How Dangerous Is Hyperkalemia?

Hyperkalemia is a potentially life-threatening electrolyte disorder appreciated with greater frequency in patients with renal disease, heart failure, and with use of certain medications such as renin angiotensin aldosterone inhibitors. The traditional views that hyperkalemia can be reliably diagnosed by electrocardiogram and that particular levels of hyperkalemia confer cardiotoxic risk have been challenged by several reports of patients with atypic presentations. Epidemiologic data demonstrate strong associations of morbidity and mortality in patients with hyperkalemia but these associations appear disconnected in certain patient populations and in differing clinical presentations. Physiologic adaptation, structural cardiac disease, medication use, and degree of concurrent illness might predispose certain patients presenting with hyperkalemia to a lower or higher threshold for toxicity. These factors are often overlooked; yet data suggest that the clinical context in which hyperkalemia develops is at least as important as the degree of hyperkalemia is in determining patient outcome. This review summarizes the clinical data linking hyperkalemia with poor outcomes and discusses how the efficacy of certain treatments might depend on the clinical presentation.

Mechanisms of type I and type II pseudohypoaldosteronism.

Pseudohypoaldosteronism (PHA) types I and II are curious genetic disorders that share hyperkalemia as a predominant finding. Together they have become windows to understanding new molecular physiology in the kidney. Autosomal recessive PHAI results from mutations in the epithelial sodium channel (ENaC), whereas autosomal dominant PHAI is characterized by mutations in the mineralocorticoid receptor. PHAII is the result of mutations in a family of serine-threonine kinases called with-no-lysine kinases (WNK)1 and WNK4. WNK4 negatively regulates the NaCl cotransporter (NCC), and PHAII mutations in WNK4 abrogate this affect. WNK4 also regulates the expression or function of renal outer medullary potassium (ROMK) channels, ENaCs, and Cl transporters. WNK1 also regulates NCC and ROMK. Aldosterone inactivates WNK1 and WNK4 activity. Whether angiotensin II can fine tune the actions of aldosterone is still unclear.

A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension. METHODS: This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (>/=130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. FINDINGS: All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0.0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events. INTERPRETATION: Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. FUNDING: Gilead Sciences.

Endothelin antagonists and resistant hypertension in chronic kidney disease.

PURPOSE OF REVIEW: Endothelin is a potent vasoconstrictor and promoter of renal disease. This review discusses recent developments in the use of endothelin receptor antagonists in resistant hypertension and chronic kidney disease. RECENT FINDINGS: Endothelin is a potent vasoconstrictor and growth factor. Endothelin production has been shown to be associated with renal disease including hypertension, chronic kidney disease, and proteinuria. Selective endothelin A receptor antagonists have been examined in clinical trials for the treatment of hypertension and proteinuric kidney disease, and appear to be effective in reducing blood pressure and improving proteinuria. However, their use is tempered by a significant side effect profile including an increase in total body sodium, which will likely limit their use to the treatment of resistant hypertension. SUMMARY: Selective endothelin antagonists are exciting new agents that could expand our antihypertensive arsenal and increase our efficacy in chronic kidney disease therapy. Specifically, they may represent a new approach in the treatment of resistant hypertension; however, their use is currently limited by significant sodium retention.

Incident chronic kidney disease and the rate of kidney function decline in individuals with hypertension.

BACKGROUND: Little is known about the decline of kidney function in patients with normal kidney function at baseline. Our objectives were to (i) identify predictors of incident chronic kidney disease (CKD) and (ii) to estimate rate of decline in kidney function. METHODS: The study used a retrospective cohort of adult patients in a hypertension registry in an inner-city health care delivery system in Denver, Colorado. The primary outcome was development of incident CKD, and the secondary outcome was rate of change of estimated glomerular filtration rate (eGFR) over time. RESULTS: After a mean follow-up of 45 months, 429 (4.1%) of 10 420 patients with hypertension developed CKD. In multivariate models, factors that independently predicted incident CKD were baseline age [odds ratio (OR) 1.13 per 10 years, 95% confidence interval (CI), 1.03-1.24], baseline eGFR (OR 0.69 per 10 units, 95% CI 0.65-0.73), diabetes (OR 3.66, 95% CI 2.97-4.51) and vascular disease (OR 1.67, 95% CI 1.32-2.10). We found no independent association between age, gender or race/ethnicity and eGFR slope. In patients who did not have diabetes or vascular disease, eGFR declined at 1.5 mL/min/1.73 m(2) per year. Diabetes at baseline was associated with an additional decline of 1.38 mL/min/1.73 m(2). CONCLUSIONS: Diabetes was the strongest predictor of both incident CKD as well as eGFR slope. Rates of incident CKD or in decline of kidney function did not differ by race or ethnicity in this cohort.

A behavioral and systems view of professionalism.

Professionalism may not be sufficient to drive the profound and far-reaching changes needed in the US health care system, but without it, the health care enterprise is lost. Formal statements defining professionalism have been abstract and principle based, without a clear description of what professional behaviors look like in practice. This article proposes a behavioral and systems view of professionalism that provides a practical approach for physicians and the organizations in which they work. A more behaviorally oriented definition makes the pursuit of professionalism in daily practice more accessible and attainable. Professionalism needs to evolve from being conceptualized as an innate character trait or virtue to sophisticated competencies that can and must be taught and refined over a lifetime of practice. Furthermore, professional behaviors are profoundly influenced by the organizational and environmental context of contemporary medical practice, and these external forces need to be harnessed to support--not inhibit--professionalism in practice. This perspective on professionalism provides an opportunity to improve the delivery of health care through education and system-level reform.

Care of undocumented individuals with ESRD: a national survey of US nephrologists.

BACKGROUND: Although Medicare covers most dialysis therapy for US citizens with end-stage renal disease (ESRD), no national standards for dialysis provision exist for undocumented (ie, immigrant) patients with ESRD. STUDY DESIGN: Cross-sectional survey. SETTING & PARTICIPANTS: Mail and internet survey from October 2006 to February 2007 of American Society of Nephrology member nephrologists. PREDICTORS: Region of the country, practicing in a state with a high undocumented population, inpatient and outpatient practice setting, and practice location. OUTCOMES: Characteristics of nephrologists who report caring for undocumented patients with ESRD and those who perceive that such patients have access to maintenance dialysis therapy. RESULTS: Response rate was 57% (990 of 1,723). Of nephrologists surveyed, 65%, representing 44 states, reported providing care to undocumented patients with ESRD and 61% reported increasing prevalence. Being from a state with a high undocumented population (OR, 1.67; 95% CI, 1.21 to 2.30) was associated with undocumented ESRD patient care; being from the Northeastern United States (OR, 0.55; 95% CI, 0.34 to 0.88) or a small town/rural area (OR, 0.27; 95% CI, 0.18 to 0.40) were negatively associated. Of the respondents, 91% reported that undocumented patients had access to emergent dialysis, but only 51% reported access to maintenance dialysis therapy. The characteristic associated with reporting access to maintenance dialysis was practicing in a state with a high undocumented population (OR, 1.91; 95% CI, 1.37 to 2.66), whereas practicing in the Southern United States was negatively associated (OR, 0.37; 95% CI, 0.24 to 0.57). Emergent-only dialysis for undocumented patients was reported by 28%. Of respondents knowledgeable about reimbursement, most reported inadequate compensation and 35% reported that outpatient dialysis units provide uncompensated dialysis care to undocumented patients with ESRD. LIMITATIONS: Selection and information biases inherent to survey methods. CONCLUSIONS: Dialysis for undocumented patients with ESRD is an increasing problem involving the majority of US nephrologists. Inadequately compensated or uncompensated care may limit the availability of long-term maintenance dialysis therapy for undocumented patients with ESRD. Regional variations argue for more rational and uniform national policy regarding this issue.

The role of obesity in the pathogenesis of hypertension.

The rapid rise in the incidence and prevalence of obesity and the concomitant increase in the incidence and prevalence of hypertension have fueled investigation into the role of obesity in the pathogenesis of hypertension. The genetic background that predisposes obese individuals to hypertension is being elucidated, and the importance of adipose tissue as an endocrine organ in the pathogenesis of hypertension is increasingly being recognized. Visceral adipose tissue is critical in the production of pathologic cytokines that are thought to mediate obesity-induced hypertension. Changes in the types and levels of adipocytokines that result from the accumulation of aberrant adipose tissue directly leads to alterations in systemic vascular resistance, sodium retention and sympathetic nervous system activity. Key changes in adipocytokine levels seen in obesity-induced hypertension include increased leptin and adiponectin levels. Another important mechanism in obesity-induced hypertension is the generation of angiotensin II and direct stimulation of aldosterone production. The increased sympathetic nervous system activity seen in obesity-associated hypertension leads to increased renal sodium retention and increased systemic vascular resistance. Increased systemic vascular resistance can also occur directly in obese individuals through vascular fibrosis and lipid deposition. Obesity should no longer be simply considered as a marker of cardiovascular risk but should be regarded as an important and primary contributor to the pathophysiology of hypertension.

Overview of Cerebral Edema During Correction of Hyperglycemic Crises.

BACKGROUND Hyperglycemic crises can cause severe neurologic impairment. One of the most dreaded consequences of hyperglycemic crises is cerebral edema, a rare complication seen during the treatment of hyperglycemic crises resulting from overly-aggressive fluid resuscitation and rapid correction of hyperglycemia and hyperosmolarity. CASE REPORT We present a case of profound hyperglycemic crisis with blood glucose greater than 2000 mg/dL, complicated by the development of new neurologic deficits after rapid correction of hyperglycemia. Brain imaging failed to reveal a diagnosis of cerebral edema or other acute intracranial process. However, the deficits did not resolve by the time of discharge, raising concern that the neurologic impairment may have been the consequence of overly-aggressive treatment of the hyperglycemic crisis. CONCLUSIONS Neurologic status must be monitored closely, with frequent re-examination, in patients who present with hyperglycemic crises. Care should be taken to prevent over-correction of hyperglycemia and hyperosmolarity following initial fluid resuscitation of these patients to prevent cerebral edema or other significant neurologic impairment.

Association of Emergency-Only vs Standard Hemodialysis With Mortality and Health Care Use Among Undocumented Immigrants With End-stage Renal Disease.

Importance: Undocumented immigrants with end-stage renal disease have variable access to hemodialysis in the United States despite evidence-based standards for frequency of dialysis care. Objective: To determine whether mortality and health care use differs among undocumented immigrants who receive emergency-only hemodialysis vs standard hemodialysis (3 times weekly at a health care center). Design, Setting, and Participants: A retrospective cohort study was conducted of undocumented immigrants with incident end-stage renal disease who initiated emergency-only hemodialysis (Denver Health, Denver, Colorado, and Harris Health, Houston, Texas) or standard (Zuckerberg San Francisco General Hospital, San Francisco, California) hemodialysis between January 1, 2007, and July 15, 2014. Exposures: Access to emergency-only hemodialysis vs standard hemodialysis. Main Outcomes and Measures: The primary outcome was mortality. Secondary outcomes were health care use (acute care days and ambulatory care visits) and rates of bacteremia. Outcomes were adjusted for propensity to undergo emergency hemodialysis vs standard hemodialysis. Results: A total of 211 undocumented patients (86 women and 125 men; mean [SD] age, 46.5 [14.6] years; 42 from the standard hemodialysis group and 169 from the emergency-only hemodialysis group) initiated hemodialysis during the study period. Patients receiving standard hemodialysis were more likely to initiate hemodialysis with an arteriovenous fistula or graft and had higher albumin and hemoglobin levels than patients receiving emergency-only hemodialysis. Adjusting for propensity score, the mean 3-year relative hazard of mortality among patients who received emergency-only hemodialysis was nearly 5-fold (hazard ratio, 4.96; 95% CI, 0.93-26.45; P = .06) greater compared with patients who received standard hemodialysis. Mean 5-year relative hazard of mortality for patients who received emergency-only hemodialysis was more than 14-fold (hazard ratio, 14.13; 95% CI, 1.24-161.00; P = .03) higher than for those who received standard hemodialysis after adjustment for propensity score. The number of acute care days for patients who received emergency-only hemodialysis was 9.81 times (95% CI, 6.27-15.35; P < .001) the expected number of days for patients who had standard hemodialysis after adjustment for propensity score. Ambulatory care visits for patients who received emergency-only hemodialysis were 0.31 (95% CI, 0.21-0.46; P < .001) times less than the expected number of days for patients who received standard hemodialysis. Conclusions and Relevance: Undocumented immigrants with end-stage renal disease treated with emergency-only hemodialysis have higher mortality and spend more days in the hospital than those receiving standard hemodialysis. States and cities should consider offering standard hemodialysis to undocumented immigrants.

Indications for renal arteriography at the time of coronary arteriography: a science advisory from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Councils on Cardiovascular Radiology and Intervention and on Kidney in Cardiovascular Disease.

Atherosclerotic renal artery stenosis is commonly present in patients with clinically manifest atherosclerosis in other vascular beds and is independently associated with increased cardiovascular morbidity and mortality. Screening tests such as renal angiography should be selectively applied to patients at high risk for renal artery stenosis who are potential candidates for revascularization. This multispecialty consensus document describes the rationale for patient selection for screening renal angiography at the time of cardiac catheterization.

Controversies in renal artery stenosis: a review by the American Society of Nephrology Advisory Group on Hypertension.

Renovascular hypertension is a recognized secondary potentially curable cause of hypertension since the work of Harry Goldblatt. Operative treatments for renal artery stenosis (RAS) have been offered for decades and percutaneous interventions have been widely available for 20 years. Stenting has largely obviated recurrence and modern techniques have contributed greatly to the safety of the procedure. Nevertheless, controversy abounds and prospective randomized trials have not successfully documented the value of intervention in patients with atherosclerotic RAS. The patient population has also changed remarkably. Whereas earlier patients with RAS were identified on clinical grounds, RAS is now commonly found serendipitously during angiography for other reasons. Whether or not these patients benefit from 'drive by' stenting is unknown. The practice may be hazardous and should be critically examined. A dialog and closer cooperation between cardiologists and nephrologists is warranted and organized programs should be formulated to address this problem.

Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study.

In this phase 2, randomized, double-blind, placebo-controlled forced dose-titration study, 115 patients with resistant hypertension, receiving background therapy with >/=3 antihypertensive medications including a diuretic at full doses, were randomized 2:1 to increasing doses of darusentan (10, 50, 100, 150, and 300 mg), a selective endothelin receptor antagonist, or matching placebo once daily for 10 weeks. Darusentan treatment decreased mean systolic and diastolic blood pressure levels in a dose-dependent fashion compared with placebo; the largest reductions were observed at week 10 (300-mg dose) (systolic, -11.5+/-3.1 mm Hg [P=.015;] diastolic, -6.3+/-2.0 mm Hg [P=.002]). Darusentan (300 mg) also decreased mean 24-hour, daytime, and nighttime ambulatory blood pressures from baseline to week 10. Darusentan was generally well tolerated; mild to moderate edema and headache were the most common adverse events. This study demonstrates a clinical benefit from a new class of antihypertensive agent in patients classified as resistant by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.

Qualitative Interviews Exploring Palliative Care Perspectives of Latinos on Dialysis.

BACKGROUND AND OBJECTIVES: Compared with non-Latino whites with advanced illness, Latinos are less likely to have an advance directive or to die with hospice services. To improve palliative care disparities, international ESRD guidelines call for increased research on culturally responsive communication of advance care planning (ACP). The objective of our study was to explore the preferences of Latino patients receiving dialysis regarding symptom management and ACP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Qualitative study design using semistructured face-to-face interviews of 20 Latinos on hemodialysis between February and July of 2015. Data were analyzed using thematic analysis. RESULTS: Four themes were identified: Avoiding harms of medication (fear of addiction and damage to bodies, effective distractions, reliance on traditional remedies, fatalism: the sense that one's illness is deserved punishment); barriers and facilitators to ACP: faith, family, and home (family group decision-making, family reluctance to have ACP conversations, flexible decision-making conversations at home with family, ACP conversations incorporating trust and linguistic congruency, family-first and faith-driven decisions); enhancing wellbeing day-to-day (supportive relationships, improved understanding of illness leads to adherence, recognizing new self-value, maintaining a positive outlook); and distressing aspects of living with their illness (dietary restriction is culturally isolating and challenging for families, logistic challenges and socioeconomic disadvantage compounded by health literacy and language barriers, required rapid adjustments to chronic illness, demanding dialysis schedule). CONCLUSIONS: Latinos described unique cultural preferences such as avoidance of medications for symptom alleviation and a preference to have family group decision-making and ACP conversations at home. Understanding and integrating cultural values and preferences into palliative care offers the potential to improve disparities and achieve quality patient-centered care for Latinos with advanced illness.

The Illness Experience of Undocumented Immigrants With End-stage Renal Disease.

Importance: The exclusion of undocumented immigrants from Medicare coverage for hemodialysis based on a diagnosis of end-stage renal disease (ESRD) requires physicians in some states to manage chronic illness in this population using emergent-only hemodialysis. Emergent-only dialysis is expensive and burdensome for patients. Objective: To understand the illness experience of undocumented immigrants with ESRD who lack access to scheduled hemodialysis. Design, Setting, and Participants: A qualitative, semistructured, interview study was conducted in a Colorado safety-net hospital from July 1 to December 31, 2015, with 20 undocumented immigrants (hereinafter referred to as undocumented patients) with ESRD and no access to scheduled hemodialysis. Demographic information was collected from the participants' medical records. The interviews were audiorecorded, translated, and then transcribed verbatim. The interviews were analyzed using inductive qualitative theme analysis by 4 research team members from March 1 to June 30, 2016. Main Outcomes and Measures: Themes and subthemes from semistructured interviews. Results: All 20 undocumented patients included in the study (10 men and 10 women; mean [SD] age, 51.4 [13.8] years) had been in the United States for at least 5 years preceding their diagnosis with ESRD. They described the following 4 main themes: (1) a distressing symptom burden and unpredictable access to emergent-only hemodialysis, (2) death anxiety associated with weekly episodes of life-threatening illness, (3) family and social consequences of accommodating emergent-only hemodialysis, and (4) perceptions of the health care system. Conclusions and Relevance: Undocumented patients with ESRD experience debilitating, potentially life-threatening physical symptoms and psychosocial distress resulting from emergent-only hemodialysis. States excluding undocumented immigrants with ESRD from scheduled dialysis should reconsider their policies.

Data and Safety Monitoring Board evaluation and management of a renal adverse event signal in TOPCAT.

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.