Successful treatment of unusual life-threatening complications of idiopathic edema.

Idiopathic edema (IE) is a disease that occurs predominantly in women. It is characterized by increasing weight gain of >1.4 kg from morning to night, increasing edema, increasing truncal and abdominal girth with bloating when assuming an upright position and nocturia that is unrelated to menses. There is an increase in morbidity but not mortality. Increased capillary membrane leakage appears to be the underlying pathophysiologic abnormality that explains the myriad of clinical presentations. We present 2 cases of life-threatening complications of IE that resulted in seizures related to acute hyponatremia in one and extreme postural dizziness and fainting induced by postural hypotension in the other. The first patient was successfully treated with salt restriction, timely use of furosemide and limitation of water intake; the other was successfully treated by use of support hose. Treatment of these patients required a fundamental understanding of the intricate pathophysiological consequences of a leaky capillary membrane, an understanding of Starling forces and detailing the effectiveness of a low salt diet, use of diuretics and limited water intake in one and why support hose would be beneficial in the other patient. Both patients experienced significant physical and emotional benefits that substantially improved quality of life.

High prevalence of renal salt wasting induced by haptoglobin-related protein without signal peptide is linked to new syndrome of salt wasting in Alzheimer disease.

The subject of hyponatremia is undergoing significant changes after developing a more pathophysiologic approach that is superior to the ineffective volume approach and can more effectively identify the different causes of hyponatremia. This new approach identified cerebral salt wasting (CSW) in 24 (38%) of 62 hyponatremic patients from the medical wards of the hospital with 21 showing no evidence of cerebral disease to support our proposal to change CSW to renal salt wasting (RSW). RSW had to be differentiated from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) because of diametrically opposite therapeutic goals of water-restricting water-logged patients with SIADH or administering salt water to volume-depleted patients with RSW. Both syndromes present with identical clinical parameters that require a difficult protocol to make such a differentiation possible. We describe rat clearance studies demonstrating natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) and eventually identify the protein as haptoglobin-related protein without signal peptide, which can serve as a biomarker to simplify diagnosis of RSW and delivery of the proper management to improve clinical outcomes. We also discuss the introduction of a new syndrome of RSW in AD and its implications. The high prevalence of RSW and identification of the natriuretic factor have created debates over the existence of RSW with none questioning or addressing the pathophysiologic data that identified patients with RSW. We also discuss the potentially large group of patients with RSW who are normonatremic.

Haptoglobin-Related Protein without Signal Peptide as Biomarker of Renal Salt Wasting in Hyponatremia, Hyponatremia-Related Diseases and as New Syndrome in Alzheimer's Disease.

The application of pathophysiologic tenets has created significant changes in our approach to hyponatremia and hyponatremia-related conditions. This new approach incorporated the determination of fractional excretion (FE) of urate before and after the correction of hyponatremia and the response to isotonic saline infusion to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from renal salt wasting (RSW). FEurate simplified the identification of the different causes of hyponatremia, especially the diagnosis of a reset osmostat and Addison's disease. Differentiating SIADH from RSW has been extremely difficult because both syndromes present with identical clinical parameters, which could be overcome by successfully carrying out the difficult protocol of this new approach. A study of 62 hyponatremic patients from the general medical wards of the hospital identified 17 (27%) to have SIADH, 19 (31%) with reset osmostat, and 24 (38%) with RSW with 21 of these RSW patients presenting without clinical evidence of cerebral disease to warrant changing the nomenclature from cerebral to renal salt wasting. The natriuretic activity found in the plasma of 21 and 18 patients with neurosurgical and Alzheimer's disease, respectively, was later identified as haptoglobin-related protein without signal peptide (HPRWSP). The high prevalence of RSW creates a therapeutic dilemma of deciding whether to water-restrict water-logged patients with SIADH as compared to administering saline to volume-depleted patients with RSW. Future studies will hopefully achieve the following: 1. Abandon the ineffective volume approach; 2. Develop HPRWSP as a biomarker to identify hyponatremic and a projected large number of normonatremic patients at risk of developing RSW, including Alzheimer's disease; 3. Facilitate differentiating SIADH from RSW on the first encounter and improve clinical outcomes.

New Approach to Hyponatremia: High Prevalence of Cerebral/Renal Salt Wasting, Identification of Natriuretic Protein That Causes Salt Wasting.

Our understanding of hyponatremic conditions has undergone major alterations. There is a tendency to treat all patients with hyponatremia because of common subtle symptoms that include unsteady gait that lead to increased falls and bone fractures and can progress to mental confusion, irritability, seizures, coma and even death. We describe a new approach that is superior to the ineffectual volume approach. Determination of fractional excretion (FE) of urate has simplified the diagnosis of a reset osmostat, Addison's disease, edematous causes such as congestive heart failure, cirrhosis and nephrosis, volume depletion from extrarenal salt losses with normal renal tubular function and the difficult task of differentiating the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C/RSW). SIADH and C/RSW have identical clinical and laboratory parameters but have diametrically opposite therapeutic goals of water-restricting water-loaded patients with SIADH or administering salt water to dehydrated patients with C/RSW. In a study of nonedematous patients with hyponatremia, we utilized FEurate and response to isotonic saline infusions to differentiate SIADH from C/RSW. Twenty-four (38%) of 62 hyponatremic patients had C/RSW with 21 having no clinical evidence of cerebral disease to support our important proposal to change cerebral to renal salt wasting (RSW). Seventeen (27%) had SIADH and 19 (31%) had a reset osmostat. One each from hydrochlorothiazide and Addison's disease. We demonstrated natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) in rat clearance studies and have now identified the natriuretic protein to be haptoglobin related protein without signal peptide (HPRWSP). We introduce a new syndrome of RSW in AD that needs further confirmation. Future studies intend to develop HPRWSP as a biomarker to simplify the diagnosis of RSW in hyponatremic and normonatremic patients and explore other clinical applications that can improve clinical outcomes.

COVID-19 Antibodies and Outcomes among Outpatient Maintenance Hemodialysis Patients.

Background: Patients on maintenance hemodialysis are particularly vulnerable to infection and hospitalization from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to immunocompromised patients and the clustering that occurs in outpatient dialysis units, the seroprevalence of COVID-19 antibodies in this population is unknown and has significant implications for public health. Also, little is known about their risk factors for hospitalization. Methods: Three outpatient maintenance hemodialysis units affiliated with a major teaching hospital in the New York area were studied. We determined rates of SARS-CoV-2 positivity via nasopharyngeal, real-time, reverse-transcriptase PCR (RT-PCR); SARS-CoV-2 IgG seropositivity; hospitalization; and mortality. Results: Of 367 patients, 28% had either SARS-CoV-2 seropositivity or PCR positivity. Prevalence across the three respective units was 7%, 32%, and 70%. Those who were either antibody or PCR positive were significantly younger (65 versus 69 years, P=0.05), and had a higher prevalence of Black race (43% versus 30%, P=0.001) and Hispanic ethnicity (32% versus 12%, P<0.001) compared with those who tested negative. Higher positivity rates were also observed among those who took taxis and ambulettes to and from dialysis, compared with those who used personal transportation. Antibodies were detected in all of the patients with a positive PCR result who underwent serologic testing. Of those that were seropositive, 32% were asymptomatic. The hospitalization rate on the basis of either antibody or PCR positivity was 35%, with a hospital mortality rate of 33%. Aside from COPD, no other variables were more prevalent in patients who were hospitalized. Conclusions: We observed significant differences in rates of COVID-19 infection within three outpatient dialysis units, with universal seroconversion. Among patients with ESKD, rates of asymptomatic infection appear to be high, as do hospitalization and mortality rates.

The association between serum chloride levels and chronic kidney disease progression: a cohort study.

BACKGROUND: Limited data suggest serum chloride levels associate with mortality in heart failure, chronic kidney disease (CKD), and pulmonary arterial hypertension. Randomized trials have also shown that administration of crystalloid intravenous fluids with lower chloride concentration may have better renal outcomes. However, chloride has not been studied longitudinally for CKD progression. METHODS: We used a prospective cohort of subjects with stage 3 and 4 CKD recruited from a nephrology clinic at a single medical center. Linear regression, linear regression with generalized estimating equations, and Cox proportional hazards models were created for outcomes of overall change in estimated glomerular filtration rate (eGFR), longitudinal changes in eGFR, and time to > 30% decline in eGFR, respectively. Baseline chloride was modeled continuously and categorically, and models were adjusted for potential confounders. RESULTS: Median follow-up was 1.7 years. Baseline median age was 72 years and median eGFR was 35.7 mL/min/1.73m2. In multivariable analysis, higher serum chloride associated with worsened eGFR decline. Every 1 mEq/L increase in chloride associated with an overall eGFR decline of 0.32 mL/min/1.73m2 (p = 0.003), while the difference in eGFR decline in the highest quartile of chloride was 3.4 mL/min/1.73m2 compared to the lowest quartile (p = 0.004). No association between serum chloride and time to 30% decline in eGFR was observed in multivariable analysis (hazard ratio 1.05 per 1 mEq/L increase in serum chloride, p = 0.103). CONCLUSIONS: In CKD patients, higher serum chloride associated with a modestly steeper rate of eGFR decline, and may be a useful biomarker to predict CKD progression. Further studies are needed to determine causality.

Depression in Chronic Kidney Disease and End-Stage Renal Disease: Similarities and Differences in Diagnosis, Epidemiology, and Management.

Depression is highly prevalent and is associated with poor quality of life and increased mortality among adults with chronic kidney disease (CKD), including those with end-stage renal disease (ESRD). However, there are several important differences in the diagnosis, epidemiology, and management of depression between patients with non-dialysis-dependent CKD and ESRD. Understanding these differences may lead to a better understanding of depression in these 2 distinct populations. First, diagnosing depression using self-reported questionnaires may be less accurate in patients with ESRD compared with CKD. Second, although the prevalence of interview-based depression is approximately 20% in both groups, the risk factors for depression may vary. Third, potential mechanisms of depression might also differ in CKD versus ESRD. Finally, considerations regarding the type and dose of antidepressant medications vary between CKD and ESRD. Future studies should further examine the mechanisms of depression in both groups, and test interventions to prevent and treat depression in these populations.

A pilot trial to examine the association between circulating endothelial cell levels and vascular injury in patients with diabetes and chronic kidney disease.

Objective While albuminuria is a marker for progressive chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM), both albuminuric and normoalbuminuric patients appear prone to vascular injury. This pilot study examines the association between circulating endothelial cell (CEC) levels and vascular injury in patients with T2DM and CKD. Methods In this cross-sectional study, eligible adult patients had T2DM, and stage 3 CKD (estimated glomerular filtration rate between 30 and 60 mL/min/1.73m (2)). CEC levels were tested by Janssen Diagnostics, LLC using an immuno-magnetic bead-based assay. CEC levels were compared to levels in a previously tested normal population. Correlations between CEC levels and other vascular injury markers (urine albumin, von-Willebrand factor antigen, hs-CRP, uric acid) were performed. Results Patients included 40 adults of which nineteen were normoalbuminuric.  Mean CEC levels (38.7, SD 38.1 cells) were significantly higher than the normal population (M = 21±18 cells, p<0.001; N = 249), including in the normoalbuminuric subgroup (M = 42.9±42.5 cells, p<0.001). CEC levels were significantly correlated with uric acid levels (r=0.33, p=0.039). Conclusions CEC levels in patients with T2DM and CKD, both albuminuric and normoalbuminuric, are significantly higher than a normal population, suggesting the presence of vascular injury in both groups. Future studies are needed to evaluate the role of CECs as a biomarker to predict outcomes in normoalbuminuric patients with CKD.

Awareness of Chronic Kidney Disease and Depressive Symptoms: National Health and Nutrition Examination Surveys 2005-2010.

BACKGROUND: Depressive symptoms are common in patients with chronic kidney disease (CKD) and may stem from distress associated with CKD awareness. So far, no studies have examined this association. The objective of this study was to evaluate the association between awareness of CKD and depressive symptoms. METHODS: We included adults with stages 1-4 CKD (estimated glomerular filtration rate 15-60 ml/min/1.73 m2 or urine albumin-to-creatinine ratio ≥30 mg/g) using the National Health and Nutrition Examination Surveys from 2005 to 2010. Depressive symptoms were categorized as minimal (9-item Patient Health Questionnaire (PHQ-9) score 0-4), subthreshold (PHQ-9 score 5-14) and severe (PHQ-9 score ≥15). Participants were classified as aware of CKD if they answered yes to the question: 'Have you ever been told you have weak or failing kidneys?' Multivariable logistic regression was used to identify variables independently associated with at least subthreshold depressive symptoms (PHQ-9 ≥5). RESULTS: In 2,500 participants with CKD, the weighted prevalence was 21.4% for subthreshold and 3.1% for severe depressive symptoms. The weighted prevalence of CKD awareness was 6.4%. Independent predictors of depressive symptoms included younger age, female gender, never been married, less than high-school education, annual family income <$20,000, obesity, smoking, cardiovascular comorbidity and mental health visit in the past year. CKD awareness was independently associated with a 1.66 greater odds of depressive symptoms (95% CI 1.01-2.74, p < 0.05). CONCLUSIONS: Awareness of CKD is significantly associated with depressive symptoms independent of known confounding factors. Future studies should examine mediators of this association, especially in light of national efforts to promote CKD awareness.

Underprescription of renin-angiotensin system blockers in moderate to severe chronic kidney disease.

BACKGROUND: Renin-angiotensin system (RAS) blockers slow the progression of chronic kidney disease (CKD). Despite this, up to 40% of patients with CKD and an indication for RAS blockade do not receive these medications. The purpose of this study was to examine variables associated with the prescription of RAS blockers in patients with CKD and to identify opportunities to increase their use. METHODS: The electronic medical records of patients with moderate to severe CKD and an indication for RAS blockade were reviewed. For patients with an indication for RAS blockade who were not prescribed these medications, previous notes were reviewed to ascertain reasons why RAS blockade was not prescribed. RESULTS: Six hundred twenty-seven patients with moderate to severe CKD and an indication for RAS blockade were identified. Of these patients, 225 (36%) were not prescribed RAS blockade. This group was found to have significantly less diabetes, to be significantly older and to have significantly lower estimated glomerular filtration rate and blood pressure than the group on RAS blockade. For the majority (59%), no documented reason for not being prescribed RAS blockade was found. Among documented reasons, hyperkalemia and a history of acute kidney injury were the most common. CONCLUSIONS: The authors found that a large proportion of patients with CKD and an indication for RAS blockade were not prescribed these medications. For the majority, there was no provider-documented reason explaining why these medications were not prescribed, and the findings suggest that there may be opportunities to increase RAS blocker prescribing.