Clinical Focus

  • Kidney Stones
  • Nephrology

Academic Appointments

Honors & Awards

  • Phi Beta Kappa, Stanford University (1994)
  • Dr. Lee B. Harrison Scholarship, Washington University School of Medicine (1997)
  • John S. Miller Award, University of Texas Southwestern Medical Center (2001)
  • SPARK Scholar, Stanford University (2010, 2021)
  • Elected member, Research on Calculus Kinetics (ROCK) Society (kidney stone research society) (2022)

Professional Education

  • Board Certification: American Board of Internal Medicine, Nephrology (2016)
  • Fellowship: UCSF Dept of Nephrology (2006) CA
  • Residency: University of Texas Southwestern Medical Center (2001) TX
  • M.D., Washington University, Medicine (1998)
  • B.S., Stanford University, Biological Sciences (1994)

Current Research and Scholarly Interests

We are broadly interested in how the kidneys control salt, water, and electrolyte homeostasis in the body. Our disease focus is on kidney stone disease. We use cultured kidney cells, transgenic mice, human plasma/urine samples, and electronic health record data to study the pathogenesis of kidney stone disease. Our therapeutic focus is on the development of small molecule compounds that can be used for kidney stone prevention.

2023-24 Courses

Stanford Advisees

Graduate and Fellowship Programs

All Publications

  • Representation of Real-World Adults With Chronic Kidney Disease in Clinical Trials Supporting Blood Pressure Treatment Targets. Journal of the American Heart Association Li, J., An, J., Huang, M., Zhou, M., Montez-Rath, M. E., Niu, F., Sim, J. J., Pao, A. C., Charu, V., Odden, M. C., Kurella Tamura, M. 2024: e031742


    Little is known about how well trial participants with chronic kidney disease (CKD) represent real-world adults with CKD. We assessed the population representativeness of clinical trials supporting the 2021 Kidney Disease: Improving Global Outcomes blood pressure (BP) guidelines in real-world adults with CKD.Using a cross-sectional analysis, we identified patients with CKD who met the guideline definition of hypertension based on use of antihypertensive medications or sustained systolic BP ≥120 mm Hg in 2019 in the Veterans Affairs and Kaiser Permanente of Southern California. We applied the eligibility criteria from 3 BP target trials, SPRINT (Systolic Pressure Intervention Trial), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and AASK (African American Study of Kidney Disease), to estimate the proportion of adults with a systolic BP above the guideline-recommended target and the proportion who met eligibility criteria for ≥1 trial. We identified 503 480 adults in the Veterans Affairs and 73 412 adults in Kaiser Permanente of Southern California with CKD and hypertension in 2019. We estimated 79.7% in the Veterans Affairs and 87.3% in the Kaiser Permanente of Southern California populations had a systolic BP ≥120 mm Hg; only 23.8% [23.7%-24.0%] in the Veterans Affairs and 20.8% [20.5%-21.1%] in Kaiser Permanente of Southern California were trial-eligible. Among trial-ineligible patients, >50% met >1 exclusion criteria.Major BP target trials were representative of fewer than 1 in 4 real-world adults with CKD and hypertension. A large proportion of adults who are at risk for cardiovascular morbidity from hypertension and susceptible to adverse treatment effects lack relevant treatment information.

    View details for DOI 10.1161/JAHA.123.031742

    View details for PubMedID 38533947

  • Clinical Outcomes after a Kidney Stone Event in Kidney Transplant Recipients. Clinical journal of the American Society of Nephrology : CJASN Ganesan, C., Liu, S., Montez-Rath, M., Leppert, J. T., Pao, A. C. 2024

    View details for DOI 10.2215/CJN.0000000000000451

    View details for PubMedID 38480494

  • The Nephrologist's Role in the Management of Kidney Cancer: A Renaissance. American journal of kidney diseases : the official journal of the National Kidney Foundation Ganesan, C., Pao, A. C., Leppert, J. T. 2023

    View details for DOI 10.1053/j.ajkd.2023.08.003

    View details for PubMedID 37855784

  • Treatment and Control of Hypertension Among Adults With Chronic Kidney Disease, 2011 to 2019. Hypertension (Dallas, Tex. : 1979) Martinez, J. D., Thomas, I. C., Montez-Rath, M. E., Pao, A. C., Fung, E., Charu, V., Sim, J. J., An, J., Odden, M. C., Kurella Tamura, M. 2023


    Hypertension frequently accompanies chronic kidney disease (CKD) as etiology and sequela. We examined contemporary trends in hypertension treatment and control in a national sample of adults with CKD.We evaluated 5% cross-sectional samples of adults with CKD between 2011 and 2019 in the Veterans Health Administration. We defined CKD as a sustained estimated glomerular filtration rate value <60 mL/min per 1.73 m2 or a urine albumin-to-creatinine ratio ≥30 mg/g. The main outcomes were blood pressure (BP) control, defined as a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg based on the mean of monthly BP measurements, and prescriptions for antihypertensive medications.The annual samples ranged between n=22 110 and n=33 039 individuals, with a mean age of 72 years, 96% of whom were male. Between 2011 and 2014, the age-adjusted proportion of adults with controlled BP declined from 78.0% to 72.2% (P value for linear trend, <0.001), reached a nadir of 71.0% in 2015, and then increased to 72.9% by 2019 (P value for linear trend, <0.001). Among adults with BP above goal, the age-adjusted proportion who did not receive antihypertensive treatment increased throughout the decade from 18.8% to 21.6%, and the age-adjusted proportion who received ≥3 antihypertensive medications decreased from 41.8% to 36.3%. Prescriptions for first-line antihypertensive agents also decreased.Among adults with CKD treated in the Veterans Health Administration, the proportion with controlled BP declined between 2011 and 2015 followed by a modest increase, coinciding with fewer prescriptions for antihypertensive medications.

    View details for DOI 10.1161/HYPERTENSIONAHA.123.21523

    View details for PubMedID 37706307

  • Hypocitraturia and Risk of Bone Disease in Patients With Kidney Stone Disease. JBMR plus Ganesan, C., Thomas, I. C., Montez-Rath, M. E., Chertow, G. M., Leppert, J. T., Pao, A. C. 2023; 7 (9): e10786


    Patients with kidney stone disease are at higher risk for bone disease. Hypocitraturia is common in patients with kidney stone disease and a key risk factor for stone recurrence. In this retrospective cohort study, we sought to determine whether hypocitraturia is also a risk factor for incident bone disease in patients with kidney stone disease. We used nationwide data from the Veterans Health Administration and identified 9025 patients with kidney stone disease who had a 24-hour urine citrate measurement between 2007 and 2015. We examined clinical characteristics of patients by level of 24-hour urine citrate excretion (<200, 200-400, and >400 mg/d) and the time to osteoporosis or fracture according to 24-hour urine citrate excretion level. Almost one in five veterans with kidney stone disease and a 24-hour urine citrate measurement had severe hypocitraturia, defined as <200 mg/d. Patients with severe hypocitraturia were at risk for osteoporosis or fracture (hazard ratio [HR] = 1.23; confidence interval [CI] 1.03-1.48), but after adjustment for demographic factors, comorbid conditions, and laboratory abnormalities associated with hypocitraturia, the association was no longer statistically significant (HR = 1.18; CI 0.98-1.43). Our results in a predominantly male cohort suggest a modest association between hypocitraturia and osteoporosis or fracture; there are likely to be other explanations for the potent association between kidney stone disease and diminished bone health. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

    View details for DOI 10.1002/jbm4.10786

    View details for PubMedID 37701146

    View details for PubMedCentralID PMC10494504

  • A widely distributed gene cluster compensates for uricase loss in hominids. Cell Liu, Y., Jarman, J. B., Low, Y. S., Augustijn, H. E., Huang, S., Chen, H., DeFeo, M. E., Sekiba, K., Hou, B. H., Meng, X., Weakley, A. M., Cabrera, A. V., Zhou, Z., van Wezel, G., Medema, M. H., Ganesan, C., Pao, A. C., Gombar, S., Dodd, D. 2023; 186 (16): 3400-3413.e20


    Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

    View details for DOI 10.1016/j.cell.2023.06.010

    View details for PubMedID 37541197

  • Response to Alkali Administration in Women and Men With and Without CKD. Kidney medicine Pao, A. C., Shahzad, S. R., Song, S., Ganesan, C., Conti, S., Leppert, J., Cheung, A. K., Ix, J. H., Isakova, T., Wolf, M., Raj, D. S., Sprague, S. M., Fried, L. F., Gassman, J., Fong, P., Koike, S., Raphael, K. L. 2023; 5 (7): 100670

    View details for DOI 10.1016/j.xkme.2023.100670

    View details for PubMedID 37492113

    View details for PubMedCentralID PMC10363557

  • Groundwater constituents and the incidence of kidney cancer. Cancer Soerensen, S. J., Montez-Rath, M. E., Cheng, I., Gomez, S. L., Oh, D. L., Jackson, C., Li, J., Rehkopf, D., Chertow, G. M., Langston, M. E., Ganesan, C., Pao, A. C., Chung, B. I., Leppert, J. T. 2023


    Kidney cancer incidence demonstrates significant geographic variation suggesting a role for environmental risk factors. This study sought to evaluate associations between groundwater exposures and kidney cancer incidence.The authors identified constituents from 18,506 public groundwater wells in all 58 California counties measured in 1996-2010, and obtained county-level kidney cancer incidence data from the California Cancer Registry for 2003-2017. The authors developed a water-wide association study (WWAS) platform using XWAS methodology. Three cohorts were created with 5 years of groundwater measurements and 5-year kidney cancer incidence data. The authors fit Poisson regression models in each cohort to estimate the association between county-level average constituent concentrations and kidney cancer, adjusting for known risk factors: sex, obesity, smoking prevalence, and socioeconomic status at the county level.Thirteen groundwater constituents met stringent WWAS criteria (a false discovery rate <0.10 in the first cohort, followed by p values <.05 in subsequent cohorts) and were associated with kidney cancer incidence. The seven constituents directly related to kidney cancer incidence (and corresponding standardized incidence ratios) were chlordane (1.06; 95% confidence interval [CI], 1.02-1.10), dieldrin (1.04; 95% CI, 1.01-1.07), 1,2-dichloropropane (1.04; 95% CI, 1.02-1.05), 2,4,5-TP (1.03; 95% CI, 1.01-1.05), glyphosate (1.02; 95% CI, 1.01-1.04), endothall (1.02; 95% CI, 1.01-1.03), and carbaryl (1.02; 95% CI, 1.01-1.03). Among the six constituents inversely related to kidney cancer incidence, the standardized incidence ratio furthest from the null was for bromide (0.97; 95% CI, 0.94-0.99).This study identified several groundwater constituents associated with kidney cancer. Public health efforts to reduce the burden of kidney cancer should consider groundwater constituents as environmental exposures that may be associated with the incidence of kidney cancer.

    View details for DOI 10.1002/cncr.34898

    View details for PubMedID 37287332

  • Kidney Stone Events after Kidney Transplant in the United States. Clinical journal of the American Society of Nephrology : CJASN Ganesan, C., Holmes, M., Liu, S., Montez-Rath, M., Conti, S., Chang, T. C., Lenihan, C. R., Cheng, X. S., Chertow, G. M., Leppert, J. T., Pao, A. C. 2023


    BACKGROUND: Kidney stone disease is common and can lead to complications such as acute kidney injury, urinary tract obstruction, and urosepsis. In kidney transplant recipients, complications from kidney stone events can also lead to rejection and allograft failure. There is limited information on the incidence of kidney stone events in transplant recipients.METHODS: We identified 83,535 patients from the United States Renal Data System who received their first kidney transplant between January 1st, 2007 and December 31st, 2018. We examined the incidence of kidney stone events and identified risk factors associated with a kidney stone event in the first 3 years after transplantation.RESULTS: We found 1,436 (1.7%) patients who were diagnosed with a kidney stone in the 3 years following kidney transplant. The unadjusted incidence rate for a kidney stone event was 7.8 per 1000 person-years. The median time from transplant to a kidney stone diagnosis was 0.61 (25%,75% range 0.19-1.46) years. Patients with a prior history of kidney stones were at greatest risk for a kidney stone event after transplant (HR 4.65; 95% CI, 3.82-5.65). Other notable risk factors included a diagnosis of gout (HR 1.53; 95% CI, 1.31-1.80), hypertension (HR 1.29; 95% CI, 1.00-1.66), and a dialysis of vintage of > 9 years (HR 1.48; 95% CI, 1.18-1.86; ref vintage < 2.5 years).CONCLUSIONS: Approximately 2% of kidney transplant recipients were diagnosed with a kidney stone in the 3 years following kidney transplant. Risk factors for a kidney stone event include a prior history of kidney stones and longer dialysis vintage.

    View details for DOI 10.2215/CJN.0000000000000176

    View details for PubMedID 37071657

  • Estimated Effect of Parathyroidectomy on Long-Term Kidney Function in Adults With Primary Hyperparathyroidism. Annals of internal medicine Seib, C. D., Ganesan, C., Furst, A., Pao, A. C., Chertow, G. M., Leppert, J. T., Suh, I., Montez-Rath, M. E., Harris, A. H., Trickey, A. W., Kebebew, E., Tamura, M. K. 2023


    BACKGROUND: Multidisciplinary guidelines recommend parathyroidectomy to slow the progression of chronic kidney disease in patients with primary hyperparathyroidism (PHPT) and an estimated glomerular filtration rate (eGFR) less than 60mL/min/1.73 m2. Limited data address the effect of parathyroidectomy on long-term kidney function.OBJECTIVE: To compare the incidence of a sustained decline in eGFR of at least 50% among patients with PHPT treated with parathyroidectomy versus nonoperative management.DESIGN: Target trial emulation was done using observational data from adults with PHPT, using an extended Cox model with time-varying inverse probability weighting.SETTING: Veterans Health Administration.PATIENTS: Patients with a new biochemical diagnosis of PHPT in 2000 to 2019.MEASUREMENTS: Sustained decline of at least 50% from pretreatment eGFR.RESULTS: Among 43697 patients with PHPT (mean age, 66.8years), 2928 (6.7%) had a decline of at least 50% in eGFR over a median follow-up of 4.9years. The weighted cumulative incidence of eGFR decline was 5.1% at 5years and 10.8% at 10 years in patients managed with parathyroidectomy, compared with 5.1% and 12.0%, respectively, in those managed nonoperatively. The adjusted hazard of eGFR decline did not differ between parathyroidectomy and nonoperative management (hazard ratio [HR], 0.98 [95% CI, 0.82 to 1.16]). Subgroup analyses found no heterogeneity of treatment effect based on pretreatment kidney function. Parathyroidectomy was associated with a reduced hazard of the primary outcome among patients younger than 60years (HR, 0.75 [CI, 0.59 to 0.93]) that was not evident among those aged 60years or older (HR, 1.08 [CI, 0.87 to 1.34]).LIMITATION: Analyses were done in a predominantly male cohort using observational data.CONCLUSION: Parathyroidectomy had no effect on long-term kidney function in older adults with PHPT. Potential benefits related to kidney function should not be the primary consideration for PHPT treatment decisions.PRIMARY FUNDING SOURCE: National Institute on Aging.

    View details for DOI 10.7326/M22-2222

    View details for PubMedID 37037034

  • Breaking the Cycle of Recurrent Calcium Stone Disease. Advances in kidney disease and health Malieckal, D. A., Ganesan, C., Mendez, D. A., Pao, A. C. 2023; 30 (2): 164-176


    Calcium stones are common and recurrent in nature, yet few therapeutic tools are available for secondary prevention. Personalized approaches for stone prevention have been informed by 24-hour urine testing to guide dietary and medical interventions. However, current evidence is conflicting about whether an approach guided by 24-hour urine testing is more effective than a generic one. The available medications for stone prevention, namely thiazide diuretics, alkali, and allopurinol, are not always prescribed consistently, dosed correctly, or tolerated well by patients. New treatments on the horizon hold the promise of preventing calcium oxalate stones by degrading oxalate in the gut, reprogramming the gut microbiome to reduce oxalate absorption, or knocking down expression of enzymes involved in hepatic oxalate production. New treatments are also needed to target Randall's plaque, the root cause of calcium stone formation.

    View details for DOI 10.1053/j.akdh.2022.12.004

    View details for PubMedID 36868731

  • Specialist Care, Metabolic Testing, and Testing Completeness Among U.S. Veterans with Urinary Stone Disease. Urology practice Hsi, R. S., Valicevic, A. N., Patel, S. R., Oerline, M. K., Pao, A. C., Leppert, J. T., Hollingsworth, J. M., Shahinian, V. 2023; 10 (1): 49-56


    Purpose: Recent observational studies reporting a lack of benefit from 24-hour urine testing for urinary stone disease (USD) prevention assumed testing included all components recommended from clinical guidelines. We sought to assess the completeness of 24-hour urine testing in the VA population.Materials and methods: From the VHA Corporate Data Warehouse (2012-2019), we identified patients with USD (n=198,621) and determined those who saw a urologist and/or nephrologist, and received 24-hour urine testing within 12 months of their index USD encounter. Through Logical Observation Identifiers Names and Codes, we evaluated each collection's completeness, defined as including all of urine volume, calcium, oxalate, citrate, uric acid, and creatinine. We then fit a multilevel logistic regression model with random effects for VHA facility to evaluate factors associated with specialist follow-up, testing, and testing completeness.Results: Specialist follow-up occurred in 54.3% and was stable over time. Testing occurred in 8.4%, declining from 9.3% in 2012 to 7.2% in 2019. Of tests performed, 54.6% were complete (43.7% increasing to 62.7% from 2012-2019). In adjusted analysis, there was high between-facility variation in specialist follow-up (median OR 2.0; 95% CI 1.7-2.0), testing (median OR 2.2, 95% CI 1.9-2.4), and testing completeness (median OR, 6.0, 95% CI 4.5-7.3). Individual facilities contributed 52% (intraclass correlation coefficient, 0.52; 95% CI, 0.44-0.57) towards the observed variation in testing completeness.Conclusions: Approximately 1 in 12 U.S. Veterans with USD receive metabolic testing and half of these tests are complete. Addressing facility level variation in testing completeness may improve USD care.

    View details for DOI 10.1097/upj.0000000000000356

    View details for PubMedID 36545539

  • National Imaging Trends for Suspected Urinary Stone Disease in the Emergency Department. JAMA internal medicine Ganesan, C., Stedman, M. R., Liu, S., Conti, S. L., Chertow, G. M., Leppert, J. T., Pao, A. C. 2022

    View details for DOI 10.1001/jamainternmed.2022.4939

    View details for PubMedID 36315134

  • Chronic activation of vasopressin-2 receptors induces hypertension in Liddle mice by promoting Na+ and water retention. American journal of physiology. Renal physiology Stockand, J. D., Mironova, E. V., Xiang, H., Soares, A. G., Contreras, J., McCormick, J. A., Gurley, S. B., Pao, A. C. 2022; 323 (4): F468-F478


    The renin-angiotensin-aldosterone and arginine vasopressin-V2 receptor-aquaporin-2 (AQP2) systems converge on the epithelial Na+ channel (ENaC) to regulate blood pressure and plasma tonicity. Although it is established that V2 receptors initiate renal water reabsorption through AQP2, whether V2 receptors can also induce renal Na+ retention through ENaC and raise blood pressure remains an open question. We hypothesized that a specific increase in V2 receptor-mediated ENaC activity can lead to high blood pressure. Our approach was to test effects of chronic activation of V2 receptors in Liddle mice, a genetic mouse model of high ENaC activity, and compare differences in ENaC activity, urine Na+ excretion, and blood pressure with control mice. We found that ENaC activity was elevated in Liddle mice and could not be stimulated further by administration of desmopressin (dDAVP), a V2 receptor-specific agonist. In contrast, Liddle mice showed higher levels of expression of AQP2 and aquaporin-3, but they could still respond to dDAVP infusion by increasing phospho-AQP2 expression. With dDAVP infusion, Liddle mice excreted smaller urine volume and less urine Na+ and developed higher blood pressure compared with control mice; this hypertension was attenuated with administration of the ENaC inhibitor benzamil. We conclude that V2 receptors contribute to hypertension in the Liddle mouse model by promoting primary Na+ and concomitant water retention.NEW & NOTEWORTHY Liddle syndrome is a classic model for hypertension from high epithelial Na+ channel (ENaC) activity. In the Liddle mouse model, vasopressin-2 receptors stimulate both ENaC and aquaporin-2, which increases Na+ and water retention to such an extent that hypertension ensues. Liddle mice will preserve plasma tonicity at the expense of a higher blood pressure; these data highlight the inherent limitation in which the kidney must use ENaC as a pathway to regulate both plasma tonicity and blood pressure.

    View details for DOI 10.1152/ajprenal.00384.2021

    View details for PubMedID 35900342

    View details for PubMedCentralID PMC9485005

  • Acid-Mediated Kidney Injury Across the Spectrum of Metabolic Acidosis. Advances in chronic kidney disease Ravikumar, N. P., Pao, A. C., Raphael, K. L. 2022; 29 (4): 406-415


    Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.

    View details for DOI 10.1053/j.ackd.2022.04.009

    View details for PubMedID 36175078

  • Role of insulin resistance and the gut microbiome on urine oxalate excretion in ob/ob mice. Physiological reports Xiang, H., Chen, H., Liu, Y., Dodd, D., Pao, A. C. 2022; 10 (14): e15357


    Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob mice. We developed a new liquid chromatography-mass spectrometry assay for urine oxalate and first compared urine oxalate excretion in ob/ob mice before and after ablation of intestinal bacteria with a standard antibiotic cocktail. We then compared urine oxalate excretion in ob/ob mice before and after leptin replacement or pioglitazone treatment, two maneuvers that reduce insulin resistance in ob/ob mice. Ob/ob mice excreted more oxalate into the urine in a 24-h period compared to wild type mice, but antibiotic, leptin, or pioglitazone treatment did not change urine oxalate excretion in ob/ob mice. Unexpectedly, we found that when food intake was carefully matched between ob/ob and wild type mice, the amount of 24-h urine oxalate excretion did not differ between the two mouse strains, suggesting that ob/ob mice excrete more urine oxalate because of hyperphagia. Since the level of urine oxalate excretion in wild type mice in our study was higher than those reported in prior studies, future work will be needed to standardize the measurement of urine oxalate and to define the range of urine oxalate excretion in wild type mice so that accurate and valid comparisons can be made between wild type mice and ob/ob mice or other mouse models.

    View details for DOI 10.14814/phy2.15357

    View details for PubMedID 35851836

  • Kidney stone events following parathyroidectomy vs. non-operative management for primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism Seib, C. D., Ganesan, C., Arnow, K. D., Pao, A. C., Leppert, J. T., Barreto, N. B., Kebebew, E., Tamura, M. K. 2022


    CONTEXT: Primary hyperparathyroidism (PHPT) is associated with an increased risk of kidney stones. Few studies account for PHPT severity or stone risk when comparing stone events after parathyroidectomy vs. non-operative management.OBJECTIVE: Compare the incidence of kidney stone events in PHPT patients treated with parathyroidectomy vs. non-operative management.DESIGN: Longitudinal cohort study with propensity score inverse probability weighting and multivariable Cox proportional hazards regression.SETTING: Veterans Health Administration integrated health care system.PATIENTS: 44,978 patients with >2 years follow-up after PHPT diagnosis (2000-2018). 5,244 patients (11.7%) were treated with parathyroidectomy.MAIN OUTCOMES MEASURE: Clinically significant kidney stone event.RESULTS: The cohort had a mean age of 66.0 years, was 87.8% male, 66.4% White. Patients treated with parathyroidectomy had higher mean serum calcium (11.2 vs. 10.8mg/dL) and were more likely to have a history of kidney stone events. Among patients with baseline history of kidney stones, the unadjusted incidence of ≥1 kidney stone event was 30.5% in patients managed with parathyroidectomy (mean follow-up 5.6 years) compared to 18.0% in those managed non-operatively (mean follow-up 5.0 years). Patients treated with parathyroidectomy had a higher adjusted hazard of recurrent kidney stone events (hazard ratio[HR] 1.98, 95%CI 1.56-2.51); however, this association declined over time (parathyroidectomy*time HR 0.80, 95%CI 0.73-0.87).CONCLUSION: In this predominantly male cohort with PHPT, patients treated with parathyroidectomy continued to be at higher risk of kidney stone events in the immediate years after treatment than patients managed non-operatively, although the adjusted risk of stone events declined with time, suggesting a benefit to surgical treatment.

    View details for DOI 10.1210/clinem/dgac193

    View details for PubMedID 35363858

  • Renal Morbidity Following Radical Cystectomy in Patients with Bladder Cancer. European urology open science Schmidt, B., Velaer, K. N., Thomas, I., Ganesan, C., Song, S., Pao, A. C., Thong, A. E., Liao, J. C., Chertow, G. M., Skinner, E. C., Leppert, J. T. 1800; 35: 29-36


    Background: Patients with chronic kidney disease (CKD) are poor candidates for standard treatments for muscle-invasive bladder cancer (MIBC) and may be more likely to experience adverse outcomes when diagnosed with MIBC.Objective: To investigate factors associated with the development of advanced CKD following radical cystectomy.Design setting and participants: Using national Veterans Health Administration utilization files, we identified 3360 patients who underwent radical cystectomy for MIBC between 2004 and 2018.Outcome measurements and statistical analysis: We examined factors associated with the development of advanced CKD (estimated glomerular filtration rate [eGFR] of <30 ml/min/1.73 m2) after radical cystectomy using multivariable logistic and proportional hazard regression, with and without consideration of competing risks. We examined survival using Kaplan-Meier product limit estimates and proportional hazard regression.Results and limitations: The median age at surgery was 67 yr and the mean preoperative eGFR was 69.1 ± 20.3 ml/min/1.73 m2. Approximately three out of ten patients (n = 962, 29%) progressed to advanced CKD within 12 mo. Older age (hazard ratio [HR] per 5-yr increase 1.15, 95% confidence interval [CI] 1.10-1.20), preoperative hydronephrosis (HR 1.50, 95% CI 1.29-1.76), adjuvant chemotherapy (HR 1.19, 95% CI 1.00-1.41), higher comorbidity index (HR 1.13, 95% CI 1.11-1.16 per point), and lower baseline kidney function (HR 0.75, 95% CI 0.73-0.78) were associated with the development of advanced CKD. Baseline kidney function at the time of surgery was associated with survival. Generalizability is limited due to the predominantly male cohort.Conclusions: Impaired kidney function at baseline is associated with progression to advanced CKD and mortality after radical cystectomy. Preoperative kidney function should be incorporated into risk stratification algorithms for patients undergoing radical cystectomy.Patient summary: Impaired kidney function at baseline is associated with progression to advanced chronic kidney disease and mortality after radical cystectomy.

    View details for DOI 10.1016/j.euros.2021.11.001

    View details for PubMedID 35024629

  • Twenty-four-hour Urine Testing and Urinary Stone Disease Recurrence in Veterans UROLOGY Song, S., Thomas, I., Ganesan, C., Velaer, K. N., Chertow, G. M., Pao, A. C., Leppert, J. T. 2022; 159: 33-40
  • Urine oxalate and citrate excretion in patients with kidney stone disease: An ab initio clinical prediction. Physiological reports Ganesan, C., Pao, A. C. 2021; 9 (15): e14966

    View details for DOI 10.14814/phy2.14966

    View details for PubMedID 34337888

  • Risk of Postpartum Urinary Stone Disease in Women with History of Urinary Stone Disease During Pregnancy. Journal of endourology Spradling, K., Zhang, C. A., Pao, A. C., Liao, J. C., Leppert, J. T., Elliott, C. S., Conti, S. L. 2021


    OBJECTIVE: To determine the risk of postpartum urinary stone disease in women with a history of stone disease during pregnancy.METHODS: Using the Optum de-identified Clinformatics Datamart we identified pregnant women with urinary stone disease in the United States between January 2003 to December 2017 by standardized ICD-9, ICD-10, and CPT code criteria. We limited the cohort to include women without evidence of urinary stone disease prior to pregnancy. We abstracted patient demographic characteristics, clinical risk factors for stone disease, and data for urinary stone disease encounters and related procedures after pregnancy. Encounters occurring within 1 year of pregnancy were excluded. Cox proportional hazard models were used to analyze for significance.RESULTS: We identified a total of 1,395,783 pregnant women with a median postpartum follow-up of 4.0 years, including 5,971 (0.4%) women diagnosed with a urinary stone during pregnancy. Of these, 736 (12.3%) had an additional urinary stone diagnosis claim after pregnancy, compared with 13,275 (0.95%) women without a history of stone disease during pregnancy (p < 0.0001). In multivariable proportional hazards models urinary stone disease during pregnancy (HR 12.8, 95% CI [11.8 - 13.8]) was independently associated with a higher hazard of urinary stone disease after pregnancy.CONCLUSION: Women urinary stone disease during pregnancy were more likely to present with recurrent urinary stone disease after pregnancy. Given the 1 in 8 chance of needing further care, women with history of stone disease during pregnancy may benefit from risk counseling, surveillance, or secondary prevention efforts in the postpartum period.

    View details for DOI 10.1089/end.2021.0223

    View details for PubMedID 34235965

  • Association of parathyroidectomy with 5-year clinically significant kidney stone events in patients with primary hyperparathyroidism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Seib, C. D., Ganesan, C., Arnow, K. D., Suh, I., Pao, A. C., Leppert, J. T., Tamura, M. K., Trickey, A. W., Kebebew, E. 2021


    OBJECTIVE: Patients with primary hyperparathyroidism (PHPT) are at increased risk of kidney stones. Guidelines recommend parathyroidectomy in PHPT patients with a history of stone disease. This study aimed to compare the 5-year incidence of clinically significant kidney stone events in patients with PHPT treated with parathyroidectomy vs. non-operative management.METHODS: We performed a longitudinal cohort study of patients with PHPT in a national commercial insurance claims database (2006-2019). Propensity score inverse probability weighting-adjusted multivariable regression models were calculated.RESULTS: We identified 7,623 patients ≥35 years-old with continuous enrollment >1 year before and >5 years after PHPT diagnosis. 2,933 patients (38.5%) were treated with parathyroidectomy. The cohort had a mean age of 66.5 years, 78.1% were female, 72.4% were White. Over 5 years, the unadjusted incidence of ≥1 kidney stone event was higher in patients managed with parathyroidectomy compared to those managed non-operatively overall (5.4% vs. 4.1%) and among those with a history of kidney stones at PHPT diagnosis (17.9% vs. 16.4%). On multivariable analysis, parathyroidectomy was associated with no statistically significant difference in the odds of 5-year kidney stone event among patients with a history of kidney stones (OR 1.03, 95%CI 0.71-1.50) or those without history of kidney stones (OR 1.16, 95%CI 0.84-1.60).CONCLUSION: Based on this claims analysis, there was no difference in the odds of 5-year kidney stone events in PHPT patients treated with parathyroidectomy vs. non-operative management. Time-horizon for benefit should be considered when making treatment decisions for PHPT based on risk of kidney stone events.

    View details for DOI 10.1016/j.eprac.2021.06.004

    View details for PubMedID 34126246

  • Removing Race from eGFR calculations: Implications for Urologic Care. Urology Vilson, F. L., Schmidt, B., White, L., Soerensen, S. J., Ganesan, C., Pao, A. C., Enemchukwu, E., Chertow, G. M., Leppert, J. T. 2021


    Equations estimating the glomerular filtration rate are important clinical tools in detecting and managing kidney disease. Urologists extensively use these equations in clinical decision making. For example, the estimated glomerular function rate is used when considering the type of urinary diversion following cystectomy, selecting systemic chemotherapy in managing urologic cancers, and deciding the type of cross-sectional imaging in diagnosing or staging urologic conditions. However, these equations, while widely accepted, are imprecise and adjust for race which is a social, not a biologic construct. The recent killings of unarmed Black Americans in the US have amplified the discussion of racism in healthcare and has prompted institutions to reconsider the role of race in eGFR equations and raced-based medicine. Urologist should be aware of the consequences of removing race from these equations, potential alternatives, and how these changes may affect Black patients receiving urologic care.

    View details for DOI 10.1016/j.urology.2021.03.018

    View details for PubMedID 33798557

  • Osteoporosis, Fractures, and Bone Mineral Density Screening in Veterans With Kidney Stone Disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Ganesan, C., Thomas, I., Romero, R., Song, S., Conti, S., Elliott, C., Chertow, G. M., Tamura, M. K., Leppert, J. T., Pao, A. C. 2021


    Whether a link exists between kidney stone disease and osteoporosis or fractures remains an open question. In this retrospective cohort study, we sought to determine the prevalence of osteoporosis and fractures and rate of bone mineral density screening by dual-energy X-ray absorptiometry (DXA) in patients with kidney stone disease. We examined nationwide data from the Veterans Health Administration and identified 531,431 patients with kidney stone disease between 2007 and 2015. Nearly 1 in 4 patients (23.6%, 95% confidence interval [CI] 23.5-23.7) with kidney stone disease had a prevalent diagnosis of osteoporosis or fracture. In patients with no prior history of osteoporosis or bone mineral density assessment before a kidney stone diagnosis, 9.1% were screened with DXA after their kidney stone diagnosis, of whom 20% were subsequently diagnosed with osteoporosis. Our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, a group less well recognized as at risk for osteoporosis or fractures. © 2021 American Society for Bone and Mineral Research (ASBMR).

    View details for DOI 10.1002/jbmr.4260

    View details for PubMedID 33655611

  • Evaluation of Patient Treatment Preferences for 15-20mm Kidney Stones: A Conjoint Analysis. Journal of endourology Spradling, K., Bhambhvani, H. P., Chang, T. C., Pao, A. C., Liao, J. C., Leppert, J. T., Welk, B., Harris, C. R., Conti, S. L., Elliott, C. S. 2020


    INTRODUCTION AND OBJECTIVE: Ureteroscopy (URS) and percutaneous nephrolithotomy (PCNL) are standard surgical treatments for intermediate-size (15-20mm) kidney stones but differ in their postoperative recovery, stone-free rates, and complication risks. We aimed to evaluate what affects patient treatment preferences.METHODS: Patients with urinary stone disease completed a choice-based conjoint analysis exercise assessing four treatment attributes associated with URS and PCNL. A sensitivity analysis using a market simulator was performed and the relative importance of each attribute was calculated. Differences in treatment preferences by demographic subgroup were assessed.RESULTS: A total of 58 patients completed the conjoint analysis exercise. Stone-free rate was the most important treatment attribute while length of hospital stay and cosmesis were less important. Overall, sensitivity analysis based on market simulation scenarios predicted almost equal preference for URS (52.4%) compared to PCNL (47.6%) for treatment of an intermediate-size stone. Older patients (>65 yo) expressed stronger preferences for lower infection rates and shorter hospital stays, and were more likely to prefer URS (67.2%, 95% CI: 52 - 82.5%) compared to younger patients (20-34 yo) (20.3%, 95% CI: 0 - 41.5%) who preferred higher procedure success rates and fewer repeat procedures.CONCLUSION: Conjoint analysis predicts nearly equal patient preference for URS or PCNL for the treatment of intermediate-size kidney stones. Older patients prefer the lower UTI risk and shorter hospital stay associated with URS, while younger patients prefer higher stone-free rates associated with PCNL. These results can help guide urologists in counseling patients and improve the shared decision-making process.

    View details for DOI 10.1089/end.2020.0370

    View details for PubMedID 32867549

  • Analysis of Primary Hyperparathyroidism Screening Among US Veterans With Kidney Stones. JAMA surgery Ganesan, C., Weia, B., Thomas, I., Song, S., Velaer, K., Seib, C. D., Conti, S., Elliott, C., Chertow, G. M., Kurella Tamura, M., Leppert, J. T., Pao, A. C. 2020


    Importance: Approximately 3% to 5% of patients with kidney stones have primary hyperparathyroidism (PHPT), a treatable cause of recurrent stones. However, the rate of screening for PHPT in patients with kidney stones remains unknown.Objectives: To estimate the prevalence of parathyroid hormone (PTH) testing in veterans with kidney stones and hypercalcemia and to identify the demographic, geographic, and clinical characteristics of veterans who were more or less likely to receive PTH testing.Design, Setting, and Participants: This cohort study obtained Veterans Health Administration (VHA) health records from the Corporate Data Warehouse for veterans who received care in 1 of the 130 VHA facilities across the United States from January 1, 2008, through December 31, 2013. Historical encounters, medical codes, and laboratory data were assessed. Included patients had diagnostic or procedural codes for kidney or ureteral stones, and excluded patients were those with a previous serum PTH level measurement. Data were collected from January 1, 2006, to December 31, 2014. Data analysis was conducted from June 1, 2019, to January 31, 2020.Exposures: Elevated serum calcium concentration measurement between 6 months before and 6 months after kidney stone diagnosis.Main Outcomes and Measures: Proportion of patients with a serum PTH level measurement and proportion of patients with biochemical evidence of PHPT who underwent parathyroidectomy.Results: The final cohort comprised 7561 patients with kidney stones and hypercalcemia and a mean (SD) age of 64.3 (12.3) years. Of these patients, 7139 were men (94.4%) and 5673 were white individuals (75.0%). The proportion of patients who completed a serum PTH level measurement was 24.8% (1873 of 7561). Across the 130 VHA facilities included in the study, testing rates ranged from 4% to 57%. The factors associated with PTH testing included the magnitude of calcium concentration elevation (odds ratio [OR], 1.07 per 0.1 mg/dL >10.5 mg/dL; 95% CI, 1.05-1.08) and the number of elevated serum calcium concentration measurements (OR, 1.08 per measurement >10.5 mg/dL; 95% CI, 1.06-1.10) as well as visits to both a nephrologist and a urologist (OR, 6.57; 95% CI, 5.33-8.10) or an endocrinologist (OR, 4.93; 95% CI, 4.11-5.93). Of the 717 patients with biochemical evidence of PHPT, 189 (26.4%) underwent parathyroidectomy within 2 years of a stone diagnosis.Conclusions and Relevance: This cohort study found that only 1 in 4 patients with kidney stones and hypercalcemia were tested for PHPT in VHA facilities and that testing rates varied widely across these facilities. These findings suggest that raising clinician awareness to PHPT screening indications may improve evaluation for parathyroidectomy, increase the rates of detection and treatment of PHPT, and decrease recurrent kidney stone disease.

    View details for DOI 10.1001/jamasurg.2020.2423

    View details for PubMedID 32725208

  • SLIPS-LAB-A bioinspired bioanalysis system for metabolic evaluation of urinary stone disease. Science advances Li, H., Shkolyar, E., Wang, J., Conti, S., Pao, A. C., Liao, J. C., Wong, T. S., Wong, P. K. 2020; 6 (21)


    Urinary stone disease is among the most common medical conditions. Standard evaluation of urinary stone disease involves a metabolic workup of stone formers based on measurement of minerals and solutes excreted in 24-hour urine samples. Nevertheless, 24-hour urine testing is slow, expensive, and inconvenient for patients, which has hindered widespread adoption in clinical practice. Here, we demonstrate SLIPS-LAB (Slippery Liquid-Infused Porous Surface Laboratory), a droplet-based bioanalysis system, for rapid measurement of urinary stone-associated analytes. The ultra-repellent and antifouling properties of SLIPS, which is a biologically inspired surface technology, allow autonomous liquid handling and manipulation of physiological samples without complicated sample preparation procedures and supporting equipment. We pilot a study that examines key urinary analytes in clinical samples from patients with urinary stone. The simplicity and speed of SLIPS-LAB hold the potential to provide actionable diagnostic information for patients with urinary stone disease and rapid feedback for responses to dietary and pharmacologic treatments.

    View details for DOI 10.1126/sciadv.aba8535

    View details for PubMedID 32937323

  • The Urine Albumin-Creatinine Ratio and Kidney Function after Nephrectomy. The Journal of urology Sun, A. J., Thomas, I., Velaer, K. N., Ganesan, C., Song, S., Pao, A. C., Wagner, T. H., Brooks, J. D., Chertow, G. M., Leppert, J. T. 2020: 101097JU0000000000001005


    BACKGROUND: Patients with kidney cancer are at risk of developing chronic kidney disease (CKD) after radical and partial nephrectomy. We sought to determine if the urine albumin-creatinine ratio (UACR) is independently associated with progressive CKD after nephrectomy.METHODS: We performed a cohort study based within a large, integrated health care system. We identified patients who underwent radical or partial nephrectomy from 2004 to 2014 with UACR measured in the 12 months prior to surgery. We fit multivariable models to determine if the UACR was associated with the time to CKD progression (defined as reaching stage 4 or 5 CKD, eGFR <30 mL/min/1.73m2). We performed a parallel analysis measuring the time to stage 3b, 4 or 5 CKD (eGFR <45 mL/min/1.73m2) among patients with normal or near-normal preoperative kidney function (eGFR ≥60 mL/min/1.73 m2). We also examined the association between UACR and survival.RESULTS: 1930 patients underwent radical or partial nephrectomy and had preoperative UACR and pre- and post-operative eGFR. Of these, 658 (34%) and 157 (8%) had moderate (UACR 30-300mg/g) or severe albuminuria (UACR > 300mg/g), respectively. Albuminuria severity was independently associated with progressive CKD after radical (moderate albuminuria HR 1.7, 95%CI 1.4-2.2; severe albuminuria HR 2.3, 95%CI 1.7-3.1) and partial nephrectomy (moderate albuminuria HR 1.8, 95%CI 1.2-2.7; severe albuminuria HR 4.3, 95%CI 2.7-7.0). Albuminuria was also associated with survival following radical and partial nephrectomy.CONCLUSIONS: In patients undergoing radical or partial nephrectomy, the severity of albuminuria can stratify risk of progressive CKD.

    View details for DOI 10.1097/JU.0000000000001005

    View details for PubMedID 32125227

  • Urinary Stone Disease in Pregnancy: Current Management Practices in a Large National Cohort. Urology Spradling, K. n., Sohlberg, E. M., Li, S. n., Zhang, C. A., Brubaker, W. D., Dallas, K. n., Pao, A. C., Liao, J. n., Leppert, J. T., Elliott, C. S., Chung, B. I., Min, G. E., Conti, S. L. 2020


    To define current national practice patterns of imaging modalities and urologic procedures in pregnant women with urinary stone disease.Using the IBM® MarketScan® national insurance claims database, we identified pregnant women with urinary stone disease and their corresponding gestational age between 2011-2016 using administrative claims data. We then assessed each encounter for urinary stone disease or stone-related urologic procedure during their pregnancy. We abstracted demographic information as well as codes for stone procedures and imaging.We identified 14,298 pregnant women with urinary stone disease during the study period. Of the 12,315 undergoing abdominal imaging (86.1%), magnetic resonance imaging (MRI) in 2.8%, x-ray in 9%, and ultrasound in 74.3%. Computed tomography was not used as a diagnostic modality during pregnancy. Procedural intervention was performed in 749 women (5.2%): 476 (3.3%) ureteral stent placement without definitive stone treatment, 93 (0.6%) percutaneous nephrostomy placement, and 180 (1.3%) ureteroscopy (URS) for definitive stone treatment. URS was most commonly performed before 34 weeks gestation with only 27 cases (15%) performed after.This large national cohort reveals the current imaging and procedural practice patterns for urinary stone disease during pregnancy and provides a critical baseline as these practice patterns evolve in the future.

    View details for DOI 10.1016/j.urology.2020.03.050

    View details for PubMedID 32311447

  • Urinary Stone Disease in Pregnancy: A Claims-Based Analysis of 1.4 Million Patients. The Journal of urology Sohlberg, E. M., Brubaker, W. D., Zhang, C. A., Anderegg, L. D., Dallas, K., Song, S., Ganesan, C., Chertow, G., Pao, A., Liao, J., Leppert, J. T., Elliott, C. S., Conti, S. L. 2019: 101097JU0000000000000657


    PURPOSE: Urinary stone disease during pregnancy is poorly understood but is thought to be associated with increased maternal and fetal morbidity. We sought to determine the prevalence of urinary stone disease in pregnancy and whether urinary stone disease during pregnancy is associated with adverse pregnancy outcomes.MATERIALS AND METHODS: We identified all pregnant women from 2003 through 2017 in the Optum national insurance claims database. We used diagnosis claims to identify urinary stone disease and assess medical comorbidity. We established the prevalence of urinary stone disease during pregnancy, stratified by week of pregnancy. We further evaluated associations among urinary stone disease and maternal complications and pregnancy outcomes in both univariable and multivariable analyses.RESULTS: Urinary stone disease affects 8/1000 pregnancies and is more common in white women and women with more comorbid conditions. In fully adjusted models, pregnancies complicated by urinary stone disease had higher rates of adverse fetal outcomes, including prematurity and spontaneous abortions. This analysis is limited by its retrospective administrative claims design.CONCLUSIONS: The rate of urinary stone disease during pregnancy is higher than previously reported. Urinary stone disease is associated with adverse pregnancy outcomes.

    View details for DOI 10.1097/JU.0000000000000657

    View details for PubMedID 31738114

  • Ultra-low-dose CT: An Effective Follow-up Imaging Modality for Ureterolithiasis. Journal of endourology Cheng, R. Z., Shkolyar, E., Chang, T. C., Spradling, K., Ganesan, C., Song, S., Pao, A. C., Leppert, J. T., Elliott, C. S., To'o, K., Conti, S. L. 2019


    BACKGROUND AND PURPOSE: Classically, abdominal X-ray (KUB), ultrasound or a combination of both have been routinely used for ureteral stone surveillance after initial diagnosis. More recently, ultra-low-dose CT (ULD CT) has emerged as a CT technique that reduces radiation dose while maintaining high sensitivity and specificity for urinary stone detection. We aim to evaluate our initial experience with ULD CT for patients with ureterolithiasis, measuring real-world radiation doses and stone detection performance.METHODS: We reviewed all ULD CT scans performed at the Veterans Affairs Palo Alto Health Care System between 2016 and 2018. We included patients with ureteral stones and calculated the mean effective radiation dose per scan. We determined stone location and size, if the stone was visible on the associated KUB or CT scout film, and if hydronephrosis was present. We performed logistic regression to identify variables associated with visibility on KUB or CT scout film and hydronephrosis.RESULTS: One-hundred and eighteen ULD scans were reviewed, of which 50 detected ureteral stones. The mean effective radiation dose was 1.04 ± 0.41 mSv. Of the ULD CTs that detected ureterolithiasis, 38% lacked visibility on KUB/CT scout film and had no associated hydronephrosis, suggesting they would be missed with a combination of KUB and ultrasound. Larger stones (OR: 1.40, 95% CI: 1.08-1.96 for every 1mm increase in stone size) were more likely to be detected by KUB/CT scout or ultrasound, while stones in the distal ureter (OR: 0.18, 95% CI: 0.03-0.81) were more likely to be missed by KUB/CT scout or hydronephrosis.CONCLUSION: Based on our institutions' initial experience with ULD CT, ULD CT detects small and distal ureteral stones that would likely be missed by KUB or ultrasound, while maintaining a low effective radiation dose. An ULD CT protocol should be considered when re-imaging for ureteral stones is necessary.

    View details for DOI 10.1089/end.2019.0574

    View details for PubMedID 31663371

  • Prevalence of twenty-four hour urine testing in Veterans with urinary stone disease. PloS one Ganesan, C. n., Thomas, I. C., Song, S. n., Sun, A. J., Sohlberg, E. M., Kurella Tamura, M. n., Chertow, G. M., Liao, J. C., Conti, S. n., Elliott, C. S., Leppert, J. T., Pao, A. C. 2019; 14 (8): e0220768


    The American Urological Association guidelines recommend 24-hour urine testing in patients with urinary stone disease to decrease the risk of stone recurrence; however, national practice patterns for 24-hour urine testing are not well characterized. Our objective is to determine the prevalence of 24-hour urine testing in patients with urinary stone disease in the Veterans Health Administration and examine patient-specific and facility-level factors associated with 24-hour urine testing. Identifying variations in clinical practice can inform future quality improvement efforts in the management of urinary stone disease in integrated healthcare systems.We accessed national Veterans Health Administration data through the Corporate Data Warehouse (CDW), hosted by the Veterans Affairs Informatics and Computing Infrastructure (VINCI), to identify patients with urinary stone disease. We defined stone formers as Veterans with one inpatient ICD-9 code for kidney or ureteral stones, two or more outpatient ICD-9 codes for kidney or ureteral stones, or one or more CPT codes for kidney or ureteral stone procedures from 2007 through 2013. We defined a 24-hour urine test as a 24-hour collection for calcium, oxalate, citrate or sulfate. We used multivariable regression to assess demographic, geographic, and selected clinical factors associated with 24-hour urine testing.We identified 130,489 Veterans with urinary stone disease; 19,288 (14.8%) underwent 24-hour urine testing. Patients who completed 24-hour urine testing were younger, had fewer comorbidities, and were more likely to be White. Utilization of 24-hour urine testing varied widely by geography and facility, the latter ranging from 1 to 40%.Fewer than one in six patients with urinary stone disease complete 24-hour urine testing in the Veterans Health Administration. In addition, utilization of 24-hour urine testing varies widely by facility identifying a target area for improvement in the care of patients with urinary stone disease. Future efforts to increase utilization of 24-hour urine testing and improve clinician awareness of targeted approaches to stone prevention may be warranted to reduce the morbidity and cost of urinary stone disease.

    View details for DOI 10.1371/journal.pone.0220768

    View details for PubMedID 31393935

  • Spironolactone plus patiromer: proceed with caution. Lancet (London, England) Ganesan, C. n., Pao, A. C. 2019; 394 (10208): 1486–88

    View details for DOI 10.1016/S0140-6736(19)32485-7

    View details for PubMedID 31657725

  • Twenty-Four Hour Urine Testing and Prescriptions for Urinary Stone Disease-Related Medications in Veterans. Clinical journal of the American Society of Nephrology : CJASN Song, S. n., Thomas, I. C., Ganesan, C. n., Sohlberg, E. M., Chertow, G. M., Liao, J. C., Conti, S. n., Elliott, C. S., Pao, A. C., Leppert, J. T. 2019


    Current guidelines recommend 24-hour urine testing in the evaluation and treatment of persons with high-risk urinary stone disease. However, how much clinicians use information from 24-hour urine testing to guide secondary prevention strategies is unknown. We sought to determine the degree to which clinicians initiate or continue stone disease-related medications in response to 24-hour urine testing.We examined a national cohort of 130,489 patients with incident urinary stone disease in the Veterans Health Administration between 2007 and 2013 to determine whether prescription patterns for thiazide diuretics, alkali therapy, and allopurinol changed in response to 24-hour urine testing.Stone formers who completed 24-hour urine testing (n=17,303; 13%) were significantly more likely to be prescribed thiazide diuretics, alkali therapy, and allopurinol compared with those who did not complete a 24-hour urine test (n=113,186; 87%). Prescription of thiazide diuretics increased in patients with hypercalciuria (9% absolute increase if urine calcium 201-400 mg/d; 21% absolute increase if urine calcium >400 mg/d, P<0.001). Prescription of alkali therapy increased in patients with hypocitraturia (24% absolute increase if urine citrate 201-400 mg/d; 34% absolute increase if urine citrate ≤200 mg/d, P<0.001). Prescription of allopurinol increased in patients with hyperuricosuria (18% absolute increase if urine uric acid >800 mg/d, P<0.001). Patients who had visited both a urologist and a nephrologist within 6 months of 24-hour urine testing were more likely to have been prescribed stone-related medications than patients who visited one, the other, or neither.Clinicians adjust their treatment regimens in response to 24-hour urine testing by increasing the prescription of medications thought to reduce risk for urinary stone disease. Most patients who might benefit from targeted medications remain untreated.

    View details for DOI 10.2215/CJN.03580319

    View details for PubMedID 31712387

  • Payer Type, Race/Ethnicity, and the Timing of Surgical Management of Urinary Stone Disease JOURNAL OF ENDOUROLOGY Brubaker, W. D., Dallas, K. B., Elliott, C. S., Pao, A. C., Chertow, G. M., Leppert, J. T., Conti, S. L. 2019; 33 (2): 152–58
  • Unplanned Emergency Department Visits and Hospital Admissions Following Ureteroscopy: Do Ureteral Stents Make a Difference? UROLOGY Mittakanti, H. R., Conti, S. L., Pao, A. C., Chertow, G. M., Liao, J. C., Leppert, J. T., Elliott, C. S. 2018; 117: 44–49
  • Redefining the Stone Belt: Precipitation is Associated with Increased Risk of Urinary Stone Disease. Journal of endourology Dallas, K. B., Conti, S. L., Liao, J. C., Sofer, M. n., Pao, A. C., Leppert, J. T., Elliott, C. S. 2017


    Objectives The American Southeast has been labeled the "Stone Belt" due to its relatively high burden of urinary stone disease, presumed to be related to its higher temperatures. However, other regions with high temperatures (e.g. the Southwest) do not have the same disease prevalence as the southeast. We seek to explore the association of stone disease to other climate-associated factors beyond temperature including precipitation and temperature variation.We identified all patients who underwent a surgical procedure for urinary stone disease from the California Office of Statewide Health Planning and Development (OSHPD) databases (2010-2012). Climate data obtained from the National Oceanic and Atmospheric Administration was compared to population adjusted county operative stone burden, controlling for patient and county demographic data as potential confounders.A total of 63,994 unique patients underwent stone procedures in California between 2010-2012. Multivariate modeling revealed higher precipitation (0.019 average increase in surgeries per 1000 persons per inch, p<0.01) and higher mean temperature (0.029 average increase in surgeries per 1000 persons per degree, p<0.01) were both independently associated with an increased operative stone disease burden. Controlling for county level patient factors did not change these observed effects. Conclusion In the state of California, higher precipitation and higher mean temperature are associated with increased rates of stone surgery. Our results appear to agree with the larger trends seen throughout the United States where the areas of highest stone prevalence have warm wet climates, and not warm arid, climates.

    View details for PubMedID 28830242

  • Crescentic Glomerulonephritis With Immunoglobulin G4-Related Disease. The American journal of the medical sciences Raber, I. n., Ediriwickrema, A. n., Higgins, J. n., Kambham, N. n., Pao, A. C. 2017; 354 (3): 236–39


    Immunoglobulin G4 (IgG4)-related disease is an uncommon autoimmune disease that affects multiple organ systems. Renal involvement typically presents as tubulointerstitial nephritis and less commonly as membranous glomerulonephritis. In this case report, we discuss a 68-year-old patient who presented with rapidly progressive glomerulonephritis. His renal biopsy revealed a membranoproliferative pattern of injury with fibrocellular crescents and extensive infiltration of the tubulointerstitium with IgG4-positive plasma cells. We treated the patient with both corticosteroids and rituximab because of the aggressive nature of crescentic glomerulonephritis. The patient demonstrated a partial improvement in kidney function after 2 cycles of rituximab with a decrease in serum creatinine levels from 6.9-4.7mg/dL after 6 months from presentation. This case illustrates the importance of considering IgG4-related disease in cases of rapidly progressive glomerulonephritis and the need for effective treatments for more aggressive forms of this recently recognized disease entity.

    View details for PubMedID 28918828

  • An experimentum crucis in salt sensitivity. American journal of physiology. Renal physiology Pao, A. C., Chang, T. I. 2017; 312 (1): F190-F191

    View details for DOI 10.1152/ajprenal.00510.2016

    View details for PubMedID 27654894

  • SGK1 regulation by miR-466g in cortical collecting duct cells AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Jacobs, M. E., Kathpalia, P. P., Chen, Y., Thomas, S. V., Noonan, E. J., Pao, A. C. 2016; 310 (11): F1251-F1257


    MicroRNAs (miRNAs) are non-coding RNAs that bind target mRNA transcripts and modulate gene expression. In the cortical collecting duct (CCD), aldosterone stimulates the expression of genes that increase activity of the epithelial sodium channel (ENaC); in the early phase of aldosterone induction, one such gene is serum and glucocorticoid regulated kinase 1 (SGK1). We hypothesized that aldosterone regulates the expression of miRNAs in the early phase of induction to control the expression of target genes that stimulate ENaC activity. We treated mpkCCDc14 cells with aldosterone or vehicle for 1 hour and used a miRNA microarray to analyze differential miRNA expression. We identified miR-466g as a miRNA that was decreased by 57% after 1 hour of aldosterone treatment. Moreover, we identified a putative miR-466g binding site in the 3'-UTR of SGK1. We constructed an SGK1 3'-UTR luciferase reporter and found that co-transfection of miR-466g suppressed luciferase activity in HEK293 cells in a dose dependent manner. Deletion or introduction of point mutations that disrupt the miR-466g target site attenuated miR-466g-directed suppression of luciferase activity. Finally, we generated stably transduced mpkCCDc14 cell lines over-expressing miR-466g. Cells over-expressing miR-466g demonstrated 12.9 fold lower level of SGK1 mRNA compared to control cells after 6 hours of aldosterone induction; moreover, cells over-expressing miR-466g exhibited 25% decrease in amiloride-sensitive current after 6 hours of aldosterone induction and complete loss of amiloride-sensitive current after 24 hours of aldosterone induction. Our findings implicate miR-466g as a novel aldosterone responsive miRNA that regulates SGK1 and ENaC in CCD cells.

    View details for DOI 10.1152/ajprenal.00024.2016

    View details for PubMedID 26911843

  • There and back again: insulin, ENaC, and the cortical collecting duct. Physiological reports Pao, A. C. 2016; 4 (10)

    View details for DOI 10.14814/phy2.12809

    View details for PubMedID 27233302

    View details for PubMedCentralID PMC4886174

  • Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2. Biochemical pharmacology Wang, H., Xu, D., Toh, M. F., Pao, A. C., You, G. 2016; 102: 120-129


    Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by serum- and glucocorticoid-inducible kinase 2 (sgk2) in the kidney COS-7 cells. We showed that sgk2 stimulated hOAT4 transport activity. Such stimulation mainly resulted from an increased cell surface expression of the transporter, kinetically revealed as an increased maximal transport velocity Vmax without significant change in substrate-binding affinity Km. We further showed that regulation of hOAT4 activity by sgk2 was mediated by ubiquitin ligase Nedd4-2. Overexpression of Nedd4-2 enhanced hOAT4 ubiquitination, and inhibited hOAT4 transport activity, whereas overexpression of ubiquitin ligase-dead mutant Nedd4-2/C821A or siRNA knockdown of endogenous Nedd4-2 had opposite effects on hOAT4. Our co-immunoprecipitation experiment revealed that sgk2 weakened the association between hOAT4 and Nedd4-2. In conclusion, our study demonstrated for the first time that sgk2 stimulated hOAT4 transport activity by abrogating the inhibitory effect of Nedd4-2 on the transporter.

    View details for DOI 10.1016/j.bcp.2015.11.024

    View details for PubMedID 26740304

  • Harvest and primary culture of the murine aldosterone-sensitive distal nephron. American journal of physiology. Renal physiology Labarca, M., Nizar, J. M., Walczak, E. M., Dong, W., Pao, A. C., Bhalla, V. 2015; 308 (11): F1306-15


    The aldosterone-sensitive distal nephron (ASDN) exhibits axial heterogeneity in structure and function from the distal convoluted tubule to the medullary collecting duct. Ion and water transport is primarily divided between the cortex and medulla of the ASDN, respectively. Transcellular transport in this segment is highly regulated in health and disease and is integrated across different cell types. We currently lack an inexpensive, high-yield, and tractable technique to harvest and culture cells for the study of gene expression and physiologic properties of mouse cortical ASDN. To address this need, we harvested tubules bound to Dolichos biflorus agglutinin (DBA) lectin-coated magnetic beads from kidney cortex and characterized these cell preparations. We determined that these cells are enriched for markers of distal convoluted tubule, connecting tubule, and cortical collecting duct, including principal and intercalated cells. In primary culture these cells develop polarized monolayers with high-resistance (1000-1500 Ω*cm(2)), and maintain expression and activity of key channels. These cells demonstrate an amiloride-sensitive short-circuit current that can be enhanced with aldosterone and maintain measurable potassium and anion secretion. Our method can be easily adopted to study the biology of the ASDN and to investigate phenotypic differences between wild-type and transgenic mouse models.

    View details for DOI 10.1152/ajprenal.00668.2014

    View details for PubMedID 25810438

  • Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma. American journal of physiology. Renal physiology Mironova, E., Chen, Y., Pao, A. C., Roos, K. P., Kohan, D. E., Bugaj, V., Stockand, J. D. 2015; 308 (3): F237-43


    Vasopressin (AVP) activates the epithelial Na+ channel (ENaC). The physiological significance of this activation is unknown. The current studies test if activation of ENaC contributes to AVP-sensitive urinary concentration. Consumption of a 3% NaCl solution induced hypernatremia and plasma hypertonicity in mice. Plasma [AVP] and urine osmolality increased in hypernatremic mice in an attempt to compensate for increases in plasma tonicity. ENaC activity was elevated in mice consuming 3% NaCl solution compared to mice consuming a diet enriched in Na+ with ad libitum tap water. The latter diet does not cause hypernatremia. To determine whether the increase in ENaC activity in mice consuming 3% NaCl solution served to compensate for hypernatremia, mice were treated with the ENaC inhibitor benzamil. Co-administration of benzamil with 3% NaCl solution decreased urinary osmolality and increased urine flow so that urinary Na+ excretion increased with no effect on urinary [Na+]. This decrease in urinary concentration further increased plasma [Na+], osmolality, and [AVP] in these already hypernatremic mice. Benzamil similarly compromised urinary concentration in water deprived mice and in mice treated with desmopressin. These results demonstrate that stimulation of ENaC by AVP plays a critical role in water homeostasis by facilitating urinary concentration, which can compensate for hypernatremia or exacerbate hyponatremia. The current findings are consistent with ENaC in addition to serving as a final effector of the renin-angiotensin-aldosterone system and blood pressure homeostasis, also playing a key role in water homeostasis by regulating urine concentration and dilution of plasma.

    View details for DOI 10.1152/ajprenal.00246.2014

    View details for PubMedID 25391898

  • Urine electrolyte composition and diuretic therapy in heart failure: back to the future? Circulation. Heart failure Pao, A. C., Chertow, G. M. 2014; 7 (5): 697-698
  • Update on the Guytonian view of hypertension. Current opinion in nephrology and hypertension Pao, A. C. 2014; 23 (4): 391-398


    Dr Arthur Guyton hypothesized that the capacity of the kidney to excrete sodium ultimately dictates long-term changes in blood pressure. This model has had a profound influence on our understanding of blood pressure regulation. The goal of this article is to review a selection of classic studies and highlight more recent molecular studies supporting or refuting the Guyton model of blood pressure regulation.Molecular characterizations of human disorders of sodium homeostasis and blood pressure, and phenotypic analysis of transgenic mouse models, strongly support the Guytonian view that the kidney plays a central role in blood pressure control. However, recent studies also support the view that primary changes in the vasculature and nervous system significantly contribute to long-term changes in blood pressure.The findings from provocative studies, particularly those that demonstrate how primary changes in the vasculature alter blood pressure without affecting renal sodium handling, challenge the Guyton model and need to be reconciled with the basic tenets of this model. Future characterization of these exceptions to the Guyton model will be critical in gaining a more complete understanding of the physiology of blood pressure regulation. This path of discovery will undoubtedly lead to new approaches for the diagnosis and treatment of hypertension.

    View details for DOI 10.1097/01.mnh.0000450777.17698.8e

    View details for PubMedID 24901409

  • Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells. American journal of physiology. Cell physiology Rajagopal, M., Thomas, S. V., Kathpalia, P. P., Chen, Y., Pao, A. C. 2014; 306 (3): C263-78


    Under conditions of high dietary salt intake, prostaglandin E2 (PGE2) production is increased in the collecting duct and promotes urinary sodium chloride (NaCl) excretion; however, the molecular mechanisms by which PGE2 increases NaCl excretion in this context have not been clearly defined. We used the mIMCD-K2 cell line to characterize mechanisms underlying PGE2-regulated NaCl transport. When epithelial Na(+) channels were inhibited, PGE2 exclusively stimulated basolateral EP4 receptors to increase short-circuit current (Isc(PGE2)). We found that Isc(PGE2) was sensitive to inhibition by H-89 and CFTR-172, indicating that EP4 receptors signal through protein kinase A to induce Cl- secretion via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Unexpectedly, we also found that IscPGE2 was sensitive to inhibition by BAPTA-AM (Ca(2+) chelator), 2-APB (IP3 receptor blocker), and FFA (Ca(2+) activated Cl(-) channel (CACC) inhibitor), suggesting that EP4 receptors also signal through Ca(2+) to induce Cl(-) secretion via CACC. Additionally, we observed that PGE2 stimulated an increase in Isc through crosstalk between cAMP and Ca(2+) signaling: BAPTA-AM or 2-APB inhibited a component of Isc(PGE2) that was sensitive to CFTR-172 inhibition; H-89 inhibited a component of Isc(PGE2) that was sensitive to FFA inhibition. Together, our findings indicate that PGE2 activates basolateral EP4 receptors and signals through both cAMP and Ca(2+) to stimulate Cl(-) secretion in IMCD-K2 cells. We propose that these signaling pathways, and the crosstalk between them, may provide a concerted mechanism for enhancing urinary NaCl excretion under conditions of high dietary NaCl intake.

    View details for DOI 10.1152/ajpcell.00381.2012

    View details for PubMedID 24284792

  • Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Trac, D., Liu, B., Pao, A. C., Thomas, S. V., Park, M., Downs, C. A., Ma, H., Helms, M. N. 2013; 305 (7): F995-F1005


    Nadph oxidase 4 is an important cellular source of reactive oxygen species (ROS) generation in the kidney. Novel antioxidant drugs, such as Nox4 inhibitor compounds, are being developed. There is, however, very little experimental evidence for the biological role and regulation of Nadph oxidase isoforms in the kidney. Herein, we show that Fulvene-5 is an effective inhibitor of Nox-generated ROS and report the role of Nox isoforms in activating epithelial sodium channels (ENaC) in A6 distal nephron cells via oxidant signaling and cell stretch activation. Using single-channel patch-clamp analysis, we report that Fulvene-5 blocked the increase in ENaC activity that is typically observed with H2O2 treatment of A6 cells: average ENaC NPo values decreased from a baseline level of 1.04 ± 0.18 (means ± SE) to 0.25 ± 0.08 following Fulvene-5 treatment. H2O2 treatment failed to increase ENaC activity in the presence of Fulvene-5. Moreover, Fulvene-5 treatment of A6 cells blocked the osmotic cell stretch response of A6 cells, indicating that stretch activation of Nox-derived ROS plays an important role in ENaC regulation. Together, these findings indicate that Fulvene-5, and perhaps other classes of antioxidant inhibitors, may represent a novel class of compounds useful for the treatment of pathological disorders stemming from inappropriate ion channel activity, such as hypertension.

    View details for DOI 10.1152/ajprenal.00098.2013

    View details for Web of Science ID 000325353900010

    View details for PubMedID 23863470

    View details for PubMedCentralID PMC3798745

  • Novel diuretic targets AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Denton, J. S., Pao, A. C., Maduke, M. 2013; 305 (7): F931-F942


    As the molecular revolution continues to inform a deeper understanding of disease mechanisms and pathways, there exist unprecedented opportunities for translating discoveries at the bench into novel therapies for improving human health. Despite the availability of several different classes of antihypertensive medications, only about half of the 67 million Americans with hypertension manage their blood pressure appropriately. A broader selection of structurally diverse antihypertensive drugs acting through different mechanisms would provide clinicians with greater flexibility in developing effective treatment regimens for an increasingly diverse and aging patient population. An emerging body of physiological, genetic, and pharmacological evidence has implicated several renal ion-transport proteins, or regulators thereof, as novel, yet clinically unexploited, diuretic targets. These include the renal outer medullary potassium channel, ROMK (Kir1.1), Kir4.1/5.1 potassium channels, ClC-Ka/b chloride channels, UTA/B urea transporters, the chloride/bicarbonate exchanger pendrin, and the STE20/SPS1-related proline/alanine-rich kinase (SPAK). The molecular pharmacology of these putative targets is poorly developed or lacking altogether; however, recent efforts by a few academic and pharmaceutical laboratories have begun to lessen this critical barrier. Here, we review the evidence in support of the aforementioned proteins as novel diuretic targets and highlight examples where progress toward developing small-molecule pharmacology has been made.

    View details for DOI 10.1152/ajprenal.00230.2013

    View details for Web of Science ID 000325353900001

    View details for PubMedID 23863472

    View details for PubMedCentralID PMC3798746

  • Landscape of ENaC regulation in the kidney AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Pao, A. C. 2012; 303 (9): F1287-F1288

    View details for DOI 10.1152/ajprenal.00518.2012

    View details for Web of Science ID 000310644600004

    View details for PubMedID 22993072

  • Prostaglandin E-2 mediates proliferation and chloride secretion in ADPKD cystic renal epithelia AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Liu, Y., Rajagopal, M., Lee, K., Battini, L., Flores, D., Gusella, G. L., Pao, A. C., Rohatgi, R. 2012; 303 (10): F1425-F1434


    Prostaglandin E(2) (PGE(2)) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE(2) induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE(2) induces proliferation and chloride (Cl(-)) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl(-) secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE(2) in cell proliferation. Exogenous administration of PGE(2) increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% (P < 0.05). Next, we tested whether PGE(2)-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE(2) and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE(2)-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE(2)-dependent Cl(-) secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I(sc)). Addition of PGE(2) induced a fivefold higher increase in I(sc) in PC-1-deficient cells compared with PC-1-replete cells. This PGE(2)-induced increase in I(sc) in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE(2) activates CFTR and calcium-activated Cl(-) channels. In conclusion, PGE(2) activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE(2) inhibition and EP4 receptor antagonism.

    View details for DOI 10.1152/ajprenal.00010.2012

    View details for Web of Science ID 000311208200004

    View details for PubMedID 22933297

    View details for PubMedCentralID PMC3517629

  • SGK regulation of renal sodium transport CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION Pao, A. C. 2012; 21 (5): 534-540


    The serum and glucocorticoid regulated kinase (SGK) family of protein kinases shares similar biochemical and hormonal signaling properties; however, the SGK kinases also exhibit distinct differences in regulating renal sodium (Na(+)) transport. This review will highlight recent advances in our understanding of the specificity of SGK kinase signaling and regulation of renal Na(+) transport.Differential expression of SGK kinases at the cellular and subcellular levels contributes to signaling specificity. New evidence indicates that SGK1 associates with the apical cell membrane of cortical collecting duct cells to regulate open probability of the epithelial Na(+) channel (ENaC). Scaffold proteins can also recruit SGK1 to multiprotein complexes for regulation of ENaC expression in the apical membrane. Recent SGK1 knockout models have implicated the NaCl co-transporter (NCC) as another target of SGK1 regulation. Less is known about the function of SGK2 or SGK3, but both kinases can regulate Na(+)/H(+) exchanger 3 (NHE3) activity.The SGK kinases assume distinct roles in regulating Na transport in both proximal and distal elements of the kidney tubule. Future examination of the molecular mechanisms by which the SGK kinases regulate specific substrates will inform our understanding of how these kinases contribute to the physiology of renal Na(+) transport.

    View details for DOI 10.1097/MNH.0b013e32835571be

    View details for Web of Science ID 000307649300012

    View details for PubMedID 22691875

  • Differential effects of extracellular ATP on chloride transport in cortical collecting duct cells AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Rajagopal, M., Kathpalia, P. P., Widdicombe, J. H., Pao, A. C. 2012; 303 (4): F483-F491


    Extracellular ATP in the cortical collecting duct can inhibit epithelial sodium channels (ENaC) but also stimulate calcium-activated chloride channels (CACC). The relationship between ATP-mediated regulation of ENaC and CACC activity in cortical collecting duct cells has not been clearly defined. We used the mpkCCD(c14) cortical collecting duct cell line to determine effects of ATP on sodium (Na(+)) and chloride (Cl(-)) transport with an Ussing chamber system. ATP, at a concentration of 10(-6) M or less, did not inhibit ENaC-mediated short-circuit current (I(sc)) but instead stimulated a transient increase in I(sc). The macroscopic current-voltage relationship for ATP-inducible current demonstrated that the direction of this ATP response changes from positive to negative when transepithelial voltage (V(te)) is clamped to less than -10 mV. We hypothesized that this negative V(te) might be found under conditions of aldosterone stimulation. We next stimulated mpkCCD(c14) cells with aldosterone (10(-6) M) and then clamped the V(te) to -50 mV, the V(te) of aldosterone-stimulated cells under open-circuit conditions. ATP (10(-6) M) induced a transient increase in negative clamp current, which could be inhibited by flufenamic acid (CACC inhibitor) and BAPTA-AM (calcium chelator), suggesting that ATP stimulates Cl(-) absorption through CACC. Together, our findings suggest that the status of ENaC activity, by controlling V(te), may dictate the direction of ATP-stimulated Cl(-) transport. This interplay between aldosterone and purinergic signaling pathways may be relevant for regulating NaCl transport in cortical collecting duct cells under different states of extracellular fluid volume.

    View details for DOI 10.1152/ajprenal.00062.2012

    View details for Web of Science ID 000307791200001

    View details for PubMedID 22647633

    View details for PubMedCentralID PMC3423110

  • Prostaglandin E2 Activates Basal EP4 Receptors to Stimulate Chloride Secretion Via Both cAMP and Calcium Mediated Pathways Rajagopal, M., Kathpalia, P. P., Pao, A. C. FEDERATION AMER SOC EXP BIOL. 2012
  • ßPix is a New Player in Renal Physiology. Frontiers in physiology Hamilton, K. L., Pao, A. C. 2012; 3: 268-?

    View details for DOI 10.3389/fphys.2012.00268

    View details for PubMedID 22833724

    View details for PubMedCentralID PMC3401196

  • Epithelial Sodium Channel Regulation by Cell Surface-associated Serum- and Glucocorticoid-regulated Kinase 1 JOURNAL OF BIOLOGICAL CHEMISTRY Thomas, S. V., Kathpalia, P. P., Rajagopal, M., Charlton, C., Zhang, J., Eaton, D. C., Helms, M. N., Pao, A. C. 2011; 286 (37): 32074-32085


    Serum- and glucocorticoid-regulated kinase 1 (sgk1) participates in diverse biological processes, including cell growth, apoptosis, and sodium homeostasis. In the cortical collecting duct of the kidney, sgk1 regulates sodium transport by stimulating the epithelial sodium channel (ENaC). Control of subcellular localization of sgk1 may be an important mechanism for modulating specificity of sgk1 function; however, which subcellular locations are required for sgk1-regulated ENaC activity in collecting duct cells has yet to be established. Using cell surface biotinylation studies, we detected endogenous sgk1 at the apical cell membrane of aldosterone-stimulated mpkCCD(c14) collecting duct cells. The association of sgk1 with the cell membrane was enhanced when ENaC was co-transfected with sgk1 in kidney cells, suggesting that ENaC brings sgk1 to the cell surface. Furthermore, association of endogenous sgk1 with the apical cell membrane of mpkCCD(c14) cells could be modulated by treatments that increase or decrease ENaC expression at the apical membrane; forskolin increased the association of sgk1 with the apical surface, whereas methyl-β-cyclodextrin decreased the association of sgk1 with the apical surface. Single channel recordings of excised inside-out patches from the apical membrane of aldosterone-stimulated A6 collecting duct cells revealed that the open probability of ENaC was sensitive to the sgk1 inhibitor GSK650394, indicating that endogenous sgk1 is functionally active at the apical cell membrane. We propose that the association of sgk1 with the apical cell membrane, where it interacts with ENaC, is a novel means by which sgk1 specifically enhances ENaC activity in aldosterone-stimulated collecting duct cells.

    View details for DOI 10.1074/jbc.M111.278283

    View details for PubMedID 21784856

  • Activation of P2Y(1) and P2Y(2) receptors induces chloride secretion via calcium-activated chloride channels in kidney inner medullary collecting duct cells AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Rajagopal, M., Kathpalia, P. P., Thomas, S. V., Pao, A. C. 2011; 301 (3): F544-F553


    Dysregulation of urinary sodium chloride (NaCl) excretion can result in extracellular fluid (ECF) volume expansion and hypertension. Recent studies demonstrated that urinary nucleotide excretion increases in mice ingesting a high-salt diet and that these increases in extracellular nucleotides can signal through P2Y(2) receptors in the kidney collecting duct to inhibit epithelial Na(+) channels (ENaC). However, under conditions of ECF volume expansion brought about by high-dietary salt intake, ENaC activity should already be suppressed. We hypothesized that alternative pathways exist by which extracellular nucleotides control renal NaCl excretion. We used an inner medullary collecting duct (mIMCD-K2) cell line in an Ussing chamber system as a model to study additional ion transport pathways that are regulated by extracellular nucleotides. When ENaC was inhibited, the addition of adenosine triphosphate (ATP) to the basal side of cell sheets activated both P2Y(1) and P2Y(2) receptors, inducing a transient increase in short-circuit current (I(sc)); addition of ATP to the apical side activated only P2Y(2) receptors, inducing first a transient and then a sustained increase in I(sc). The ATP-induced increases in I(sc) were blocked by pretreatment with a phospholipase C (PLC) inhibitor, a calcium (Ca(2+)) chelator, or Ca(2+)-activated Cl(-) channel (CACC) inhibitors, suggesting that ATP signals through both PLC and intracellular Ca(2+) to activate CACC. We propose that P2Y(1) and P2Y(2) receptors operate in tandem in IMCD cells to provide an adaptive mechanism for enhancing urinary NaCl excretion in the setting of high-dietary NaCl intake.

    View details for DOI 10.1152/ajprenal.00709.2010

    View details for Web of Science ID 000294551400011

    View details for PubMedID 21653634

    View details for PubMedCentralID PMC3174549

  • The natriuretic mechanism of Gamma-Melanocyte-Stimulating Hormone PEPTIDES Kathpalia, P. P., Charlton, C., Rajagopal, M., Pao, A. C. 2011; 32 (5): 1068-1072


    Gamma-Melanocyte Stimulating Hormone (Gamma-MSH) regulates sodium (Na(+)) balance and blood pressure through activation of the melanocortin receptor 3 (MC3-R). The mechanism of the natriuretic effect is proposed to involve binding of MC3-R either in the kidney to directly inhibit tubular Na(+) transport or in the brain to inhibit central neural pathways that control renal tubular Na(+) absorption. This study aimed to clarify the mechanism involved in the natriuretic effect of Gamma-MSH on MC3-R in kidney cells. In Ussing chamber studies, we observed no effects of Gamma-MSH on NaCl transport in the mouse inner medullary collecting duct cell line (mIMCD-K2). We also found that neither MC3-R protein nor mRNA was expressed in mouse kidney, suggesting that renal Gamma-MSH action may not be mediated through direct effects on tubular Na(+) transport but rather through effects on central neural pathways that innervate the kidney.

    View details for DOI 10.1016/j.peptides.2011.02.006

    View details for Web of Science ID 000291286200032

    View details for PubMedID 21335042

    View details for PubMedCentralID PMC3112371

  • Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Pao, A. C., Bhargava, A., Di Sole, F., Quigley, R., Shao, X., Wang, J., Thomas, S., Zhang, J., Shi, M., Funder, J. W., Moe, O. W., Pearce, D. 2010; 299 (6): F1496-F1506


    Serum and glucocorticoid-regulated kinase 2 (sgk2) is 80% identical to the kinase domain of sgk1, an important mediator of mineralocorticoid-regulated sodium (Na(+)) transport in the distal nephron of the kidney. The expression pattern and role in renal function of sgk2 are virtually uncharacterized. In situ hybridization and immunohistochemistry of rodent kidney coupled with real-time RT-PCR of microdissected rat kidney tubules showed robust sgk2 expression in the proximal straight tubule and thick ascending limb of the loop of Henle. Sgk2 expression was minimal in distal tubule cells with aquaporin-2 immunostaining but significant in proximal tubule cells with Na(+)/H(+) exchanger 3 (NHE3) immunostaining. To ascertain whether mineralocorticoids regulate expression of sgk2 in a manner similar to sgk1, we examined sgk2 mRNA expression in the kidneys of adrenalectomized rats treated with physiological doses of aldosterone together with the glucocorticoid receptor antagonist RU486. Northern blot analysis and in situ hybridization showed that, unlike sgk1, sgk2 expression in the kidney was not altered by aldosterone treatment. Based on the observation that sgk2 is expressed in proximal tubule cells that also express NHE3, we asked whether sgk2 regulates NHE3 activity. We heterologously expressed sgk2 in opossum kidney (OKP) cells and measured Na(+)/H(+) exchange activity by Na(+)-dependent cell pH recovery. Constitutively active sgk2, but not sgk1, stimulated Na(+)/H(+) exchange activity by >30%. Moreover, the sgk2-mediated increase in Na(+)/H(+) exchange activity correlated with an increase in cell surface expression of NHE3. Together, these results suggest that the pattern of expression, regulation, and role of sgk2 within the mammalian kidney are distinct from sgk1 and that sgk2 may play a previously unrecognized role in the control of transtubular Na(+) transport through NHE3 in the proximal tubule.

    View details for DOI 10.1152/ajprenal.00075.2010

    View details for Web of Science ID 000285084700030

    View details for PubMedID 20926631

    View details for PubMedCentralID PMC3006302

  • Adenosine Activates A2b Receptors and Enhances Chloride Secretion in Kidney Inner Medullary Collecting Duct Cells HYPERTENSION Rajagopal, M., Pao, A. C. 2010; 55 (5): 1123-U89


    In the kidney, defects in the regulation of urine salt excretion can result in extracellular fluid volume expansion, leading to salt-sensitive hypertension. Previous studies have demonstrated that, when rats are maintained on a high sodium chloride (NaCl) diet, adenosine production increases in the renal medulla with parallel changes in adenosine receptor expression. These studies suggest that adenosine signaling in the kidney can respond to high NaCl loading; however, the functional consequences of these changes in adenosine signaling are not clear. We used the immortalized cell line mIMCD-K2, a murine model system for the renal inner medullary collecting duct, to study the direct effects of adenosine on NaCl transport across the inner medullary collecting duct epithelium with an Ussing chamber system. When epithelial Na(+) channels were inhibited, the addition of adenosine to the apical side of mIMCD-K2 cell sheets stimulated short-circuit current in a dose-dependent manner. This increase in short-circuit current was inhibited by a cystic fibrosis transmembrane conductance regulator Cl(-) channel inhibitor. Pharmacological studies with a panel of adenosine receptor agonists and antagonists demonstrated that adenosine activates apical A2b adenosine receptors to enhance the short-circuit current. Furthermore, adenosine application to mIMCD-K2 cell sheets increased intracellular cAMP, whereas inhibition of protein kinase A completely blocked the adenosine response. Together, our findings indicate that adenosine stimulates Cl(-) secretion through the cystic fibrosis transmembrane conductance regulator in mIMCD-K2 cells by activating apical A2b receptors and signaling through cAMP/protein kinase A. We propose that this adenosine receptor pathway may provide one mechanism for enhancing urine NaCl excretion in the setting of high dietary NaCl intake.

    View details for DOI 10.1161/HYPERTENSIONAHA.109.10404

    View details for Web of Science ID 000276672500013

    View details for PubMedID 20308611

    View details for PubMedCentralID PMC2885947

  • Melamine nephrotoxicity: an emerging epidemic in an era of globalization KIDNEY INTERNATIONAL Bhalla, V., Grimm, P. C., Chertow, G. M., Pao, A. C. 2009; 75 (8): 774-779


    Recent outbreaks of nephrolithiasis and acute kidney injury among children in China have been linked to ingestion of milk-based infant formula contaminated with melamine. These cases provide evidence in humans for the nephrotoxicity of melamine, which previously had been described only in animals. The consequences of this outbreak are already severe and will likely continue to worsen. Herein we summarize the global impact of the melamine milk contamination, the reemergence of melamine-tainted animal feed, and potential mechanisms of melamine nephrotoxicity. Large-scale epidemiologic studies are necessary to further characterize this disease and to assess its potential long-term sequelae. This epidemic of environmental kidney disease highlights the morbidity associated with adulterated food products available in today's global marketplace and reminds us of the unique vulnerability of the kidney to environmental insults. Melamine is the latest in a growing list of diverse potentially toxic compounds about which nephrologists and other health-care providers responsible for the diagnosis and management of kidney disease must now be aware.

    View details for DOI 10.1038/ki.2009.16

    View details for PubMedID 19212415

  • NH2 terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Pao, A. C., McCormick, J. A., Li, H., Siu, J., Govaerts, C., Bhalla, V., Soundararajan, R., Pearce, D. 2007; 292 (6): F1741-F1750


    Serum and glucocorticoid regulated kinase 1 (SGK1) has been identified as a key regulatory protein that controls a diverse set of cellular processes including sodium (Na(+)) homeostasis, osmoregulation, cell survival, and cell proliferation. Two other SGK isoforms, SGK2 and SGK3, have been identified, which differ most markedly from SGK1 in their NH(2)-terminal domains. We found that SGK1 and SGK3 are potent stimulators of epithelial Na(+) channel (ENaC)-dependent Na(+) transport, while SGK2, which has a short NH(2) terminus, is a weak stimulator of ENaC. Further characterization of the role of the SGK1 NH(2) terminus revealed that its deletion does not affect in vitro kinase activity but profoundly limits the ability of SGK1 either to stimulate ENaC-dependent Na(+) transport or inhibit Forkhead-dependent gene transcription. The NH(2) terminus of SGK1, which shares sequence homology with the phosphoinositide 3-phosphate [PI(3)P] binding domain of SGK3, binds phosphoinositides in protein lipid overlay assays, interacting specifically with PI(3)P, PI(4)P, and PI(5)P, but not with PI(3,4,5)P(3). Moreover, a point mutation that reduces phosphoinositide binding to the NH(2) terminus also reduces SGK1 effects on Na(+) transport and Forkhead activity. These data suggest that the NH(2) terminus, although not required for PI 3-kinase-dependent modulation of SGK1 catalytic activity, is required for multiple SGK1 functions, including stimulation of ENaC and inhibition of the proapoptotic Forkhead transcription factor. Together, these observations support the idea that the NH(2)-terminal domain acts downstream of PI 3-kinase-dependent activation to target the kinase to specific cellular compartments and/or substrates, possibly through its interactions with a subset of phosphoinositides.

    View details for DOI 10.1152/ajprenal.00027.2007

    View details for Web of Science ID 000247942000010

    View details for PubMedID 17356130

  • Disinhibitory pathways for control of sodium transport: regulation of ENaC by SGK1 and GILZ AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Bhalla, V., Soundararajan, R., Pao, A. C., Li, H., Pearce, D. 2006; 291 (4): F714-F721


    Regulation of ENaC occurs at several levels. The principal hormonal regulator of ENaC, aldosterone, acts through the mineralocorticoid receptor to modulate ENaC-mediated sodium transport, and considerable attention has focused on defining the components of the early phase of this response. Two genes, SGK1 and GILZ, have now been implicated in this regulation. While the functional significance of SGK1 in mediating aldosterone effects is well established, new evidence has enhanced our understanding of the mechanisms of SGK1 action. In addition, recent work demonstrates a novel role for GILZ in the stimulation of ENaC-mediated sodium transport. Interestingly, both SGK1 and GILZ appear to negatively regulate tonic inhibition of ENaC and thus use disinhibition to propagate the rapid effects of aldosterone to increase sodium reabsorption in tight epithelia.

    View details for DOI 10.1152/ajprenal.00061.2006

    View details for Web of Science ID 000240313000002

    View details for PubMedID 16720863

  • Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3 MOLECULAR ENDOCRINOLOGY Bhalla, V., Daidie, D., Li, H. Y., Pao, A. C., LaGrange, L. P., Wang, J., VANDEWALLE, A., Stockand, J. D., Staub, O., Pearce, D. 2005; 19 (12): 3073-3084


    Serum- and glucocorticoid-regulated kinase 1 (SGK1) is an aldosterone-regulated early response gene product that regulates the activity of several ion transport proteins, most notably that of the epithelial sodium channel (ENaC). Recent evidence has established that SGK1 phosphorylates and inhibits Nedd4-2 (neural precursor cell-expressed, developmentally down-regulated protein 4-2), a ubiquitin ligase that decreases cell surface expression of the channel and possibly stimulates its degradation. The mechanistic basis for this SGK1-induced Nedd4-2 inhibition is currently unknown. In this study we show that SGK1-mediated phosphorylation of Nedd4-2 induces its interaction with members of the 14-3-3 family of regulatory proteins. Through functional characterization of Nedd4-2-mutant proteins, we demonstrate that this interaction is required for SGK1-mediated inhibition of Nedd4-2. The concerted action of SGK1 and 14-3-3 appears to disrupt Nedd4-2-mediated ubiquitination of ENaC, thus providing a mechanism by which SGK1 modulates the ENaC-mediated Na(+) current. Finally, the expression pattern of 14-3-3 is also consistent with a functional role in distal nephron Na(+) transport. These results demonstrate a novel, physiologically significant role for 14-3-3 proteins in modulating ubiquitin ligase-dependent pathways in the control of epithelial ion transport.

    View details for DOI 10.1210/me.2005-0193

    View details for Web of Science ID 000233460500015

    View details for PubMedID 16099816

  • SGK1: A rapid aldosterone-induced regulator of renal sodium reabsorption PHYSIOLOGY McCormick, J. A., Bhalla, V., Pao, A. C., Pearce, D. 2005; 20: 134-139


    Recently, substantial progress has been made in understanding the mechanisms by which aldosterone rapidly stimulates sodium transport in the distal nephron and other tight epithelia. Serum- and glucocorticoid-regulated kinase 1 (SGK1) has been identified as an important mediator of this process. Its physiological relevance has been revealed through heterologous expression in cultured cells and generation of SGK1 knockout mice.

    View details for DOI 10.1152/physiol.00053.2004

    View details for Web of Science ID 000227958500008

    View details for PubMedID 15772302