ABSTRACT
About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.
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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.
Subject(s)
Kidney Calculi , Polycystic Kidney, Autosomal Dominant , Humans , Polycystic Kidney, Autosomal Dominant/diagnostic imaging , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/diagnosis , Kidney Calculi/diagnostic imaging , Kidney Calculi/diagnosis , Female , Male , AdultABSTRACT
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.
Subject(s)
Polycystic Kidney Diseases , Preimplantation Diagnosis , Pregnancy , Female , Child , Humans , Prospective Studies , Genetic Testing , Fertilization in Vitro , Polycystic Kidney Diseases/diagnosis , Polycystic Kidney Diseases/geneticsABSTRACT
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.
Subject(s)
Polycystic Kidney Diseases , Polycystic Kidney, Autosomal Dominant , Humans , Polycystic Kidney, Autosomal Dominant/diagnosis , Polycystic Kidney, Autosomal Dominant/genetics , TRPP Cation Channels/genetics , Polycystic Kidney Diseases/genetics , Genetic Testing/methods , AllelesABSTRACT
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.
Subject(s)
Kidney Calculi , Kidney Transplantation , Polycystic Kidney, Autosomal Dominant , Humans , Polycystic Kidney, Autosomal Dominant/diagnosis , Polycystic Kidney, Autosomal Dominant/therapy , Kidney , Patient CareABSTRACT
SIGNIFICANCE STATEMENT: Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management. BACKGROUND: Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated. METHODS: Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113 ) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed. RESULTS: Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18-96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients. CONCLUSIONS: Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05846113 .
Subject(s)
Renal Insufficiency, Chronic , Humans , Adult , Adolescent , Young Adult , Middle Aged , Aged , Aged, 80 and over , Prospective Studies , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/therapy , Genetic TestingABSTRACT
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.
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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.
Subject(s)
Aneurysm , Arteriovenous Fistula , Arteriovenous Shunt, Surgical , Humans , Arteriovenous Shunt, Surgical/adverse effects , Renal Dialysis , Treatment Outcome , Aneurysm/diagnostic imaging , Aneurysm/surgery , Vascular Patency , Retrospective StudiesABSTRACT
Rationale & Objective: The coronavirus disease 2019 (COVID-19) pandemic imposed several changes in the care of patients with kidney failure receiving dialysis. We explored patient care experiences during the pandemic. Study Design: The study team verbally administered surveys including Likert scale multiple-choice questions and open-ended questions and recorded responses. Setting & Participants: Surveys were administered to adults receiving dialysis through an academic nephrology practice after the first wave of the COVID-19 pandemic. Exposure: Outpatient dialysis treatment during the COVID-19 pandemic. Outcomes: Perceptions of care and changes in health. Analytical Approach: Multiple-choice responses were quantified using descriptive statistics. Thematic analysis was used to code open-ended responses and derive themes surrounding patient experiences. Results: A total of 172 patients receiving dialysis were surveyed. Most patients reported feeling "very connected" to the care teams. Seventeen percent of participants reported transportation issues, 6% reported difficulty obtaining medications, and 9% reported difficulty getting groceries. Four themes emerged as influencing patient experiences during the pandemic: 1) the COVID-19 pandemic did not significantly affect participants' experience of dialysis care; 2) the COVID-19 pandemic significantly impacted other aspects of participants' lives, which in turn were felt to affect mental and physical health; 3) regarding dialysis care experience more generally, participants valued consistency, dependability, and personal connection to staff; and 4) the COVID-19 pandemic highlighted the importance of external social support. Limitations: Surveys were administered early in the COVID-19 pandemic, and patient perspectives have not been reassessed. Further qualitative analysis using semi-structured interviews was not performed. Survey distribution in additional practice settings, using validated questionnaires, would increase generalizability of the study. The study was not powered for statistical analysis. Conclusions: Early in the COVID-19 pandemic, perceptions of dialysis care were unchanged for most patients. Other aspects of participants' lives were impacted, which affected their health. Subpopulations of patients receiving dialysis may be more vulnerable during the pandemic: those with histories of mental health conditions, non-White patients, and patients treated by in-center hemodialysis. Plain-language summary: Patients with kidney failure continue to receive life-sustaining dialysis treatments during the coronavirus disease 2019 (COVID-19) pandemic. We sought to understand perceived changes in care and mental health during this challenging time. We administered surveys to patients receiving dialysis after the initial wave of COVID-19, asking questions on topics including access to care, ability to reach care teams, and depression. Most participants did not feel that their dialysis care experiences had changed, but some reported difficulties in other aspects of living such as nutrition and social interactions. Participants highlighted the importance of consistent dialysis care teams and the availability of external support. We found that patients who are treated with in-center hemodialysis, are non-White, or have mental health conditions may have been more vulnerable during the pandemic.
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INTRODUCTION: Kidney stone type varies with age, sex, season, and medical conditions. Lower estimate glomerular filtration rate (eGFR) leads to changes in urine chemistry, and risk factors for kidney stones are thought to vary by stone type. We explore the association between eGFR, urine risk factors, and common stone compositions. METHODS: This was a retrospective cohort study of 811 kidney stone patients seen at Yale Medicine between 1994 and 2021 with serum chemistries and 24-h urine chemistries matched within 1 year of baseline stone analysis. Patients' eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. Demographics and medical history were compared by χ2 tests. 24-h urine chemistries and stone analyses were analyzed by one-way ANOVA. Linear regressions were performed to control for demographics, comorbidities, and stone composition. RESULTS: With lower eGFR, the proportion of calcium stones declined while uric acid (UA) stones increased. On univariable analysis, lower eGFR was associated with lower urine pH, calcium, citrate, UA, magnesium, phosphorus, and ammonium. On multivariable analysis, controlling for age, sex, ethnicity, body mass index, comorbidities, and stone type, these factors remained significant. Stone formers with lower eGFR had elevated supersaturation for UA, but reduced supersaturations for calcium-containing stones. Though urine oxalate was significant on univariable analysis, it was not on multivariable analysis. CONCLUSION: Changes in urine parameters are strongly correlated with eGFR regardless of stone type. Renal function may play a key role in modulating kidney stone risk factors. Strategies to mitigate stone risk may need to vary with kidney function, especially when patient urine or stone composition data are unavailable.
Subject(s)
Calcium , Kidney Calculi , Humans , Retrospective Studies , Kidney Calculi/epidemiology , Kidney Calculi/etiology , Risk Factors , KidneyABSTRACT
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.
Subject(s)
Kidney Failure, Chronic , Polycystic Kidney, Autosomal Dominant , Humans , Tolvaptan/therapeutic use , Polycystic Kidney, Autosomal Dominant/drug therapy , Antidiuretic Hormone Receptor Antagonists/therapeutic use , Kidney/pathology , Kidney Failure, Chronic/chemically inducedABSTRACT
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.
Subject(s)
Cysts , Hyperoxaluria, Primary , Kidney Calculi , Oxo-Acid-Lyases , Humans , Hyperoxaluria, Primary/genetics , Kidney , Oxo-Acid-Lyases/chemistry , Oxo-Acid-Lyases/geneticsABSTRACT
Genetic testing is increasingly used in the workup and diagnosis of kidney disease and kidney-related disorders of undetermined cause. Out-of-pocket costs for clinical genetic testing have become affordable, and logistical hurdles overcome. The interest in genetic testing may stem from the need to make or confirm a diagnosis, guide management, or the patient's desire to have a more informed explanation or prognosis. This poses a challenge for providers who do not have formal training in the selection, interpretation, and limitations of genetic tests. In this manuscript, we provide detailed discussion of relevant cases in which clinical genetic testing using a kidney gene panel was applied. The cases demonstrate identification of pathogenic variants for monogenic diseases-contrasting them from genetic risk alleles-and bring up diagnostic limitations and diagnostic utility of these tests in nephrology. This review aims to guide clinicians in formulating pretest conversations with their patients, interpreting genetic variant nomenclature, and considering follow-up investigations. Although providers are gaining experience, there is still risk of testing causing more anxiety than benefit. However, with provider education and support, clinical genetic testing applied to otherwise unexplained kidney-related disorders will increasingly serve as a valuable diagnostic tool with the potential to reshape how we consider and treat many kidney-related diagnoses.
Subject(s)
Kidney Diseases , Nephrology , Alleles , Genetic Testing , Humans , Kidney , Kidney Diseases/geneticsABSTRACT
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.