important aspects in the literature regarding the AVP-cAMP axis and the clinical use of tolvaptan in PKD.

Calcium-phosphate metabolism parameters and erythrocyte Ca 2+ concentration in autosomal dominant polycystic kidney disease patients with normal renal function

IntroductionThe aim of this study was to assess calcium-phosphate metabolism of autosomal dominant polycystic kidney disease (ADPKD) patients with a special consideration to the following serum parameters: calcium (Ca2+), inorganic phosphate (Pi), parathyroid hormone (PTH) and intracellular erythrocyte calcium ([Ca2+]i) concentrations.Material and methodsThe study included 49 adult ADPKD patients (19 males, 30 females) aged 36 ±11 years with normal renal function and no diagnosis of diabetes as well as 50 healthy controls (22 males, 28 females) matched for age and gender. Serum concentrations of sodium (Na+), potassium (K+) and magnesium (Mg2+) ions and Pi were determined with an indirect ion-selective method, while Ca2+ concentration was measured with a direct ion-selective method. The PTH was detected using a radioimmunometric method. [Ca2+]i concentration was determined with the Ca2+ sensitive fluorescent dye Fura-2 method.ResultsIn the ADPKD group, when compared to controls, the following concentrations were significantly higher: serum Ca2+ (1.18 ±0.06 mmol/l vs. 1.15 ±0.06 mmol/l, p = 0.0085), [Ca2+]i (146.9 ±110.0 nmol/l vs. 96.5 ±52.7 nmol/l, p = 0.0075), serum Na+ (139.4 ±2.7 mmol/l vs. 138.5 ±2.1 mmol/l, p = 0.060, borderline significance), and PTH (15.5 ±6.8 pg/ml vs. 13.6 ±5.3 pg/ml, p = 0.066, borderline significance), while serum Mg2+ was significantly lower (0.81 ±0.09 mmol/l vs. 0.85 ±0.05 mmol/l, p = 0.021). In the ADPKD group we observed significant negative correlations of PTH with Ca2+ serum concentrations (Rs = –0.32, p = 0.025) and with estimated glomerular filtration rate (Rs = –0.31, p = 0.033).ConclusionsThe erythrocyte Ca2+ concentration is elevated in ADPKD patients with normal renal function. It may result from a dysfunction of mutated polycystins which can affect various aspects of electrolyte metabolism.

Early renal abnormalities in autosomal dominant polycystic kidney disease.

Potential therapeutic interventions are being developed for autosomal dominant polycystic kidney disease (ADPKD). A pivotal question will be when to initiate such treatment, and monitoring disease progression will thus become more important. Therefore, the prevalence of renal abnormalities in ADPKD at different ages was evaluated. Included were 103 prevalent ADPKD patients (Ravine criteria). Measured were mean arterial pressure (MAP), total renal volume (TRV), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), and filtration fraction (FF). Twenty-four-hour urine was collected. ADPKD patients were compared with age- and gender-matched healthy controls. Patients and controls were subdivided into quartiles of age (median ages 28, 37, 42, and 52 years). Patients in the first quartile of age had almost the same GFR when compared with controls, but already a markedly decreased ERPF and an increased FF (GFR 117 +/- 32 versus 129 +/- 17 ml/min, ERPF 374 +/- 119 versus 527 +/- 83 ml/min, FF 32% +/- 4% versus 25% +/- 2%, and RVR 12 (10 to 16) versus 8 (7 to 8) dynes/cm(2), respectively). Young adult ADPKD patients also had higher 24-hour urinary volumes, lower 24-hour urinary osmolarity, and higher urinary albumin excretion (UAE) than healthy controls, although TRV in these young adult patients was modestly enlarged (median 1.0 L). Already at young adult age, ADPKD patients have marked renal abnormalities, including a decreased ERPF and increased FF and UAE, despite modestly enlarged TRV and near-normal GFR. ERPF, FF, and UAE may thus be better markers for disease severity than GFR.

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.

A comparative study of three kidney biomarker tests in autosomal-dominant polycystic kidney disease

The relationship between the progress of tubular damage and renal insufficiency in autosomal-dominant polycystic kidney disease (ADPKD) is a subject of doubtless interest, and is the object of this present work. A total of 92 adult ADPKD patients of both genders were studied, none of which presented end-stage renal disease (ESRD), and classified according to an ultrasound score based on kidney size and number of cysts. Urinary albumin and beta-N-acetylhexosaminidase (Hex) and its isoenzymes were determined, together with serum glutathione peroxidase, cystatin C, creatinine, and urea. A frequent elevation of the urinary Hex was found and an alteration of its isoenzymatic profile, with 31% of the normotensive patients with normoalbuminuria already presenting an increased proportion of Hex B isoenzyme. Keeping age constant, a partial significant correlation was found between the ultrasound score and the proportion of Hex B (r = 0.352, P < 0.05), but not with albuminuria or cystatin C. In 42 patients the different biochemical variables were again determined after 1 year, finding that in the 13 normotensive patients with normoalbuminuria there had been a significant decrease in the concentration of cystatin C (P < 0.05), and a significant increase in the urinary excretion of albumin and Hex B isoenzyme (P < 0.05). By the other hand, in the other 29 patients with micro- or macroalbuminuria and hypertension, no significant differences were found. The results point toward an important participation of tubular damage in the pathogenesis of this disease. It may also be suggested that in normotensive and normoalbuminuric ADPKD patients, a gradual increase of glomerular filtration would be produced. After the start of hypertension and microalbuminuria, the glomerular filtration rate (GFR) would decrease progressively, although more slowly.

Left ventricular hypertrophy in autosomal dominant polycystic kidney disease.

Cardiovascular complications are the most common cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). To understand this relationship, known cardiovascular risk factors were examined in ADPKD. Left ventricular hypertrophy (LVH) is a known, important risk factor for premature cardiovascular death in patients with essential hypertension. Hypertension is known to occur frequently and early in ADPKD patients. The frequency of LVH in ADPKD patients and its relation with hypertension and other risk factors, however, is not known. In this study, echocardiographic tests were performed in 116 consecutive adult ADPKD patients and 77 healthy control subjects. There was a significantly higher frequency of LVH in ADPKD men (46 versus 20%, P < 0.05) and women (37 versus 12%, P < 0.005) compared with control subjects. LVH in ADPKD patients was associated with higher systolic and diastolic arterial BP. There also was an association between LVH, diminished renal function, and increased renal volume. When comparing ADPKD patients with and without LVH, the former were older, weighed more, had a higher prevalence of hypertension, and had a lower hematocrit value and more renal impairment. LVH was also present in 23% of normotensive ADPKD patients and 16% of healthy control subjects (P = NS), but did not correlate with BP. The role of BP as a contributing factor to LVH in ADPKD patients may be due in part to earlier onset and inadequate treatment.