The Phenotypic Spectrum of COL4A3 Heterozygotes.

Introduction: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. Methods: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. Results: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system. Conclusion: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

The Phenotypic Spectrum of COL4A3 Heterozygotes.

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Integrated Digital Health System Tools to Support Decision Making and Treatment Preparation in CKD: The PREPARE NOW Study.

RATIONALE & OBJECTIVE: Digital health system tools to support shared decision making and preparation for kidney replacement treatments for patients with chronic kidney disease (CKD) are needed. STUDY DESIGN: Descriptive study of the implementation of digital infrastructure to support a patient-centered health system intervention. SETTING & PARTICIPANTS: 4 CKD clinics within a large integrated health system. EXPOSURE: We developed an integrated suite of digital engagement tools to support patients' shared decision making and preparation for kidney failure treatments. Tools included an automated CKD patient registry and risk prediction algorithm within the electronic health record (EHR) to identify and prioritize patients in need of nurse case management to facilitate shared decision making and preparation for kidney replacement treatments, an electronic patient-facing values clarification tool, a tracking application to document patients' preparation for treatments, and an EHR work flow to broadcast patients' treatment preferences to all health care providers. OUTCOMES: Uptake and acceptability. ANALYTIC APPROACH: Mixed methods. RESULTS: From July 1, 2017, through June 30, 2018, the CKD registry identified 1,032 patients in 4 nephrology clinics, of whom 243 (24%) were identified as high risk for progressing to kidney failure within 2 years. Kidney Transitions Specialists enrolled 117 (48%) high-risk patients by the end of year 1. The values tool was completed by 30/33 (91%) patients who attended kidney modality education. Nurse case managers used the tracking application for 100% of patients to document 287 planning steps for kidney replacement therapy. Most (87%) high-risk patients had their preferred kidney replacement modality documented and displayed in the EHR. Nurse case managers reported that the tools facilitated their identification of patients needing support and their navigation activities. LIMITATIONS: Single institution, short duration. CONCLUSIONS: Digital health system tools facilitated rapid identification of patients needing shared and informed decision making and their preparation for kidney replacement treatments. FUNDING: This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (IHS-1409-20967). TRIAL REGISTRATION: ClinicalTrials.gov NCT02722382.

Bisphosphonates and mortality in women with CKD and the presence or absence of cardiovascular disease.

BACKGROUND AND OBJECTIVES: A modest protective association between bisphosphonate prescription and mortality among women with CKD but without clinically manifest cardiovascular disease has been shown. Whether a prior cardiovascular event (myocardial infarction, stroke, or heart failure) modifies this association is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort of adult women with stages 3 and 4 CKD receiving primary care in a rural integrated health care system during the period 2004-2011 without history of advanced malignancy or organ transplantation (n=6756, median age=74 years, median follow-up=4.3 years) was retrospectively assembled. The primary analysis compared those patients prescribed bisphosphonates (both prevalent and incident use during follow-up) with those patients not prescribed. Additional approaches were taken to account for survival and indication biases. The primary outcome was time to death by Cox multivariable regression. RESULTS: In the primary analysis, compared with women not prescribed a bisphosphonate, the hazard ratio (95% confidence interval) for death among women prescribed a bisphosphonate was 0.90 (0.78 to 1.04) if there was no history of cardiovascular event but 1.22 (1.04 to 1.42) if there was history of cardiovascular event (P for interaction=0.004). In the additional approaches, associations between bisphosphonate prescription and mortality among those patients with a prior cardiovascular history varied: hazard ratios (95% confidence intervals) were 1.25 (1.01 to 1.57), 1.48 (1.16 to 1.88), and 0.94 (0.66 to 1.34). Interaction by prior cardiovascular event history varied across these three approaches (P=0.07, P=0.22, and P=0.05). CONCLUSION: In this study of women with CKD, the association between bisphosphonate treatment and mortality risk was inconclusive across a series of analyses designed to account for various types of selection and indication bias.

Readmission after hospitalization for heart failure among patients with chronic kidney disease: a prediction model.

AIMS: 30-day readmission rates after hospitalization for heart failure (HF) approach 25%, and patients with chronic kidney disease (CKD) are disproportionately represented. A retrospective cohort study was conducted to develop a prediction tool for 30-day readmission after hospitalization for HF among those with non-dialysis dependent CKD. METHODS: Geisinger primary care patients with Stage 3 - 5 CKD hospitalized with a primary discharge diagnosis of HF during the period July 1, 2004 through February 28, 2010 were eligible. Multivariate logistic regression was employed to build models from predictors of 30-day readmission, drawn from demographic, clinical, laboratory, and pharmaceutical variables in the electronic health record. Variables were manually removed to achieve a model with satisfactory goodness-of-fit and parsimony while maximizing area under the receiver operating characteristic curve (AUC). Internal validation was performed using the bootstrap resampling method (1,000 samples) to provide a bias-corrected AUC. RESULTS: 607 patients with CKD were admitted for HF during the study period; 116 (19.1%) were readmitted within 30 days. A model incorporating 23 variables across domains of medical history, active outpatient pharmaceuticals, vital signs, laboratory tests, and recent inpatient and outpatient resource utilization yielded an AUC (95% CI) of 0.792 (0.746 - 0.838). The bias-corrected AUC was 0.743. At an estimated readmission probability of 20%, the model correctly classified readmission status for 73% of the population, with a sensitivity of 69% and a specificity of 73%. CONCLUSION: A robust electronic health record may facilitate the identification of CKD patients at risk for readmission after hospitalization for HF.

Estimated glomerular filtration rate variability and risk of end-stage renal disease among patients with Stage 3 chronic kidney disease.

BACKGROUND/AIMS: Dynamic changes in estimated glomerular filtration rate (eGFR) predict death among patients with chronic kidney disease (CKD). Whether variability in serial eGFR measurements is associated with risk of end stage renal disease (ESRD) has not been reported. METHODS: We retrospectively analyzed the risk of ESRD as a function of eGFR variability (defined as the absolute value of the difference between the obtained clinical eGFR value at a given time and the eGFR value estimated by the linear regression line at the same time point) among a cohort of patients with Stage 3 CKD. The study population was comprised of adult primary care patients enrolled at Geisinger Clinic between January 1, 2004 and December 31, 2006, with Stage 3 CKD and a minimum of 4 serum creatinine results during this 3-year window, and without history of solid-organ transplant or metastatic cancer. Cohort members were followed through March 31, 2011 for ESRD (identified through linkage with the USRDS dataset of ESRD, or first outpatient eGFR < 15 ml/min/1.73 m2). A multivariate Cox proportional hazard model (adjusted for demographic factors, co-morbid conditions, medications, hospital-associated acute kidney injury, proteinuria, kidney function, and serum albumin, among other factors) was developed to test the association of eGFR variability with ESRD. RESULTS: 4,219 patients met study criteria. Those with greater eGFR variability were more likely to have diabetes, cardiovascular disease, and better baseline kidney function than those with lesser variability. 193 (4.6%) of the overall cohort developed ESRD during a median follow-up of 3.8 years, while 596 (14.1%) died prior to study end without ESRD. Results of the multivariate-adjusted Cox proportional hazard model showed that eGFR variability is not associated with ESRD (HR 1.00 for the highest-variability quartile, relative to the lowest; 95% CI 0.66 - 1.51). CONCLUSION: eGFR variability does not predict ESRD among patients with Stage 3 CKD.

Variability in estimated glomerular filtration rate is an independent risk factor for death among patients with stage 3 chronic kidney disease.

Associations between variability of glomerular filtration rate (GFR), death, and cardiovascular events have not been reported among patients with chronic kidney disease (CKD). In order to evaluate this, we retrospectively analyzed the risk of death and de novo heart failure as a function of variability in estimated GFR among a cohort of 3361 patients with stage 3 CKD. At baseline, patients with greater variability were younger, more likely to have diabetes, hypertension, and other comorbid conditions, and were more likely to have proteinuria and higher estimated GFR. In multivariate-adjusted Cox proportional hazard models over a median follow-up of 3.9 years, the risk of death associated with the highest relative to the lowest quartile of variability was 1.40 (95% confidence interval 1.05-1.87); there was no association with new-onset heart failure. The mortality association was independent of serum albumin, proteinuria, baseline estimated GFR, and the slope of the estimated GFR. Thus, variability in estimated GFR predicts death among patients with stage 3 CKD independent of previously reported risk factors. The prognostic utility of complementing existing risk stratification metrics with dynamic changes in GFR among patients with CKD warrants investigation.

Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a retrospective cohort study.

BACKGROUND: Accelerated vascular calcification contributes to cardiovascular disease burden in patients with chronic kidney disease (CKD). We hypothesized that bisphosphonate therapy would reduce the risk of mortality and cardiovascular events in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult women with stage 3 or 4 CKD receiving primary care in a large rural integrated health care system in 2004-2010. EXPOSURE: Time-dependent exposure status based on outpatient prescription for any medication within the bisphosphonate class, obtained from electronic health records. OUTCOMES: Time to death and first cardiovascular event (composite of myocardial infarction, heart failure, or stroke). RESULTS: Data from 9,604 eligible female patients with CKD were analyzed; 3,234 were treated with bisphosphonate therapy. During a median follow-up of 3.9 (25th-75th percentile, 2.3-5.4) years, there were 286 versus 881 deaths and 206 versus 571 cardiovascular events (treated vs not-treated groups, respectively). In a multivariate Cox proportional hazard model, the adjusted HR for death (treated vs not treated) was 0.78 (95% CI, 0.67-0.91; P = 0.003). In Cox modeling adjusted for similar baseline covariates, treatment with bisphosphonates was not associated with a lower risk of the composite cardiovascular outcome (adjusted HR, 1.14; 95% CI, 0.94-1.39; P = 0.2). LIMITATIONS: Residual confounding by unidentified factors, exclusion of male patients, and lack of information about longitudinal drug adherence. CONCLUSIONS: For female patients with CKD, treatment with bisphosphonates is associated with a lower risk of death, but not cardiovascular events. Confirmatory studies and investigations of potential causal mechanisms are warranted.

Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.

Acute kidney injury increases mortality risk among those with established chronic kidney disease. In this study we used a propensity score-matched cohort method to retrospectively evaluate the risks of death and de novo chronic kidney disease after reversible, hospital-associated acute kidney injury among patients with normal pre-hospitalization kidney function. Of 30,207 discharged patients alive at 90 days, 1610 with reversible acute kidney injury that resolved within the 90 days were successfully matched across multiple parameters with 3652 control patients who had not experienced acute kidney injury. Median follow-up was 3.3 and 3.4 years (injured and control groups, respectively). In Cox proportional hazard models, the risk of death associated with reversible acute kidney injury was significant (hazard ratio 1.50); however, adjustment for the development of chronic kidney injury during follow-up attenuated this risk (hazard ratio 1.18). Reversible acute kidney injury was associated with a significant risk of de novo chronic kidney disease (hazard ratio 1.91). Thus, a resolved episode of hospital-associated acute kidney injury has important implications for the longitudinal surveillance of patients without preexisting, clinically evident kidney disease.

Fat-free weight prediction in morbidly obese females.

PURPOSE: Precise estimation of creatinine clearance in obese individuals relies on the appropriate assessment of lean body weight (LBW). Anthropometric methods of predicting LBW have not been validated in morbidly obese populations. PATIENTS AND METHODS: Using an existing dataset of anthropometric data for a female cohort with morbid obesity who had undergone measured FFW with dual energy absorptiometry, we evaluated the performance of five previously reported estimating equations for the prediction of LBW. Linear regression was used to derive a new LBW prediction formula and was then compared with the other formulae. RESULTS: Seventy females (mean [standard deviation] age, weight, and body mass index 43.0 [11.0] years, 128.1 [13.8] kg, and 48.3 [4.8] kg/m(2), respectively) were identified. LBW as estimated by the method of Garrow and Webster correlated well (r = 0.87) with measured mass while demonstrating the highest accuracy, best precision, and smallest bias (93%, 2.1 kg, and 2.9 kg, respectively; P < 0.0001 for all comparisons). The derived formula further improved bias, precision, and accuracy. CONCLUSION: Among females with morbid obesity, most previously reported estimating equations for LBW predicted FFW poorly. These findings have important clinical implications for the assessment of kidney function and for safe and effective drug dosing.

GFR decline and mortality risk among patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009. RESULTS: A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were -4.8, -0.6, and 3.5 ml/min per 1.73 m(2)/yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups. CONCLUSIONS: eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated.

Acute kidney injury in the critically ill, morbidly obese patient: diagnostic and therapeutic challenges in a unique patient population.

The growing burden of morbid obesity (body mass index >40 kg/m²) on critical care resources translates to a significant incidence of acute kidney injury (AKI) in morbidly obese (MO), critically ill patients. This article examines the literature pertinent to AKI in critically ill MO patients. After a concise review of the available epidemiologic data regarding the incidence of acute renal injury in MO individuals, the authors review the limitations and available tools for estimation of renal function in the MO population (with emphasis on the critical illness). Also described are several specific types of renal injury previously described in this population that are applicable to the critical care setting. Lastly, the authors review some of the challenges and limitations in providing renal support to critically ill MO individuals, and identify potential areas for future research in this population.

Remitting seronegative symmetrical synovitis with pitting edema syndrome in a rural tertiary care practice: a retrospective analysis.

OBJECTIVE: To review the clinical and laboratory features of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) in a rural tertiary care rheumatology practice, describe treatments and outcomes, and compare our results to previous reports in the literature. PATIENTS AND METHODS: We performed a retrospective chart review of all patients diagnosed as having RS3PE who were seen in the Department of Rheumatology at Geisinger Medical Center, Danville, PA, from January 1, 1992, to December 31, 2005. RESULTS: We identified 12 men and 2 women, all of whom were white. Mean +/- SD age was 74.0 +/- 6.6 years; mean +/- SD erythrocyte sedimentation rate was 35.9 +/- 21.1 mm/h at presentation. Onset of illness was sudden in 9 patients and insidious in 5. All patients were initially treated with prednisone (15-20 mg/d). Although the response in all was excellent, 9 patients received disease-modifying antirheumatic drugs, either because of ongoing disease activity or in an effort to decrease the use of corticosteroids. Hydroxychloroquine was used alone in 7 patients. At the mean +/- SD time of last follow-up (31.4 +/- 23.1 months), 5 patients continued to receive therapy. Complications of treatment included worsening of preexisting hypertension in 3 patients, gastritis in 2, and exacerbation of preexisting diabetes mellitus in 1. Carpal tunnel syndrome occurred in 6 patients. Duration of therapy ranged from 5 to 120 months (mean, 29 months). Three patients developed malignancies, ie, non-Hodgkin lymphoma, transitional cell carcinoma of the bladder, and prostate carcinoma. CONCLUSION: Our population of patients with RS3PE is similar to those documented in previous reports: elderly, predominantly male, and responsive to corticosteroids. However, our series is clinically differentiated by a greater use of adjunctive disease-modifying antirheumatic drugs (primarily hydroxychloroquine). Confirming previous reports, we also observed a possible association between RS3PE and malignancy.

Outpatient erythropoietin administered through a protocol-driven, pharmacist-managed program may produce significant patient and economic benefits.

To assess the effect of a disease management program in anemia of chronic kidney disease (CKD), the authors reviewedthe records of all adults treated with epoetin alfa (EPO) at their institution between September 2003 and April 2006 and compared them with a group treated through a pharmacist-managed program with patients managed by PCPs in terms of time to target hemoglobin (Hb) (11-12.9 mg/dL), percent of Hb values maintained in target range, average weekly dose of EPO, and percent of iron-saturation (T-sat) values within target range (20%-50%) over a period of six months to one year. Although pharmacist-managed patients received lower weekly EPO doses than those managed by PCPs (6,698 vs. 12,000 units, respectively; P = .0001), they achieved goal Hb faster (47.5 vs. 62.5 days, P = .11) and maintained a higher percentage of Hb and T-sat values in target range (69.8% vs. 43.9%, P = .0001, and 64.8% (vs. 40.4%, respectively; P = .043). A pharmacist-managed program may present significant clinicaland economic benefits in anemia of CKD.