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John K. Maesaka - One of the best experts on this subject based on the ideXlab platform.
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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
Frontiers of Medicine in China, 2018Co-Authors: John K. Maesaka, Louis J. Imbriano, Nobuyuki MiyawakiAbstract: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.
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high prevalence of renal Salt Wasting without cerebral disease as cause of hyponatremia in general medical wards
The American Journal of the Medical Sciences, 2018Co-Authors: John K. Maesaka, Louis J. Imbriano, Nobuyuki MiyawakiAbstract:Abstract 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 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.
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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
Frontiers Media S.A., 2018Co-Authors: John K. Maesaka, Louis J. Imbriano, Nobuyuki MiyawakiAbstract: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
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More on Renal Salt Wasting Without Cerebral Disease: Response to Saline Infusion
2015Co-Authors: Solomon Bitew, Steven Fishbane, Louis J. Imbriano, Nobuyuki Miyawaki, John K. MaesakaAbstract:Background and objectives: The existence and prevalence of cerebral Salt Wasting (CSW) or the preferred term, renal Salt Wasting (RSW), and its differentiation from syndrome of inappropriate antidiuretic hormone (SIADH) have been controver-sial. This controversy stems from overlapping clinical and laboratory findings and an inability to assess the volume status of these patients. The authors report another case of RSW without clinical cerebral disease and contrast it to SIADH. Design, setting, participants, & measurements: Three patients with hyponatremia, hypouricemia, increased fractional excretion (FE) of urate, urine sodium>20 mmol/L, and concentrated urines were infused with isotonic saline after collection of baseline data. Results: One patient with RSW had pneumonia without cerebral disease and showed increased plasma aldosterone and FEphosphate, and two patients with SIADH had increased blood volume, low plasma renin and aldosterone, and normal FEphosphate. The patient with RSW responded to isotonic saline by excretion of dilute urines, prompt correction of hyponatremia, and normal water loading test after volume repletion. Hypouricemia and increased FEurate persisted after correction of hyponatremia. Two patients with SIADH failed to dilute their urines and remained hyponatremic during 48 and 110 h of saline infusion. Conclusions: The authors demonstrate appropriate stimulation of ADH in RSW. Differences in plasma renin and aldosterone levels and FEphosphate can differentiate RSW from SIADH, as will persistent hypouricemia and increased FEurate after correctio
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Differentiating SIADH from Cerebral/Renal Salt Wasting: Failure of the Volume Approach and Need for a New Approach to Hyponatremia.
Journal of Clinical Medicine, 2014Co-Authors: John K. Maesaka, Louis J. Imbriano, Naveen Bade, Dympna Gallagher, Joseph Mattana, Sairah SharifAbstract:Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to treat virtually all hyponatremics exposes the need to resolve the diagnostic and therapeutic dilemma of deciding whether to water restrict a patient with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or administer Salt and water to a renal Salt waster. In this review, we briefly discuss the pathophysiology of SIADH and renal Salt Wasting (RSW), and the difficulty in differentiating SIADH from RSW, and review the origin of the perceived rarity of RSW, as well as the value of determining fractional excretion of urate (FEurate) in differentiating both syndromes, the high prevalence of RSW which highlights the inadequacy of the volume approach to hyponatremia, the importance of changing cerebral Salt Wasting to RSW, and the proposal to eliminate reset osmostat as a subtype of SIADH, and finally propose a new algorithm to replace the outmoded volume approach by highlighting FEurate. This algorithm eliminates the need to assess the volume status with less reliance on determining urine sodium concentration, plasma renin, aldosterone and atrial/brain natriuretic peptide or the BUN to creatinine ratio.
Manoocher Soleimani - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin e2 mediated increase in calcium and phosphate excretion in a mouse model of distal nephron Salt Wasting
PLOS ONE, 2016Co-Authors: Manoocher Soleimani, Sharon Barone, Saeed Alshahrani, Marybeth Brooks, Francis X Mccormack, Roger D Smith, Kamyar ZahediAbstract:Contribution of Salt Wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe Salt Wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high Salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and Salt Wasting in pendrin/NCC dKO mice. Both high Salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe Salt Wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of Salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
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double knockout of carbonic anhydrase ii caii and na cl cotransporter ncc causes Salt Wasting and volume depletion
Cellular Physiology and Biochemistry, 2013Co-Authors: Sharon Barone, Marybeth Brooks, Manoocher SoleimaniAbstract:Background and Aims: The thiazide-sensitive Na+-Cl- cotransporter NCC and the Cl-/HCO3-exchanger pendrin are expressed on apical membranes of distal cortical nephron segments and mediate Salt absorption, with pendrin working in tandem with the epithelial Na+ channel (ENaC) and the Na+-dependent chloride/bicarbonate exchanger (NDCBE), whereas NCC is working by itself. A recent study showed that NCC and pendrin compensate for loss of each other under basal conditions, therefore masking the role that each plays in Salt reabsorption. Carbonic anhydrase II (CAII, CA2 or CAR2) plays an important role in acid-base transport and Salt reabsorption in the proximal convoluted tubule and acid-base transport in the collecting duct. Animals with CAII deletion show remodeling of intercalated cells along with the downregulation of pendrin. NCC KO mice on the other hand show significant upregulation of pendrin and ENaC. Neither model shows any significant Salt Wasting under baseline conditions. We hypothesized that the up-regulation of pendrin is essential for the prevention of Salt Wasting in NCC KO mice. Methods and Results: To test this hypothesis, we generated NCC/CAII double KO (dKO) mice by crossing mice with single deletion of NCC and CAII. The NCC/CAII dKO mice displayed significant downregulation of pendrin, along with polyuria and Salt Wasting. As a result, the dKO mice developed volume depletion, which was associated with the inability to concentrate urine. Conclusions: We conclude that the upregulation of pendrin is essential for the prevention of Salt and water Wasting in NCC deficient animals and its downregulation or inactivation will result in Salt Wasting, impaired water conservation and volume depletion in the setting of NCC inactivation or inhibition.
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double knockout of pendrin and na cl cotransporter ncc causes severe Salt Wasting volume depletion and renal failure
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Gary E Shull, Faraz Siddiqui, Hassane AmlalAbstract:The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause Salt Wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during Salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in Salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe Salt Wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with Salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.
Jean Louis Vincent - One of the best experts on this subject based on the ideXlab platform.
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hyponatremia in neurological patients cerebral Salt Wasting versus inappropriate antidiuretic hormone secretion
Intensive Care Medicine, 2008Co-Authors: Serge Brimioulle, Carlos Orellanajimenez, Adel Aminian, Jean Louis VincentAbstract:Objective To assess whether hyponatremia in acute neurological patients is associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or with the cerebral Salt-Wasting syndrome (CSWS).
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hyponatremia in neurological patients cerebral Salt Wasting versus inappropriate antidiuretic hormone secretion
Intensive Care Medicine, 2008Co-Authors: Serge Brimioulle, Carlos Orellanajimenez, Adel Aminian, Jean Louis VincentAbstract:To assess whether hyponatremia in acute neurological patients is associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or with the cerebral Salt-Wasting syndrome (CSWS). Clinical, controlled, prospective study. Department of intensive care of a tertiary care academic hospital. Forty acute neurological patients with hyponatremia suggesting SIADH or CSWS (20) or with normonatremia (20). None. Measurement of clinical and biological variables. Measurement of blood, plasma, and red blood cell volumes to discriminate SIADH and CSWS. Renal, adrenal and thyroid functions were normal in all patients. Average blood, plasma, and red blood cell volumes were 54, 37 and 17 ml/kg in control patients and 54, 37 and 18 ml/kg in hyponatremic patients, respectively. The adequate blood volumes in hyponatremic patients confirm the diagnosis of SIADH and do not support the concept of CSWS.
Kamyar Zahedi - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin e2 mediated increase in calcium and phosphate excretion in a mouse model of distal nephron Salt Wasting
PLOS ONE, 2016Co-Authors: Manoocher Soleimani, Sharon Barone, Saeed Alshahrani, Marybeth Brooks, Francis X Mccormack, Roger D Smith, Kamyar ZahediAbstract:Contribution of Salt Wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe Salt Wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high Salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and Salt Wasting in pendrin/NCC dKO mice. Both high Salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe Salt Wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of Salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
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double knockout of pendrin and na cl cotransporter ncc causes severe Salt Wasting volume depletion and renal failure
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Gary E Shull, Faraz Siddiqui, Hassane AmlalAbstract:The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause Salt Wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during Salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in Salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe Salt Wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with Salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.
Sharon Barone - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin e2 mediated increase in calcium and phosphate excretion in a mouse model of distal nephron Salt Wasting
PLOS ONE, 2016Co-Authors: Manoocher Soleimani, Sharon Barone, Saeed Alshahrani, Marybeth Brooks, Francis X Mccormack, Roger D Smith, Kamyar ZahediAbstract:Contribution of Salt Wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe Salt Wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high Salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and Salt Wasting in pendrin/NCC dKO mice. Both high Salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe Salt Wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of Salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
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double knockout of carbonic anhydrase ii caii and na cl cotransporter ncc causes Salt Wasting and volume depletion
Cellular Physiology and Biochemistry, 2013Co-Authors: Sharon Barone, Marybeth Brooks, Manoocher SoleimaniAbstract:Background and Aims: The thiazide-sensitive Na+-Cl- cotransporter NCC and the Cl-/HCO3-exchanger pendrin are expressed on apical membranes of distal cortical nephron segments and mediate Salt absorption, with pendrin working in tandem with the epithelial Na+ channel (ENaC) and the Na+-dependent chloride/bicarbonate exchanger (NDCBE), whereas NCC is working by itself. A recent study showed that NCC and pendrin compensate for loss of each other under basal conditions, therefore masking the role that each plays in Salt reabsorption. Carbonic anhydrase II (CAII, CA2 or CAR2) plays an important role in acid-base transport and Salt reabsorption in the proximal convoluted tubule and acid-base transport in the collecting duct. Animals with CAII deletion show remodeling of intercalated cells along with the downregulation of pendrin. NCC KO mice on the other hand show significant upregulation of pendrin and ENaC. Neither model shows any significant Salt Wasting under baseline conditions. We hypothesized that the up-regulation of pendrin is essential for the prevention of Salt Wasting in NCC KO mice. Methods and Results: To test this hypothesis, we generated NCC/CAII double KO (dKO) mice by crossing mice with single deletion of NCC and CAII. The NCC/CAII dKO mice displayed significant downregulation of pendrin, along with polyuria and Salt Wasting. As a result, the dKO mice developed volume depletion, which was associated with the inability to concentrate urine. Conclusions: We conclude that the upregulation of pendrin is essential for the prevention of Salt and water Wasting in NCC deficient animals and its downregulation or inactivation will result in Salt Wasting, impaired water conservation and volume depletion in the setting of NCC inactivation or inhibition.
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double knockout of pendrin and na cl cotransporter ncc causes severe Salt Wasting volume depletion and renal failure
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Gary E Shull, Faraz Siddiqui, Hassane AmlalAbstract:The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause Salt Wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during Salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in Salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe Salt Wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with Salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.
