Pharmacologic effects and clinical evaluation of Tenapanor, a new drug for hyperphosphatemia / 中国临床药理学与治疗学

Tenapanor is a novel phosphorus-lowering drug, which mainly inhibits sodium/hydrogen exchange protein 3 (NHE3), and also reduces intestinal phosphorus absorption by down-regulating the expression of sodium phosphate co-transporter protein (NAPI). Tenapanor is mainly used for the treatment of hyperphosphatemia in patients with end-stage renal disease-hemodialysis (ESRD-HD). Diarrhea is the most common adverse reaction to this product. This article reviews Tenapanor by performing a literature search on its pharmacological effects, pharmacokinetic properties, clinical evaluation, safety, drug interactions and dosage.

Renal Tubular Acidosis

Renal tubular acidosis (RTA) is a metabolic acidosis due to impaired excretion of hydrogen ion, or reabsorption of bicarbonate, or both by the kidney. These renal tubular abnormalities can occur as an inherited disease or can result from other disorders or toxins that affect the renal tubules. Disorders of bicarbonate reclamation by the proximal tubule are classified as proximal RTA, whereas disorders resulting from a primary defect in distal tubular net hydrogen secretion or from a reduced buffer trapping in the tubular lumen are called distal RTA. Hyperkalemic RTA may occur as a result of aldosterone deficiency or tubular insensitivity to its effects. The clinical classification of renal tubular acidosis has been correlated with our current physiological model of how the nephron excretes acid, and this has facilitated genetic studies that have identified mutations in several genes encoding acid and base ion transporters. Growth retardation is a consistent feature of RTA in infants. Identification and correction of acidosis are important in preventing symptoms and guide approved genetic counseling and testing.

Increased Expression of Sodium Transporters in Rats Chronically Inhibited of Nitric Oxide Synthesis

The present study was done to determine whether endogenous nitric oxide (NO) plays a role in the regulation of sodium transporters in the kidney. Male Sprague-Dawley rats were treated with NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/L drinking water) for 4 weeks. Control rats were supplied with tap water without drugs. Expression of Na, K-ATPase, type 3 Na/H exchanger (NHE3), Na/K/2Cl cotransporter (BSC1), and thiazide-sensitive Na/Cl cotransporter (TSC) proteins was determined in the kidney by Western blot analysis. Catalytic activity of Na,K-ATPase was also determined. The treatment with L-NAME significantly and steadily increased the systemic blood pressure. Total and fractional excretion of urinary sodium decreased significantly, while creatinine clearance remained unaltered. Neither plasma renin activity nor aldosterone concentration was significantly altered. The alpha1 subunit expression and the catalytic activity of Na, K-ATPase were increased in the kidney. The expression of NHE3, BSC1 and TSC was also increased significantly. These results suggest that endogenously-derived NO exerts a tonic inhibitory effect on the expression of sodium transporters, including Na, K-ATPase, NHE3, BSC1, and TSC, in the kidney.

Adaptive Responses to Dexamethasone Treatment in Rat Kidney Proximal Tubules / 대한해부학회지

Excess accumulation of glucocorticoid increases acid secretion and HCO3- reabsorption in the kidney. Reabsorption of HCO3-, which almost occurs at the proximal tubule, is mediated Na+ / H+ exchanger-3 (NHE-3) and H+ -ATPase on the apical membrane and the Na + /HCO3- cotransporter-1 (NBC-1)on the basolateral membrane. Impact of glucocorticoid was investigated by immunohistochemistry and electron microscopy to correlate the changes with the effect of in vivo dexamethasone treatment for the rat kidney proximal tubule. In a control group, immunoreactivity of NHE-3 was detected in the apical membrane and the brush borders of S1, S2 and 3 segments of the proximal tubule. Immunoreactivity of NBC-1 was detected in the basolateral membrane of S1 and S2 segments of the proximal tubule. Immunoreactivity of NHE-3 and NBC-1 protein was more pronounced in dexamethasone treated groups than the control group. Dexamethasone 1 mg/kg caused most intense immunoreactivity for NHE-3 and NBC-1 protein, however, 0.01 mg/kg and 0.1 mg/kg produced less intense immunoreactivity with no appreciable differences between these lower doses of dexamethasone groups. By electron microscopy, the tubular cells of S1 segment of the control group revealed numerous mitochondria, endocytic apparatuses, lysosomes and many basal cytoplasmic processes. In dexamethasone treated groups, the cells of S1 and S2 segments of the proximal tubule had more mitochodria and more basolateral invaginations and had an increased number of more elongated microvilli, compared with the control group. The cells of the S3 segment of the control group showed scant lateral interdigitations and had a few smaller mitochondria. The cells of the S3 segment of dexamethasone treated groups had many mitochodria and an increased number of microvilli in the brush border, but revealed no difference of basolateral invaginations among the different groups of dexamethasone. These results indicate that prolonged administration of excess glucocorticoid increases NHE-3 and NBC-1 protein, and the up-regulation of these proteins could result in increased HCO3 - reabsorption in the rat renal proximal tubules. It also suggests that these adaptive responses closely correlate to morphological alterations of proximal tubular epithelial cells.

Regulations of Bicarbonate Ions in Hypokalemic Rat Kidney / 대한해부학회지

A number of acid-base or electrolyte disorders are associated with decreased or increased HCO3- reabsorption in the renal tubules. There has been a general agreement that potassium depletion induces and maintains metabolic alkalosis in rats. However, many researchers have approached such issue only from functional studies to investigate Na+/H+ exchanger (NHE-3) and Na+/HCO(3-) cotransporter (NBC) activity which closely relates to potassium depletion. In addition the results obtained vary according to their researchers. Thus the present study was employed Western blot analysis and immunohistochemistry together, to examine the alterations of expression and distribution of NHE-3 and NBC-1 with reference to HCO3- reabsorption in the kidneys of rats fed potassium free diets according to the periods. Western blot analysis demonstrated that NHE-3 protein, ~83 kDa at molecular mass, was abundantly expressed in normal group. All potassium-depleted groups showed significantly increased NHE-3 protein compared to normal group. NBC-1 protein, ~110 kDa at molecular mass, was moderately expressed in normal group. All potassium-depleted groups had much higher amounts of the protein than normal group. There was a highly increased amount of NBC-1 protein especially in K-depleted 1 week group. Immunohistochemistry showed positive immunoreactivity of NHE-3 in the apical membranes and brush borders of proximal renal tubule cells. Its reactivity was most prominent in the S3.S1 and S2 had moderate immunoreactivity. Potassium-depleted groups had an identical pattern of cellular labeling of NHE-3 protein compared with that of normal group. However the signal intensity of NHE-3 protein in potassium-depleted groups was much higher than that of normal group. Immunoreactivity of NBC-1 was observed exclusively in the basolateral plasma membranes of proximal tubule cells. There was a strong reactivity in the S1 and S2, whereas S3 did not show any reactivity. Potassium-deprived rats exhibited an identical pattern of cellular labeling of NBC-1 protein compared with that of normal rats. However, the signal intensity of NBC-1 protein was markedly increased in potassium-deprived rats. These results suggest that increased NHE-3 and NBC-1 expression resulted from potassium depletion in the renal proximal tubules, enhances HCO3-reabsorption and consequently maintains metabolic alkalosis.

Expression of H(+)-ATPase in Inner Medullary Collecting Duct Cells of Aquaporin-3-Deficient Mice / 대한해부학회지

It has been reported that the decrease in urinary pH observed in AQP1 null mice with a urinary concentrating defect is due to upregulation of H(+)-ATPase in the IMCD. This is thought to be caused by the chronically low interstitial osmolality in these animals. To explore whether increase of H(+)-ATPase expression in the IMCD is associated with changes in the prolonged decrease of interstitial osmolality, we examined the expression of H(+)-ATPase and Na(+)-H(+) exchanger (NHE3) using light and electron microscopic immunocytochemistry in the kidneys of AQP3 null mice which are polyuric and manifest a urinary concentrating defect because of an inability to create a hypertonic medullary interstitium. In both AQP3 (-/-) and AQP1 (-/-) mouse kidneys, type A intercalated cells in cortical and medullary collecting ducts are slightly activated, and strong H(+)-ATPase immunostaining was present in the apical plasma membrane of IMCD cells, whereas no H(+)-ATPase labeling was observed in IMCD cells in wild type mice. No differences of the immunoreactivity for NHE3 in the proximal tubule and thick ascending limb of loop of Henle were observed between AQP3 or AQP1 (-/-) mice and AQP3 (+/+) mouse. These results suggest that the induction of H(+)-ATPase expression in IMCD cells of AQP3 null mice, as well as AQP1 null mice, may be related to their chronically low interstitial osmolality.

Altered Expression of Renal AQP1, AQP2 and NHE3 in Puromycin Aminonucleoside Induced Nephrotic Syndrome: Intervention by Alpha-MSH Treatment / 대한신장학회잡지

BACKGROUND: We examined whether puromycin aminonucleoside (PAN)-induced nephrotic syndrome (NS) is associated with altered renal handling of water and sodium along with changes of renal abundance of aquaporins (AQP1 and AQP2) and NHE3. Next we tested the effects of alpha-melanocyte stimulating hormone (alpha- MSH), a potent anti-inflammatory drug, on the PAN-induced renal functional derangement and the changes of renal AQPs and NHE3 abundance. METHODS: PAN was administered to Sprague-Dawley rats using two protocols: protocol 1 (180 mg/kg, single iv injection) and protocol 2 (100 mg/kg, single iv injection). RESULTS: In both protocols, PAN-induced NS was associated with decreased urine concentration, manifested by an increased urine output and decreased urine osmolality and TcH2O. Consistent with this, a marked downregulation of vasopressin-regulated collecting duct AQP2 expression was seen in PAN-induced NS. In protocol 2 where rats treated with moderate dose of PAN, alpha-MSH cotreatment prevented the reduction of urine osmolality and the increase of the FENa in the PAN-induced NS. This suggests that alpha-MSH may have protective effects against the renal functional deterioration induced by PAN. The renal abundance of the AQP1, AQP2 and NHE3 was reduced in PAN-induced NS in protocol 2, as seen in protocol 1. In contrast to the functional improvement, alpha-MSH cotreatment had marginal effects in the prevention of renal AQP1, AQP2 and NHE3 downregulation in PAN-induced NS. CONCLUSION: PAN-induced NS was associated with decreased urine concentration along with reduced renal AQP2, AQP1 and NHE3 abundance. Alpha-MSH may have protective effects against the renal functional deterioration (e.g., urine osmolality and FENa). However, alpha-MSH treatment alone is less likely to prevent the marked reduction of AQP2, AQP1 and NHE3 abundance in PAN-induced NS, in contrast to the previously known dramatic effects against the ischemia-reperfusion injury in kidney and small intestine.

Changes of Urinary Acidification and Collecting Duct H(+)-ATPase Abundance in Response to Chronic Diuretic Administration / 대한신장학회잡지

PURPOSE: Commonly used diuretics such as furosemide and hydrochlorothiazide may cause metabolic alkalosis by increasing proton secretion from distal nephron. We evaluated changes in urinary acidification and abundance of proton-secreting transporters in response to chronic subcutaneous infusion of diuretics. METHODS: Osmotic minipumps were implanted into Sprague-Dawley rats to deliver 12 mg/day furoemide or hydrochlorothiazide 7.5 mg/day for 7 days. All animals were offered tap water and a solution containing 0.8% NaCl and 0.1% KCl as drinking fluid. RESULTS: Compared with vehicle-infused controls, diuretic and natriuretic responses were evident from furosemide or hydrochlorothiazide infusion. However, there were no changes in body weight, serum aldosterone and creatinine clearance between diuretic- infused(n=6) and control(n=6) rats. In both furosemide-infused and hydrochlorothiazide-infused rats, urine pH was significantly lowered compared with controls. Furosemide-infused rats showed significantly larger excretion of urinary ammonium. Semiquantitative immunoblotting was carried out from rat kidneys to investigate abundance of proximal tubule or medullary thick ascending limb Na(+)/H(+) exchanger type 3(NHE3) and collecting duct H(+)- ATPase using specific polyclonal antibodies to NHE3 and H(+)-ATPase B1 subunit, respectively. The abundance of NHE3 from cortical homogenates was not changed by either furosemide or hydrochlorothiazide infusion. However, the abundance of NHE3 from outer medullary homogenates was increased by furosemide infusion. The H(+)-ATPase B1 subunit abundance was increased by furosemide or hydrochlorothiazide infusion in both cortical and outer medullary homogenates. CONCLUSION: These increases in the abundance of proton-secreting transporters may account for the enhanced distal urinary acidification in response to chronic diuretic administration.