Potassium Wasting Research Articles

Dent Disease 1 Presented Early with Bartter-Like Syndrome Features and Rickets: a Case Report

Introduction: Dent disease (DD) is characterized by a triad of low-molecular-weight proteinuria, hypercalciuria, and nephrocalcinosis/nephrolithiasis. However, some cases were confounded by other clinical symptoms and signs, namely hypokalemia and rickets, which resulted in misleading diagnoses. A diagnosis of DD could be delayed even in high-resource countries due to its variability of phenotypes and rarity, causing a lack of awareness in both medical practitioners and parents. Moreover, in low-resource countries, laboratory test limitations can hinder the diagnosis. Case presentation: A thirteen-year-old boy presented with an acute episode of severe hypokalemia following vomiting due to COVID medication side effects. He had lower extremities weakness, salt craving, and polydipsia since childhood which were not thought to be unusual by the parents. He had a history of intrauterine polyhydramnios and maternal miscarriages. A physical examination showed hypotension, short stature, and genu valgum. His laboratory workup displayed hypokalemic metabolic alkalosis and increased urine potassium, chloride, transtubular potassium gradient, and calcium/creatinine ratio. He also had hypophosphatemia, hypomagnesemia, and decreased kidney function. Severe osteopenia was prominent on radiologic examination of all extremities. Subsequent laboratory samples sent overseas revealed low-molecular-weight proteinuria and a pathogenic variant in the CLCN5 gene confirming X-linked Dent disease 1. Conclusion: This case report highlights the importance of considering DD in differential diagnoses of children with the pseudo-Bartter syndrome, that is, renal salt and potassium wasting, with or without hypercalciuria and nephrocalcinosis. Additionally, in children with rickets and proteinuria, urinary low-molecular-weight protein measurement could assist in screening for the possibility of DD, particularly in low-resource settings.

Increased Spironolactone Dosing in Acute Heart Failure Alters Potassium Homeostasis but Does not Enhance Decongestion

The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) clinical trial found no improvements in natriuretic peptide levels or clinical congestion when spironolactone 100 mg/day for 96 hours was used in addition to usual treatment for acute heart failure. We performed a post hoc analysis of ATHENA-HF to determine whether spironolactone treatment induced any detectable pharmacodynamic effects and whether patients with potentially greater aldosterone activity experienced additional decongestion. Trial subjects previously treated with spironolactone were excluded. We first examined for changes in renal potassium handling. Using the baseline serum potassium level as a surrogate marker of spironolactone activity, we then divided each treatment arm into tertiles of baseline serum potassium and explored for differences in laboratory and clinical congestion outcomes. Among spironolactone-naïve patients, the change in serum potassium did not differ after 24 hours or 48 hours but was significantly greater with spironolactone treatment compared to placebo at 72 hours (0.23 ± 0.55 vs 0.03 ± 0.60 mEq/L; P = 0.042) and 96 hours (0.32 ± 0.51 vs 0.13 ± 0.72 mEq/L; P = 0.046). Potassium supplementation was similar at treatment start and at 24 hours, but spironolactone-treated patients required substantially less potassium replacement at 48 hours (24% vs 36%; P = 0.048), 72 hours (21% vs 37%; P = 0.013), and 96 hours (11% vs 38%; P < 0.001). When the treatment arms were divided into tertiles of baseline serum potassium, there were no differences in the 96-hour log N-terminal pro-B-type natriuretic peptide levels, net fluid loss, urine output, or dyspnea relief in any of the potassium groups, with no effect modification by treatment exposure. Spironolactone 100 mg/day for 96 hours in patients receiving intravenous loop diuresis for acute heart failure has no clear added decongestive ability but does meaningfully limit potassium wasting.

Control of sodium appetite by hindbrain aldosterone-sensitive neurons

Mineralocorticoids play a key role in hydromineral balance by regulating sodium retention and potassium wasting. Through favoring sodium, mineralocorticoids can cause hypertension from fluid overload under conditions of hyperaldosteronism, such as aldosterone-secreting tumors. An often-overlooked mechanism by which aldosterone functions to increase sodium is through stimulation of salt appetite. To drive sodium intake, aldosterone targets neurons in the hindbrain which uniquely express 11β-hydroxysteroid dehydrogenase type 2 (HSD2). This enzyme is a necessary precondition for aldosterone-sensing cells as it metabolizes glucocorticoids – preventing their activation of the mineralocorticoid receptor. In this review, we will consider the role of hindbrain HSD2 neurons in regulating sodium appetite by discussing HSD2 expression in the brain, regulation of hindbrain HSD2 neuron activity, and the circuitry mediating the effects of these aldosterone-sensitive neurons. Reducing the activity of hindbrain HSD2 neurons may be a viable strategy to reduce sodium intake and cardiovascular risk, particularly for conditions of hyperaldosteronism.

Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2

The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.

Ruxolitinib Rescues Multiorgan Clinical Autoimmunity in Patients with APS-1

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.

Renal Wasting of Electrolytes: Effect of Amikacin Used to Treat Infections - Tip of Iceberg for the Physicians

Objective: To measure prospectively the effect of treatment with the Amikacin on renal magnesium, potassium and phosphate wasting in patients with extrarenal infections. Study Design: Case series. Place and Duration of Study: Department of Nephrology, Pak Emirates Military Hospital, Rawalpindi Pakistan from Jul toDec 2019. Methodology: A total of 40 cases were included in this study in liaison with other departments who were put on Amikacinstandard dose. Urinary electrolytes including potassium, magnesium and phosphate were measured at day 4 after the use of Amikacin. Factors like age, gender, cause for which Amikacin was used, day 1 creatinine and day 4 creatinine were correlated with presence of electrolyte wasting in the target population. Results: Mean age of study participants was 39.1±12.56 years. 25(62.5%) were males while 15(37.5%) were females. Commonest cause for the use of Amikacin was drug resistant tuberculosis followed by fractures. Mean urinary magnesium was 39.1±12.56 mmol/24 hours, while potassium was 26.1±15.60 meq/24 hours. Mean phosphate was 66.4±53.55 mg/24 hours. Pearson chi-square test revealed that advanced age and day 4 creatinine were strongly linked with the presence of urinary electrolyte wasting among the patients receiving Amikacin for extra-renal infections with p-value&lt;0.05. Conclusion: Electrolyte wasting emerged as a common finding in the patients put on Amikacin suffering from extra renal infections. Patients with advancing age put on Amikacin should be given special attention and screened for electrolyte wasting at priority. ..

The exacerbated hypokalemia in membranous glomerulonephritis due to proximal tubular injury: a neglect issue from a case report and literature review

BackgroundMembranous glomerulonephritis is the most common primary etiology for the nephrotic syndrome in adults. Beyond the clinical hallmark of nephrotic syndrome such as fluid overloading, dyslipidemia and hypoalbuminemia, the dysregulated homeostasis of potassium and its possible mechanism is seldomly discussed, and its association with the clinical course of membranous GN is lacking.Case presentationA 65 year-old female attended to our emergent department for progressive lower leg edema after taking 15-h of flight. Hypoalbuminemia and hyperlipidemia were both noted, and 24-h urinary total protein was up to 17,950 mg/day. Elevated creatin-phospho-kinase developed at the initial presentation with hypokalemia due to excressive renal excretion. Glycosuria without elevated glycated Hemoglobin occurred. The pathology of kidney biopsy revealed subepithelial immunocomplex deposits with spike formation in the electron microscopy and the positive anti-Phosphlipase A2 receptor antibodies(PLA-2R) with hallmark of membranous glomerulonephritis. In the light microscopy, the vacuolization of proximal tubules was noted, which contributed to the potassium wasting. After 1 year following up duration, the patient’s proteinuria persisted after maintenance treatment with calcineurin inhibitor.ConclusionHypokalemia is a neglected issue in the membranous glomerulonephritis. Unlike the previous literature, our patient had the vacuolization of proximal tubule at the initial presentation with hypokalemia, which might contribute the potassium wasting. The proximal tubular damage with hypokalemia might be a predictive factor for membranous glomerulonephritis.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Hypernatremia and hypokalemia with Entrectinib therapy: A case of possible nephrogenic diabetes insipidus

Introduction: Hypernatremia and hypokalemia have been reported with the use of Tropomyosin Receptor Kinase Inhibitors (TRKI) but the pathophysiology is not clear. We hereby describe a 72-year-old male with metastatic papillary thyroid carcinoma presenting with hypernatremia and hypokalemia after starting Entrectinib therapy. Case description: A 72-year-old male with metastatic papillary thyroid carcinoma was admitted to the hospital for failure to thrive and worsening mental status 6 weeks after starting Entrectinib therapy. He was found to have hypernatremia at 154 mmol/L and hypokalemia at 2.9 mmol/L. Serum and urine osmolalities were 320 and 293 mOsm/kg, respectively with an elevated 24 h urinary potassium of 132 mmol. Polydipsia and polyuria were reported raising the suspicion for underlying diabetes insipidus (DI). Twenty-four hour urine output was around 4.5 L. A DDAVP challenge was performed with no change in hourly urine output and a trivial change in urine osmolality toward 339 mOsm/kg indicating a possible partial nephrogenic DI. Potassium was supplemented and patient was treated with free water enterally and parenterally while stopping Entrectinib therapy. One week later, a water deprivation test failed to elicit a hypernatremic response. Unfortunately, urine osmolality variations with water deprivation were not checked but urine volumes dropped significantly suggesting resolution of presumed nephrogenic DI. Conclusion: Hypernatremia has been reported with Tyrosine Kinase Inhibitors but no pathophysiology has been proposed. Hypokalemia however has not been reported. This case reports hypokalemia and hypernatremia in association with Entrectinib therapy with renal potassium wasting and partial nephrogenic as possible pathophysiologic bases respectively. These pathologies seem to be reversible with drug cessation. With the growing use of targeted therapies in oncology and beyond, it seems prudent to better understand the unique electrolyte and water balance abnormalities that might occur so that patients can be counseled and managed appropriately.

37-Year-Old Man With Headache and Nasal Congestion

37-Year-Old Man With Headache and Nasal Congestion

A case of Gitelman syndrome with membranous nephropathy

BackgroundGitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we report, for the first time, a case of GS overlapping nephrotic syndrome (NS) related to PLA2R-associated membranous nephropathy (MN).Case presentationWe described a male patient had a 4-year history of recurrent fatigue. Serum biochemistry revealed hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hyperreninemia, hypocalciuria, as well as nephrotic-range proteinuria, hypoalbuminemia, and elevated serum anti-phospholipase A2 receptor (PLA2R) antibody. Gene sequencing identified compound heterozygous mutations in SLC12A3 [c.536T > A(p.V179D) and c.1456G > A(p.D486N)]. The unusual association of SLTs and nephrotic-range glomerular proteinuria prompted us to perform a renal biopsy. Renal biopsy showed idiopathic MN. Due to the potential to activate the sodium-chloride co-transporter (NCC) and cause hyperkalemia, tacrolimus was selected to treat NS. Following treatment with potassium chloride, magnesium oxide, low-dose glucocorticoid combined with tacrolimus, the fatigue significantly improved, and concurrently hypokalemia, hypomagnesemia were corrected and NS was remitted.ConclusionsRenal biopsy should be warranted for GS patients with moderate to nephrotic-range proteinuria. Tacrolimus was preferred to the management of GS patients with NS.

Review of the Pathophysiologic and Clinical Aspects of Hypokalemia in Children and Young Adults: an Update.

This article examines the regulatory function of the skeletal muscle, renal, and adrenergic systems in potassium homeostasis. The pathophysiologic bases of hypokalemia, systematic approach for an early diagnosis, and therapeutic strategy to avert life-threatening complications are highlighted. By promoting skeletal muscle uptake, intense physical exercise (post), severe trauma, and several toxins produce profound hypokalemia. Hypovolemia due to renal and extra-renal fluid losses and ineffective circulation activate secondary aldosteronism causing urinary potassium wasting. In addition to hypokalemic alkalosis, primary aldosteronism causes low-renin hypertension. Non-aldosterone mineralocorticoid activation leading to low-renin and low-aldosterone hypertension occurs in Liddle’s syndrome and apparent mineralocorticoid excess. Although there is enzymatic inhibition of cortisol synthesis in congenital adrenal hyperplasia, precursors of aldosterone produce low-renin hypokalemic hypertension. In addition to the glucocorticoid effect, hypercortisolism activates mineralocorticoid receptors in Cushing’s syndrome. Genetic mutations involving furosemide-sensitive Na+-K+-2Cl− co-transporters and thiazide-sensitive Na+-Cl− transporters result in (non-hypertensive) salt-wasting nephropathy. Proximal and distal renal tubular acidosis is associated with hypokalemia. Eating disorders causing hypokalemia include bulimia, laxative abuse, and diuretic misuse. Low urinary potassium (<15 mmol/day) and/or low urinary chloride (<20 mol/L) suggest a gastrointestinal pathology. Co-morbidity of hypokalemia with chronic pulmonary and cardiovascular diseases may increase the fatality rate.

Syndromes of Pseudo-Hyperaldosteronism.

Syndromes of Pseudo-Hyperaldosteronism.

Idiopathic Hypokalemia in Lupus Nephritis: A Newly Recognized Entity.

Various causes of hypokalemia (HK) from renal potassium wasting, including distal renal tubular acidosis (RTA), have been described in lupus nephritis (LN). We report a phenomenon of otherwise unexplained HK among a population with LN. From our population of 403 patients with LN, we identified a cohort of 20 patients with idiopathic HK, defined by serum potassium <3.5 mmol/L without any apparent explanation. This cohort is compared with 90 LN controls (CON) and ten patients with LN with distal RTA from the same population. The patients with HK had lower median serum potassium compared with CON and RTA subjects (3.26 versus 4.00 versus 3.75 mmol/L, respectively; P<0.001). The median serum bicarbonate was normal in HK and CON, but low in RTA (26.0 versus 25.0 versus 19.4 mmol/L; P<0.001). The median urine pH was abnormally high only in the RTA group (6.00 versus 6.25 versus 6.67; P=0.012). The median serum magnesium was modestly lower in HK compared with the CON and RTA groups (1.73 versus 2.00 versus 1.85 mg/dl; P=0.002). Although both HK and RTA showed a higher rate of seropositivity than CON for anti-Ro/SSA (79% and 80% versus 37%, respectively; P<0.001), only HK revealed a higher rate of seropositivity than CON for anti-RNP (84% versus 42%; P=0.003) and only RTA showed a higher rate of seropositivity than CON for anti-La/SSB (40% versus 12%; P=0.05). A syndrome of idiopathic HK was revealed in 20 out of 403 (5%) of patients within our LN population, and proved to be distinct from the RTA that occurs in LN. Furthermore, it was associated with a distinct pattern of autoantibodies. We speculate that idiopathic HK is the result of a novel target of autoimmunity in LN, affecting renal tubular potassium transport.

Monogenic forms of low-renin hypertension: clinical and molecular insights.

Monogenic disorders of hypertension are a distinct group of diseases causing dysregulation of the renin-angiotensin-aldosterone system and are characterized by low plasma renin activity. These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). The final common pathway is plasma volume expansion and catecholamine/sympathetic excess that causes urinary potassium wasting; hypokalemia and early-onset refractory hypertension are characteristic. However, several single gene defects may show phenotypic heterogeneity, presenting with mild hypertension with normal electrolytes. Evaluation is based on careful attention to family history, physical examination, and measurement of blood levels of potassium, renin, and aldosterone. Genetic sequencing is essential for precise diagnosis and individualized therapy. Early recognition and specific management improves prognosis and prevents long-term sequelae of severe hypertension.

MO053GITELMAN'S SYNDROME AND PREGNANCY: TWO SUCCESSFUL CASE REPORTS

Abstract Background and Aims Gitelman’s Syndrome (GS) is a rare autosomal recessive hereditary salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. Pregnancy in women with GS often aggravates hypokalemia and hypomagnesemia. However, there are few reports of pregnancies in GS. Here, we report the course of two Chinese women who were diagnosed as GS during pregnancy in 2019 and 2020 respectively. Method Case 1: A 21-year-old woman was referred to our hospital at 9 weeks gestation of her first pregnancy. She had complained of muscle weakness and cramps for one year. Before the referral she was diagnosed as hypokalemia and treated by oral potassium supplementation. However, her symptoms became severer after pregnancy. Case 2: A 20-year-old woman was admitted to the hospital because of elevated plasma glucose level and hypokalemia at 27 weeks gestation of her first pregnancy. The woman was asymptomatic and denied history of chronic diseases. The laboratory examinations were taken after admission. Genetic testing was conducted for pathogenic mutations in SLC12A3 (GS) and SLC12A1, KCNJ1, CLCKNB and BSND (Bartter syndrome 1-4). Results Case 1: Initial biochemistry examinations revealed hypokalemia (2.3 mmol/L, normal range 3.5-5.3 mmol/L) with inappropriate renal potassium wasting (urine potassium 254 mmol/24h, normal range &amp;lt; 20 mmol/24h), alkalosis (arterial blood gas pH 7.49), hypomagnesemia (0.55 mmol/L, normal range 0.67-1.04 mmol/L), hypocalciuria (urine calcium 1.6 mmol/24h, normal range 2.5-7.5 mmol/24h) and elevated renin (276 pg/ml, normal range 4-24 pg/ml) and aldosterone (825 pg/ml, normal range 10-160 pg/ml) levels. The blood pressure was normal-low (97/68 mmHg, 12.9/9.0 kPa) and the renal ultrasound was normal. Homozygous mutations [c.179C&amp;gt;T (Thr60Met)] were identified. The woman’s father and sister had a heterozygous c.179C&amp;gt;T, but had no electrolyte disorders. After the treatment of oral potassium supplementation (KCl 3g tid) and spironolactone (40mg bid), her serum potassium level increased to 3.4-4.0 mmol/L and muscle weakness was relieved. The woman delivered a healthy female infant weighing 2600 g at 39 weeks gestation via cesarean section. Maternal serum potassium level remained normal and no symptoms reoccured after delivery. Case 2: Initial biochemistry examinations identified hypokalemia (2.3 mmol/L, normal range 3.5-5.3 mmol/L) with inappropriate renal potassium wasting (urine potassium 81 mmol/24h, normal range &amp;lt; 20 mmol/24h), hypomagnesemia (0.49 mmol/L, normal range 0.67-1.04 mmol/L), hypocalciuria (urine calcium 0.3 mmol/24h, normal range 2.5-7.5 mmol/24h) and elevated renin (54 pg/ml, normal range 4-24 pg/ml) and aldosterone (834 pg/ml, normal range 10-160 pg/ml) levels. The blood pressure and renal ultrasound were normal. Heterozygous mutations [c.179C&amp;gt;T (Thr60Met), c.658G&amp;gt;A (Gly220Ser)] were identified. The woman was treated by oral potassium supplementation (KCl 3g tid) and her serum potassium level maintained normal during pregnancy. She had a normal delivery of a healthy female infant weighing 3050 g at 40 weeks gestation. After delivery she discontinued oral potassium supplementation and her serum potassium level ranged from 3.0-3.4 mmol/L without symptoms. Conclusion The outcome of mother and fetus of GS pregnancies appears favorable. Intensive monitoring of electrolyte levels and sufficient electrolyte supplementation are advised during pregnancy.

Hyperaldosteronism in a Patient With Gastrointestinal Potassium Wasting

Background: Medical conditions causing hypokalemia can be masked by a diet very rich in potassium. The following case presents a patient who developed new onset symptoms of hypokalemia after immigrating to the United States. Clinical Case: A 35 year old man, native of Mali, had a history of intermittent muscle spasms and serum potassium of 3.0 mmol/L first recognized elsewhere in 2019. He was not on any home medications. He was admitted with postprandial generalized abdominal pain, diarrhea, and bright blood in his stools. Serum potassium was 2.7 (nl 3.5–5.1mmol/L). He required at least 120 mEq of intravenous and oral potassium chloride per day while hospitalized to achieve and maintain serum potassium in the normal range. Colonoscopy found segmental colitis and it was thought that his hypokalemia was due to gastrointestinal losses. However, studies demonstrated urinary potassium wasting. A 1.9 cm nodular mass of the left adrenal gland was found on CT of the abdomen, and the differential diagnosis was expanded to include hypokalemia secondary to primary hyperaldosteronism or renal tubulopathies such as Bartter and Gitleman syndromes. The patient was normotensive and had biochemical findings that were consistent with Bartter syndrome including metabolic alkalosis, hypercalciuria, elevated urine sodium and chloride, and normal serum magnesium levels. However, he had low plasma rennin activity with an elevated serum aldosterone on three tests over two months (the last test was more than one month after normalization of bowel function). On all of these, the aldosterone to renin ratio was greater than 20 ng/mL/hour. The persistent suppression of plasma rennin with elevated aldosterone in the setting of left adrenal mass narrowed the differential diagnosis to primary hyperaldosteronism, as elevated rennin would be expected in Bartter syndrome. Since discharge, he has received 80 meq of daily oral potassium in divided doses, which has kept serum potassium at or below the lower limit of normal. Further management will consist of either pharmacologic or surgical treatment with or without adrenal venous sampling. Conclusion: The patient had hypokalemia for which an endocrine etiology could have been easily overlooked and attributed to gastrointestinal losses. This case demonstrates the very close clinical similarities between primary hyperaldosteronism and renal tubulopathies. However, there are biochemical patterns that can be relied on to help differentiate amongst these disorders. This patient with primary hyperaldosteronism may not have been hypokalemic in his native country due to consuming a diet rich in potassium.

A randomized double-blinded placebo-controlled clinical trial on protective effects of pentoxifylline on gentamicin nephrotoxicity in infectious patients.

Renal toxicity has limited gentamicin use in clinical practice. The aim of the present clinical trial was to assess the possible nephroprotective effects of pentoxifylline (PTX) against gentamicin nephrotoxicity. A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted on patients who had the indication for systemic gentamicin for at least 7days. Sixty people were selected and randomly assigned. For patients in the intervention and control groups, 400mg PTX sustained release tablet and placebo were given orally three times daily, respectively. Demographic, clinical, laboratory, and therapeutic information of patients were recorded. malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) levels in serum were measured on days 0 and 7. The incidence of nephrotoxicity in the placebo group was 19.6 times higher than that in the PTX group (OR = 19.6, 95%CI = 3.08-114.32; P value = 0.001). The mean ± SD time onset of ATN was 4.00 ± 2.32 and 5.58 ± 1.59days in PTX and placebo recipients, respectively (P value < 0.001). No significant differences were observed for hypokalemia, hypomagnesemia, potassium and magnesium wasting between the two groups. The mean ± SD levels of serum MDA and TNF-α at day 7 were significantly lower in the PTX compared to those in the placebo group (P value < 0.001 for both indexes). The co-administration of 400mg PTX orally three times daily along with gentamicin was both well-tolerated and effective in preventing the nephrotoxicity of gentamicin in patients with different infectious diseases.

Kidney stones and moderate proteinuria as the rare manifestations of Gitelman syndrome

BackgroundGitelman syndrome (GS) is an autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we describe, for the first time, a case of GS without Gitelman-like features and with concomitant kidney stones, cysts and diabetic nephropathy (DN).Case presentationWe described a male patient had a 19-year history of recurrent fatigue. From childhood, he had polydipsia and polyuria, paroxysmal tetany and palpitation. Serum biochemistry revealed chronic hypokalemia, metabolic alkalosis, normomagnesemia, mildly elevated Cr. Concomitant 24 h urine collection showed inappropriate renal potassium wasting, borderline hypercalciuria, moderate proteinuria consisting of major glomerular. Ultrasound of urinary tract showed bilateral and multiple kidney stones and cysts. Whole exome sequencing (WES) identified compound heterozygous mutations of SLC12A3. The unusual association of SLTs and glomerular proteinuria prompted us to perform a renal biopsy. Renal pathology showed renal involvement consistent with GS and early stage of diabetic nephropathy (DN). After treatment with KCl, magnesium oxide, perindopril and acarbose, the patient had been cured. The fatigue didn’t relapse.ConclusionGS had high variability of phenotype, GS may have no Gitelman-like features, kidney stones are not the exclusion criteria of GS. Renal biopsy should be warranted for GS patients with moderate to massive glomerular proteinuria.

Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects.

Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (P<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (P=0.02) and all other neurohormones were similar (P<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (P=0.20) or renal dysfunction (P>0.11 for all biomarkers), whereas both serum magnesium (P<0.001) and uric acid levels (P=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.