Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Claudins in kidney health and disease

Claudins are strategically located to exert their physiologic actions along with the nephron segments from the glomerulus. Claudin-1 is normally located in the Bowman’s capsule, but its overexpression can reach the podocytes and lead to albuminuria. In the proximal tubule (PT), claudin-2 forms paracellular channels selective for water, Na+, K+, and Ca2+. Claudin-2 gene mutations are associated with hypercalciuria and kidney stones. Claudin-10 has two splice variants, -10a and -10b; Claudin-10a acts as an anion-selective channel in the PT, and claudin-10b functions as a cation-selective pore in the thick ascending limb (TAL). Claudin-16 and claudin-19 mediate paracellular transport of Na+, Ca2+, and Mg2+ in the TAL, where the expression of claudin-3/16/19 and claudin-10b are mutually exclusive. The claudin-16 or -19 mutation causes familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Claudin- 14 polymorphisms have been linked to increased risk of hypercalciuria. Claudin-10b mutations produce HELIX syndrome, which encompasses hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. Hypercalciuria and magnesuria in metabolic acidosis are related to downregulation of PT and TAL claudins. In the TAL, stimulation of calcium-sensing receptors upregulates claudin-14 and negatively acts on the claudin-16/19 complex. Claudin-3 acts as a general barrier to ions in the collecting duct. If this barrier is disturbed, urine acidification might be impaired. Claudin-7 forms a nonselective paracellular channel facilitating Cl– and Na+ reabsorption in the collecting ducts. Claudin-4 and -8 serve as anion channels and mediate paracellular Cl– transport; their upregulation may contribute to pseudohypoaldosteronism II and salt-sensitive hypertension.

J-shaped Relationship Between Chronic Kidney Disease and Serum Uric Acid Levels: A Cross-sectional Study on the Korean Population

Objective@#Both hypouricemia and hyperuricemia are reportedly associated with reduced kidney function. This study investigated the association between uric acid levels and the risk of reduced renal function in men and women. @*Methods@#We conducted a cross-sectional study using data from a government-funded health examinee cohort of a Korean genome and epidemiological study. A total of 172,970 participants (58,981 men, 113,989 women) aged 40∼79 years were included. A logistic regression test was performed, and the odds ratio (OR) and 95% confidence interval (CI) were calculated to examine the relationship between stratified uric acid levels and the frequency of chronic kidney disease. @*Results@#As the uric acid level increased, the risk of reduced renal function increased. Moreover, for uric acid levels ≤2.0 mg/dL, the risk of reduced renal function was higher than that of the reference group. Among the total, man, and woman groups, a statistically significant association was observed in men (OR 1.71, 95% CI 0.945∼3.111, OR 5.003, 95% CI 1.405∼17.809, and OR 1.377, 95% CI 0.696∼2.724, respectively). @*Conclusion@#The OR of reduced renal function according to uric acid levels formed a J-shaped curve in both genders.

J-shaped Relationship Between Chronic Kidney Disease and Serum Uric Acid Levels: A Cross-sectional Study on the Korean Population

Objective@#Both hypouricemia and hyperuricemia are reportedly associated with reduced kidney function. This study investigated the association between uric acid levels and the risk of reduced renal function in men and women. @*Methods@#We conducted a cross-sectional study using data from a government-funded health examinee cohort of a Korean genome and epidemiological study. A total of 172,970 participants (58,981 men, 113,989 women) aged 40∼79 years were included. A logistic regression test was performed, and the odds ratio (OR) and 95% confidence interval (CI) were calculated to examine the relationship between stratified uric acid levels and the frequency of chronic kidney disease. @*Results@#As the uric acid level increased, the risk of reduced renal function increased. Moreover, for uric acid levels ≤2.0 mg/dL, the risk of reduced renal function was higher than that of the reference group. Among the total, man, and woman groups, a statistically significant association was observed in men (OR 1.71, 95% CI 0.945∼3.111, OR 5.003, 95% CI 1.405∼17.809, and OR 1.377, 95% CI 0.696∼2.724, respectively). @*Conclusion@#The OR of reduced renal function according to uric acid levels formed a J-shaped curve in both genders.

SGLT2 Inhibition for Diabetic and Non-diabetic Kidney Disease / 대한내과학회지

Chronic kidney disease (CKD) can be progressive, and its prognosis is worse because of increased mortality when it is associated with diabetes and cardiac disease. The outcomes of diabetic kidney disease (DKD) need to be improved, despite multifactorial interventions including glucose and blood pressure (BP) control, and the use of renin-angiotensin system (RAS) inhibitors, statins, and aspirin. Recent clinical trials suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors offer additional cardiorenal protection in DKD and non-diabetic CKD on top of RAS inhibition. The action of SGLT2 inhibitors is derived from the proximal tubule of the kidney, but their systemic effects beyond glucose-lowering involve hemodynamic and non-hemodynamic mechanisms. First, SGLT2 inhibitors restore tubuloglomerular feedback and relieve glomerular hypertension and albuminuria. Second, natriuresis and renal glycosuria lead to fluid and weight loss, resulting in BP lowering and prevention of heart failure. Third, SGLT2 inhibitors have anti-inflammatory and anti-oxidative actions that can reduce renal and cardiac inflammation and fibrosis, probably via adenosine monophosphate-activated protein kinase and sirtuin-1 activation. Finally, the proximal tubular workload is relieved, accompanied by increased erythropoiesis. Hypoxia-inducible factor 1 may be stimulated by renal outer medullary hypoxia when tubular sodium transport shifts from the proximal convoluted tubule to the proximal straight tubule and thick ascending limb, due to SGLT2 inhibition. These effects may also be beneficial in non-diabetic CKD, and we anticipate that SGLT2 inhibitors will prove effective for albuminuria reduction and preservation of kidney function in primary kidney diseases, including glomerulonephritis.

Urate Transporters in the Kidney: What Clinicians Need to Know

Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of urate removal and has a pivotal role in the regulation of urate homeostasis. Approximately 10% of the glomerular filtered urate is excreted in the urine, and the remainder is reabsorbed by the proximal tubule. However, the transport of urate in the proximal tubule is bidirectional: reabsorption and secretion. Thus, an increase in reabsorption or a decrease in secretion may induce hyperuricemia.In contrast, a decrease in reabsorption or an increase in secretion may result in hyperuricosuria. In the proximal tubule, urate reabsorption is mainly mediated by apical URAT1 (SLC22A12) and basolateral GLUT9 (SLC2A9) transporter. OAT4 (SLC22A11) also acts in urate reabsorption in the apical membrane, and its polymorphism is associated with the risk of hyperuricemia. Renal hypouricemia is caused by SLC22A12 or SLC2A9 loss-of-function mutations, and it may be complicated by exercise-induced acute kidney injury. URAT1 and GLUT9 are also drug targets for uricosuric agents. Sodium-glucose cotransporter inhibitors may induce hyperuricosuria by inhibiting GLUT9b located in the apical plasma membrane. Urate secretion is mediated by basolateral OAT1 (SLC22A6) and OAT3 (SLC22A8) and apical ATP-binding cassette super-family G member 2 (>ABCG2), NPT1 (SLC17A1), and NPT4 (SLC17A3) transporter in the proximal tubule. NPT1 and NPT4 may be key players in renal urate secretion in humans, and deletion of SLC22A6 and SLC22A8 in mice leads to decreased urate excretion. Dysfunctional variants of >ABCG2 inhibit urate secretion from the gut and kidney and may cause gout. In summary, the net result of urate transport in the proximal tubule is determined by the dominance of transporters between reabsorption (URAT1, OAT4, and GLUT9) and secretion (ABCG2, NPT1, NPT4, OAT1, and OAT3).

Comparison of Different Types of Oral Adsorbent Therapy in Patients with Chronic Kidney Disease:A Multicenter, Randomized, Phase IV Clinical Trial

Purpose@#Oral adsorbents delay disease progression and improve uremic symptoms in patients with chronic kidney disease (CKD). DW-7202 is a newly developed oral adsorbent with high adsorptive selectivity for uremic toxins. We evaluated patient preference for and adherence to DW-7202 versus AST-120 therapy and compared treatment efficacy and safety in patients with pre-dialysis CKD. @*Materials and Methods@#A seven-center, randomized, open-label, two-way crossover, active-controlled, phase IV clinical trial was conducted. Patients with stable CKD were randomly assigned to receive DW-7202 (capsule type) or AST-120 (granule type) for 12 weeks. The groups then switched to the other adsorbent and took it for the next 12 weeks. Patient preference was the primary outcome. Secondary outcomes included changes in estimated glomerular filtration rate (eGFR) and serum creatinine, cystatin C, and indoxyl sulfate (IS) levels. @*Results@#Significantly more patients preferred DW-7202 than AST-120 (p<0.001). Patient adherence improved after switching from AST-120 to DW-7202; there was no apparent change in adherence after switching from DW-7202 to AST-120. Changes in eGFR and serum creatinine, cystatin C, and IS levels were not significantly different according to adsorbent type. There was also no significant difference in the incidences of adverse events during treatment with DW-7202 and AST-120. @*Conclusion@#DW-7202 can be considered as an alternative to AST-120 in patients who cannot tolerate or show poor adherence to granule type adsorbents. Further studies to evaluate factors affecting patient preferences and improved adherence are warranted (Clinical trial registration No. NCT02681952).

Distribution of serum uric acid levels and prevalence of hyper- and hypouricemia in a Korean general population of 172,970

Background/Aims@#We investigated the distribution of serum uric acid (SUA) levels and estimated the prevalence of hyperuricemia and hypouricemia in the Korean population. @*Methods@#This cross-sectional study used data from the Korean Genome and Epidemiology Study and included 172,970 participants (58,981 men and 113,989 women) aged 40 to 79 years. Hypouricemia and hyperuricemia were defined as SUA level ≤ 2.0 mg/dL and > 7 mg/dL, respectively. The prevalence of hyperuricemia and hypouricemia was evaluated by age and sex. @*Results@#The mean SUA levels were significantly higher in men than in women (5.71 ± 1.27 mg/dL vs. 4.21 ± 0.96 mg/dL, p < 0.001). The mean SUA levels and prevalence of hyperuricemia increased with age in women but not in men. The overall prevalence of hyperuricemia and that in men and women was 50.82, 133.25, and 8.17 per 1,000 persons, respectively; the overall prevalence of hypouricemia and that in men and women was 4.16, 1.10, and 5.75 per 1,000 persons, respectively. The prevalence of hypouricemia in men was similar across all age groups; however, that in women was the highest in the age group of 40 to 49 years and the lowest in the age group of 50 to 59 years. @*Conclusions@#The distribution of SUA levels and prevalence of hyperuricemia and hypouricemia differed according to age and sex. Age and sex should be considered in studies on uric acid-related diseases.

Surgical Outcomes of Subtotal Parathyroidectomy for Renal Hyperparathyroidism

Objectives@#. The aim of this study was to evaluate the effectiveness of subtotal parathyroidectomy for patients with renal hyperparathyroidism. @*Methods@#. We studied 25 patients with renal hyperparathyroidism who underwent subtotal parathyroidectomy from October 2002 to October 2017. We analyzed serum intact parathyroid hormone (iPTH), calcium, and inorganic phosphorus levels before and at multiple time points following surgery, and evaluated the surgical outcomes and complications. @*Results@#. Of the 25 patients, 13 (52%) were male and 12 (48%) were female, and the mean age was 53.4±9.3 years. The mean duration of dialysis before parathyroidectomy was 156.8±79.5 months. Mean preoperative serum iPTH and calcium levels were 1,199.0±571.3 pg/mL and 10.5±1.0 mg/dL, respectively. At 6 months postoperatively, the mean iPTH and calcium levels decreased to 49.2±47.6 pg/mL (P<0.01) and 8.0±1.0 mg/dL (P<0.01), respectively. Recurrent hyperparathyroidism occurred in two patients: one subsequently underwent kidney transplantation and the other continued hemodialysis and maintained normal calcium levels. One patient developed postoperative permanent hypoparathyroidism. @*Conclusion@#. Subtotal parathyroidectomy is a safe and effective surgical treatment for renal hyperparathyroidism.

Urinary Concentration Defect and Renal Glycosuria in Cyclosporine-treated Rats

Background@#Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity. @*Methods@#We explored two possible mechanisms that may underlie cyclosporineinduced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II). @*Results@#In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88 ±3%, p<0.05). @*Conclusion@#Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Voriconazole-induced Severe Hyperkalemia Precipitated by Multiple Drug Interactions

Voriconazole, a triazole antifungal agent used to treat serious fungal infections, has a pharmacokinetic characteristic of undergoing hepatic metabolism by the cytochrome P450 system. Few cases of hyperkalemia have been reported, which presented only when the serum voriconazole level was exceptionally elevated by drugdrug interactions. Additionally, azole antifungals may interfere with the biosynthesis of adrenal steroids and therefore can predispose patients to aldosterone deficiency. However, it is unclear whether voriconazole itself can induce hypoaldosteronism or hyperkalemia. Here, we report a case of voriconazole-induced hyperkalemia in a patient administered concurrent medications to treat comorbidities. Voriconazole was orally administered for pulmonary aspergillosis, and three episodes of severe hyperkalemia recurred, which improved with emergency treatment. In the first episode, renin-angiotensin-aldosterone system inhibitors were associated. We found that dronedarone might have increased the voriconazole level in the second episode. At that time, severe hypercalcemia was concurrent, which improved with acute hemodialysis and eliminating dronedarone. Finally, severe hyperkalemia recurred without concurrent medications known to interact with voriconazole. Upon switching from voriconazole to itraconazole, the hyperkalemia was resolved. Drug level monitoring is necessary when voriconazole is used. Genetic susceptibility, such as through CYP2C19 polymorphism, may be investigated for patients with adverse reactions to voriconazole.

Association of Proteinuria with Urinary Concentration Defect in Puromycin Aminonucleoside Nephrosis

Background@#Puromycin aminonucleoside (PA) can induce nephrotic syndrome in rats, and proteinuria is an important mediator of tubulointerstitial injury in glomerulopathy. We assumed that glomerular proteinuria may affect tubular function, such as urinary concentration, and investigated whether a urinary concentration defect is associated with proteinuria in puromycin aminonucleoside nephrosis (PAN). We also investigated the defect response to enalapril. @*Methods@#Glomerular proteinuria was induced by a single intraperitoneal injection of PA (150 mg/kg BW) in male Sprague-Dawley rats. In a half of these rats, enalapril (35 mg/kg BW) was administered daily in a food mixture for two weeks.After the animal experiment, kidneys were harvested for immunoblot analysis and histopathologic examination. @*Results@#Compared with the control group, PA-treated rats had severe proteinuria, polyuria, and a lower urine osmolality. PA treatment induced remarkable tubulointerstitial injury and significant reductions in protein abundances of aquaporin-1 and Na-K-2Cl co-transporter type 2 (NKCC2). Proteinuria significantly correlated with osteopontin expression in the kidney and inversely correlated with renal expression of aquaporin-1, aquaporin-2, and NKCC2. The degree of tubulointerstitial injury significantly correlated with proteinuria, urine output, and osteopontin expression and inversely correlated with urine osmolality and renal expression of aquaporin-1, aquaporin-2, and NKCC2. No significant differences in parameters were found between PA-treated rats with and without enalapril. @*Conclusion@#In PAN, glomerular proteinuria was associated with tubulointerstitial injury and water diuresis. Downregulation of aquaporin-1 and NKCC2 can impair countercurrent multiplication and cause a urinary concentration defect in PAN.

Hyponatremia Associated with Pulmonary Arterial Hypertension: Syndrome of Inappropriate Antidiuresis Versus Right Heart Failure

Because it is associated with mortality, hyponatremia is an important feature of pulmonary arterial hypertension. Its mechanisms remain unclear, although right heart failure resulting from pulmonary arterial hypertension may lead to systemic congestion and arterial underfilling. However, most patients with pulmonary arterial hypertension are clinically euvolemic and have no peripheral edema. Unlike patients with underlying heart disease, neurohumoral activation is not demonstrated in hyponatremic patients with pulmonary arterial hypertension, who show features of congestive heart failure only at later stages in their disease. Here, a case vignette is introduced, and the pathophysiology of hyponatremia in pulmonary arterial hypertension will be discussed. Syndrome of inappropriate antidiuresis (SIAD) appears to underlie hyponatremia in the initial phase of pulmonary arterial hypertension. The mechanisms by which various lung diseases can lead to SIAD remain an enigma.

Urinary Concentration Defect and Renal Glycosuria in Cyclosporine-treated Rats

Background@#Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity. @*Methods@#We explored two possible mechanisms that may underlie cyclosporineinduced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II). @*Results@#In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88 ±3%, p<0.05). @*Conclusion@#Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Voriconazole-induced Severe Hyperkalemia Precipitated by Multiple Drug Interactions

Voriconazole, a triazole antifungal agent used to treat serious fungal infections, has a pharmacokinetic characteristic of undergoing hepatic metabolism by the cytochrome P450 system. Few cases of hyperkalemia have been reported, which presented only when the serum voriconazole level was exceptionally elevated by drugdrug interactions. Additionally, azole antifungals may interfere with the biosynthesis of adrenal steroids and therefore can predispose patients to aldosterone deficiency. However, it is unclear whether voriconazole itself can induce hypoaldosteronism or hyperkalemia. Here, we report a case of voriconazole-induced hyperkalemia in a patient administered concurrent medications to treat comorbidities. Voriconazole was orally administered for pulmonary aspergillosis, and three episodes of severe hyperkalemia recurred, which improved with emergency treatment. In the first episode, renin-angiotensin-aldosterone system inhibitors were associated. We found that dronedarone might have increased the voriconazole level in the second episode. At that time, severe hypercalcemia was concurrent, which improved with acute hemodialysis and eliminating dronedarone. Finally, severe hyperkalemia recurred without concurrent medications known to interact with voriconazole. Upon switching from voriconazole to itraconazole, the hyperkalemia was resolved. Drug level monitoring is necessary when voriconazole is used. Genetic susceptibility, such as through CYP2C19 polymorphism, may be investigated for patients with adverse reactions to voriconazole.

Association of Proteinuria with Urinary Concentration Defect in Puromycin Aminonucleoside Nephrosis

Background@#Puromycin aminonucleoside (PA) can induce nephrotic syndrome in rats, and proteinuria is an important mediator of tubulointerstitial injury in glomerulopathy. We assumed that glomerular proteinuria may affect tubular function, such as urinary concentration, and investigated whether a urinary concentration defect is associated with proteinuria in puromycin aminonucleoside nephrosis (PAN). We also investigated the defect response to enalapril. @*Methods@#Glomerular proteinuria was induced by a single intraperitoneal injection of PA (150 mg/kg BW) in male Sprague-Dawley rats. In a half of these rats, enalapril (35 mg/kg BW) was administered daily in a food mixture for two weeks.After the animal experiment, kidneys were harvested for immunoblot analysis and histopathologic examination. @*Results@#Compared with the control group, PA-treated rats had severe proteinuria, polyuria, and a lower urine osmolality. PA treatment induced remarkable tubulointerstitial injury and significant reductions in protein abundances of aquaporin-1 and Na-K-2Cl co-transporter type 2 (NKCC2). Proteinuria significantly correlated with osteopontin expression in the kidney and inversely correlated with renal expression of aquaporin-1, aquaporin-2, and NKCC2. The degree of tubulointerstitial injury significantly correlated with proteinuria, urine output, and osteopontin expression and inversely correlated with urine osmolality and renal expression of aquaporin-1, aquaporin-2, and NKCC2. No significant differences in parameters were found between PA-treated rats with and without enalapril. @*Conclusion@#In PAN, glomerular proteinuria was associated with tubulointerstitial injury and water diuresis. Downregulation of aquaporin-1 and NKCC2 can impair countercurrent multiplication and cause a urinary concentration defect in PAN.

Hyponatremia Associated with Pulmonary Arterial Hypertension: Syndrome of Inappropriate Antidiuresis Versus Right Heart Failure

Because it is associated with mortality, hyponatremia is an important feature of pulmonary arterial hypertension. Its mechanisms remain unclear, although right heart failure resulting from pulmonary arterial hypertension may lead to systemic congestion and arterial underfilling. However, most patients with pulmonary arterial hypertension are clinically euvolemic and have no peripheral edema. Unlike patients with underlying heart disease, neurohumoral activation is not demonstrated in hyponatremic patients with pulmonary arterial hypertension, who show features of congestive heart failure only at later stages in their disease. Here, a case vignette is introduced, and the pathophysiology of hyponatremia in pulmonary arterial hypertension will be discussed. Syndrome of inappropriate antidiuresis (SIAD) appears to underlie hyponatremia in the initial phase of pulmonary arterial hypertension. The mechanisms by which various lung diseases can lead to SIAD remain an enigma.

Hepcidin as a Biomarker of Cardiorenal Syndrome

No abstract available.

Subtotal Parathyroidectomy for Tertiary Hyperparathyroidism: a Case Report and Literature Review

Despite the correction of secondary renal hyperparathyroidism after successful kidney transplantation, some recipients have persistent hyperparathyroidism due to autonomous hypertrophied parathyroid glands. St. Goar first identified and termed this disease as tertiary hyperparathyroidism. Surgery, either subtotal parathyroidectomy or total parathyroidectomy with autotransplantation, is the main treatment for tertiary hyperparathyroidism. Here, we report a case of a patient with tertiary hyperparathyroidism after two times of kidney transplantation who underwent subtotal parathyroidectomy and also review the relevant literature.

Pharmacologic Treatment of Chronic Hyperkalemia in Patients with Chronic Kidney Disease

Hyperkalemia is frequently complicated in patients with advanced chronic kidney disease (CKD) because kidney is the major route of potassium excretion. Urinary potassium excretion is reduced according to the decline in glomerular filtration rate, and the risk of hyperkalemia is increased in patients with high potassium intake, advanced age, diabetes mellitus, congestive heart failure, and medications such as renin-angiotensin-aldosterone system(RAAS) blockades. On the other hand, the benefits of RAAS blockades and a high-potassium diet should be considered in CKD patients. To overcome these contradictory treatment strategies, potassium binders have emerged as new options to enhance fecal potassium excretion. In different regions of the world, four types of potassium binders are preferentially used. Whereas sodium polystyrene sulfonate (SPS) exchanges sodium for potassium, calcium polystyrene sulfonate (CPS) has the advantage of avoiding hypervolemia because it exchanges calcium for potassium. SPS was first introduced in the 1950s and used for a long time in western countries, and CPS is currently prescribed in Asia including South Korea. In contrast with the paucity of clinical studies using SPS or CPS, the recent randomized, controlled trials reported that two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), effectively and safely reduce serum potassium levels in CKD patients taking RAAS blockades. Our experiences showed that the long-term administration of a small dose of CPS was also effective and safe in treatment of chronic hyperkalemia. Further comparative trials among patiromer, ZS-9, and CPS are required to provide guides to cost-effective management of hyperkalemia in CKD patients.