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Evolution and evolving resolution of controversy over existence and prevalence of cerebral/renal salt wasting

Maesaka, John K; Imbriano, Louis J; Miyawaki, Nobuyuki
PURPOSE OF REVIEW/OBJECTIVE:The topic of hyponatremia is in a state of flux. We review a new approach to diagnosis that is superior to previous methods. It simplifies identifying the causes of hyponatremia, the most important issue being the differentiation of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (RSW). We also report on the high prevalence of RSW without cerebral disease in the general wards of the hospital. RECENT FINDINGS/RESULTS:We applied our new approach to hyponatremia by utilizing sound pathophysiologic criteria in 62 hyponatremic patients. Seventeen (27%) had SIADH, 19 (31%) had a reset osmostat, 24 (38%) had RSW with 21 having no evidence of cerebral disease, 1 had Addison's disease, and 1 was because of hydrochlorothiazide. Many had urine sodium concentrations (UNa) less than 30 mmol/l. SUMMARY/CONCLUSIONS:RSW is much more common than perceived in the general wards of the hospital. It is important to change the terminology from cerebral to RSW and to differentiate SIADH from RSW. These changes will improve clinical outcomes because of divergent therapeutic goals of water-restricting in SIADH and administering salt and water to a dehydrated patient with RSW. The present review will hopefully spur others to reflect and act on the new findings and different approaches to hyponatremia.
PMID: 31904619
ISSN: 1473-6543
CID: 4258152

Macrophage lipid accumulation in the presence of immunosuppressive drugs mycophenolate mofetil and cyclosporin A

Voloshyna, Iryna; Teboul, Isaac; Kasselman, Lora J; Salama, Michael; Carsons, Steven E; DeLeon, Joshua; Mattana, Joseph; Miyawaki, Nobuyuki; Reiss, Allison B
OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.
PMID: 31227843
ISSN: 1420-908x
CID: 3954772

CKD, arterial calcification, atherosclerosis and bone health: Inter-relationships and controversies

Reiss, Allison B; Miyawaki, Nobuyuki; Moon, Jane; Kasselman, Lora J; Voloshyna, Iryna; D'Avino, Robert; De Leon, Joshua
Mineral bone disease (MBD) is a common complication of chronic kidney disease (CKD) characterized by disruption of normal mineral homeostasis within the body. One or more of the following may occur: hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism (SHPT), decreased vitamin D and vascular calcification (VC). The greater the decrease in renal function, the worse the progression of CKD-MBD. These abnormalities may lead to bone loss, osteoporosis and fractures. CKD-MBD is a major contributor to the high morbidity and mortality among patients with CKD. Another well-known complication of CKD is cardiovascular disease (CVD) caused by increased atherosclerosis and VC. CVD is the leading cause of morbidity and mortality in CKD patients. VC is linked to reduced arterial compliance that may lead to widened pulse pressure and impaired cardiovascular function. VC is a strong predicator of cardiovascular mortality among patients with CKD. Elevated phosphorus levels and increased calcium-phosphorus product promote VC. Controlling mineral disturbances such as hyperphosphatemia and SHPT is still considered among the current strategies for treatment of VC in CKD through restriction of calcium based phosphate binders in hyperphosphatemic patients across all severities of CKD along with dietary phosphate restriction and use of calciminetics. Additionally, Vitamin D insufficiency is common in CKD and dialysis patients. The causes are multifactorial and a serious consequence is SHPT. Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD. Vitamin D may also have atheroprotective effects on the arterial wall, but clinical studies do not show clear evidence of reduced cardiovascular mortality with vitamin D administration. This review discusses the issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment.
PMID: 30253289
ISSN: 1879-1484
CID: 3534982

High Prevalence of Renal Salt Wasting Without Cerebral Disease as Cause of Hyponatremia in General Medical Wards

Maesaka, John K; Imbriano, Louis J; Miyawaki, Nobuyuki
BACKGROUND:The approach to hyponatremia is in a state of flux, especially in differentiating syndrome of inappropriate antidiuretic hormone secretion (SIADH) from cerebral-renal salt wasting (RSW) because of diametrically opposite therapeutic goals. Considering RSW can occur without cerebral disease, we determined the prevalence of RSW in the general hospital wards. METHODS:To differentiate SIADH from RSW, we used an algorithm based on fractional excretion (FE) of urate and nonresponse to saline infusions in SIADH as compared to excretion of dilute urines and prompt increase in serum sodium in RSW. RESULTS:Of 62 hyponatremic patients, (A) 17 patients (27%) had SIADH, 11 were nonresponsive to isotonic saline, and 5 normalized a previously high FEurate after correction of hyponatremia; (B) 19 patients (31%) had a reset osmostat based on normal FEurates and spontaneously excreted dilute urines; (C) 24 patients (38%) had RSW, 21 had no clinical evidence of cerebral disease, 19 had saline-induced dilute urines; 2 had undetectable plasma ADH levels when urine was dilute, 10 required 5% dextrose in water to prevent rapid increase in serum sodium, 11 had persistently increased FEurate after correction of hyponatremia and 10 had baseline urinary sodium < 20 mEq/L; (D) 1 patient had Addison disease with a low FEurate and (E) 1 patient (1.6%) had hyponatremia due to hydrochlorothiazide. CONCLUSIONS:Of the 24 patients with RSW, 21 had no cerebral disease, supporting our proposal to change cerebral-renal salt wasting to renal salt wasting. Application of established pathophysiological standards and a new algorithm based on determination of FEurate were superior to the volume approach for determination of urinary sodium when identifying the cause of hyponatremia.
PMID: 30049325
ISSN: 1538-2990
CID: 3464612

Determining Fractional Urate Excretion Rates in Hyponatremic Conditions and Improved Methods to Distinguish Cerebral/Renal Salt Wasting From the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Maesaka, John K; Imbriano, Louis J; Miyawaki, Nobuyuki
Our evaluation of hyponatremic patients is in a state of confusion because the assessment of the volume status of the patient and determinations of urine sodium concentrations (UNa) >30-40 mEq/L have dominated our approach despite documented evidence of many shortcomings. Central to this confusion is our inability to differentiate cerebral/renal salt wasting (C/RSW) from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), syndromes with diametrically opposing therapeutic goals. The recent proposal to treat most or all hyponatremic patients makes differentiation even more important and reports of C/RSW occurring without cerebral disease leads to a clinically important proposal to change cerebral to renal salt wasting (RSW). Differentiating SIADH from RSW is difficult because of identical clinical parameters that characterize both syndromes. Determination of fractional urate excretion (FEurate) is central to a new algorithm, which has proven to be superior to current methods. We utilized this algorithm and differences in physiologic response to isotonic saline infusions between SIADH and RSW to evaluate hyponatremic patients from the general medical wards of the hospital. In 62 hyponatremic patients, 17 (27%) had SIADH, 19 (31%) had reset osmostat (RO), 24 (38%) had RSW, 1 due to HCTZ and 1 Addison's disease. Interestingly, 21 of 24 with RSW had no evidence of cerebral disease and 10 of 24 with RSW had UNa < 20 mEqL. We conclude that 1. RSW is much more common than is perceived, 2.the term cerebral salt wasting should be changed to RSW 3. RO should be eliminated as a subclass of SIADH, 4. SIADH should be redefined 5. The volume approach is ineffective and 6. There are limitations to determining UNa, plasma renin, aldosterone or atrial/brain natriuretic peptides. We also present data on a natriuretic peptide found in sera of patients with RSW and Alzheimer's disease.
PMCID:6284366
PMID: 30560127
ISSN: 2296-858x
CID: 3679612

Application of established pathophysiologic processes brings greater clarity to diagnosis and treatment of hyponatremia [Editorial]

Maesaka, John K; Imbriano, Louis J; Miyawaki, Nobuyuki
Hyponatremia, serum sodium < 135 mEq/L, is the most common electrolyte abnormality and is in a state of flux. Hyponatremic patients are symptomatic and should be treated but our inability to consistently determine the causes of hyponatremia has hampered the delivery of appropriate therapy. This is especially applicable to differentiating syndrome of inappropriate antidiuresis (SIAD) from cerebral salt wasting (CSW) or more appropriately, renal salt wasting (RSW), because of divergent therapeutic goals, to water-restrict in SIAD and administer salt and water in RSW. Differentiating SIAD from RSW is extremely difficult because of identical clinical parameters that define both syndromes and the mindset that CSW occurs rarely. It is thus insufficient to make the diagnosis of SIAD simply because it meets the defined characteristics. We review the pathophysiology of SIAD and RSW, the evolution of an algorithm that is based on determinations of fractional excretion of urate and distinctive responses to saline infusions to differentiate SIAD from RSW. This algorithm also simplifies the diagnosis of hyponatremic patients due to Addison's disease, reset osmostat and prerenal states. It is a common perception that we cannot accurately assess the volume status of a patient by clinical criteria. Our algorithm eliminates the need to determine the volume status with the realization that too many factors affect plasma renin, aldosterone, atrial/brain natriuretic peptide or urine sodium concentration to be useful. Reports and increasing recognition of RSW occurring in patients without evidence of cerebral disease should thus elicit the need to consider RSW in a broader group of patients and to question any diagnosis of SIAD. Based on the accumulation of supporting data, we make the clinically important proposal to change CSW to RSW, to eliminate reset osmostat as type C SIAD and stress the need for a new definition of SIAD.
PMID: 28316939
ISSN: 2220-6124
CID: 3464722

NOVEL INSIGHT INTO IMPAIRED CHOLESTEROL TRANSPORT IN CHRONIC KIDNEY DISEASE: DEMONSTRATION OF REVERSIBILITY WITH VITAMIN D AND ACE-INHIBITOR [Meeting Abstract]

Daccueil, Farah; Siegart, Nicolle M; Reiss, Allison B; Renna, Heather A; Arain, Hirra A; Kasselman, Lora J; Mattana, Joseph; De Leon, Joshua; Miyawaki, Nobuyuki
ISI:000399374600015
ISSN: 1708-8267
CID: 2678002

Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges

Shirazian, Shayan; Aina, Olufemi; Park, Youngjun; Chowdhury, Nawsheen; Leger, Kathleen; Hou, Linle; Miyawaki, Nobuyuki; Mathur, Vandana S
Chronic kidney disease-associated pruritus (CKD-aP) is a distressing, often overlooked condition in patients with CKD and end-stage renal disease. It affects ~40% of patients with end-stage renal disease and has been associated with poor quality of life, poor sleep, depression, and mortality. Prevalence estimates vary based on the instruments used to diagnose CKD-aP, and standardized diagnostic instruments are sorely needed. Treatment studies have often yielded conflicting results. This is likely related to studies that are limited by small sample size, flawed designs, and nonstandardized diagnostic instruments. Several large well-designed treatment trials have recently been completed and may soon influence CKD-aP management.
PMCID:5271405
PMID: 28176969
ISSN: 1178-7058
CID: 3534972

Cholesterol Metabolism in CKD

Reiss, Allison B; Voloshyna, Iryna; De Leon, Joshua; Miyawaki, Nobuyuki; Mattana, Joseph
Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.
PMCID:4658227
PMID: 26337134
ISSN: 1523-6838
CID: 2677482

Prostaglandin D2 synthase: Apoptotic factor in alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines and dialysis dementia

Maesaka, John K; Sodam, Bali; Palaia, Thomas; Ragolia, Louis; Batuman, Vecihi; Miyawaki, Nobuyuki; Shastry, Shubha; Youmans, Steven; El-Sabban, Marwan
BACKGROUND:Apoptosis, reactive oxygen species (ROS) and inflammatory cytokines have all been implicated in the development of Alzheimer's disease (AD). OBJECTIVES/OBJECTIVE:The present study identifies the apoptotic factor that was responsible for the fourfold increase in apoptotic rates that we previously noted when pig proximal tubule, LLC-PK1, cells were exposed to AD plasma as compared to plasma from normal controls and multi-infarct dementia. PATIENTS AND METHODS/METHODS:The apoptotic factor was isolated from AD urine and identified as lipocalin-type prostaglandin D2 synthase (L-PGDS). L-PGDS was found to be the major apoptotic factor in AD plasma as determined by inhibition of apoptosis approximating control levels by the cyclo-oxygenase (COX) 2 inhibitor, NS398, and the antibody to L-PGDS. Blood levels of L-PGDS, however, were not elevated in AD. We now demonstrate a receptor-mediated uptake of L-PGDS in PC12 neuronal cells that was time, dose and temperature-dependent and was saturable by competition with cold L-PGDS and albumin. Further proof of this endocytosis was provided by an electron microscopic study of gold labeled L-PGDS and immunofluorescence with Alexa-labeled L-PGDS. RESULTS:The recombinant L-PGDS and wild type (WT) L-PGDS increased ROS but only the WTL-PGDS increased IL6 and TNFα, suggesting that differences in glycosylation of L-PGDS in AD was responsible for this discrepancy. CONCLUSIONS:These data collectively suggest that L-PGDS might play an important role in the development of dementia in patients on dialysis and of AD.
PMID: 24475446
ISSN: 2251-8363
CID: 3464702