Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical and Demographic Characteristics of Patient-Initiated Encounters Before the 6-Week Postpartum Visit.

OBJECTIVE: To identify characteristics associated with a higher likelihood of patient-initiated encounters with a health care professional before the scheduled 6-week postpartum visit. METHODS: We performed a retrospective cohort study of postpartum persons who received prenatal care and delivered at a single academic level IV maternity care center in 2019. We determined associations between maternal sociodemographic and obstetric characteristics and the likelihood of patient-initiated early postpartum encounters with χ2 tests for categorical variables and Wilcoxon rank sum tests for continuous and ordinal variables. RESULTS: A total of 796 patients were included in our analysis, and 324 (40.7%) initiated an early postpartum encounter. Significantly more postpartum persons who initiated early postpartum encounters were primiparous persons (54.3%) than multiparous (33.8%) persons (P < .001). Postpartum persons who desired breastfeeding or who had prolonged maternal hospitalization, episiotomy, or cesarean or operative vaginal delivery were also significantly more likely to initiate early postpartum encounters (all P≤.002). Of postpartum persons who initiated early encounters, 44 (13.6%) initiated in-person visits, 138 (42.6%) initiated telephone or patient portal communication, and 142 (43.8%) initiated encounters of both types. Specifically, 39.2% of postpartum persons initiated at least one early postpartum encounter for lactation support, and nearly half of early postpartum encounters occurred during the first week after hospital discharge. CONCLUSION: Early postpartum encounters were more common among primiparas and postpartum persons who were breastfeeding or had prolonged hospitalization, episiotomy, cesarean delivery, or operative vaginal delivery. Future studies should focus on the development of evidence-based guidelines for recommending early postpartum visits.

Outpatient Antibiotic Use is Not Associated with an Increased Risk of First-Time Symptomatic Kidney Stones.

SIGNIFICANCE STATEMENT: Antibiotics modify human microbiomes and may contribute to kidney stone risk. In a population-based case-control study using 1247 chart-validated first-time symptomatic kidney stone formers and 4024 age- and sex-matched controls, the risk of kidney stones was transiently higher during the first year after antibiotic use. However, this risk was no longer evident after adjustment for comorbidities and excluding participants with prior urinary symptoms. Findings were consistent across antibiotic classes and the number of antibiotic courses received. This suggests that antibiotics are not important risk factors of kidney stones. Rather, kidney stones when they initially cause urinary symptoms are under-recognized, resulting in antibiotic use before a formal diagnosis of kidney stones ( i.e. , reverse causality). BACKGROUND: Antibiotics modify gastrointestinal and urinary microbiomes, which may contribute to kidney stone formation. This study examined whether an increased risk of a first-time symptomatic kidney stone episode follows antibiotic use. METHODS: A population-based case-control study surveyed 1247 chart-validated first-time symptomatic kidney stone formers with a documented obstructing or passed stone (cases) in Olmsted County, Minnesota, from 2008 to 2013 and 4024 age- and sex-matched controls. All prescriptions for outpatient oral antibiotic use within 5 years before the onset of symptomatic stone for the cases and their matched controls were identified. Conditional logistic regression estimated the odds ratio (OR) of a first-time symptomatic kidney stone across time after antibiotic use. Analyses were also performed after excluding cases and controls with prior urinary tract infection or hematuria because urinary symptoms resulting in antibiotic prescription could have been warranted because of undiagnosed kidney stones. RESULTS: The risk of a symptomatic kidney stone was only increased during the 1-year period after antibiotic use (unadjusted OR, 1.31; P = 0.001), and this risk was attenuated after adjustment for comorbidities (OR, 1.16; P = 0.08). After excluding cases and controls with prior urinary symptoms, there was no increased risk of a symptomatic kidney stone during the 1-year period after antibiotic use (unadjusted OR, 1.04; P = 0.70). Findings were consistent across antibiotic classes and the number of antibiotic courses received. CONCLUSIONS: The increased risk of a first-time symptomatic kidney stone with antibiotic use seems largely due to both comorbidities and prescription of antibiotics for urinary symptoms. Under-recognition of kidney stones that initially cause urinary symptoms resulting in antibiotic use may explain much of the perceived stone risk with antibiotics ( i.e. , reverse causality).

Rapid Exclusion of Acute Myocardial Injury and Infarction With a Single High-Sensitivity Cardiac Troponin T in the Emergency Department: A Multicenter United States Evaluation.

BACKGROUND: There are good data to support using a single high-sensitivity cardiac troponin T (hs-cTnT) below the limit of detection of 5 ng/L to exclude acute myocardial infarction. Per the US Food and Drug Administration, hs-cTnT can only report to the limit of quantitation of 6 ng/L, a threshold for which there are limited data. Our goal was to determine whether a single hs-cTnT below the limit of quantitation of 6 ng/L is a safe strategy to identify patients at low risk for acute myocardial injury and infarction. METHODS: The efficacy (proportion identified as low risk based on baseline hs-cTnT<6 ng/L) of identifying low-risk patients was examined in a multicenter (n=22 sites) US cohort study of emergency department patients undergoing at least 1 hs-cTnT (CV Data Mart Biomarker cohort). We then determined the performance of a single hs-cTnT<6 ng/L (biomarker alone) to exclude acute myocardial injury (subsequent hs-cTnT >99th percentile in those with an initial hs-cTnT<6 ng/L). The clinically intended rule-out strategy combining a nonischemic ECG with a baseline hs-cTnT<6 ng/L was subsequently tested in an adjudicated cohort in which the diagnostic performance for ruling out acute myocardial infarction and safety (myocardial infarction or death at 30 days) were evaluated. RESULTS: A total of 85 610 patients were evaluated in the CV Data Mart Biomarker cohort, among which 24 646 (29%) had a baseline hs-cTnT<6 ng/L. Women were more likely than men to have hs-cTnT<6 ng/L (38% versus 20%, P<0.0001). Among 11 962 patients with baseline hs-cTnT<6 ng/L and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% (95% CI, 98.6-99.0) and sensitivity of 99.6% (95% CI, 99.5-99.6). In the adjudicated cohort, a nonischemic ECG with hs-cTnT<6 ng/L identified 33% of patients (610/1849) as low risk and resulted in a negative predictive value and sensitivity of 100% and a 30-day rate of 0.2% for myocardial infarction or death. CONCLUSIONS: A single hs-cTnT below the limit of quantitation of 6 ng/L is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.

Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria.

PURPOSE: Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS: We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS: Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS: Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

Reduced calf muscle pump function is a risk factor for venous thromboembolism: a population-based cohort study.

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998 to 2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date, and patients with reduced CPF (rCPF) were compared with patients with normal CPF. A total of 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included; 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range, 0-22.0 years). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted hazard ratio (HR) for incident VTE was 2.0 (95% confidence interval [CI], 1.2-3.4) and after adjusting for age, BMI, and Charlson Comorbidity Index, the HR was 1.68 (95% CI, 0.98-2.89). The adjusted HR for ipsilateral deep vein thrombosis was evaluated in 3064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI, 1.03-2.84). Mortality was significantly higher in both the bilateral (P < .001) and unilateral (P < .001) rCPF groups compared with normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function.

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.

Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2.

BACKGROUND: Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. METHODS: Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). RESULTS: PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients. CONCLUSIONS: Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

High-Sensitivity Cardiac Troponin T for the Detection of Myocardial Injury and Risk Stratification in COVID-19.

BACKGROUND: Limited data exist on high-sensitivity cardiac troponin (hs-cTn) for risk-stratification in COVID-19. METHODS: We conducted a multicenter, retrospective, observational, US-based study of COVID-19 patients undergoing hs-cTnT. Outcomes included short-term mortality (in-hospital and 30-days post-discharge) and a composite of major adverse events, including respiratory failure requiring mechanical ventilation, cardiac arrest, and shock within the index presentation and/or mortality during the index hospitalization or within 30-days post-discharge. RESULTS: Among 367 COVID-19 patients undergoing hs-cTnT, myocardial injury was identified in 46%. They had a higher risk for mortality (20% vs 12%, P < 0.0001; unadjusted HR 4.44, 95% CI 2.13-9.25, P < 0.001) and major adverse events (35% vs. 11%, P < 0.0001; unadjusted OR 4.29, 95% CI 2.50-7.40, P < 0.0001). Myocardial injury was associated with major adverse events (adjusted OR 3.84, 95% CI 2.00-7.36, P < 0.0001) but not mortality. Baseline (adjusted OR 1.003, 95% CI 1.00-1.007, P = 0.047) and maximum (adjusted OR 1.005, 95% CI 1.001-1.009, P = 0.0012) hs-cTnT were independent predictors of major adverse events. Most (95%) increases were due to myocardial injury, with 5% (n = 8) classified as type 1 or 2 myocardial infarction. A single hs-cTnT <6 ng/L identified 26% of patients without mortality, with a 94.9% (95% CI 87.5-98.6) negative predictive value and 93.1% sensitivity (95% CI 83.3-98.1) for major adverse events in those presenting to the ED. CONCLUSIONS: Myocardial injury is frequent and prognostic in COVID-19. While most hs-cTnT increases are modest and due to myocardial injury, they have important prognostic implications. A single hs-cTnT <6 ng/L at presentation may facilitate the identification of patients with a favorable prognosis.

Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria.

Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had one or more stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. Thus, these data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group. BACKGROUND: Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. METHODS: We assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. RESULTS: Mean ± SD age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had ≥1 stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. CONCLUSIONS: These data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group.

Clinical features of genetically confirmed patients with primary hyperoxaluria identified by clinical indication versus familial screening.

Primary hyperoxaluria is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage. Most patients with primary hyperoxaluria are diagnosed after clinical suspicion based on symptoms. Since some patients are detected by family screening following detection of an affected family member, we compared the clinical phenotype of these two groups. Patients with primary hyperoxaluria types 1, 2, and 3 enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry were retrospectively analyzed following capture of clinical and laboratory results in the Registry. Among 495 patients with primary hyperoxaluria, 47 were detected by family screening. After excluding 150 patients with end stage kidney disease at diagnosis, 300 clinical suspicion and 45 family screening individuals remained. Compared to patients with clinical suspicion, those identified by family screening had significantly fewer stones at diagnosis (mean 1.2 vs. 3.6), although initial symptoms occurred at a similar age (median age 6.1 vs. 7.6 years). Urinary oxalate did not differ between these groups. The estimated glomerular filtration rate at diagnosis and its decline over time were similar for the two groups. Altogether, five of 45 in family screening and 67 of 300 of clinical suspicion individuals developed end stage kidney disease at last follow-up. Thus, patients with primary hyperoxaluria identified through family screening have significant disease despite no outward clinical suspicion at diagnosis. Since promising novel treatments are emerging, genetic screening of family members is warranted because they are at significant risk for disease progression.

Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts.

BACKGROUND: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. METHODS: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α1-microglobulin (α1M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α1M/Cr, α1M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. RESULTS: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α1M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α1M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. CONCLUSIONS: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Association between the Charlson comorbidity index and outcomes after implantable cardioverter defibrillator generator replacement.

BACKGROUND: Recipients of implantable cardioverter defibrillator (ICD) generator replacement with multiple medical comorbidities may be at higher risk of adverse outcomes that attenuate the benefit of ICD replacement. The aim of this investigation was to study the association between the Charlson comorbidity index (CCI) and outcomes after ICD generator replacement. METHODS: All patients undergoing first ICD generator replacement at Mayo Clinic, Rochester and Beth Israel Deaconess Medical Center, Boston between 2001 and 2011 were identified. Outcomes included: (a) all-cause mortality, (b) appropriate ICD therapy, and (c) death prior to appropriate therapy. Multivariable Cox regression analysis was performed to assess association between CCI and outcomes. RESULTS: We identified 1421 patients with mean age of 69.6 ± 12.1 years, 81% male and median (range) CCI of 3 (0-18). During a mean follow-up of 3.9 ± 3 years, 52% of patients died, 30.6% experienced an appropriate therapy, and 23.6% died without experiencing an appropriate therapy. In multivariable analysis, higher CCI score was associated with increased all-cause mortality (Hazard ratio, HR 1.10 [1.06-1.13] per 1 point increase in CCI, P < .001), death without prior appropriate therapy (HR 1.11 [1.07-1.15], P < .0001), but not associated with appropriate therapy (HR 1.01 [0.97-1.05], P = .53). Patients with CCI ≥5 had an annual risk of death of 12.2% compared to 8.7% annual rate of appropriate therapy. CONCLUSIONS: CCI is predictive of mortality following ICD generator replacement. The benefit of ICD replacement in patients with CCI score ≥5 should be investigated in prospective studies.

Risk of ESRD and Mortality in Kidney and Bladder Stone Formers.

RATIONALE & OBJECTIVES: Kidney stones have been associated with increased risk for end-stage renal disease (ESRD). However, it is unclear whether there is also an increased risk for mortality and if these risks are uniform across clinically distinct categories of stone formers. STUDY DESIGN: Historical matched-cohort study. SETTING & PARTICIPANTS: Stone formers in Olmsted County, MN, between 1984 and 2012 identified using International Classification of Diseases, Ninth Revision codes. Age- and sex-matched individuals who had no codes for stones were the comparison group. PREDICTOR: Stone formers were placed into 5 mutually exclusive categories after review of medical charts: incident symptomatic kidney, recurrent symptomatic kidney, asymptomatic kidney, bladder only, and miscoded (no stone). OUTCOMES: ESRD, mortality, cardiovascular mortality, and cancer mortality. ANALYTICAL APPROACH: Cox proportional hazards models with adjustment for baseline comorbid conditions. RESULTS: Overall, 65 of 6,984 (0.93%) stone formers and 102 of 28,044 (0.36%) non-stone formers developed ESRD over a mean follow-up of 12.0 years. After adjusting for baseline hypertension, diabetes mellitus, dyslipidemia, gout, obesity, and chronic kidney disease, risk for ESRD was higher in recurrent symptomatic kidney (HR, 2.34; 95% CI, 1.08-5.07), asymptomatic kidney (HR, 3.94; 95% CI, 1.65-9.43), and miscoded (HR, 6.18; 95% CI, 2.25-16.93) stone formers, but not in incident symptomatic kidney or bladder stone formers. The adjusted risk for all-cause mortality was higher in asymptomatic kidney (HR, 1.40; 95% CI, 1.18-1.67) and bladder (HR, 1.37; 95% CI, 1.12-1.69) stone formers. Chart review of asymptomatic and miscoded stone formers suggested increased risk for adverse outcomes related to diagnoses including urinary tract infection, cancer, and musculoskeletal or gastrointestinal pain. CONCLUSIONS: The higher risk for ESRD in recurrent symptomatic compared with incident symptomatic kidney stone formers suggests that stone events are associated with kidney injury. The clinical indication for imaging in asymptomatic stone formers, the correct diagnosis in miscoded stone formers, and the cause of a bladder outlet obstruction in bladder stone formers may explain the higher risk for ESRD or death in these groups.

Time to achieving therapeutic international normalized ratio increases hospital length of stay after heart valve replacement surgery.

BACKGROUND: Achieving a therapeutic international normalized ratio (INR) before hospital discharge is an important inpatient goal for patients undergoing mechanical cardiac valve replacement (MCVR). The use of clinical algorithms has reduced the time to achieve therapeutic INR (TTI) with warfarin therapy. Whether TTI prolongs length of stay (LOS) is unknown. METHODS: Patients who underwent MCVR over a consecutive 42-month period were included. Clinical data were obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery database and electronic medical records. Therapeutic INR was defined as per standard guidelines. Warfarin dose was prescribed using an inpatient pharmacy-managed algorithm and computer-based dosing tool. International normalized ratio trajectory, procedural needs, and drug interactions were included in warfarin dose determination. RESULTS: There were 708 patients who underwent MCVR, of which 159 were excluded for reasons that would preclude or interrupt warfarin use. Among the remainder of 549 patients, the average LOS was 6.4days and mean TTI was 3.5days. Landmark analysis showed that subjects in hospital on day 4 (n=542) who achieved therapeutic INR were more likely to be discharged by day 6 compared with those who did not achieve therapeutic INR (75% vs 59%, P<.001). Multivariable proportional hazards regression with TTI as a time-dependent effect showed a strong association with discharge (P=.0096, hazard ratio1.3) after adjustment for other significant clinical covariates. CONCLUSIONS: Time to achieve therapeutic INR is an independent predictor of LOS in patients requiring anticoagulation with warfarin after MCVR surgery. Alternative dosing and anticoagulation strategies will need to be adopted to reduce LOS in these patients.

Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria.

Stone formation and nephrocalcinosis are both very common features of primary hyperoxaluria, yet the extent of each disease varies markedly between patients. Here we studied whether kidney damage from nephrocalcinosis and/or stone related events contributed to end-stage kidney disease (ESKD). Clinical information was analyzed from 348 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria registry and included demographic, laboratory and imaging features. Among all patients there were 277 with type 1, 37 with type 2, and 34 with type 3 primary hyperoxaluria. Overall, 58% passed a stone (mean 0.3/year) and one or more urologic procedures were required by 70% of patients (mean 0.15/year). Nephrocalcinosis was found in 34% of patients, including 41% with type 1 primary hyperoxaluria. High urine oxalate was associated with increased risk for both nephrocalcinosis and stone number, while low urine citrate was a risk factor for stone events and stone number. After adjustment for the type of primary hyperoxaluria, diagnosis by family screening and age at first image, the overall adjusted hazard ratio for ESKD among those with a history of nephrocalcinosis was 1.7 [95% CI 1.0-3.0], while the risk was 4.0 [1.9-8.5] for new onset nephrocalcinosis during follow-up. In contrast, the number of stones and stone events were not significantly associated with ESKD risk. Thus, nephrolithiasis and nephrocalcinosis appear to be pathophysiologically distinct entities. The presence of nephrocalcinosis implies increased risk for ESKD.

Kidney stones are common after bariatric surgery.

Obesity, a risk factor for kidney stones and chronic kidney disease (CKD), is effectively treated with bariatric surgery. However, it is unclear whether surgery alters stone or CKD risk. To determine this we studied 762 Olmsted County, Minnesota residents who underwent bariatric surgery and matched them with equally obese control individuals who did not undergo surgery. The majority of bariatric patients underwent standard Roux-en-Y gastric bypass (RYGB; 78%), with the remainder having more malabsorptive procedures (very long limb RYGB or biliopancreatic diversion/duodenal switch; 14%) or restrictive procedures (laparoscopic banding or sleeve gastrectomy; 7%). The mean age was 45 years with 80% being female. The mean preoperative body mass index (BMI) was 46.7 kg/m(2) for both cohorts. Rates of kidney stones were similar between surgery patients and controls at baseline, but new stone formation significantly increased in surgery patients (11.0%) compared with controls (4.3%) during 6.0 years of follow-up. After malabsorptive and standard surgery, the comorbidity-adjusted hazard ratio of incident stones was significantly increased to 4.15 and 2.13, respectively, but was not significantly changed for restrictive surgery. The risk of CKD significantly increased after the malabsorptive procedures (adjusted hazard ratio of 1.96). Thus, while RYGB and malabsorptive procedures are more effective for weight loss, both are associated with increased risk of stones, while malabsorptive procedures also increase CKD risk.

Extended antimicrobial use in patients undergoing percutaneous nephrolithotomy and associated antibiotic related complications.

PURPOSE: Despite global concern about antibiotic related complications the duration of antibiotic therapy at percutaneous nephrolithotomy varies based on individual physician practice. We evaluated perioperative antibiotic related complications in patients who received extended antimicrobial therapy at percutaneous nephrolithotomy. MATERIALS AND METHODS: We reviewed the records of 227 consecutive patients treated with percutaneous nephrolithotomy from 2009 to 2013. Patients with positive urine or stone cultures received extended antimicrobial treatment. All others received 7 days of empirical therapy preoperatively and postoperatively. Adverse antibiotic related events were recorded for up to 3 months. RESULTS: The median duration of antibiotic therapy was 14 days (IQR 14-34). Perioperatively 143 (63%), 67 (30%), 75 (33%) and 41 patients (18%) received nitrofurantoin, trimethoprim/sulfamethoxazole, fluoroquinolones and other antibiotics, respectively. Antibiotic related complications developed in 23 patients (10%) at a median of 12 days (IQR 8-19). Common complications included rash in 7 cases (3%), gastrointestinal upset in 6 (3%) and Clostridium difficile colitis in 1 (0.4%). Trimethoprim/sulfamethoxazole was associated with an increased likelihood of an adverse event (p = 0.04) but patient age, gender, and therapy type (therapeutic vs prophylactic) and duration were not. Finally, antibiotic and multidrug resistance developed in 4 (36%) and 3 patients (27%), respectively, who experienced a urinary tract infection. CONCLUSIONS: We report a low rate of adverse antibiotic related events in patients treated with percutaneous nephrolithotomy who received extended perioperative antibiotic therapy. Exposure to trimethoprim/sulfamethoxazole was the only identifiable risk factor for a complication. These findings should be considered when counseling patients on the risks of perioperative antimicrobial therapy at percutaneous nephrolithotomy.

Outcomes in patients with sustained ventricular tachyarrhythmias occurring within 48 h of acute myocardial infarction: when is ICD appropriate?

AIMS: Recent guidelines for implantable cardioverter-defibrillator (ICD) use in patients with early ventricular arrhythmia (VA) after acute myocardial infarction (MI) are based on systolic function and revascularization status, yet decision to implant an ICD remains highly subjective. We aimed to determine characteristics, utilization of ICDs, and long-term outcomes of survivors of early VA (<48 h) after acute MI. METHODS AND RESULTS: We retrospectively analyzed clinical characteristics, ICD therapies, and survival in 128 patients with early VA after acute MI from 2002-12. Patients were classified for appropriateness of ICD implantation, per 2013 Appropriate Use Criteria (AUC). In 128 early VA survivors after MI, older age, female gender, history of coronary artery bypass graft surgery (CABG) or MI, non-ST-elevation MI or ventricular tachycardia (VT) at presentation predicted worse overall survival (all P < 0.05). While left ventricular ejection fraction (LVEF) did not predict mortality (HR = 1; P = 0.86), post-MI ventricular fibrillation (VF) portended a better long-term prognosis than VT (HR = 0.37; P = 0.001). Twenty-six (20%) early VA survivors received ICD, corresponding well with AUC. Implantable cardioverter-defibrillator recipients had lower post-MI LVEF (P = 0.02) and more frequently presented with non-ST-elevation MI (P = 0.007). Over 2.4 years of median follow-up, ICD recipients had a greater mortality rate than non-ICD recipients (42 vs. 17%; P = 0.02). Appropriate and inappropriate ICD discharges were high in ICD recipients. CONCLUSION: Early VA survivors after MI receiving ICD due to suspected non-reversible arrhythmogenic substrate have high rates of appropriate ICD therapy and mortality. Our ICD implantation practice corresponds well with the AUC. Sustained monomorphic VT and non-ST-elevation MI at presentation predict increased risk for death. Larger prospective studies are necessary to confirm our findings, such as to provide evidence for future ICD guidelines.