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.

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease.

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 .

Risk Factors for Common Kidney Stones Are Correlated with Kidney Function Independent of Stone Composition.

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.

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.

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.

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.

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.

Revisiting racial differences in ESRD due to ADPKD in the United States.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) affects all races. Whether the progression of ADPKD varies by race remains unclear. METHODS: In this retrospective cohort study from 2004 to 2013 non-Hispanic blacks and non-Hispanic whites of all ages classified in the US Renal Data System (USRDS) with incident ESRD from ADPKD (n = 23,647), hypertension/large vessel disease (n = 296,352), or diabetes mellitus (n = 451,760) were stratified into five-year age categories ranging from < 40 to > 75 (e.g., < 40, 40-44, 45-49, …, 75+). The Cochran-Mantel-Haenszel test was used to determine the association of race and incidence of ESRD from ADPKD, diabetes, or hypertension. The difference in the proportions of ESRD in non-Hispanic black and non-Hispanic white patients at each age categorical bin was compared by two-sample proportion test. The age of ESRD onset between non-Hispanic black and non-Hispanic white patients at each year was compared using two-sample t-test with unequal variance. RESULTS: 1.068% of non-Hispanic blacks and 2.778% of non-Hispanic whites had ESRD attributed to ADPKD. Non-Hispanic blacks were less likely than non-Hispanic whites to have ESRD attributed to ADPKD (odds ratio (OR) (95% CI) = 0.38 (0.36-0.39), p <  0.0001). Using US Census data as the denominator to adjust for population differences non-Hispanic blacks were still slightly under-represented (OR (95% CI) 0.94 (0.91-0.96), p = 0.004). However, non-Hispanic blacks with ADPKD had a younger age of ESRD (54.4 years ±13) than non-Hispanic whites (55.9 years ±12.8) (p <  0.0001). For those < 40 years old, more non-Hispanic blacks had incident ESRD from ADPKD than non-Hispanic whites (9.49% vs. 7.68%, difference (95% CI) = 1.81% (0.87-2.84%), p <  0.001) for the combined years examined. CONCLUSIONS: As previously shown, we find the incidence of ESRD from ADPKD in non-Hispanic blacks is lower than in non-Hispanic whites. Among the younger ADPKD population (age < 40), however, more non-Hispanic blacks initiated dialysis than non-Hispanic whites. Non-Hispanic blacks with ADPKD initiated dialysis younger than non-Hispanic whites. A potential implication of these findings may be that black race should be considered an additional risk factor for progression in ADPKD.

A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan.

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

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.

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.

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.

Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

CT urography for the diagnosis of medullary sponge kidney.

BACKGROUND: Medullary sponge kidney (MSK) is characterized by malformation of the terminal collecting ducts and is associated with an increased risk of nephrolithiasis, nephrocalcinosis, urinary tract infections, renal acidification defects, and reduced bone density. It has been historically diagnosed with intravenous pyelography (IVP), which is falling out of favor as an imaging modality. CT urography (CTU) performed with multidetector CT (MDCT) has been shown to create images of the renal collecting system with similar detail as IVP; however, its utility in diagnosing MSK has not been defined. CASE REPORT: We present the first 15 patients with recurrent symptomatic nephrolithiasis who were evaluated in our renal stone clinic with CTU. Four patients were diagnosed with MSK after visualization of the characteristic radiologic findings. DISCUSSION: CTU effectively demonstrates the characteristic radiologic findings of MSK including collecting tubule dilatation, medullary nephrocalcinosis, nephrolithiasis, and medullary cysts. Dose reduction protocols can reduce radiation exposure below that associated with conventional IVP. We propose CTU be considered for the diagnosis of MSK.

Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): considerations for routine screening and management.

Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease, marked by progressive increase of bilateral renal cysts, resulting in chronic kidney disease (CKD) and often leading to end-stage renal disease (ESRD). Apart from renal cysts, patients often have extra-renal disease, involving the liver, heart and vasculature. Other less common but equally important extra-renal manifestations of ADPKD include diverticular disease, hernias, male infertility and pain. Extra-renal disease burden is often asymptomatic, but may result in increased morbidity and mortality. If the disease burden is significant, screening may prove beneficial. We review the rationale for current screening recommendations and propose some guidelines for screening and management of ADPKD patients.

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.

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.

Cystic kidney disease in a patient with systemic toxicity from long-term D-penicillamine use.

D-penicillamine, used to treat cystinuria, is known to cause impaired collagen deposition and dysfunction in elastic fibers. D-penicillamine also has been associated with glomerular abnormalities, typically membranous glomerulonephritis. We describe a patient with severe bilateral cystic kidney disease that developed after long-term D-penicillamine use for treatment of cystinuria. The cysts in the kidneys were noted during an evaluation for acute kidney injury. The patient had no evidence of cysts on prior renal imaging at a time when his kidney function was normal. Simultaneously, he presented with multiorgan manifestations of D-penicillamine toxicity, including the skin findings of cutix laxa and elastosis perforans serpiginosa. Consequently, D-penicillamine treatment was discontinued, after which the progression of cystic kidney disease gradually ceased, along with the other systemic manifestations of toxicity. To our knowledge, this is the first report of cystic kidney disease associated with and perhaps caused by long-term d-penicillamine therapy. The proposed mechanism of cyst formation is the malfunction of the extracellular matrix of the kidney by d-penicillamine that leads to an impaired repair process after kidney injury.

Acute kidney injury in a patient with sarcoidosis: hypercalciuria and hypercalcemia leading to calcium phosphate deposition.

Sarcoidosis can affect kidney function through many different mechanisms. We present a patient with sarcoidosis who developed acute kidney injury (AKI). He had a high 1,25-OH vitamin D level and hypercalciuria. As his renal function declined he developed hypercalcemia. A kidney biopsy showed acute tubular necrosis (ATN) with giant cell formation around calcium phosphate crystals. Calcium phosphate deposition is uncommon in sarcoid. We speculate that early interstitial calcium phosphate deposition may in time lead to the development of Randall's plaques and to the more typical calcium oxalate nephrolithiasis seen in sarcoidosis.