scholarly journals Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

2021 ◽  
pp. ASN.2020111587
Author(s):  
Karl P. Schlingmann ◽  
Aparna Renigunta ◽  
Ewout J. Hoorn ◽  
Anna-Lena Forst ◽  
Vijay Renigunta ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Genetic Defect ◽  
Sensorineural Deafness ◽  
Transport Systems ◽  
Candidate Gene Approach ◽  
Disease Phenotype ◽  
Acid Base ◽  
Salt Wasting ◽  
Renal Salt Wasting ◽  
Hypokalemic Alkalosis

BackgroundThe transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.MethodsA candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.ResultsWe identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents.ConclusionsBiallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.

Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2

2001 ◽  
Vol 281 (4) ◽  
pp. F718-F727 ◽  
Author(s):  
Clara Ledoussal ◽  
John N. Lorenz ◽  
Michelle L. Nieman ◽  
Manoocher Soleimani ◽  
Patrick J. Schultheis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Hypovolemic Shock ◽  
Fractional Excretion ◽  
Fluid Volume ◽  
Restricted Diet ◽  
Metabolic Disturbances ◽  
Acid Base ◽  
Salt Wasting ◽  
Renal Salt Wasting

To study the role of Na+/H+ exchanger isoform 2 (NHE2) and isoform 3 (NHE3) in sodium-fluid volume homeostasis and renal Na+ conservation, mice with Nhe2( Nhe2 −/−) and/or Nhe3( Nhe3 −/−) null mutations were fed a Na+-restricted diet, and urinary Na+ excretion, blood pressure, systemic acid-base and electrolyte status, and renal function were analyzed. Na+-restricted Nhe2 −/− mice, on either a wild-type or Nhe3 heterozygous mutant ( Nhe3 +/−) background, did not exhibit excess urinary Na+ excretion. After 15 days of Na+ restriction, blood pressure, fractional excretion of Na+, and the glomerular filtration rate (GFR) of Nhe2 −/− Nhe3 +/− mice were similar to those of Nhe2 +/+ and Nhe3 +/− mice, and no metabolic disturbances were observed. Nhe3 −/− mice maintained on a Na+-restricted diet for 3 days exhibited hyperkalemia, urinary salt wasting, acidosis, sharply reduced blood pressure and GFR, and evidence of hypovolemic shock. These results negate the hypothesis that NHE2 plays an important renal function in sodium-fluid volume homeostasis; however, they demonstrate that NHE3 is critical for systemic electrolyte, acid-base, and fluid volume homeostasis during dietary Na+ restriction and that its absence leads to renal salt wasting.

Chloride transport by the cortical and outer medullary collecting duct

1987 ◽  
Vol 253 (2) ◽  
pp. F203-F212 ◽  
Author(s):  
V. L. Schuster ◽  
J. B. Stokes
Keyword(s):  
Chloride Transport ◽  
Collecting Duct ◽  
Exchange Process ◽  
Basolateral Membrane ◽  
Fine Tuning ◽  
Transport Systems ◽  
Acid Base ◽  
Intercalated Cell ◽  
Cl Channel ◽  
Collecting Tubule

The processes by which chloride is transported by the cortical and outer medullary collecting tubule have been most extensively studied using in vitro microperfusion of rabbit tubules. Chloride appears to be transported by three major mechanisms. First, Cl can be actively reabsorbed by an electroneutral Cl-HCO3 exchanger localized to the apical membrane of the HCO3-secreting (beta-type) intercalated cell. Cl exits this cell via a basolateral Cl channel. This anion exchange process can also operate in a Cl self-exchange mode, is stimulated acutely by beta-adrenergic agonists and cAMP, and is regulated chronically by in vivo acid-base status. Second, Cl can diffuse passively down electrochemical gradients via the paracellular pathway. Although this pathway does not appear to be selectively permeable to Cl, it is large enough to allow for significant passive reabsorption. Third, Cl undergoes recycling across the basolateral membrane of the H+-secreting (alpha-type) intercalated cell. HCO3 exit from this cell brings Cl into the cell via electroneutral Cl-HCO3 exchange; Cl then exits the cell via a Cl channel. Cl transport is thus required for acidification and alkalinization of the urine. Both of these processes exist in the cortical collecting tubule. Their simultaneous operation allows fine tuning of acid-base excretion. In addition, these transport systems, when functioning at equal rates, effect apparent electrogenic net Cl absorption without changing net HCO3 transport. These systems may play an important role in regulating Cl balance.

scholarly journals 5-Azacytidine and renal tubular dysfunction

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 182-185 ◽  
Author(s):  
BA Peterson ◽  
AJ Collins ◽  
NJ Vogelzang ◽  
CD Bloomfield
Keyword(s):  
Renal Toxicity ◽  
Tubular Damage ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Normal Range ◽  
Acid Base ◽  
Salt Wasting ◽  
Renal Tubular ◽  
Renal Abnormalities ◽  
Electrolyte Abnormalities

Abstract During initial trials of 5-azacytidine in adults with advanced acute leukemia, we unexpectedly observed acid-base, fluid, and electrolyte abnormalities that contributed directly to the deaths of two early patients. To evaluate this toxicity further, we studied 22 patients who received a total of 33 courses of combination chemotherapy that included 5-azacytidine. During 29 courses (88%) of treatment, polyuria, glucosuria, and/or transient changes in the serum concentrations of bicarbonate or phosphorus were detected. Spontaneous polyuria with demonstrable salt wasting and orthostatic hypotension occurred during seven courses (21%) of treatment. Inappropriate glucosuria was observed in nine courses (27%). In 24 courses (73%) the serum bicarbonate fell below the normal range. The urine became alkaline during 12 of these instances; the anion gap was not increased during the acidosis. Hypophosphatemia with serum phosphorus concentrations as low as 0.3 mg/dl occurred in 21 of 32 evaluable courses (66%). In the three patients studied the tubular reabsorption of phosphorus was 10%-18%. The renal abnormalities that were observed suggest both proximal and distal tubular damage from 5-azacytidine. Patients receiving 5- azacytidine should be monitored closely for manifestations of renal toxicity.

Identification of a novel natriuretic protein in patients with cerebral-renal salt wasting - implications for enhanced diagnosis

2020 ◽  
Author(s):  
John K. Maesaka ◽  
Louis J. Imbriano ◽  
Aaron Pinkhasov ◽  
Rajanandini Muralidharan ◽  
Xiaomin Song ◽  
...  
Keyword(s):  
Salt Wasting ◽  
Renal Salt Wasting

Renal Salt-Wasting Increases Vasopressin Excretion in Preterm Infants

2015 ◽  
pp. 179-184
Author(s):  
Branislav Lichardus ◽  
Endre Sulyok ◽  
L�szl� Kov�cs ◽  
Nikolaj Michajlovskij ◽  
Veronika Lehotsk� ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Salt Wasting ◽  
Renal Salt Wasting
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