Abstract available in the JACC Cardiovascular Interventions.

Abstract available in the JACC Cardiovascular Interventions.

Abstract available in the JACC Cardiovascular Interventions.

Indiana University-Purdue University Indianapolis (IUPUI) / FGF23 is an osteocyte produced hormone necessary for maintaining systemic phosphate handling, and thus bone structure and function in both rare and common disorders such as chronic kidney disease (CKD). FGF23 is a critical factor in CKD, with elevated levels causing alterations in mineral metabolism and increased odds for mortality. However, the mechanisms directing the production of key modulators of skeletal homeostasis and biomineralization within osteocytes, and how this is altered in chronic kidney disease, remain unclear. The experimental focus of this dissertation was to dissect the molecular systems and role of oxygen sensing in the regulated production of FGF23. In CKD, up to 75% of patients have anemia and concomitant marked elevations in FGF23, increasing mortality odds. Anemia is a potent driver of FGF23 secretion, therefore, current and emerging therapies, including recombinant EPO and the hypoxia inducible factorprolyl hydroxylase inhibitors (HIF-PHI) FG-4592 and BAY 85-3934, were used to improve anemia in the adenine diet-induced mouse model of CKD. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by 65-85% after delivery of EPO or HIF-PHI, with no changes in serum phosphate. This was associated with improved systemic iron utilization and reductions in mRNA markers of renal fibrosis. In osteocyte-like cell cultures treated with HIF-PHI, integrative RNAseq and ATACseq analysis identified candidate genes upregulated in response to mimicked hypoxia, concomitant with elevated Fgf23 expression. These genes were found to be downregulated in CKD bone, therefore, knock-out cells were generated using CRISPR/Cas9 technology. These cells were found to be functionally similar to in vivo conditional knockout models that have enhanced bone mass and elevated FGF23. Taken together, these results further define novel factors involved in the regulation of FGF23 and identify new therapeutic targets. / 2023-05-26

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) currently affects ~37 million Americans and causes substantially increased risk of skeletal fracture and fracture-related mortality. Current methods to treat CKD-related bone loss remain alarmingly ineffective. Skeletal fragility in CKD is predominately driven by deteriorations in cortical bone, highlighted by significant cortical porosity development. It is hypothesized that cortical porosity is largely driven by chronically high levels of parathyroid hormone (PTH), which alters the balance of bone remodeling in favor of rampant osteoclast activity and bone resorption. Restricting cortical bone deterioration and the development of cortical pores is likely essential to improve CKD patients’ bone health and reduce their fracture risk. The goal of this series of studies was to answer the following key questions: (1) to what degree do bisphosphonates, an approved pharmacological agent used in metabolic bone disease, accumulate in the skeleton of animals with CKD; (2) can smaller and more frequent doses of bisphosphonates alter skeletal accumulation and improve cortical architecture and the mechanical integrity of bone; (3) can non-bisphosphonate pharmacological interventions more specifically affect cortical bone deterioration. Utilizing epi-fluorescence and two-photon microscopy, our results show that bisphosphonates accumulate more in rats with renal impairment and fractionating bisphosphonates lowered skeletal accumulation irrespective of disease state. Further, studies in both rat and mouse models of CKD demonstrated different bisphosphonate treatments alone do not recover declines in cortical microarchitecture or mechanical properties in CKD. These findings demonstrate that a single intervention is not sufficient in managing CKD-induced bone alterations. Utilizing individual pore tracking analysis, we demonstrated cortical pores can be modulated with therapeutic interventions and can infill, despite the presence of CKD. Potent suppression of PTH led to significant pore infilling while more subtle reductions in PTH, via a calcimimetic, had less striking effects on bone. Calcimimetics mitigated cortical microarchitecture deterioration and reduced the rate of cortical pore expansion. Overall, these findings highlight the importance of PTH management for treating cortical deterioration in CKD. Although bisphosphonates can be utilized in ways that reduce skeletal accumulation, they appear to need co-therapies to reduce skeletal fragility associated with CKD.

INTRODUCTION Apixaban has revolutionized anticoagulation in patients with atrial fibrillation in preventing strokes. Anticoagulant-induced nephropathy with warfarin is well known, but nephropathy with apixaban is a rare entity, and here we present a case of Apixaban-induced nephropathy. Case Description A 71-year-old patient with a medical history of persistent atrial fibrillation on apixaban, Ischemic cardiomyopathy, and chronic kidney disease stage (CKD) IIIa presented to the hospital with complaints of dyspnea and hemoptysis and tea-colored urine of three-day duration. On admission, the patient had acute kidney injury (AKI) on CKD, Methicillin sensitive Staphylococcus aureus (MSSA) bacteremia, and elevated international normalized ratio (INR) and apixaban were held. The hemoptysis worsened and prompted bronchoscopy revealing diffuse alveolar hemorrhage. The urinalysis showed gross hematuria with high red blood cell (RBC) count and 1+ proteinuria presumed secondary to MSSA associated glomerulonephritis. Evaluation for coagulopathy with serum mixing studies and autoimmune workup has been unremarkable. The patient's coagulopathy was considered secondary to decreased clearance of apixaban with AKI on CKD. However, the patient's kidney function continued to worsen, needing continuous renal replacement therapy and a kidney biopsy for a definitive diagnosis for his decline in kidney function. Kidney biopsy revealed IgA dominant infection associated glomerulitis with one out of hundred glomeruli with the crescent formation and signs of anticoagulant induced nephropathy with several intratubular RBC casts out of proportion to the degree of glomerular injury causing acute tubular damage. The patient's INR improved on dialysis. However, he continued to be oliguric before being terminally extubated. DISCUSSION With the increasing incidence of atrial fibrillation and the use of oral anticoagulants, it is vital to have anticoagulant induced as a differential in patients presenting with supra therapeutic INR and AKI. Apixaban-induced nephropathy is a subset of anticoagulant-induced nephropathy and an uncommon cause of the acute decline in kidney function needing dialysis. Prompt recognition and treatment will prevent further deterioration in kidney function and possible improvement.

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) results in an increased fracture risk, partially due to elevations in parathyroid hormone (PTH) that lead to substantial bone loss. On its own, bone loss does not explain bone fragility in CKD, suggesting that changes in skeletal tissue (bone quality) may also be present. Understanding the factors that lead to fracture in these patients will have a substantial impact on patient care and could lead to a better understanding of how to reduce their fracture risk. Due to their suppression of PTH, calcitriol and its analogues are the current standard of care for bone disease in CKD. Yet, surprisingly little is known of their effects on bone. Agents effective in treating osteoporosis are not recommended in advanced CKD due to the lack of data regarding their efficacy and safety in these patients. The goals of the current study were to determine (1) the impact of CKD on bone quality, (2) the ability of calcitriol to improve skeletal parameters, and (3) the efficacy of various pharmacological interventions (calcium, bisphosphonates, anti-sclerostin antibody, and raloxifene) on bone mass, quality, and mechanical properties in CKD bone disease. Using a slowly progressive rat model of CKD, renal and mineral metabolism, bone morphology, bone quality, and bone mechanics (at several length scales) were assessed. Primarily due to elevated PTH, mechanical testing and tissue-level assessments revealed compromised bone quantity (high cortical porosity and low trabecular volume) and quality (high collagen cross-linking and low matrix bound water). Despite clinically relevant reductions in PTH, calcitriol treatment had no positive impact on skeletal properties. Most agents were only effective when PTH levels were normal. Raloxifene, however, led to greater whole bone and material toughness (the ability of bone to tolerate existing damage) despite modest PTH suppression. While the examination of bone quality in CKD is still in its infancy, these results indicate that enhancing bone quality with raloxifene may be an effective means to compensate for bone loss in CKD.

No description available.

First year death rates remain unacceptable high for the end-stage renal disease (ESRD) population. New effective methods are vital to improve first year morbidity and mortality outcomes for the population transitioning from Stage 4 chronic kidney disease (CKD) to ESRD)/Stage 5 CKD. Based on current methods, evidence-based recommendations made by nephrology providers are frequently not heeded by patients in Stage 4 CKD. Low levels of patient knowledge, self-efficacy, and a poor ability to self-manage CKD negatively influence a patient’s ability to follow provider recommendations. The group visit (GV) intervention has demonstrated improvements in disease-related outcomes through increased levels of patient knowledge, self-efficacy, and disease self-management for other chronic diseasses such as diabetes and congestive heart failure (CHF). No data are available for the use of GVs in CKD The purpose of the study was to develop and test a nurse practitioner-facilitated chronic CKD GV model versus usual nephrology care for Stage 4 CKD patients (knowledge, selfefficacy/self-management, physiological data, and satisfaction). As classified by the National Kidney Foundation’s (NKF) staging system, Stage 4 CKD is considered severe kidney disease, with a decrease in the functional capacity of the kidney as determined by a glomerular filtration rate (GFR) of 15-30 ml/min. It is common for patients with Stage 4 CKD to progress to Stage 5 CKD/end-stage renal disease (ESRD), requiring dialysis or transplantation to survive. Preliminary instrumentation and feasibility studies were conducted prior to a pilot study of a CKD GV model. The development and validation of the Stage 4 CKD Knowledge Instrument was completed with 59 Stage 4 patients. Findings supported reliability (KuderRichardson-20 [KR] = .89) and content validity (I-CVI = .97, S-CVI= 1.0) Feasibility of the CKD GV model was assessed with a single group, pretest-posttest design using a convenience iv sample of eight Stage 4 patients. Results demonstrated an improvement in knowledge of CKD from a median of 69% to 86% (p =.012). No improvements were noted in self-efficacy scores (p = .230). GV satisfaction ranged from very good to excellent. Feasibility was supported by a high retention rate (100%). No barriers to participant recruitment or GV implementation were encountered. The pilot study used a two-group, repeated measures experimental design, with a sample of 30 Stage 4 CKD patients from two office locations of an outpatient nephrology practice. Patients were randomized to the GV intervention or to usual nephrology care. CKD-knowledge, self-efficacy, and self-management scores were collected at baseline, six months, and nine months. Physiological data were measured at baseline, six months, and nine months. GV satisfaction was obtained after the completion of GVs (six months). Nephrology practice satisfaction was obtained from by both groups at nine months. MANOVA for repeated measures was calculated for data collected at the three time points. Twenty-six of 30 patients completed the study, with four patients ineligible to complete the study due to progression to ESRD and dialysis initiation. GV attendance was 92%. CKD knowledge was statistically improved for both groups (F(1.498, 34.446) = 6.363, P = .008). While not statistically significant, a favorable upward trend in the mean scores for the subscales of self-management (communication, partnership in care, and self-care) was demonstrated in the GV patients, with a lack of improvement found in the usual care group for these subscales. Selfefficacy scores revealed a non-significant improvement in mean scores for the GV patients during the GVs, not seen with usual care patients. GV satisfaction was again high with the vast majority of patients requesting use of GVs in their future nephrology care. v Current methods of intervention in the Stage 4 CKD population have made little impact on reducing first-year ESRD mortality and morbidity rates. Opportunities to intervene in the poor outcomes begin in the predialysis care of Stage 4 patients. Based on the documented success of multidisciplinary approaches in predialysis care, of GVs in other chronic diseases, and of chronic illness care based on the CCM, a high probability for success exists with the application of GVs in CKD. Although limited by a small sample size, promising improvements in the subscales of disease self-management, self-efficacy, CKD knowledge, and high satisfaction with the GV model for GV participants were revealed in this study. Further research is warranted for the CKD GV model on a larger randomized sample in other locations. Much needed data would be provided on which to base decisions for use of the CKD GV intervention in the predialysis care of Stage 4 patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by gradual kidney enlargement and cyst growth prior to loss of kidney function. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) created a standard magnetic resonance imaging (MRI) protocol to be used for ADPKD patients to determine if changes in total kidney volumes can be detected over a short period of time, and if they correlate with decline in renal function early in the disease course. CRISP guided researchers and physicians to use a T1-weighted sequence with gadolinium contrast to measure kidney volumes. After the Food and Drug Administration discouraged the use of gadolinium contrast in individuals with kidney diseases, total kidney volume measured by MRI for ADPKD patients was done using the T1-weighted pulse sequence without contrast enhancement. STUDY OBJECTIVE: The retrospective cohort study will aim to assess reliability of the T2 sequence and total kidney volume measurements compared to total kidney volume measurements performed on a T1 sequence. METHODS: The study collected intra-reader and inter-reader cases from four imaging studies, each with an abdominal MRI performed. Repeated volume measurements were performed within an individual reader (intra-reader) and between different readers (inter-readers). The stereology method was used to quantify kidney volume from T1 images for three studies and T2 images for one study. Mean and standard deviation were used to analyze volume differences between repeated measurements for intra-reader and inter-reader data for each MRI sequence. The intra-class correlation coefficient and Bland-Altman plot were used to describe correlation between kidney volumes, for intra-reader and inter-reader data respectively. RESULTS: Analyses show a significant difference in the repeated volume measurements from the T1 sequence in inter-reader data. Reliability for the T2 and T1 sequence was represented by high correlations in both the intra-reader and inter-reader total kidney volumes. CONCLUSION: MR measures of total kidney volume are reliable in patients when measured on both the T1 sequence and the T2 sequence. ADPKD kidney volumes for future clinical trials can be reliably measured on either sequence.