Management of Hyperkalemia in Patients with Chronic Kidney Disease Using Renin Angiotensin Aldosterone System Inhibitors.

PURPOSE OF REVIEW: Use of renin-angiotensin-aldosterone system (RAAS) inhibiting medications is critical in the prevention of cardiovascular disease and kidney function decline in patients with chronic kidney disease (CKD); however, these agents can lead to hyperkalemia, an electrolyte disorder associated with risk of arrythmia, conduction disorders, and increased overall mortality. Discontinuation, or reduction of dose, of RAAS inhibitor therapy in hyperkalemic patients with CKD can lead to loss of kidney and cardiovascular protection afforded by these medications. Given the high prevalence of hyperkalemia among patients with CKD utilizing RAAS inhibitors, clear management principles are critical to minimize risk and maximize benefit when facing this clinical dilemma. RECENT FINDINGS: Strategies to mitigate hyperkalemia that do not interfere with optimal RAAS inhibitor therapy should be prioritized when managing potassium elevation in patients with CKD. These strategies include discontinuing non-RAAS inhibitor medications known to cause hyperkalemia, correction of metabolic acidosis, and maximization of medication therapies that lower serum potassium, including diuretics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Initiation of potassium exchange resins should also be considered to allow for sustained RAAS inhibitor utilization. An approach which employs multiple strategies concurrently is important to mitigate hyperkalemia and maintain long-term use of RAAS-inhibitors. Persistence of RAAS inhibitor use in patients with CKD is important to slow kidney function decline, delay onset of dialysis or the need for kidney transplant, and prevent adverse cardiovascular outcomes. When hyperkalemia develops among patients with CKD utilizing a RAAS inhibitor, a deliberate effort to reduce serum potassium levels using an approach that allows for continuation of maximally dosed RAAS inhibitor therapy is important. Patient education and engagement in the potassium management process is important for sustained success.

Burden of Renal Cysts Imaging: A Survey of Patients among the Greater Plains Collaborative.

PURPOSE: Renal cysts are a frequent incidental finding on cross-sectional radiographic imaging. While most cysts are indolent, individuals with such cysts are frequently monitored for interval growth and potential malignant transformation, which is ultimately rare. In this study, we aimed to assess patients' values and preferences (believes and attitudes) about renal cysts. METHODS: We deployed a cross-sectional survey to a random sample of patients with a diagnosis of renal cysts who were identified by billing code and self-identification. We collected data about demographics, insurance status, family history and overall health, and characteristics of patients with renal cysts. We performed a binary regression analysis (adjusted for age, gender, family history of cancer and kidney disease, and treatment plan for renal cysts) to determine anxiety predictors in patients with renal cysts. RESULTS: We included 301 respondents in whom billing code and self-identification corresponded; of these, 138 had renal cysts and 163 did not. In an adjusted regression analysis, there was a suggestion that a clear management plan (OR = 0.49, 95% CI [0.22-1.11]) (p value 0.08) may be associated with less anxiety and a family history of renal disease may be associated with more anxiety (OR = 1.94 [0.76-4.94]) (p value 0.17). Family history of cancer also did not significantly predict anxiety (OR = 0.54 [0.24-1.19]) (p value 0.13). All these results were not statistically significant and had wide confidence intervals of the effect estimates make the results imprecise. CONCLUSION: Findings of this pilot study suggest a clear management plan for the renal cyst(s) management may be associated with a lower level of anxiety, thereby by emphasizing the importance of good communication, patient engagement and evidence-based guidance. More definitive, adequately powered studies are needed to evaluate this finding further. In addition, further studies exploring differences in imaging practices, patient symptomatology and patient engagement by different provider types would be insightful. Ultimately, tools to improve shared decision-making are needed to provide more patient-centered care.

Community Violence, PTSD, Hopelessness, Substance Use, and Perpetuation of Violence in an Urban Environment.

We investigated the relationships among chronic violence exposure, post-traumatic stress disorder (PTSD) symptom severity, hopelessness, substance use, and perpetuation of violence to facilitate the development of trauma-related interventions for residents of Newark, NJ. A convenience sample of Newark residents (N = 153) was recruited from community centers during various events in 2016-2017. Anonymous, self-report survey measures included a PTSD screen (PCL-C), Beck's Hopelessness Scale, the CAGE questionnaire, and a CDC Health Behavior Scale. Descriptive statistics, Pearson's correlations, Chi square analyses, logistic, and linear regressions were used for analysis. Thirty percent (95% CI [22.7, 37.4]) of our sample screened positive for PTSD. Drug and alcohol use, fighting, and hopelessness were related to severity of PTSD symptoms (p < 0.05). Female gender, CAGE scores, and hopelessness predicted the severity of PTSD symptoms (R2 = 0.354, p < 0.05). Our data has informed the development of a resilience support group currently in the pilot stage for community members.

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management.

PURPOSE: A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management. METHODS: Retrospective review of patients seen over a two-year period in the RGC. RESULTS: One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified. CONCLUSION: An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.

KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results.

BACKGROUND: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. METHODS: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. RESULTS: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. CONCLUSION: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

Hepatocyte Nuclear Factor-1ß Regulates Urinary Concentration and Response to Hypertonicity.

The transcription factor hepatocyte nuclear factor-1ß (HNF-1ß) is essential for normal kidney development and function. Inactivation of HNF-1ß in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1ß specifically in renal collecting ducts (CDs). CD-specific HNF-1ß mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1ß mutant mice exhibited polyuria and polydipsia. Before the development of significant renal structural abnormalities, mutant mice exhibited low urine osmolality at baseline and after water restriction and administration of desmopressin. However, mutant and wild-type mice had similar plasma vasopressin and solute excretion levels. HNF-1ß mutant kidneys showed increased expression of aquaporin-2 mRNA but mislocalized expression of aquaporin-2 protein in the cytoplasm of CD cells. Mutant kidneys also had decreased expression of the UT-A urea transporter and collectrin, which is involved in apical membrane vesicle trafficking. Treatment of HNF-1ß mutant mIMCD3 cells with hypertonic NaCl inhibited the induction of osmoregulated genes, including Nr1h4, which encodes the transcription factor FXR that is required for maximal urinary concentration. Chromatin immunoprecipitation and sequencing experiments revealed HNF-1ß binding to the Nr1h4 promoter in wild-type kidneys, and immunoblot analysis revealed downregulated expression of FXR in HNF-1ß mutant kidneys. These findings reveal a novel role of HNF-1ß in osmoregulation and identify multiple mechanisms, whereby mutations of HNF-1ß produce defects in urinary concentration.

Transcription Factor Hepatocyte Nuclear Factor-1ß Regulates Renal Cholesterol Metabolism.

HNF-1ß is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1ß develop kidney cysts, and HNF-1ß regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1ß-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1ß in murine kidney epithelial cells. Pathway analysis predicted that HNF-1ß regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1ß or kidney-specific inactivation of HNF-1ß decreased the expression of genes that are essential for cholesterol synthesis, including sterol regulatory element binding factor 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). HNF-1ß mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Additionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1ß on the proteins encoded by Srebf2 and Hmgcr, and HNF-1ß directly controlled the renal epithelial expression of proprotein convertase subtilisin-like kexin type 9, a key regulator of cholesterol uptake. These findings reveal a novel role of HNF-1ß in a transcriptional network that regulates intrarenal cholesterol metabolism.

Correction: CVVHD results in longer filter life than pre-filter CVVH: Results of a quasi-randomized clinical trial.

[This corrects the article DOI: 10.1371/journal.pone.0278550.].

MicroRNAs and Polycystic Kidney Disease.

Polycystic kidney disease (PKD), the most common genetic cause of chronic renal failure, is characterized by the presence of numerous fluid-filled cysts in renal parenchyma. Despite recent progress, no FDA-approved therapy is available to retard cyst growth. Here, we review current evidence implicating two groups of miRNAs - the miR-17~92 cluster and miR-200s - in the pathogenesis of PKD. We present a new hypothesis for cyst growth involving miRNAs and regulation of PKD gene dosage. We propose that manipulating miRNA function in an attempt to normalize PKD gene dosage represents a novel therapeutic strategy in PKD.

MicroRNAs and fibrosis.

PURPOSE OF REVIEW: MicroRNAs (miRNAs) are short noncoding RNAs that inhibit gene expression in plants and animals. miRNAs have emerged as key players in virtually all aspects of mammalian biology. Aberrant miRNA expression is observed in numerous human diseases such as diabetes, hypercholesterolemia, cancer, and tissue fibrosis. Therefore, approaches to correct miRNA expression represent the novel therapeutic strategies for these diseases. RECENT FINDINGS: miRNAs are essential for kidney development and homeostasis. Aberrant miRNA expression is observed in the mouse models of kidney fibrosis. Three TGF-ß-regulated miRNA families, miR-21, miR-200, and miR-29 have been shown to modulate renal fibrosis. miR-21, through a feed-forward loop, amplifies TGF-ß signaling and promotes fibrosis. Conversely, miR-200 and miR-29 reduce fibrosis by inhibiting epithelial-to-mesenchymal transition and preventing the deposition of extracellular matrix, respectively. Inhibition of miR-21 expression or augmenting miR-29 expression prevents kidney fibrosis in mice. SUMMARY: Aberrant miRNA expression perturbs signaling pathways that lead to progression of kidney fibrosis. Thus, miRNAs represent novel biomarkers and therapeutic targets in the treatment of kidney fibrosis.

Hepatitis C increases the risk of progression of chronic kidney disease in patients with glomerulonephritis.

BACKGROUND/AIMS: We have shown that hepatitis C does not increase the risk of developing chronic kidney disease (CKD), but it is not known if hepatitis C worsens progression of existing CKD. METHODS: We retrospectively identified patients with primary glomerulonephritis on biopsy over 4 years, evaluating the progression of CKD over time. RESULTS: The cohort consisted of 111 patients: 21% were positive for hepatitis C, 61% were negative for hepatitis C and 18% were not tested. The hepatitis C-positive subjects were more likely to be African American (p = 0.031), followed for fewer days (p = 0.007) and have diabetes and focal segmental glomerulosclerosis on biopsy (p < 0.001). Longitudinal follow-up of CKD progression using multiple creatinine measures analyzed by repeated measures ANCOVA demonstrated that patients with hepatitis C had a worsening creatinine over time compared to the hepatitis C-negative and not tested groups (p < 0.001). By Cox hazards regression analyses, risk of death/end-stage renal disease (ESRD) was decreased in patients who tested negative for hepatitis C compared to testing positive (0.46, CI 0.27-0.88), but this became nonsignificant after adjustment for mean arterial pressure and hemoglobin. CONCLUSION: Our results support that infection with hepatitis C in patients with glomerulonephritis is associated with an increased risk of progression of CKD. Prospective studies are required to confirm these observations.

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass.

The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.

Calciphylaxis: Approach to Diagnosis and Management.

Calciphylaxis is a rare disorder of poor prognosis that can lead to intense, painful lesions involving the skin and subcutaneous tissue. Although mostly described in dialysis patients, it can affect patients with normal kidney function. The diagnosis of calciphylaxis is complicated by the absence of a gold standard marker of disease such as a clear histopathological finding. Late diagnosis and advanced lesions can significantly shorten life expectancy. Calciphylaxis wounds can have a major influence on the quality of life of patients, usually due to the immense unbearable pain these patients suffer from. The management of calciphylaxis mainly comprises aggressive wound care and symptomatic management. Therapeutic options are few and far between and are limited to off-label uses. Recent understanding of the pathogenesis of lesions has enabled development of novel therapeutic options, some of which are being studied in clinical trials (sodium thiosulfate, vitamin K). Vascular calcification and thrombosis underlie development of these lesions and research has been aimed at studying drugs that counteract such processes. Future research is required to establish clear causal pathways and improve on the treatment options currently available to patients.

Modulation of total ceramide and constituent ceramide species in the acutely and chronically hypoxic mouse heart at different ages.

Ceramide has been implicated in regulatory processes vital for cell survival under different stressors, most notably hypoxia. Little has been done to investigate the contributions of the different ceramide species to the regulation of cell survival. This study aims to highlight the patterns of variation in total ceramide and its species in the growing and hypoxic mouse heart. Mus musculus mice were placed in a hypoxic environment at birth. Control animals remained in room air. The hearts were extracted at different time points: 1 day, 1 week, 4 weeks, and 8 weeks. The total ceramide content and the amounts of component species were assayed by a modified diacylglycerol kinase assay and high-performance liquid chromatography-tandem mass spectroscopy, respectively. Data was collected from both ventricles in hypoxic and control conditions. There was significant polycythemia in the hypoxic versus control animals with a nearly twofold increase in hematocrit levels. Hypoxic right ventricle (RV) mass significantly increased over that of controls at different age groups. When ceramide content was compared in the hypoxic versus control animals, there was a significant increase at day 1 and a significant decrease at week 4 in the left ventricle, whereas a significant decrease was found in the RV at 1 week, 4 weeks, and 8 weeks. There was also a differential involvement of the RV with regard to levels of N-palmitoyl-D-erythro-sphingosine (C16-Cer) and its synthetic precursor dihydro-N-palmitoyl-D-erythro-sphinganine (DHC-16-Cer). The decrease in C16-Cer observed in both hypoxic and control RV's over time was paralleled by a significant increase in DHC-16-Cer in hypoxic (142.1+/-15.0 pmol; p<0.05) but not control (52.8+/-4.0 pmol) RV's suggesting a role for DHC-16-Cer in the RV adaptive response to hypoxia. Another species, N-arachidoyl-D-erythro-sphingosine (C20-Cer), was specifically and significantly decreased in the hypoxic RV. These studies support the presence of distinct roles for different ceramide species and their precursors. A better assessment of cyanotic congenital heart disease in light of the mechanism and timing of cardiomyocyte death, will lead to punctual interventions and even novel cardioprotective strategies.

Total pancreatectomy with islet cell transplantation vs intrathecal narcotic pump infusion for pain control in chronic pancreatitis.

AIM: To evaluate pain control in chronic pancreatitis patients who underwent total pancreatectomy with islet cell transplantation or intrathecal narcotic pump infusion. METHODS: We recognized 13 patients who underwent intrathecal narcotic pump (ITNP) infusion and 57 patients who underwent total pancreatectomy with autologous islet cell transplantation (TP + ICT) for chronic pancreatitis (CP) pain control between 1998 and 2008 at Indiana University Hospital. All patients had already failed multiple other modalities for pain control and the decision to proceed with either intervention was made at the discretion of the patients and their treating physicians. All patients were evaluated retrospectively using a questionnaire inquiring about their pain control (using a 0-10 pain scale), daily narcotic dose usage, and hospital admission days for pain control before each intervention and during their last follow-up. RESULTS: All 13 ITNP patients and 30 available TP + ICT patients were evaluated. The mean age was approximately 40 years in both groups. The median duration of pain before intervention was 6 years and 7 years in the ITNP and TP + ICT groups, respectively. The median pain score dropped from 8 to 2.5 (on a scale of 0-10) in both groups on their last follow up. The median daily dose of narcotics also decreased from 393 mg equivalent of morphine sulfate to 8 mg in the ITNP group and from 300 mg to 40 mg in the TP + ICT group. No patient had diabetes mellitus (DM) before either procedure whereas 85% of those who underwent pancreatectomy were insulin dependent on their last evaluation despite ICT. CONCLUSION: ITNP and TP + ICT are comparable for pain control in patients with CP however with high incidence of DM among those who underwent TP + ICT. Prospective comparative studies and longer follow up are needed to better define treatment outcomes.