Lisa E. Vaughan

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

BACKGROUND AND OBJECTIVES Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models. RESULTS Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8). CONCLUSIONS Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.

Stone Composition Among First-Time Symptomatic Kidney Stone Formers in the Community

OBJECTIVE To determine the variation in kidney stone composition and its association with risk factors and recurrence among first-time stone formers in the general population. PATIENTS AND METHODS Medical records were manually reviewed and validated for symptomatic kidney stone episodes among Olmsted County, Minnesota, residents from January 1, 1984, through December 31, 2012. Clinical and laboratory characteristics and the risk of symptomatic recurrence were compared between stone compositions. RESULTS There were 2961 validated first-time symptomatic kidney stone formers. Stone composition analysis was obtained in 1508 (51%) at the first episode. Stone formers were divided into the following mutually exclusive groups: any brushite (0.9%), any struvite (0.9%), any uric acid (4.8%), and majority calcium oxalate (76%) or majority hydroxyapatite (18%). Stone composition varied with clinical characteristics. A multivariable model had a 69% probability of correctly estimating stone composition but assuming calcium oxalate monohydrate stone was correct 65% of the time. Symptomatic recurrence at 10 years was approximately 50% for brushite, struvite, and uric acid but approximately 30% for calcium oxalate and hydroxyapatite stones (P<.001). Recurrence was similar across different proportions of calcium oxalate and hydroxyapatite (P for trend=.10). However, among calcium oxalate stones, 10-year recurrence rate ranged from 38% for 100% calcium oxalate dihydrate to 26% for 100% calcium oxalate monohydrate (P for trend=.007). CONCLUSION Calcium stones are more common (93.5% of stone formers) than has been previously reported. Although clinical and laboratory factors associate with the stone composition, they are of limited utility for estimating stone composition. Rarer stone compositions are more likely to recur.

Perinatal Outcomes with Tamsulosin Therapy for Symptomatic Urolithiasis

PURPOSE Medical expulsive therapy represents an effective adjunctive treatment for nonpregnant patients with symptomatic urolithiasis. Tamsulosin is classified by the FDA (Food and Drug Administration) as a category B medication. However, to our knowledge no published data exist for human pregnancy. We explored the safety and efficacy of tamsulosin therapy for symptomatic urolithiasis occurring during pregnancy. MATERIALS AND METHODS We retrospectively identified patients treated with tamsulosin for stone disease during pregnancy at the Mayo Clinic during 2000 to 2014. This medical expulsive therapy cohort was matched 2:1 to pregnant women with symptomatic urolithiasis during pregnancy who did not receive medical expulsive therapy. Groups were compared using linear mixed models for continuous variables and exact conditional logistic regression models for nominal variables to take into account correlation due to matching. RESULTS A total of 27 patients receiving medical expulsive therapy comprised the study cohort. Median duration of antepartum tamsulosin exposure was 3 days (range 1 to 110), occurring during the first, second and third trimester in 3 (11%), 11 (40.7%) and 18 (67%) patients, respectively. Mean gestational age at delivery was 38.1 weeks (SD 2.4) and 6 (22%) infants were born preterm. All infant birthweights were considered appropriate for gestational age, and no cases of spontaneous abortion, intrauterine demise or neonatal congenital anomalies were encountered. Comparison between the medical expulsive therapy and control groups demonstrated no significant differences in maternal or infant outcomes for any of the examined variables. CONCLUSIONS Tamsulosin medical expulsive therapy does not appear to be associated with adverse maternal or fetal outcomes and may be considered as adjunctive therapy for urolithiasis during pregnancy.

Glomerular Pathology in Dent Disease and Its Association with Kidney Function

BACKGROUND AND OBJECTIVES Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was recently reported in several patients. Thus, Dent disease renal histopathologic features were characterized and assessed, and their association with kidney function was assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Clinical renal pathology reports and slides (where available) were collected from 30 boys and men in eight countries who had undergone clinical renal biopsy between 1995 and 2014. RESULTS Median (25th, 75th percentiles) age at biopsy was 7.5 (5, 19) years with an eGFR of 69 (44, 94) ml/min per 1.73 m2 and a 24-hour urine protein of 2000 (1325, 2936) mg. A repeat biopsy for steroid-resistant proteinuria was performed in 13% (four of 30) of the patients. Prominent histologic findings included focal global glomerulosclerosis in 83% (25 of 30; affecting 16%±19% glomeruli), mild segmental foot process effacement in 57% (13 of 23), focal interstitial fibrosis in 60% (18 of 30), interstitial lymphocytic infiltration in 53% (16 of 30), and tubular damage in 70% (21 of 30). Higher percentages of globally sclerotic glomeruli, foot process effacement, and interstitial inflammation were associated with lower eGFR at biopsy, whereas foot process effacement was associated with steeper annual eGFR decline. CONCLUSIONS These associations suggest a potential role for glomerular pathology, specifically involving the podocyte, in disease progression, which deserves further study. Furthermore, Dent disease should be suspected in boys and men who have unexplained proteinuria with focal global glomerulosclerosis and segmental foot process effacement on renal biopsy.

Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients with Severe Polycystic Liver Disease

OBJECTIVE To observe the effect on total liver volume (TLV) on and off therapy in selected symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PLD) who received octreotide long-acting release (OctLAR) for up to 4 years. PATIENTS AND METHODS Twenty-eight of 42 participants in a prospective 2-year clinical trial of OctLAR (40 mg monthly) consisting of double-blind, randomized (year 1) and open-label treatment (year 2) phases reenrolled in a 2-year open-label extension (OLE) study after being off OctLAR a mean of 8.3 months (original study: July 1, 2007, through June 30, 2013). Participants underwent magnetic resonance imaging at baseline, years 1 and 2, reenrollment, and study completion. Primary end point: change in TLV; secondary end points: changes in total kidney volume, glomerular filtration rate, quality of life (QoL), safety, vital signs, and laboratory parameters. RESULTS Twenty-five participants (59.5%) completed the OLE. Off therapy, TLVs increased a mean ± SD of 3.4%±8.2% per year; after resuming therapy, TLVs decreased a mean ± SD of -4.7%±6.1% per year. Despite regrowth off treatment, overall reductions were observed, with a median (interquartile range) TLV of 4047 mL (3107-7402 mL) at baseline and 3477 (2653-7131 mL) at study completion (-13.2%; P<.001) and with improved health-related QoL. Total kidney volumes increased, and glomerular filtration rates declined from 58.2 mL/min to 54.5 mL/min (n=16) in patients with ADPKD on therapy from baseline to study completion. CONCLUSION Therapy with OctLAR over 4 years in selected patients with symptomatic PLD arrested PLD progression, alleviating symptoms and improving health-related QoL. Discontinuation led to organ regrowth. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00426153.

The Changing Incidence and Presentation of Urinary Stones Over 3 Decades

Objective: To evaluate trends in the incidence of kidney stones and characteristics associated with changes in the incidence rate over 3 decades. Patients and Methods: Adult stone formers in Olmsted County, Minnesota, from January 1, 1984, to December 31, 2012, were validated and characterized by age, sex, stone composition, and imaging modality. The incidence of kidney stones per 100,000 person‐years was estimated. Characteristics associated with changes in the incidence rate over time were assessed using Poisson regression models. Results: There were 3224 confirmed symptomatic (stone seen), 606 suspected symptomatic (no stone seen), and 617 incidental asymptomatic kidney stone formers. The incidence of confirmed symptomatic kidney stones increased from the year 1984 to 2012 in both men (145 to 299/100,000 person‐years; incidence rate ratio per 5 years, 1.14, P<.001) and women (51 to 217/100,000 person‐years; incidence rate ratio per 5 years, 1.29, P<.001). Overall, the incidence of suspected symptomatic kidney stones did not change, but that of asymptomatic kidney stones increased. Utilization of computed tomography for confirmed symptomatic stones increased from 1.8% in 1984 to 77% in 2012; there was a corresponding higher increased incidence of symptomatic small stones (≤3 mm) than of larger stones (>3 mm). Confirmed symptomatic kidney stones with documented spontaneous passage also increased. The incidence of kidney stones with unknown composition increased more than that of stones with known composition. Conclusion: The incidence of both symptomatic and asymptomatic kidney stones has increased dramatically. The increased utilization of computed tomography during this period may have improved stone detection and contributed to the increased kidney stone incidence.

Periprocedural Outcomes Comparing Fibroid Embolization and Focused Ultrasound: a Randomized Controlled Trial and Comprehensive Cohort Analysis.

BACKGROUND: Uterine fibroids are a common problem for reproductive‐aged women, yet little comparative effectiveness research is available to guide treatment choice. Uterine artery embolization and magnetic resonance imaging–guided focused ultrasound surgery are minimally invasive therapies approved by the US Food and Drug Administration for treating symptomatic uterine fibroids. The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study is the first randomized controlled trial to compare these 2 fibroid treatments. OBJECTIVE: The objective of the study was to summarize treatment parameters and compare recovery trajectory and adverse events in the first 6 weeks after treatment. STUDY DESIGN: Premenopausal women with symptomatic uterine fibroids seen at 3 US academic medical centers were enrolled in the randomized controlled trial (n = 57). Women meeting identical criteria who declined randomization but agreed to study participation were enrolled in a nonrandomized parallel cohort (n = 34). The 2 treatment groups were analyzed by using a comprehensive cohort design. All women undergoing focused ultrasound and uterine artery embolization received the same postprocedure prescriptions, instructions, and symptom diaries for comparison of recovery in the first 6 weeks. Return to work and normal activities, medication use, symptoms, and adverse events were captured with postprocedure diaries. Data were analyzed using the Wilcoxon rank sum test or χ2 test. Multivariable regression was used to adjust for baseline pain levels and fibroid load when comparing opioid medication, adverse events, and recovery time between treatment groups because these factors varied at baseline between groups and could affect outcomes. Adverse events were also collected. RESULTS: Of 83 women in the comprehensive cohort design who underwent treatment, 75 completed postprocedure diaries. Focused ultrasound surgery was a longer procedure than embolization (mean [SD], 405 [146] vs 139 [44] min; P <.001). Of women undergoing focused ultrasound (n = 43), 23 (53%) underwent 2 treatment days. Immediate self‐rated postprocedure pain was higher after uterine artery embolization than focused ultrasound (median [interquartile range], 5 [1–7] vs 1 [1–4]; P = .002). Compared with those having focused ultrasound (n = 39), women undergoing embolization (n = 36) were more likely to use outpatient opioid (75% vs 21%; P < .001) and nonsteroidal antiinflammatory medications (97% vs 67%; P < .001) and to have a longer median (interquartile range) recovery time (days off work, 8 [6–14] vs 4 [2–7]; P < .001; days until return to normal, 15 [10–29] vs 10 [10–15]; P = .02). There were no significant differences in the incidence or severity of adverse events between treatment arms; 86% of adverse events (42 of 49) required only observation or nominal treatment, and no events caused permanent sequelae or death. After adjustment for baseline pain and uterine fibroid load, uterine artery embolization was still significantly associated with higher opioid use and longer time to return to work and normal activities (P < .001 for each). Results were similar when restricted to the randomized controlled trial. CONCLUSION: Women undergoing uterine artery embolization have longer recovery times and use more prescription medications, but women undergoing focused ultrasound have longer treatment times. These findings were independent of baseline pain levels and fibroid load.

Risk of Hypertension among First-Time Symptomatic Kidney Stone Formers

BACKGROUND AND OBJECTIVES Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. RESULTS Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone formers and 110 controls developed hypertension. Median follow-up time was 7.8 years in stone formers and 9.6 years in controls. Stone formers were found to have a higher risk of hypertension compared with controls (hazard ratio, 1.50; 95% confidence interval, 1.18 to 1.92), even after adjusting for age, sex, body mass index, serum creatinine, CKD, diabetes, gout, coronary artery disease, dyslipidemia, tobacco use, and alcohol abuse (hazard ratio, 1.58; 95% confidence interval, 1.12 to 2.21). Results were similar after excluding patients who were ever on a thiazide diuretic (hazard ratio, 1.65; 95% confidence interval, 1.16 to 2.38). Stone composition, radiographic stone burden, number of subsequent stone events, and stone removal surgeries were not associated with hypertension (P>0.05 for all). CONCLUSIONS The risk of hypertension was higher after the first symptomatic kidney stone event. However, kidney stone severity, type, and treatment did not associate with hypertension.

Quantitative Prediction of Stone Fragility From Routine Dual Energy CT: Ex vivo proof of Feasibility

RATIONALE AND OBJECTIVES Previous studies have demonstrated a qualitative relationship between stone fragility and internal stone morphology. The goal of this study was to quantify morphologic features from dual-energy computed tomography (CT) images and assess their relationship to stone fragility. MATERIALS AND METHODS Thirty-three calcified urinary stones were scanned with micro-CT. Next, they were placed within torso-shaped water phantoms and scanned with the dual-energy CT stone composition protocol in routine use at our institution. Mixed low- and high-energy images were used to measure volume, surface roughness, and 12 metrics describing internal morphology for each stone. The ratios of low- to high-energy CT numbers were also measured. Subsequent to imaging, stone fragility was measured by disintegrating each stone in a controlled ex vivo experiment using an ultrasonic lithotripter and recording the time to comminution. A multivariable linear regression model was developed to predict time to comminution. RESULTS The average stone volume was 300 mm3 (range: 134-674 mm3). The average comminution time measured ex vivo was 32 seconds (range: 7-115 seconds). Stone volume, dual-energy CT number ratio, and surface roughness were found to have the best combined predictive ability to estimate comminution time (adjusted R2 = 0.58). The predictive ability of mixed dual-energy CT images, without use of the dual-energy CT number ratio, to estimate comminution time was slightly inferior, with an adjusted R2 of 0.54. CONCLUSIONS Dual-energy CT number ratios, volume, and morphologic metrics may provide a method for predicting stone fragility, as measured by time to comminution from ultrasonic lithotripsy.

Kidney Function After the First Kidney Stone Event

OBJECTIVE To determine whether there is a persistent decline in kidney function after the first kidney stone event. PATIENT AND METHODS Incident symptomatic stone formers and age- and sex-matched controls underwent 2 study visits 90 days apart to assess kidney function, complete a survey, and have their medical records reviewed. Kidney function was compared between stone formers and controls adjusting for clinical, blood, and urine risk factors. RESULTS There were 384 stone formers and 457 controls. At visit 1, a median of 104 days after the stone event, stone formers compared with controls had similar serum creatinine (0.86 vs 0.84 mg/dL; P=.23), higher serum cystatin C (0.83 vs 0.72 mg/L; P<.001), higher urine protein (34.2 vs 19.7 mg/24 h; P<.001) levels, and were more likely to have albuminuria (24 h urine albumin >30 mg: 5.4% vs 2.2%; P=.02). Findings were similar after adjustment for risk factors and at visit 2, a median of 92 days after visit 1. In the 173 stone formers with serum creatinine levels from care before study participation, the mean serum creatinine level was 0.84 mg/dL before the stone event, increased to 0.97 mg/dL (P<.001) at the stone event, but returned to 0.85 mg/dL (P=.38) after the stone event (visit 1). CONCLUSIONS Incident symptomatic stone formers have a rise in serum creatinine levels that resolves. However, stone formers have sustained higher cystatin C levels and proteinuria that may affect long-term risk of chronic kidney disease.