Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Vascular Access Outcomes in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading hereditary cause of end-stage kidney disease (ESKD), often utilising hemodialysis as a form of kidney replacement therapy. Patients with ADPKD may also present with extrarenal manifestations, including arterial aneurysms. The gold standard for hemodialysis access is an arteriovenous vascular access (VA), such fistulas (AVFs) or grafts (AVGs). However, limitations, such as low VA flow and inadequate AVF outward remodelling, impact VA utilization. This study aimed to explore whether ADPKD impacts patency rates of AVFs/AVGs in comparison to other underlying ESKD causes. We conducted a retrospective cohort study using data from the Swedish Renal Registry from 2011 to 2020, with follow-up until 2022. We included 496 ADPKD patients and 4321 propensity-score matched controls. VA patency rates of ADPKD patients were compared to those of non-ADPKD patients using Kaplan-Meier survival curves and the Mantel-Cox log-rank test. Interventions to maintain or restore patency were also analysed. Patients with ADPKD constituted 8.0% of all patients, with a higher proportion in the pre-ESKD phase during VA creation (51.6% vs. 40.6%). No significant differences were observed in primary, post-cannulation primary, secondary, or functional patency between ADPKD and non-ADPKD patients. However, more VAs were ligated in ADPKD patients (10.5% vs. 7.7%, p=0.03), and they underwent more first interventions to re-establish flow (49.4% vs. 41.9%, p=0.02). These findings suggest that AVF/AVG patency remains comparable in ESKD patients with or without ADPKD, and vascular access monitoring and treatment strategies for ADPKD patients should align with those for individuals with other ESKD causes.

Exploring Adiponectin in Autosomal Dominant Kidney Disease: Insight and Implications.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common monogenic disorder characterized by renal cysts and progressive renal failure. In kidney diseases, adipose tissue undergoes functional changes that have been associated with increased inflammation and insulin resistance mediated by release of adipokines. Adiponectin is involved in various cellular processes, such as energy and inflammatory and oxidative processes. However, it remains to be determined whether adiponectin is involved in the concomitant metabolic dysfunctions present in PKD. In this scenario, we aimed to analyze: (a) PPARγ, ADIPOQ, ADIPOR1 and ADIPOR2 gene variations in 92 ADPKD patients through PCR-Sanger sequencing; and (b) adiponectin levels and its oligomerization state by ELISA and Western Blot. Our results indicated that: (a) 14 patients carried the PPARγ SNP, 29 patients carried the ADIPOQ SNP rs1501299, and 25 patients carried the analyzed ADIPOR1 SNPs. Finally, 82 patients carried ADIPOR2 SNPs; and (b) Adiponectin is statistically lower in ADPKD patients compared to controls, and further statistically lower in ESRD than in non-ESRD patients. An inverse relationship between adiponectin and albumin and between adiponectin and creatinine and a direct relationship between adiponectin and eGFR were found. Interestingly, significantly lower levels of adiponectin were found in patients bearing the ADIPOQ rs1501299 SNP and associated with low levels of eGFR. In conclusion, adiponectin levels and the presence of ADIPOQ rs1501299 genotype are significantly associated with a worse ADPKD phenotype, indicating that both could potentially provide important insights into the disease. Further studies are warranted to understand the pathophysiological role of adiponectin in ADPKD patients.

Notch3 as a novel therapeutic target for the treatment of ADPKD by regulating cell proliferation and renal cyst development

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which blocks a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo. Subsequent mechanistic study elucidated that the cleaved intracellular domain of Notch3 (N3ICD) and Hes1 could bind to the PTEN promoter, leading to transcriptional inhibition of PTEN. This further activated the downstream PI3K-AKT-mTOR pathway and promoted renal epithelial cell proliferation. Overall, Notch3 was identified as a novel contributor to renal epithelial cell proliferation and cystogenesis in ADPKD. We envision that Notch3 represents a promising target for ADPKD treatment.

Clinical Characteristics and Kidney Outcomes in Chinese Patients with Autosomal Dominant Polycystic Kidney Disease.

The management of autosomal dominant polycystic kidney disease (ADPKD) remains challenging with variable and uncertain genotype-phenotype correlations. The Mayo clinic imaging classification allows a more accurate risk stratification but is limited by the atypical imaging patterns. We aim to assess the clinical characteristics and the morphology of the cystic kidneys in a cohort of Chinese patients with ADPKD. Ninety-eight patients with ADPKD were recruited prospectively from August 2019 to December 2020 in Prince of Wales Hospital, Hong Kong. They were subsequently followed up every 6 months for a minimum of2 years. We reviewed the clinical characteristics and MRI imaging patterns at baseline and the kidney outcome at the end of the follow-up. Atypical imaging patterns included unilateral; segmental; asymmetric; lopsided and bilateral atrophy as defined by the Mayo Imaging Classification. Mean age was 51.5 ± 14.3 years old and the mean eGFR 68.7 ± 27.5 ml/min per 1.73 m2. The ninety-eight patients included 36 males:62 females. Seventy-six patients (77.6%) had a family history. Seventeen of the 98 (17.3%) patients had atypical imaging patterns. Compared to typical cases, atypical cases were older at the time of diagnosis (49.5 ± 16.0 vs 33.0 ± 13.0 years, p<0.001), at the time of starting antihypertensive medications (52.4 ± 14.8 vs 39.7 ± 11.0 years, p=0.001) and less likely to have a positive family history (58.8% vs 81.5%, p=0.042). Patients with atypical patterns showed a lower eGFR decline as compared to those with the typical pattern (-0.86 ± 4.34 vs -3.44 ± 4.07 ml/min per 1.73m2/year, p=0.022). In this cohort of Chinese patients with ADPKD, an atypical imaging pattern was observed in 17% of the cases, associated with later presentation and a milder disease course. Future genotyping studies will help to define the genetic architecture and the basis for the phenotypic spectrum in Chinese ADPKD patients.

Inhibition of pannexin-1 does not restore electrolyte balance in precystic Pkd1 knockout mice.

Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the formation of fluid-filled cysts in the kidney. In a subset of ADPKD patients, reduced blood calcium (Ca2+) and magnesium (Mg2+) concentrations are observed. As cystic fluid contains increased ATP concentrations and purinergic signaling reduces electrolyte reabsorption, we hypothesized that inhibiting ATP release could normalize blood Ca2+ and Mg2+ levels in ADPKD. Inducible kidney-specific Pkd1 knockout mice (iKsp-Pkd1-/-) exhibit hypocalcemia and hypomagnesemia in a precystic stage and show increased expression of the ATP-release channel pannexin-1. Therefore, we administered the pannexin-1 inhibitor brilliant blue-FCF (BB-FCF) every other day from Day 3 to 28 post-induction of Pkd1 gene inactivation. On Day 29, both serum Ca2+ and Mg2+ concentrations were reduced in iKsp-Pkd1-/- mice, while urinary Ca2+ and Mg2+ excretion was similar between the genotypes. However, serum and urinary levels of Ca2+ and Mg2+ were unaltered by BB-FCF treatment, regardless of genotype. BB-FCF did significantly decrease gene expression of the ion channels Trpm6 and Trpv5 in both control and iKsp-Pkd1-/- mice. Finally, no renoprotective effects of BB-FCF treatment were observed in iKsp-Pkd1-/- mice. Thus, administration of BB-FCF failed to normalize serum Ca2+ and Mg2+ levels.

Native nephrectomy in polycystic kidney disease patients on transplant lists: how and when?

Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disease, accounts for approximately 10% of the patients on kidney transplantation waitlists.High rates of complications including hemorrhage, infections, nephrolithiasis and kidney size-related compressive complaints have been reported among ADPKD patients. Therefore, the need for routine native nephrectomy and timing of such procedure in ADPKD patients being prepared for transplantation are debated. Even though pre-transplant nephrectomy has the potential to provide fewer infectious complications due to lack of immunosuppressive medication use, such procedure has been associated with longer hospital stay, loss of residual kidney function and need for dialysis. Although simultaneous nephrectomy and transplantation could potentially lead to longer perioperative duration, perioperative complications and need for blood transfusions, this was not confirmed in cohort studies. Therefore, some institutions routinely perform simultaneous unilateral nephrectomy and kidney transplantation. In this narrative review, our aim is to evaluate the current evidence regarding the need andtiming of nephrectomy in ADPKD patients in relation to kidney transplantation.

Renal Hemodynamic and Functional Changes in ADPKD Patients.

Although the mechanisms underlying cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) are becoming clearer, those of renal dysfunction are not fully understood. In particular, total kidney volume (TKV) and renal function do not always correspond. To elucidate this discrepancy, we studied in detail glomerular hemodynamic changes during ADPKD progression. Sixty-one ADPKD patients with baseline height-adjusted TKV (Ht-TKV) of 933±537 ml/m and serum creatinine of 1.16±0.62 mg/dl were followed for 2 years. Glomerular filtration rate (GFR) and renal plasma flow (RPF) slopes were calculated from inulin clearance (Cin) and para-aminohippuric acid (PAH) clearance (CPAH), respectively, while glomerular hydrostatic pressure (Pglo), afferent resistance (RA), and efferent resistance (RE) were estimated using the Gomez formulae. Each parameter was compared with baseline Ht-TKV. Patients were also subclassified into 1A-1B and 1C-1E groups according to the baseline Mayo imaging classification (MIC), and then compared with respect to GFR, RPF, FF and glomerular hemodynamics. After 2 years, Ht-TKV increased (933±537 to 1000±648 ml/m, P<0.01), GFR decreased (66.7±30 to 57.3±30.1 ml/min/1.73m2, P<0.001), and RPF decreased (390±215 to 339±190 ml/min/1.73m2, P<0.05). Further, Pglo was decreased and RA was increased. Baseline Ht-TKV was inversely correlated with GFR (r=-0.29, P<0.05), but there was no association between baseline Ht-TKV and RPF, Pglo, RA, or RE annual changes. However, despite an increase in RE in 1A-1B group, RE was decreased in 1C-1E group. As a result, RE slope was significantly lower in 1C-1E group than 1A-1B group over time (-83(-309 to 102) to 164(-34 to 343) dyne・s・cm-5, P<0.01). This is the first report examining yearly changes of GFR (Inulin), RPF (PAH), and renal microcirculation parameters in ADPKD patients. Our results demonstrate that GFR reduction was caused by RA increase, which was faster due to RE decrease in subjects with faster Ht-TKV increase.

Elevated hemoglobin levels in renal transplant recipients with polycystic kidney disease versus other etiologies: exploring mechanisms and implications for outcomes.

Autosomal dominant polycystic kidney disease (ADPKD)-related end-stage kidney disease (ESKD) often necessitates transplantation. However, the impact of ADPKD on post-transplant outcomes, specifically hemoglobin levels, remains unknown. We retrospectively analyzed 513 Kidney Transplant Recipients (KTRs), of whom 81 had ESKD due to ADPKD (20 with pre-transplant native nephrectomy and 61 without). Hemoglobin levels were evaluated at multiple time intervals post-transplant. Kidney transplant recipients with ADPKD vs. KTRs with ESKD due to other causes exhibited significantly higher hemoglobin levels in repeated measurement analysis. Multivariable analyses confirmed ADPKD as an independent predictor for elevated hemoglobin levels. In a multivariable logistic regression analysis, the odds for maximum hemoglobin > 15mg/dL at 3-12months post-transplant were more than twice as high in ADPKD patients vs. all the other KTRs (Odds Ratio [OR] 2.31, 95% Confidence Interval [CI] 1.3-4.13, p < 0.001). Pre-transplant native nephrectomy revealed a trend toward lower hemoglobin levels. Elevated hemoglobin levels were linked to improved estimated glomerular filtration rate (eGFR) at one year post-transplant. Patient survival was enhanced among KTRs with ADPKD compared to other ESKD causes. Kidney transplant recipients with ADPKD exhibited elevated hemoglobin levels post-transplant, possibly due to prolonged native kidney erythropoietin production. These elevated hemoglobin levels were linked to improved outcomes, including allograft function and patient survival. Future research should further investigate the underlying mechanisms driving favorable ADPKD KTR outcomes.

US Veterans Administration Autosomal Dominant Polycystic Kidney Disease Cohort: Demographic, Comorbidity, and Key Laboratory Data Characteristics.

We used the largest integrated US health care system, the Veterans Health Administration (VHA), to establish a robust resource for demographic, longitudinal outcome, and predictive modeling studies in autosomal dominant polycystic kidney disease (ADPKD). We built the ADPKD cohort by extracting the relevant electronic health record (EHR) data from nationwide VHA database (years 1999-2020). We identified 12,217 patients diagnosed with ADPKD. By the end of the 20-year study period, 5,342 ADPKD patients were deceased, 1,583 were alive but reached end-stage kidney disease (ESKD), and 4,827 remained alive without ESKD. Most demographic characteristics of this ADPKD cohort resemble the total U.S. veteran population. For example, 94% were males, 45% age 65 years or older, 85% non-Hispanic, 66% white; however, 19% were Black/African Americans (vs. 12% in the general veteran population; a relevant enrichment after considering age and sex distributions between races). The comorbidities overrepresented in the ADPKD cohort include hypertension (89% vs. 50%), diabetes (32% vs. 22%), depression (40% vs. 10%), chronic obstructive pulmonary disease (30% vs 6%), and congestive heart failure (21% vs 1%). In contrast, obesity was under-represented in veterans with ADPKD (30% vs 41%). We established a large EMR-based cohort of ADPKD veterans. Here we provide initial analysis of its demographic, comorbidity and key laboratory data.

Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.

In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups. This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV. Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all). This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.

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.

Role of Female Sex Hormones in ADPKD Progression and a Personalized Approach to Contraception and Hormonal Therapy.

This review navigates the intricate relationship between gender, hormonal influences, and the progression of autosomal dominant polycystic kidney disease (ADPKD), highlighting the limited literature on this crucial topic. The study explores the impact of female sex hormones on liver and renal manifestations, uncovering gender-specific differences in disease progression. Actually, hormonal therapy in women with ADPKD remains a challenging issue and is a source of concern regarding its potential impact on disease outcomes, particularly at the hepatic level. Notably, women with ADPKD exhibit a slower renal disease progression compared to men, attributed to hormonal dynamics. This review sheds light on the role of estrogen in regulating pathways of the renin-angiotensin-aldosterone system, revealing its complex interplay and implications for cardiovascular and renal health. Therapeutic considerations for fertile women with ADPKD, including contraception options, are discussed, emphasizing the necessity for personalized approaches. In the postmenopausal phase, the review evaluates the role of hormonal replacement therapy, considering its potential benefits and risks in the context of ADPKD. The review concludes by underscoring the imperative need for tailored treatment approaches for ADPKD patients, considering individual risks and benefits. The scarcity of literature underlines the call for further research to enhance our understanding of optimal hormonal therapies in the context of ADPKD, ultimately paving the way for innovative and personalized therapeutic interventions.

Factors associated with early-onset intracranial aneurysms in patients with autosomal dominant polycystic kidney disease.

Recently, the importance of attribute-based medicine has been emphasized. The effects of early-onset intracranial aneurysms on patients can be significant and long-lasting. Herein, we compared the factors associated with intracranial aneurysms in patients with autosomal dominant polycystic kidney disease (ADPKD) according to age categories (≥ 50years, < 50years). We included 519 ADPKD patients, with a median age of 44years, estimated glomerular filtration rate of 54.5mL/min/1.73 m2, and total follow-up duration of 3104 patient-years. Logistic regression analyses were performed to determine factors associated with intracranial aneurysms. Regarding the presence ofintracranial aneurysm, significant interactions were identified between the age category (age ≥ 50years), female sex (P = 0.0027 for the interaction) and hypertension (P = 0.0074 for the interaction). Female sex and hypertension were associated with intracranial aneurysm risk factors only in patients aged ≥ 50years. The presence of intracranial aneurysm was significantly associated with chronic kidney disease (CKD) stages 4-5 (odds ratio [OR] = 3.87, P = 0.0007) and family history of intracranial aneurysm or subarachnoid hemorrhage (OR = 2.30, P = 0.0217) in patients aged < 50years. For patients aged ≥ 50years, in addition to the abovementioned factors [OR = 2.38, P = 0.0355 for CKD stages 4-5; OR = 3.49, P = 0.0094 for family history of intracranial aneurysm or subarachnoid hemorrhage], female sex (OR = 4.51, P = 0.0005), and hypertension (OR = 5.89, P = 0.0012) were also associated with intracranial aneurysm. Kidney dysfunction and family history of intracranial aneurysm or subarachnoid hemorrhage are risk factors for early-onset intracranial aneurysm. Patients aged < 50years with a family history of intracranial aneurysm or subarachnoid hemorrhage or with CKD stages 4-5 may be at an increased risk of early-onset intracranial aneurysm.

Prevalence of Renal Neoplasia in Autosomal Dominant Polycystic Kidney Disease: Systematic Review and Meta-analysis.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition, however its relationship with renal cell carcinoma (RCC) remains unclear. This paper aims to establish the prevalence of RCC and its subtypes amongst ADPKD patients. A database search was conducted to retrieve studies reporting RCC occurrence within ADPKD patients until July 2023. Key outcomes included number and subtype of RCC cases, and number of RCCs presenting incidentally. A random-effects meta-analysis was performed. Our search yielded 569 articles, 16 met the inclusion criteria. Nephrectomy specimens from 1,147 ADPKD patients were identified. Of studies reporting per-kidney results (n = 13), 73 RCCs were detected amongst 1,493 kidneys, equating to a per-kidney prevalence of 4.3% (95% CI, 3.1 to 5.7, I2 = 15.7%). 75 ADPKD patients were found to have RCC (75/1147), resulting in a per-person prevalence of 5.7% (95% CI, 3.7 to 7.9, I2 = 40.3%) (n = 16). As 7 patients had bilateral disease, 82 RCCs were detected in total. Of these, 39 were clear cell RCC, 35 were papillary and 8 were other. As such, papillary RCCs made up 41.1% (95% CI, 25.9 to 56.9, I2 = 18.1%) of detected cancers. The majority of RCCs were detected incidentally (72.5% [95% CI, 43.7 to 95.1, I2 = 66.9%]). ADPKD appears to be associated with the papillary RCC subtype. The clinical implications of these findings are unclear, however may become apparent as outcomes and life expectancy amongst APDKD patients improve.

NnUNet for Automatic Kidney and Cyst Segmentation in Autosomal Dominant Polycystic Kidney Disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder that causes uncontrolled kidney cyst growth, leading to kidney volume enlargement and renal function loss over time. Total kidney volume (TKV) and cyst burdens have been used as prognostic imaging biomarkers for ADPKD. This study aimed to evaluate nnUNet for automatic kidney and cyst segmentation in T2-weighted (T2W) MRI images of ADPKD patients. 756 kidney images were retrieved from 95 patients in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort (95 patients × 2 kidneys × 4 follow-up scans). The nnUNet model was trained, validated, and tested on 604, 76, and 76 images, respectively. In contrast, all images of each patient were exclusively assigned to either the training, validation, or test sets to minimize evaluation bias. The kidney and cyst regions defined using a semi-automatic method were employed as ground truth. The model performance was assessed using the Dice Similarity Coefficient (DSC), the intersection over union (IoU) score, and the Hausdorff distance (HD). The test DSC values were 0.96±0.01 (mean±SD) and 0.90±0.05 for kidney and cysts, respectively. Similarly, the IoU scores were 0.91± 0.09 and 0.81±0.06, and the HD values were 12.49±8.71 mm and 12.04±10.41 mm, respectively, for kidney and cyst segmentation. The nnUNet model is a reliable tool to automatically determine kidney and cyst volumes in T2W MRI images for ADPKD prognosis and therapy monitoring.

The association between serum Perilipin-2 and kidney disease progression of patients with autosomal dominant polycystic kidney disease

Objective: We aimed to evaluate the relationship between serum perilipin-2 / adipophilin (PLIN-2 / ADRP) levels and clinical course in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).&#x0D; Methods: 80 ADPKD patients with Chronic Kidney Disease (CKD) G1-G4 status, among the patients who were regularly followed up in the nephrology outpatient clinic between 2012 and 2019, were included in the study. CKD-G5 patients were excluded from the study. Baseline PLIN-2/ADRP levels were measured. Patients were divided into 2 groups according to the median serum PLIN-2/ADRP level. During the follow-up period, data such as blood pressure, height-adjusted total kidney volume (HtTKV), proteinuria, complete blood count, and biochemical tests were recorded.&#x0D; Results: In the patients with serum PLIN-2 / ADRP level above the median value (11.675 ng / mL), BMI was significantly higher than the other group (p

Pkd2 Deficiency in Embryonic Aqp2 + Progenitor Cells Is Sufficient to Cause Severe Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a devastating disorder caused by mutations in polycystin 1 ( PKD1 ) and polycystin 2 ( PKD2 ). Currently, the mechanism for renal cyst formation remains unclear. Here, we provide convincing and conclusive data in mice demonstrating that Pkd2 deletion in embryonic Aqp2 + progenitor cells (AP), but not in neonate or adult Aqp2 + cells, is sufficient to cause severe polycystic kidney disease (PKD) with progressive loss of intercalated cells and complete elimination of α -intercalated cells, accurately recapitulating a newly identified cellular phenotype of patients with ADPKD. Hence, Pkd2 is a new potential regulator critical for balanced AP differentiation into, proliferation, and/or maintenance of various cell types, particularly α -intercalated cells. The Pkd2 conditional knockout mice developed in this study are valuable tools for further studies on collecting duct development and early steps in cyst formation. The finding that Pkd2 loss triggers the loss of intercalated cells is a suitable topic for further mechanistic studies. Most cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by mutations in PKD1 or PKD2. Currently, the mechanism for renal cyst formation remains unclear. Aqp2 + progenitor cells (AP) (re)generate ≥5 cell types, including principal cells and intercalated cells in the late distal convoluted tubules (DCT2), connecting tubules, and collecting ducts. Here, we tested whether Pkd2 deletion in AP and their derivatives at different developmental stages is sufficient to induce PKD. Aqp2Cre Pkd2f/f ( Pkd2AC ) mice were generated to disrupt Pkd2 in embryonic AP. Aqp2ECE/+Pkd2f/f ( Pkd2ECE ) mice were tamoxifen-inducted at P1 or P60 to inactivate Pkd2 in neonate or adult AP and their derivatives, respectively. All induced mice were sacrificed at P300. Immunofluorescence staining was performed to categorize and quantify cyst-lining cell types. Four other PKD mouse models and patients with ADPKD were similarly analyzed. Pkd2 was highly expressed in all connecting tubules/collecting duct cell types and weakly in all other tubular segments. Pkd2AC mice had obvious cysts by P6 and developed severe PKD and died by P17. The kidneys had reduced intercalated cells and increased transitional cells. Transitional cells were negative for principal cell and intercalated cell markers examined. A complete loss of α -intercalated cells occurred by P12. Cysts extended from the distal renal segments to DCT1 and possibly to the loop of Henle, but not to the proximal tubules. The induced Pkd2ECE mice developed mild PKD. Cystic α -intercalated cells were found in the other PKD models. AQP2 + cells were found in cysts of only 13/27 ADPKD samples, which had the same cellular phenotype as Pkd2AC mice. Hence, Pkd2 deletion in embryonic AP, but unlikely in neonate or adult Aqp2 + cells (principal cells and AP), was sufficient to cause severe PKD with progressive elimination of α -intercalated cells, recapitulating a newly identified cellular phenotype of patients with ADPKD. We proposed that Pkd2 is critical for balanced AP differentiation into, proliferation, and/or maintenance of cystic intercalated cells, particularly α -intercalated cells.

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

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.

PKD1 Truncating Mutations Accelerate eGFR Decline in Autosomal Dominant Polycystic Kidney Disease Patients.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by the accumulation of fluid-filled cysts in the kidneys, leading to renal volume enlargement and progressive kidney function impairment. Disease severity, though, may vary due to allelic and genetic heterogeneity. This study aimed to determine genotype-phenotype correlations between PKD1 truncating and non-truncating mutations and kidney function decline in ADPKD patients. We established a single center retrospective cohort study in Kuwait where we followed every patient with a confirmed PKD1-ADPKD diagnosis clinically and genetically. Renal function tests were performed annually. We fitted generalized additive mixed effects models with random intercepts for each individual to analyze repeated measures of kidney function across mutation type. We then calculated survival time to kidney failure in a cox proportional hazards model. Models were adjusted for sex, age at visit and birth year. The study included 22 truncating and 20 non-truncating (42 total) patients followed for an average of 6.6 years (range: 1 to 12 years). Those with PKD1 truncating mutations had a more rapid rate of eGFR decline (-4.7 ml/min/1.73m2 per year; 95%CI -5.0, -4.4) compared to patients with PKD1 non-truncating mutations (-3.5 ml/min/1.73m2 per year; 95%CI -4.0, -3.1) (P for interaction < 0.001). Kaplan-Meier survival analysis of time to kidney failure showed that patients with PKD1 truncating mutations had a shorter renal survival time (median 51 years) compared to those with non-truncating mutations (median 56 years) (P for log-rank = 0.008). In longitudinal and survival analyses, patients with PKD1 truncating mutations showed a faster decline in kidney function compared to patients PKD1 non-truncating mutations. Early identification of patients with PKD1 truncating mutations can, at best, inform early clinical interventions or, at least, help suggest aggressive monitoring.

DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.