Pain and Health-Related Quality of Life in Autosomal Dominant Polycystic Kidney Disease: Results from a National Patient-Powered Registry.

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) affects health-related quality of life (HRQoL) including pain, discomfort, fatigue, emotional distress, and impaired mobility. Stakeholders prioritized kidney cyst-related pain as an important core outcome domain in clinical trials, leading to the development of disease-specific assessment tools. Study Design: The ADPKD Registry is hosted online with multiple disease-specific patient-reported outcomes modules to characterize the patient experience in the United States. Setting & Participants: The ADPKD Registry allows consented participants access to a Core Questionnaire that includes demographics, comorbid conditions, current symptoms, and kidney function. Participants complete subsequent modules on a 3-month schedule, including 2 validated HRQoL tools, the ADPKD-Pain and Discomfort Scale (ADPKD-PDS), the ADPKD Impact Scale (ADPKD-IS) and a Healthcare Access and Utilization module. Exposures: Patient-reported latest estimated glomerular filtration rate or creatinine used to calculate stage of chronic kidney disease. Outcomes: Health-related quality of life, measured using validated ADPKD-specific tools; access to polycystic kidney disease-specific health care. Analytical Approach: For the 2 HRQoL tools, scores were calculated for physical, emotional, and fatigue domains; pain severity; and pain interference (based on the licensed user manuals). Associations to health care access were also assessed. Results: By July 2022, 1,086 individuals with ADPKD completed at least 1 of the HRQoL modules, and 319 completed 4 over a year. Participants were an average age of 53. In total, 71% were women, and 91% were White, with all chronic kidney disease (CKD) stages represented. In total, 2.5% reported being treated with dialysis, and 23% had a kidney transplant. CKD stage 4/5 participants reported the most dull kidney pain, whereas sharp kidney pain was evenly distributed across early CKD stages. Dull kidney pain had an impact on sleep regardless of CKD stage. There was a strong positive correlation between the ADPKD-PDS and ADPKD-IS. Patients with a neutral or positive HRQoL were less likely to have been denied access to imaging or other care. Limitations: Currently, all the information collected is patient reported without health record validation of clinical variables. Conclusions: Use of the HRQoL tools in the ADPKD Registry provided a broad cross-sectional assessment in the United States and provided granular information on the burden of pain across the CKD spectrum in ADPKD. The ADPKD Registry allowed assessment of ADPKD impact in a community that experiences decline in health and kidney function over decades.

The Autosomal Dominant Polycystic Kidney Disease Registry is a longitudinal, patient-powered research tool created with the goal to better understand the impacts of ADPKD on affected individuals in the United States. Here, we analyze pain and other health-related quality of life outcomes in 1,086 individuals using validated tools and comment on the utility of these tools for future use in clinical trials and observational studies. We found that sharp pain, dull pain, fullness discomfort, and other related impacts affected individuals across the disease spectrum, although some participants reported more dull pain in later stages (CKD stages 4 and 5). Future analysis of these trends over time will be valuable in understanding how to assess and address the burden of pain in autosomal dominant polycystic kidney disease.

The VUS Challenge in Cystic Kidney Disease: A Case-Based Review.

Genetic testing in nephrology is becoming increasingly important to diagnose patients and to provide appropriate care. This is especially true for autosomal dominant polycystic kidney disease (ADPKD) because this is a common cause of kidney failure and genetically complex. In addition to the major genes, PKD1 and PKD2 , there are at least six minor loci, and phenotypic, and in some cases, genetic overlap with other cystic disorders. Targeted next-generation sequencing, a low-cost, high-throughput technique, has made routine genetic testing viable in nephrology clinics. Appropriate pre- and post-testing genetic counseling is essential to the testing process. Carefully assessing variants is also critical, with the genetic report classifying variants in accordance with American College of Medical Genetics and Genomics guidelines. However, variant of uncertain significance (VUSs) may pose a significant challenge for the ordering clinician. In ADPKD, and particularly within PKD1 , there is high allelic heterogeneity; no single variant is present in more than 2% of families. The Mayo/Polycystic Kidney Disease Foundation variant database, a research tool, is the best current database of PKD1 and PKD2 variants containing over 2300 variants identified in individuals with polycystic kidney disease, but novel variants are often identified. In patients with a high pretest probability of ADPKD on the basis of clinical criteria, but no finding of a pathogenic (P) or likely pathogenic (LP) variant in a cystic kidney gene, additional evaluation of cystic gene VUS can be helpful. In this case-based review, we propose an algorithm for the assessment of such variants in a clinical setting and show how some can be reassigned to a diagnostic grouping. When assessing the relevance of a VUS, we consider both patient/family-specific and allele-related factors using population and variant databases and available prediction tools, as well as genetic expertise. This analysis plus further family studies can aid in making a genetic diagnosis.

State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

Beyond Loss of Kidney Function: Patient Care in Autosomal Dominant Polycystic Kidney Disease.

Patients with autosomal dominant polycystic kidney disease benefit from specialized care over their lifetimes, starting with diagnosis of the condition with ongoing discussion of both the renal course and extra-renal issues. Both renal and extra-renal issues may continue to cause major morbidity even after successful kidney transplant or initiation of RRT, and extra-renal disease aspects should always be considered as part of routine management. In this review, we will focus on updates in pain/depression screening, cardiac manifestations, liver and pancreatic cysts, kidney stone management, and genetic counseling. In some instances, we have shared our current clinical practice rather than an evidence-based guideline. We anticipate more standardization of care after the release of the Kidney Disease Improving Global Outcomes guidelines for management in autosomal dominant polycystic kidney disease later this year.

Polycystic Kidney Disease Diet: What is Known and What is Safe.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, ß -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.

Hybrid Revision of Dysfunctional Aneurysmal Arteriovenous Fistulas.

Endovascular therapy has become the first-line treatment for failing hemodialysis arteriovenous fistulas (AVFs). However, open revision remains an important modality for vascular access maintenance and the recommended approach for AVF aneurysms. This case series describes a hybrid approach for aneurysmal access revision. Three patients were referred for second opinion after failure of endovascular therapy to establish a functioning access. The medical history is briefly described to highlight the limitations of endovascular therapy and the technical advantages of the hybrid approach in these clinical scenarios.

Pharmacologic Management of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder and the fourth leading cause of end-stage kidney disease. ADPKD encompasses a wide range of morbidity in addition to chronic kidney disease and end-stage kidney disease, and its pathogenesis remains incompletely understood. Progress in the management of this condition includes the 2018 FDA approval of tolvaptan as the only mechanism-specific treatment available for individuals at risk of rapid progression. Assessing the risk of rapid progression is discussed at greater length in a separate article in this special issue. This section will address use and prescription of tolvaptan in more detail and address other therapies that may be considered in the treatment of patients with ADPKD.

Kidney cysts in patients with HOGA1 variants.

In an era of increased accessibility to genetic testing, nephrologists may be able to better understand pathophysiologic mechanisms by which their patients develop specific conditions. In this study, we describe clinical and genetic findings of two patients with kidney cysts, who were found to have variants in HOGA1, a mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme associated with primary hyperoxaluria type 3 and the development of oxalate-containing kidney stones. We describe possible mechanisms by which mutations in this enzyme could result in the kidney cyst formation seen in our two patients. We propose that patients with mutations in HOGA1 are predisposed to crystal or stone deposition, tubule dilation, and inflammasome activation, which can result in kidney cyst formation.

Design and Basic Characteristics of a National Patient-Powered Registry in ADPKD.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease worldwide. Over the past five years, the therapeutic pipeline for ADPKD has expanded, leading to a growing need for patient enrollment in clinical trials and improved understanding of patient-centered outcomes that can be used in trial design. To advance these goals, the Polycystic Kidney Disease Foundation (PKDF) established a national web-based ADPKD Registry. Methods: The ADPKD Registry is hosted on a secure, HIPAA-compliant, online platform (IQVIA, oc-meridian.com/pkdcure). Participants are consented through the online system and complete a series of modules. The Core Questionnaire includes patient-reported diagnosis, latest creatinine values, and comorbidities. Additional modules include surveys of family history, diet, quality of life, extrarenal manifestations, and attitudes surrounding research participation. Results: As of October 2021, 1563 ADPKD patients across the United States have registered and completed the Core Questionnaire. Participants have a median age of 44 years and are 72% women, 93% White, with 4% self-identifying as Hispanic/Latino and 2% as Black. All CKD stages are present, including post kidney transplant. To date, seven clinical studies have used the Registry as a recruitment tool. Additionally, quality-of-life burden scores revealed a correlation with disease stage as determined by kidney function. Conclusions: The Registry described here is the only one of its kind and is a valuable longitudinal research tool encompassing all stages of ADPKD. The registry will allow investigators to pursue a range of research questions related to the management of ADPKD, including definition of health-related quality of life (HRQoL) outcomes and recruitment for a variety of observational and therapeutic clinical protocols.

Inherited glomerular diseases in the gilded age of genomic advancements.

The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.

Risk factors and safe contrast volume thresholds for postcontrast acute kidney injury after peripheral vascular interventions.

OBJECTIVE: Postcontrast acute kidney injury (PC-AKI) is a dreaded complication of peripheral vascular interventions (PVIs) that depends on the volume of contrast administered as well as a patient's baseline kidney function. However, there is currently no guidance on the volume of contrast that is considered safe especially for patients with advanced chronic kidney disease (CKD). This study aims to characterize the incidence, risk factors for, and outcomes after PC-AKI and define thresholds of safety for contrast volume. METHODS: The Vascular Quality Initiative files for PVI (2010-2018) were reviewed. Patients on dialysis, with renal transplants, or who developed a bleeding complication were excluded. Only records with complete data on baseline creatinine, contrast volume, and PC-AKI (creatinine increase of ≥0.5 mg/dL, or new dialysis requirement) were included. The cumulative incidence of PC-AKI with contrast volume at each stage of CKD was derived. A safe threshold for contrast volume was defined as the volume at which the cumulative incidence of PC-AKI is 0.5% or less. Multivariable logistic regression was used to define risk factors for PC-AKI, and survival analysis was performed using Kaplan-Meier and multivariable Cox proportional hazards regression. RESULTS: A total of 53,780 procedures were included. There were 16,062 patients (29%) with normal kidney function or CKD1, 21,769 (39%) with CKD2, 14,234 (25%) with CKD3, 1471 (3%) with CKD4, and 199 (<1%) with CKD5. The incidence of PC-AKI was 0.9% and increased with each stage of CKD (CKD1, 0.39%; CKD2, 0.45%; CKD3, 1.5%; CKD4, 4.3%; and CKD5, 7.5%). The safe thresholds for contrast volume for advanced CKD were 50, 20, and 9 mL for CKD3, CKD4, and CKD5, respectively. Regression analysis demonstrated that white race (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.54-0.82) and elective surgery (OR, 0.77; 95% CI, 0.62-0.95) were associated with decreased risk of PC-AKI, whereas inpatient status (OR, 14.5; 95% CI, 9.97-21.2), diabetes (OR, 1.27; 95% CI, 1.02-1.58), advanced CKD (CKD3: OR, 3.65; 95% CI, 2.68-4.98; CKD4: OR, 6.98; 95% CI, 4.72-10.3; CKD5: OR, 8.94; 95% CI, 4.53-17.6), critical limb ischemia (OR, 1.51; 95% CI, 1.14-2.00), acute limb ischemia (OR, 2.47; 95% CI, 1.70-3.59), and contrast-to-eGFR ratio (CGR) (2 ≤ CGR < 3: OR, 1.33; 95% CI, 1.02-1.74; 3 ≤ CGR < 4: OR, 1.90; 95% CI, 1.32-2.75; CGR ≥ 4: OR, 1.79; 95% CI, 1.18-2.70) were significantly associated with increased risk for PC-AKI. Patients who developed PC-AKI had worse in-hospital (16.1% vs 0.45%; P < .01) mortality and long-term survival (log-rank P < .01) compared with those without PC-AKI. CONCLUSIONS: PVI are associated with low risk of PC-AKI that significantly increases when patients with advanced CKD undergo high acuity cases. Given the strong association with short-term and long-term mortality, risk of PC-AKI should be minimized by using safe thresholds of contrast volume.

Intraoperative Ultrasound Guidance for Banding of an Arteriovenous Fistula Causing High Cardiac Output Heart Failure.

The creation of an arteriovenous fistula (AVF) is the preferred mode of access for hemodialysis in patients with End-Stage Renal Disease (ESRD). High output cardiac failure is a known but rare complication of AVF resulting from high flow volume. This case report describes the use of intraoperative ultrasound as a guide for the banding of an AVF to decrease flow volume in a patient with high cardiac output failure. The access was preserved, and a gradual decline of cardiac function before and recovery after banding is demonstrated over an 18-year period.

Simple renal cysts and bovine aortic arch: markers for aortic disease.

Objective: This study aimed to assess the prevalence of thoracic aortic disease (TAD) and abdominal aortic aneurysms (AAA) among patients with simple renal cyst (SRC) and bovine aortic arch (BAA). Methods: Through a retrospective search for patients who underwent both chest and abdominal CT imaging at our institution from 2012 to 2016, we identified patients with SRC and BAA and propensity score matched them to those without these features by age, gender and presence of hypertension, hyperlipidaemia, diabetes and chronic kidney disease. Results: Of a total of 35 498 patients, 6366 were found to have SRC. Compared with the matched population without SRC, individuals with SRC were significantly more likely to have TAD (10.1% vs 3.9%), ascending aortic aneurysm (8.0% vs 3.2%), descending aortic aneurysm (3.3% vs 0.9%), type A aortic dissection (0.6% vs 0.2%), type B aortic dissection (1.1% vs 0.3%) and AAA (7.9% vs 3.3%). The 920 patients identified with BAA were significantly more likely to have TAD (21.8% vs 4.5%), ascending aortic aneurysm (18.4% vs 3.2%), descending aortic aneurysm (6.5% vs 2.0%), type A aortic dissection (1.4% vs 0.4%) and type B aortic dissection (2.4% vs 0.7%) than the matched population without BAA. SRC and BAA were found to be significantly associated with the presence of TAD (OR=2.57 and 7.69, respectively) and AAA (OR=2.81 and 2.56, respectively) on multivariable analysis. Conclusions: This study establishes a substantial increased prevalence of aortic disease among patients with SRC and BAA. SRC and BAA should be considered markers for aortic aneurysm development.

TREX1 Mutation Causing Autosomal Dominant Thrombotic Microangiopathy and CKD-A Novel Presentation.

Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.

Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling.

Quantification of Urinary Protein Biomarkers of Autosomal Dominant Polycystic Kidney Disease by Parallel Reaction Monitoring.

PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) is a life-long disease in which the genes responsible are known, but the pathogenesis of cyst formation and cyst growth are not understood. Cyst growth ultimately leads to end-stage renal failure in most patients. Analysis of the urinary proteome offers the potential to identify proteins that indicate the presence of cysts (and thus provides diagnosis) as well as the rates of cyst growth (providing prognostic information). EXPERIMENTAL DESIGN: A scheduled parallel reaction monitoring (sPRM) assay is performed on urine samples from 14 patients and 18 normal controls. For relative quantification, stable isotope-labeled synthetic peptides are spiked in the urinary protein digests prior to data collection. The data are subsequently normalized to creatinine and protein concentration in the respective urine samples to control for variations in water intake between individuals. RESULTS: Out of the 143 urinary proteins targeted for sPRM assay, 69 proteins are observed to be significantly dysregulated in ADPKD. The dysregulated proteins are used to cluster ADPKD patients into those who are more or less similar to normal controls. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that sPRM is a promising approach to rapidly screen large numbers of proteins in urine in order to provide earlier diagnosis and potentially better understand the pathogenesis of ADPKD development and progression.

Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment.

BACKGROUND: Semaphorin 7A (SEMA7A) is an immunomodulating protein implicated in lung and liver fibrosis. In autosomal-dominant polycystic kidney disease (ADPKD), the progressive expansion of renal cysts, inflammation, and subsequent renal fibrosis leads to end-stage renal disease (ESRD). SEMA7A may play a role in renal fibrosis and in ADPKD. METHODS: We evaluated Sema7a in a mouse model of renal fibrosis and determined the expression of SEMA7A in human ADPKD kidney. We analyzed SEMA7A expression on peripheral blood mononuclear cells (PBMCs), including CD45+ (leukocyte), CD14+(monocyte), CD4+ (T lymphocytes) and CD4+Foxp3+CD25+ [regulatory T lymphocytes (Tregs)] from 90 ADPKD patients (11 tolvaptan treated and 79 tolvaptan naïve), and 21 healthy volunteers, using a Fluorescence-Activated Cell Sorting (FACS). RESULTS: Sema7a is required for renal fibrosis. SEMA7A shows robust expression in ADPKD kidneys, localizing to cysts derived from distal tubules. SEMA7A is higher in circulating monocytes, but unchanged in CD4+ lymphocytes in ADPKD patients. The SEMA7A increase was detected early (stage 1 CKD) and seemed more prominent in patients with smaller kidneys (p = 0.09). Compared to tolvaptan-naïve ADPKD patients, those treated with tolvaptan showed reduced SEMA7A expression on monocytes, T lymphocytes, and Tregs, although the number of PBMCs was unchanged. After 1 month of tolvaptan treatment, SEMA7A expression on Tregs decreased. CONCLUSIONS: SEMA7A shows potential as both a therapeutic target in mammalian kidney fibrosis and as a marker of inflammation in ADPKD patients. SEMA7A expression was lower after tolvaptan treatment, which may reflect drug efficacy.