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Background/Purpose: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce. Methods: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan. Results: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432–5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation. Conclusion: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality.

Abstract Background Hyperthyroidism is frequently under-recognized and leads to heart failure and mortality. Timely identification of high-risk patients is a prerequisite to effective antithyroid therapy. Since the heart is very sensitive to hyperthyroidism and its electrical signature can be demonstrated by electrocardiography, we developed an artificial intelligence model to detect hyperthyroidism by electrocardiography and examined its potential for outcome prediction. Methods The deep learning model was trained using a large dataset of 47,245 electrocardiograms from 33,246 patients at an academic medical center. Patients were included if electrocardiograms and measurements of serum thyroid-stimulating hormone were available that had been obtained within a three day period. Serum thyroid-stimulating hormone and free thyroxine were used to define overt and subclinical hyperthyroidism. We tested the model internally using 14,420 patients and externally using two additional test sets comprising 11,498 and 596 patients, respectively. Results The performance of the deep learning model achieves areas under the receiver operating characteristic curves (AUCs) of 0.725–0.761 for hyperthyroidism detection, AUCs of 0.867–0.876 for overt hyperthyroidism, and AUC of 0.631–0.701 for subclinical hyperthyroidism, superior to a traditional features-based machine learning model. Patients identified as hyperthyroidism-positive by the deep learning model have a significantly higher risk (1.97–2.94 fold) of all-cause mortality and new-onset heart failure compared to hyperthyroidism-negative patients. This cardiovascular disease stratification is particularly pronounced in subclinical hyperthyroidism, surpassing that observed in overt hyperthyroidism. Conclusions An innovative algorithm effectively identifies overt and subclinical hyperthyroidism and contributes to cardiovascular risk assessment.

Background: Renal hyperparathyroidism can be effectively treated with parathyroidectomy. However, managing persistence or recurrence after the initial surgery is still challenging. Understanding the anatomical patterns observed in reoperative parathyroidectomies can help localize the disease during initial and subsequent surgeries. Aim: This study aimed to identify the patterns of persistence and recurrence following parathyroidectomy for renal hyperparathyroidism and assess the performance of various localization studies. Methods: A retrospective cohort study was conducted on dialysis patients who underwent reoperative parathyroidectomy at a single center. Patient demographics, laboratory test results, localization study findings, surgical details, and postoperative outcomes were obtained through the chart reviews. Persistence was defined as an intact parathyroid hormone level >300 pg/mL within 6 months after the primary surgery; otherwise, recurrence was defined as > 6 months. Results: Among 377 patients who underwent parathyroidectomies, 20 (5.3%) required reoperations. Supernumerary glands were the primary cause of persistence (70%) and recurrence (50%), predominantly located posteriorly within the tracheoesophageal groove. Besides, overgrowth of the forearm graft accounted for 30% of recurrences. Neck ultrasound (US) showed 6 out of 19 false negatives (68% sensitivity and 100% specificity), whereas 99mTc-sestamibi scintigraphy with single-photon emission computed tomography (SPECT)/computed tomography (CT) had one false negative (95% sensitivity and 100% specificity). CT scans accurately localized the disease in cases where US and sestamibi scintigraphy yielded discordant results. Conclusion: Supernumerary glands frequently contribute to the persistence and recurrence of renal hyperparathyroidism after parathyroidectomy. In the reoperative context, sestamibi SPECT/CT and CT scans detect affected parathyroid tissue in the neck and mediastinum more effectively than neck USs.

ContextAlthough a monoallelic mutation in the calcium-sensing receptor (CASR) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited.ObjectiveA 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and characterized the functional and pathophysiological mechanisms, and then linked the mutation to calcimimetics treatment in vitro.DesignSanger sequencing of the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation model was used to predict the function of the identified mutant. In vitro studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte™ 520 Ca2+ detection, and half-maximal effective concentration (EC50), were examined.ResultsThis proband was found to carry a de novo heterozygous missense I554N in the cysteine-rich domain of CASR, which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that CASR I554N mutation decreased its binding energy with Ca2+. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+ response to gradient extracellular Ca2+ (eCa2+) concentration. The EC50 study also demonstrated the correctable effect of calcimimetics on the function of the CASR I554N mutation.ConclusionThis novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+ corrected by therapeutic calcimimetics.

Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.

Abstract Background Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. Methods To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia–Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. Results In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. Conclusions RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study. Graphical Abstract

BackgroundRare cases of de novo or relapsed kidney diseases associated with vaccination against coronavirus disease 2019 (COVID-19) have been increasingly reported. The aim of this study was to report the incidence, etiologies, and outcomes of acute kidney disease (AKD) following COVID-19 vaccination.MethodsThis retrospective study extracted cases from renal registry of a single medical center from 1 March 2021 to 30 April 2022, prior to the significant surge in cases of the Omicron variant of COVID-19 infection in Taiwan. Adult patients who developed AKD after COVID-19 vaccination were included. We utilized the Naranjo score as a causality assessment tool for adverse vaccination reactions and charts review by peer nephrologists to exclude other causes. The etiologies, characteristics, and outcomes of AKD were examined.ResultsTwenty-seven patients (aged 23 to 80 years) with AKD were identified from 1,897 vaccines (estimated rate of 13.6 per 1000 patient-years within the renal registry). A majority (77.8%) of vaccine received messenger RNA-based regimens. Their median (IQR) Naranjo score was 8 (6-9) points, while 14 of them (51.9%) had a definite probability (Naranjo score ≥ 9). The etiologies of AKD included glomerular disease (n = 16) consisting of seven IgA nephropathy, four anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis (AAN), three membranous glomerulonephritis, two minimal change diseases, and chronic kidney disease (CKD) with acute deterioration (n = 11). Extra-renal manifestations were found in four patients. Over a median (IQR) follow-up period of 42 (36.5–49.5) weeks, six patients progressed to end-stage kidney disease (ESKD).ConclusionBesides glomerulonephritis (GN), the occurrence of AKD following COVID-19 vaccination may be more concerning in high-risk CKD patients receiving multiple doses. Patients with the development of de novo AAN, concurrent extra-renal manifestations, or pre-existing moderate to severe CKD may exhibit poorer kidney prognosis.

Magnesium (Mg2+) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein and nucleic acid synthesis, and regulation of ion channels. Consequences of hypomagnesemia affecting multiple organs can be in overt or subtle presentations. Besides detailed history and complete physical examination, the assessment of urinary Mg2+ excretion is help to differentiate renal from extra-renal (gastrointestinal, tissue sequestration, and shifting) causes of hypomagnesemia. Renal hypomagnesemia can be caused by an increased glomerular filtration and impaired reabsorption in proximal tubular cells, thick ascending limb of the loop of Henle or distal convoluted tubules. A combination of renal Mg2+ wasting, familial history, age of onset, associated features, and exclusion of acquired etiologies point to inherited forms of renal hypomagnesemia. Based on clinical phenotypes, its definite genetic diagnosis can be simply grouped into specific, uncertain, and unknown gene mutations with a priority of genetic approach methods. An unequivocal molecular diagnosis could allow for prediction of clinical outcome, providing genetic counseling, avoiding unnecessary studies or interventions, and possibly uncovering the pathogenic mechanism. Given numerous identified genes responsible for Mg2+ transport in renal hypomagnesemia over the past two decades, several potential and specific molecular and cellular therapeutic strategies to correct hypomagnesemia are promising.

Background: Acute-on-chronic-liver failure (ACLF) demonstrates high short-term mortality rates and usually requires intensive care unit (ICU) admission. Accurate prognostication of these patients is pivotal for timely referral for liver transplantation. The superiority of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores in Asian patients with ACLF admitted to an ICU remains inconclusive. Aims: To compare the predictive performance of CLIF-C ACLF, CLIF-C ACLF lactate, and NACSELD-ACLF scores for one-month mortality. Methods: 276 consecutive cirrhotic patients with ACLF admitted to ICU were enrolled. The prognostic values for one-month mortality were assessed by AUROC analysis. Results: The primary cause of cirrhosis in this cohort was alcohol abuse (56.5%). AUROC analysis (95% confidence intervals) demonstrated that CLIF-C ACLF lactate [0.802 (0.747–0.856)] outperformed both CLIF-C ACLF [0.791 (0.733–0.848)] and NACSELD-ACLF [0.673 (0.606–0.740)] in predicting one-month mortality. However, no statistically significant difference was observed between the predictive abilities of CLIF-C ACLF and CLIF-C ACLF lactate. Conclusions: In critically ill cirrhotic patients with ACLF admitted to the hepatology ICU, CLIF ACLF-lactate outperformed CLIF-C ACLF and NACSELD-ACLF in predicting one-month mortality. Nevertheless, no statistically significant difference was observed between CLIF-C ACLF and CLIF-C ACLF lactate. Larger-scale multi-center prospective studies are warranted to validate these results.

Background: Although osmotic demyelination syndrome (ODS) has been well known to be associated with a rapid correction of sodium (Na+) in patients with chronic hyponatremia, its risk factors and clinical outcomes have not been examined in Taiwan. Aim: The aim of the study was to analyze the underlying causes and overlooked risk factors in patients with ODS. Methods: We retrospectively collected chronic hyponatremic patients developing ODS and analyzed their clinical characteristics. Results: Fourteen patients (7 males and 7 females) with a mean age of 62.7 ± 17.9 years old were enrolled. Their underlying causes included gastrointestinal illness with poor intake (n = 7), chronic use of diuretics (n = 2), syndrome of inappropriate antidiuretic hormone (n = 2), pneumonia (n = 2), and hypopituitarism (n = 1). Their serum Na+ was 107.2 ± 1.2 mmol/L with mild hypokalemia (potassium 3.1 ± 7 mmol/L), hypoalbuminemia (albumin, 3.4 ± 0.6 g/dL), and hypophosphatemia (phosphorus, 2.3 ± 1.0 mg/dL). Their mean Na+ correction rate was 8.4 ± 9 mmol/L/day and most patients (60%) developed ODS in first 3 days. Their manifestations included delirium, seizures, unstable gait, aphasia, and drowsy consciousness. Brain magnetic resonance imaging demonstrated that 42.8% had isolated central pontine myelinolysis. Totally, 43% of ODS patients had unfavorable outcome with death and disability. In addition, patients with rapid Na+ correction rate (>12 mmol/L/day, n = 4) usually exhibited significant hypokalemia (2.5 ± 0.4 vs. 3.5 ± 0.7 mmol/L, P < 0.05) as compared with those without. Conclusion: Nutritional status and concurrent electrolyte deficiencies such as hypokalemia are major risk factors in patients with ODS. Clinicians should timely recognize these potential risks of ODS and reduce Na+ correction rate to avoid catastrophic outcomes.

Abstract Dyskalemias are common electrolyte disorders associated with high cardiovascular risk. Artificial intelligence (AI)-assisted electrocardiography (ECG) has been evaluated as an early-detection approach for dyskalemia. The aims of this study were to determine the clinical accuracy of AI-assisted ECG for dyskalemia and prognostic ability on clinical outcomes such as all-cause mortality, hospitalizations, and ED revisits. This retrospective cohort study was done at two hospitals within a health system from May 2019 to December 2020. In total, 26,499 patients with 34,803 emergency department (ED) visits to an academic medical center and 6492 ED visits from 4747 patients to a community hospital who had a 12-lead ECG to estimate ECG-K+ and serum laboratory potassium measurement (Lab-K+) within 1 h were included. ECG-K+ had mean absolute errors (MAEs) of ≤0.365 mmol/L. Area under receiver operating characteristic curves for ECG-K+ to predict moderate-to-severe hypokalemia (Lab-K+ ≤3 mmol/L) and moderate-to-severe hyperkalemia (Lab-K+ ≥ 6 mmol/L) were >0.85 and >0.95, respectively. The U-shaped relationships between K+ concentration and adverse outcomes were more prominent for ECG-K+ than for Lab-K+. ECG-K+ and Lab-K+ hyperkalemia were associated with high HRs for 30-day all-cause mortality. Compared to hypokalemic Lab-K+, patients with hypokalemic ECG-K+ had significantly higher risk for adverse outcomes after full confounder adjustment. In addition, patients with normal Lab-K+ but dyskalemic ECG-K+ (pseudo-positive) also exhibited more co-morbidities and had worse outcomes. Point-of-care bloodless AI ECG-K+ not only rapidly identified potentially severe hypo- and hyperkalemia, but also may serve as a biomarker for medical complexity and an independent predictor for adverse outcomes.

Statin treatment for hypercholesterolemia may cause reversible rhabdomyolysis and acute kidney injury in susceptible patients. However, persistent rhabdomyolysis and acute kidney injury following discontinuation of statins require careful evaluation of the underlying causes to avoid missing a curable disease. We describe a 50-year-old woman with hypercholesterolemia [total cholesterol 345 mg/dl, low-density lipoprotein cholesterol (LDL-C) 266 mg/dL] on atorvastatin therapy (40 mg daily) for 1 month that presented with myalgia and muscle weakness. Relevant laboratory studies revealed persistent higher hypercholesterolemia with total cholesterol (312 mg/dL), high creatine kinase (CK) (5,178 U/L), and high creatinine levels (1.5 mg/dL) without dysmorphic red blood cells and proteinuria. Despite the cessation of statin therapy, serum CK level increased to 9,594 U/L, and creatinine remained at 1.5 mg/dL. A thorough work-up to assess potential underlying causes indicated low T3 and free T4 and high thyroid-stimulating hormone (TSH) levels, consistent with hypothyroidism. With aggressive thyroxine replacement for 1 month, all of the clinical features, along with elevated serum CK and creatinine levels, were completely resolved. This case highlights the fact that hypothyroidism must be kept in mind as a potential cause of concomitant myopathy and kidney injury, especially in patients with statin-resistant hypercholesterolemia.

Abstract Recurrent mutations in the SLC12A3 gene responsible for autosomal recessive Gitelman syndrome (GS) are frequently reported, but the exact prevalence is unknown. The rapid detection of recurrent SLC12A3 mutations may help in the early diagnosis of GS. This study was aimed to investigate the prevalence of recurrent SLC12A3 mutations in a Taiwan cohort of GS families and develop a simple and rapid method to detect recurrent SLC12A3 mutations. One hundred and thirty independent Taiwan families with genetically confirmed GS were consecutively enrolled to define recurrent SLC12A3 mutations and determine their prevalence. Using TaqMan probe-based real-time polymerase chain reaction, we designed a mutation detection plate with all recurrent mutations. We validated this mutation detection plate and tested its feasibility in newly diagnosed GS patients. A total of 57 mutations in the SLC12A3 gene were identified and 22 including 2 deep intronic mutations were recurrent mutations consisting of 87.1% (242/278, 18 triple) of all allelic mutations. The recurrent mutation-based TaqMan assays were fully validated with excellent sensitivity and specificity in genetically diagnosed GS patients and healthy subjects. In clinical validation, recurrent mutations were recognized in 92.0% of allelic mutations from 12 GS patients within 4 h and all were confirmed by direct sequencing. Recurrent SLC12A3 mutations are very common in Taiwan GS patients and can be rapidly identified by this recurrent mutation-based SLC12A3 mutation plate.

Concurrent severe rhabdomyolysis and acute liver damage are rarely reported in the setting of acute high-altitude illness (AHAI). We described a 53-year-old healthy mountain climber who experienced headache and dyspnea at the summit of Snow Mountain (Xueshan; 3,886 m above sea level) and presented to the emergency room with generalized malaise, diffuse muscle pain, and tea-colored urine. His consciousness was alert, and he had a blood pressure of 114/74 mmHg, heart rate of 66/min, and body temperature of 36.8°C. Myalgia of the bilateral lower limbs, diminished skin turgor, dry oral mucosa, and tea-colored urine were notable. Urinalysis showed positive occult blood without red blood cells. The most striking blood laboratory data included creatine kinase (CK) 33,765 IU/L, inappropriately high aspartate aminotransferase (AST) 2,882 IU/L and alanine aminotransferase (ALT) 2,259 IU/L (CK/AST ratio 11.7, CK/ALT ratio 14.9), creatinine 1.5 mg/dl, serum urea nitrogen (BUN) 26 mg/dl, total bilirubin 1.7 mg/dl, ammonia 147 μg/ml, lactate 2.5 mmol/L, and prothrombin time 17.8 s. The meticulous search for the underlying causes of acute liver injury was non-revealing. With volume repletion, mannitol use, and urine alkalization coupled with avoidance of nephrotoxic and hepatotoxic agents, his clinical features and laboratory abnormality completely resolved in 3 weeks. Despite rarity, severe rhabdomyolysis and/oracute liver injury as a potential life-threatening condition requiring urgent management may occur in high-altitude hypobaric hypoxia.

Cefazolin-induced neurotoxicity with the documented toxic concentration has not been reported in uremic patients on continuous ambulatory peritoneal dialysis (CAPD). We described an elderly female on CAPD for years presented with newly-onset status epilepticus. Her body weight was 60 kg. And she had received intraperitoneal ceftazidime and cefazolin 1.5 g once daily for her CAPD peritonitis 5 days earlier. She was disoriented but afebrile with normal blood pressure. Laboratory data showed WBC 18,480/uL, pH 6.93, HCO3- 8.5 mmol/L, free Ca2+ 3.5 mmol/L, and albumin 2.8 g/dL. Although antiepileptic drugs and hypocalcemia correction ceased the seizure, her consciousness remained semi-coma. Image studies of brain were unremarkable. Despite undetectable serum ceftazidime, her cefazolin trough level was 149.5 μg/mL. Emergent hemodialysis rapidly resolved her neurological features accompanied by a markedly declined serum cefazolin concentration (28.6 μg/mL). Higher intraperitoneal cefazolin dosing in patients on CAPD may cause drug-induced neurotoxicity with status epilepticus which could be rapidly corrected by hemodialysis.

CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. Mutations in CNNM2 have been reported to cause hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome. However, the clinical and functional effect of CNNM2 mutations remains incompletely understood. We report our clinical encounter with a 1-year-old infant with HSMR features. Mutation screening for this trio family was performed using next-generation sequencing (NGS)-based whole exome sequencing (WES) with the identified mutation verified by Sanger sequencing. We identified a de novo heterozygous mutation c.G1439T (R480L) in the essential cystathionine β-synthase (CBS) domain of CNNM2 encoding CNNM2 (cyclin M2) without any other gene mutations related to hypomagnesemia. The amino acid involved in this missense mutation was conserved in different species. It was also found to be pathogenic based on the different software prediction models and ACGME criteria. In vitro studies revealed a higher expression of the CNNM2-R480L mutant protein compared to that of the wild-type CNNM2. Like the CNNM2-wild type, proper localization of CNNM2-R480L was shown on immunocytochemistry images. The Mg2+ efflux assay in murine DCT (mDCT) cells revealed a significant increase in intracellular Mg2+ green in CNNM2-R480L compared to that in CNNM2-WT. By using a simulation model, we illustrate that the R480L mutation impaired the interaction between CNNM2 and ATP-Mg2+. We propose that this novel R480L mutation in the CNNM2 gene led to impaired binding between Mg2+-ATP and CNNM2 and diminished Mg2+ efflux, manifesting clinically as refractory hypomagnesemia.

Key Clinical Message Abnormal acid‐base status (metabolic acidosis or alkalosis), inappropriate urine electrolytes excretion (high or low Na+ and Cl−), and higher required dose of potassium supplement (4‐5 mmol/kg) are suggestive of non‐TPP causes of hypokalemia.

Background/Purpose: End-stage kidney disease (ESKD) is a global burden that reflects each country's unique condition. We used the National Health Insurance Research Database (NHIRD) of Taiwan to decipher changes in the mortality and international survival rates and to determine the effectiveness of the pre-end-stage renal disease care program (pre-ESRD care program) to guide future health policies for ESKD. Methods: We conducted a retrospective cohort analysis of the NHIRD data along with records from the catastrophic illness certificate program of ESKD patients from 2010 to 2018. Results: From 2010 to 2018, the annual dialysis-related mortality rate in Taiwan increased from 10.6 to 11.8 deaths per hundred patient-years. The mortality rate for patients below 40 years appears to be decreasing, reflecting the improved quality of care for ESKD patients. Patients above 75 years showed increasing mortality, indicating the prolonged survival and aging of the ESKD population. Patients undergoing dialysis who participated in the pre-ESRD care program had a higher post-dialysis initiation life expectancy than those who did not participate. Among the program enrollees, the post-dialysis initiation life expectancy was higher in patients who had participated for more than one year. Taiwan has one of the highest ESKD patient survival rates globally. Conclusion: From 2010 to 2018, the reduced mortality in young patients and aging of the ESKD population might indicate that the quality of care in Taiwan for ESKD has improved. Furthermore, a better survival rate after dialysis initiation was observed in the pre-ESRD care program participants.

Severe lactic acidosis, a mitochondrial toxicity caused by the recommended standard dosage of linezolid (LZD), may occur in patients with impaired renal function. We describe an adult male who underwent kidney transplantation with stably impaired renal function, severe dyspnea, and abdominal discomfort. He received a standard oral dose of LZD (600 mg twice daily) and azithromycin for three weeks with a reduced immunosuppressant dose due to pulmonary non-tuberculosis mycobacterial infection. He was alert and afebrile, with a blood pressure of 140/60 mmHg. Pertinent laboratory data showed: pH 7.12, PaCO2 13.6 mmHg; HCO3- 4.3 mmol/L and serum lactate 18.4 mmol/L. His trough serum LZD concentration reached toxic levels (21.4 μg/mL). With hemodialysis, his clinical symptoms improved, with a decline in serum LZD (9.8μg/mL) and lactate (3.2 mmol/L). Chronic standard dose LZD in patients with impaired renal function can lead to life-threatening lactic acidosis, especially in coexisting conditions that reduce LZD metabolism.

The rare and severe adverse effects associated with coronavirus disease of 2019 (COVID-19) vaccination have been under-appreciated, resulting in many instances of inappropriate management. We describe the case of an elderly woman who developed anti-neutrophil cytoplasmic antibody-associated vasculitis with pulmonary renal syndrome approximately 3 weeks after the first dose of COVID-19 mRNA vaccination (Moderna). Her nasopharyngeal polymerase chain reaction test for the COVID-19 RNA virus was negative. Gross hematuria, heavy proteinuria, acute renal failure (serum creatinine up to 6.5 mg/dL), and hemoptysis coupled with a marked increase in serum anti-myeloperoxidase-O antibody were observed. Renal biopsy showed severe vasculitis with pauci-immune crescent glomerulonephritis. The pulmonary hemorrhage was resolved and renal function improved following combined plasma exchange and the administration of systemic steroids and anti-CD20 therapy. The early examination of urinalysis and renal function may be crucial for identifying glomerulonephritis and acute renal failure in susceptible patients after COVID-19 vaccination.

Cardiovascular events such as myocarditis following mRNA COVID-19 vaccination are increasing. We present a 67-year-old postmenopausal woman with Takotsubo Syndrome and Graves’ disease after mRNA COVID-19 vaccination. She developed chest pain and shortness of breath one week after vaccination. An electrocardiogram revealed ST elevation in the precordial leads. Coronary angiography revealed the absence of obstructive coronary artery disease, and the left ventriculography showed a typical feature with apical ballooning. Laboratory workup showed the elevation of free T4 and thyrotropin receptor antibodies. It was presumed that Takotsubo Syndrome and Graves’ disease were probably related to the COVID-19 mRNA vaccination. The patient was treated with low-dose bisoprolol, diuretics, carbimazole, and steroid and discharged uneventfully. The mRNA COVID-19 vaccination is still safe and effective to defend against COVID-19 pandemic. However, clinicians should be aware of the possible cardiovascular adverse events other than myocarditis following vaccination.

Background: The utility of urinary extracellular vesicles (uEVs) to faithfully represent the changes of renal tubular protein expression remains unclear. We aimed to evaluate renal tubular sodium (Na+) or potassium (K+) associated transporters expression from uEVs and kidney tissues in patients with Gitelman syndrome (GS) caused by inactivating mutations in SLC12A3.Methods: uEVs were isolated by ultracentrifugation from 10 genetically-confirmed GS patients. Membrane transporters including Na+-hydrogen exchanger 3 (NHE3), Na+/K+/2Cl− cotransporter (NKCC2), NaCl cotransporter (NCC), phosphorylated NCC (p-NCC), epithelial Na+ channel β (ENaCβ), pendrin, renal outer medullary K1 channel (ROMK), and large-conductance, voltage-activated and Ca2+-sensitive K+ channel (Maxi-K) were examined by immunoblotting of uEVs and immunofluorescence of biopsied kidney tissues. Healthy and disease (bulimic patients) controls were also enrolled.Results: Characterization of uEVs was confirmed by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. Compared with healthy controls, uEVs from GS patients showed NCC and p-NCC abundance were markedly attenuated but NHE3, ENaCβ, and pendrin abundance significantly increased. ROMK and Maxi-K abundance were also significantly accentuated. Immunofluorescence of the representative kidney tissues from GS patients also demonstrated the similar findings to uEVs. uEVs from bulimic patients showed an increased abundance of NCC and p-NCC as well as NHE3, NKCC2, ENaCβ, pendrin, ROMK and Maxi-K, akin to that in immunofluorescence of their kidney tissues.Conclusion: uEVs could be a non-invasive tool to diagnose and evaluate renal tubular transporter adaptation in patients with GS and may be applied to other renal tubular diseases.

Abstract Background Renal artery stenosis is one of the secondary causes of pediatric hypertension. Cases with critical unilateral renal artery stenosis manifesting with the hyponatremic hypertensive syndrome are rare and a comprehensive description of this disorder in the pediatric population is lacking in the literature. Case presentation We describe a 4-year-old boy who presented with severe hypertension, profound hyponatremia, hypokalemia, nephrotic range proteinuria, and polyuria. Distinctly, the diagnosis of hyponatremic hypertensive syndrome secondary to unilateral renal artery stenosis was confirmed in light of laboratory and radiographic findings of severe natriuresis, elevated renin, and unilateral small kidney. Two weeks following nephrectomy, there was resolution of hyponatremia, hypokalemia, nephrotic range proteinuria and hypertension. Conclusions Findings of hyponatremia, hypokalemia, hypertension, polyuria, and unilateral renal hypoplasia can be attributed to a unifying pathology of unilateral renal artery stenosis.

Abstract Background Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS. Results Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an “aged face” comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities. Conclusions Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.

Objective: Renal thrombotic microangiopathy (TMA) is associated with complement overactivation and poor outcome in patients with lupus nephritis (LN). The role of genetic makeup of complement system in these patients remains to be elucidated.Methods: The clinical and laboratory characteristics of 100 patients with LN during 2010–2017 were retrospectively analyzed. LN patients with renal TMA and condition-matched LN patients without renal TMA were studied. Twenty normal subjects were also enrolled for comparison. Whole exome sequence followed by Sanger sequence was used in our study cohort.Results: Eight patients with renal TMA and eight condition-matched patients were enrolled from 100 LN patients with mean age 11.2 ± 2.0 years. Compared with condition-matched LN patients without renal TMA, LN patients with renal TMA exhibited statistically higher serum urea. Although most patients with renal TMA responded to plasma exchange, they had significantly higher relapse rate of nephritis, lower remission rate, and higher risk of end-stage renal disease and mortality. Compared with patients without renal TMA and normal subjects, those with renal TMA had significantly lower serum complement factor H (CFH) and plasma ADAMTS13 activity. Molecular analysis of all 100 patients with LN uncovered that three patients with renal TMA harbored mutations, two missense and non-sense, on CFI and CFHR2. The non-sense mutation, E302X, on CFI may impair its interaction C3b/CFH complex by loss of the heavy chain of complement factor I on simulation model.Conclusion: In addition to low serum CFH level and plasma ADAMTS13 activity, defects in genes responsible for complement regulatory proteins may contribute to the development of renal TMA in patients with LN.

A phytobezoar is defined as an accumulation of poorly digested fruit and vegetable fibers in the gastrointestinal tract. Phytobezoar-induced small bowel obstruction is an uncommon entity and is usually removed surgically. We herein describe an elderly man undergoing dialysis who developed a phytobezoar because of excessive consumption of high-fiber fruits and inappropriate chewing. His potential predisposing factors were dialysis-related lifestyle changes, reduced activity levels, fluid restriction, and gastrointestinal motility dysfunction; however, he had no history of gastric surgery. The patient’s clinical history and characteristic imaging features aided in the diagnosis. He underwent medical treatment, and his recovery was uneventful. This case highlights the importance of an awareness of phytobezoar-induced small bowel obstruction in patients at increased risk of developing bezoars and demonstrates that this condition can occur in the absence of previous gastric surgery. We believe that elderly patients undergoing dialysis are at increased risk of developing bezoars. Excessive consumption of a strictly fibrous diet and insufficient chewing exacerbate the risk. A detailed dietary history and imaging features can aid in early diagnosis, leading to appropriate medical or surgical care. Surgical treatment is not inevitable in all cases. Individualized dietary suggestions in these patients are important for effective preventive control.

Introduction: Na+-K+-2Cl− cotransporter isoform 1 (NKCC1) is important in regulating intracellular K+ and Cl− homeostasis and cell volume. In this study, we investigated a role of NKCC1 in regulating glioma K+ influx and proliferation in response to apoptosis inducing chemotherapeutic drug temozolomide (TMZ). The efficacy of a new bumetanide (BMT)-derivative NKCC1 inhibitor STS66 [3-(butylamino)-2-phenoxy-5-[(2, 2, 2-trifluoroethylamino) methyl] benzenesulfonamide] in blocking NKCC1 activity was compared with well-established NKCC1 inhibitor BMT.Methods: NKCC1 activity in cultured mouse GL26 and SB28-GFP glioma cells was measured by Rb+ (K+) influx. The WNK1-SPAK/OSR1-NKCC1 signaling and AKT/ERK-mTOR signaling protein expression and activation were assessed by immunoblotting. Cell growth was determined by bromodeoxyuridine (BrdU) incorporation assay, MTT proliferation assay, and cell cycle analysis. Impact of STS66 and BMT on cell Rb+ influx and growth was measured in glioma cells treated with or without TMZ.Results: Rb+ influx assay showed that 10 μM BMT markedly decreased the total Rb+ influx and no additional inhibition detected at >10 μM BMT. In contrast, the maximum effects of STS66 on Rb+ influx inhibition were at 40–60 μM. Both BMT and STS66 reduced TMZ-mediated NKCC1 activation and protein upregulation. Glioma cell growth can be reduced by STS66. The most robust inhibition of glioma growth, cell cycle, and AKT/ERK signaling was achieved by the TMZ + STS66 treatment.Conclusion: The new BMT-derivative NKCC1 inhibitor STS66 is more effective than BMT in reducing glioma cell growth in part by inhibiting NKCC1-mediated K+ influx. TMZ + STS66 combination treatment reduces glioma cell growth via inhibiting cell cycle and AKT-ERK signaling.

Chronic kidney disease (CKD) refers to the phenomenon of progressive decline in the glomerular filtration rate accompanied by adverse consequences, including fluid retention, electrolyte imbalance, and an increased cardiovascular risk compared to those with normal renal function. The triggers for the irreversible renal function deterioration are multifactorial, and diabetes mellitus serves as a major contributor to the development of CKD, namely diabetic kidney disease (DKD). Recently, epigenetic dysregulation emerged as a pivotal player steering the progression of DKD, partly resulting from hyperglycemia-associated metabolic disturbances, rising oxidative stress, and/or uncontrolled inflammation. In this review, we describe the major epigenetic molecular mechanisms, followed by summarizing current understandings of the epigenetic alterations pertaining to DKD. We highlight the epigenetic regulatory processes involved in several crucial renal cell types: Mesangial cells, podocytes, tubular epithelia, and glomerular endothelial cells. Finally, we highlight epigenetic biomarkers and related therapeutic candidates that hold promising potential for the early detection of DKD and the amelioration of its progression.

We describe the case of a 62-year-old woman with schizophrenia and intellectual disability, who presented with intermittent muscle cramping for 2 weeks. A dysmorphic face and a positive Trousseau’s sign, but without ecchymosis or petechial lesion were noted. Laboratory data revealed impaired renal function (creatinine level = 1.6 mg/dL), severe hypocalcaemia (total calcium level = 5.7 mg/dL) with low urinary calcium excretion (13.2 mg/day), hyperphosphatemia (phosphate level = 7.3 mg/dL), and low intact parathyroid hormone level (52.5 pg/mL)—indicating primary hypoparathyroidism. A blood smear revealed thrombocytopenia (30,000 thrombocytes/µL) and giant platelets—indicating macrothrombocytopenia. Chromosome 22q11.2 deletion syndrome (22q11.2DS) in the deficient chromosome 22 was confirmed using multiplex ligation-dependent probe amplification showing haploinsufficiency in GP1BB and TBX-1. Cooccurrence of hypoparathyroidism and macrothrombocytopenia in 22q11.2DS is rare and can easily be misdiagnosed as idiopathic thrombocytopenia purpura and inappropriate splenectomy or chemotherapy can aggravate hypoparathyroidism. Early diagnosis of 22q11.2DS, characterized by hypoparathyroidism and macrothrombocytopenia, in elderly patients with schizophrenia can facilitate in avoiding circuitous diagnosis and inappropriate management.

Abstract Background The clinical consequences of starting chronic peritoneal dialysis (PD) after emergent dialysis via a temporary hemodialysis (HD) catheter has rarely been evaluated within a full spectrum of treated end-stage renal disease (ESRD). We investigated the longer-term outcomes of patients undergoing emergent-start PD in comparison with that of other practices of PD or HD in a prospective cohort of new-onset ESRD. Methods This was a 2-year prospective observational study. We enrolled 507 incident ESRD patients, among them 111 chose PD (43 planned-start, 68 emergent-start) and 396 chose HD (116 planned-start, 280 emergent-start) as the long-term dialysis modality. The logistic regression model was used to identify variables associated with emergent-start dialysis. The Kaplan–Meier survival analysis was used to determine patient survival and technique failure. The propensity score-adjusted Cox regression model was used to identify factors associated with patient outcomes. Results During the 2-year follow-up, we observed 5 (4.5%) deaths, 15 (13.5%) death-censored technique failures (transfer to HD) and 3 (2.7%) renal transplantations occurring in the PD population. Lack of predialysis education, lower predialysis estimated glomerular filtration rate and serum albumin were predictors of being assigned to emergent dialysis initiation. The emergent starters of PD displayed similar risks of patient survival, technique failure and overall hospitalization, compared with the planned-start counterparts. By contrast, the concurrent planned-start and emergent-start HD patients with an arteriovenous fistula or graft were protected from early overall death and access infection-related mortality, compared with the emergent HD starters using a central venous catheter. Conclusions In late-referred chronic kidney disease patients who have initiated emergent dialysis via a temporary HD catheter, post-initiation PD can be a safe and effective long-term treatment option. Nevertheless, due to the potential complications and cost concerns, such practice of PD initiation would better be replaced with a planned-start mode by employing more effective predialysis therapeutic education and timely catheter placement.

Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

In this study, based on the slope of power versus voltage, a novel maximum-power-point tracking algorithm using a neural network compensator was proposed and implemented on a TI TMS320F28335 digital signal processing chip, which can easily process the input signals conversion and the complex floating-point computation on the neural network of the proposed control scheme. Because the output power of the photovoltaic system is a function of the solar irradiation, cell temperature, and characteristics of the photovoltaic array, the analytic solution for obtaining the maximum power is difficult to obtain due to its complexity, nonlinearity, and uncertainties of parameters. The innovation of this work is to obtain the maximum power of the photovoltaic system using a neural network with the idea of transferring the maximum-power-point tracking problem into a proportional-integral current control problem despite the variation in solar irradiation, cell temperature, and the electrical load characteristics. The current controller parameters are determined via a genetic algorithm for finding the controller parameters by the minimization of a complicatedly nonlinear performance index function. The experimental result shows the output power of the photovoltaic system, which consists of the series connection of two 155-W TYN-155S5 modules, is 267.42 W at certain solar irradiation and ambient temperature. From the simulation and experimental results, the validity of the proposed controller was verified.

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.

Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

Conscious change following head injury needs a scrutiny of the "nontraumatic" cause to avoid inappropriate management and catastrophic complication. We described an 81-year-old diabetic woman with advanced chronic kidney disease (CKD) (estimated glomerular filtration rate: 6 ml/min/1.73 m 2 ) re-presented to Emergency Department with altered mentality and generalized muscular hypotonia 2 days after falling with a head injury. Her initial mentality was alert, and computed tomography of the brain was negative for organic lesions; she has been given oral baclofen 10 mg daily to control her associated spastic back pain. The repeated laboratory and imaging studies were still unrevealing. Her serum baclofen concentration was markedly elevated (1437 ng/ml). With emergent hemodialysis for two sessions, complete elimination of serum baclofen concentration was accompanied by full recovery of her consciousness. Nontraumatic causes, especially drug-induced neurotoxicity, must be kept in mind in traumatic patients with CKD and unexplained neurological feature.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Recent evidence links MHA to mutations in the MYH9 gene. MHA has not been reported in Taiwan before. We report a 25-year-old Taiwanese man who presented with prolonged bleeding after dental extraction. Examination of peripheral blood smear revealed thrombocytopenia (platelet = 35,000/μL), giant platelets, and Döhle-like cytoplasmic inclusions in neutrophils. A strong family history of thrombocytopenia favored hereditary macrothrombocytopenia over idiopathic thrombocytopenic purpura (ITP). Electron microscopy revealed a spindle shape and parallel order of filaments in the inclusions, consistent with the diagnosis of MHA. We performed mutational analysis using polymerase chain reaction followed by direct sequence of the MYH9 gene for the patient, his maternal uncle and cousin, and all showed the same heterozygous R1933X mutation in exon 40. MHA should be considered when a young patient has thrombocytopenia, frequently misdiagnosed as ITP. Morphological examination of peripheral blood smear, family history tracing and genetic studies are required to make an accurate diagnosis and avoid unnecessary and even harmful therapies such as corticosteroids and splenectomy.

Background: Coronary artery disease occurs frequently and is a major cause of morbidity and mortality in patients with chronic renal failure. Because the number of patients requiring dialysis for end-stage renal disease (ESRD) has increased, the number of patients in this population who require coronary artery bypass grafting (CABG) has increased. The aim of this study was to examine the effect of early hemodialysis (HD) on the early surgical outcomes of ESRD patients undergoing CABG. Materials and Methods: Fifty-nine dialysis-dependent patients who underwent isolated CABG with cardiopulmonary bypass (CPB) were enrolled in this study. These patients were divided into two groups based on the timing of the first postoperation HD session. In the early HD group, HD was performed within 6 h postoperation; in the scheduled HD group, HD was performed >6 h postoperation. The preoperative characteristics, operative variables, and postoperative outcomes were retrospectively analyzed. Results: The time to first HD after CABG was 2.43 ± 1.58 h in the early HD group and 20.68 ± 6.98 h in the scheduled HD group (P < 0.001). There were no significant differences in the operative variables, namely duration of operation, CPB time, and aortic cross-clamp time, between the two groups. The incidence of postoperative pneumonia was higher in the scheduled HD group (31.8%) than in the early HD group (2.7%). There was a trend of decreased incidence of postoperative pneumonia in the early HD group with marginal significance from the univariate analysis. The intensive care unit and hospital stay duration of both groups were similar. Nine patients died in the hospital, yielding an overall 30-day mortality of 8.47%. Conclusion: In dialysis-dependent patients who underwent CABG, the short-term outcomes and surgical mortality were acceptable. Dialysis-dependent renal failure should not be considered a contraindication for CABG. Early HD in the postoperative period demonstrated the trend to reduce the incidence of postoperative pneumonia; however, other parameters of surgical outcomes were insignificant.

Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr−/−) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr−/− mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease.

Idiopathic membranous nephropathy (MN) is an autoimmune-mediated glomerulonephritis and a common cause of nephrotic syndrome in adults. There are limited available treatments for MN. We assessed the efficacy of resveratrol (RSV) therapy for treatment of MN in a murine model of this disease.Murine MN was experimentally induced by daily subcutaneous administration of cationic bovine serum albumin, with phosphate-buffered saline used in control mice. MN mice were untreated or given RSV. Disease severity and pathogenesis was assessed by determination of metabolic and histopathology profiles, lymphocyte subsets, immunoglobulin production, oxidative stress, apoptosis, and production of heme oxygenase-1 (HO1).MN mice given RSV had significantly reduced proteinuria and a marked amelioration of glomerular lesions. RSV also significantly attenuated immunofluorescent staining of C3, although there were no changes of serum immunoglobulin levels or immunocomplex deposition in the kidneys. RSV treatment of MN mice also reduced the production of reactive oxygen species (ROS), reduced cell apoptosis, and upregulated heme oxygenase 1 (HO1). Inhibition of HO1 with tin protoporphyrin IX partially reversed the renoprotective effects of RSV. The HO1 induced by RSV maybe via Nrf2 signaling.Our results show that RSV increased the expression of HO1 and ameliorated the effects of membranous nephropathy in a mouse model due to its anti-complement, anti-oxidative, and anti-apoptotic effects. RSV appears to have potential as a treatment for MN.

The relationship between diabetes mellitus (DM) and cancer incidence has been evaluated in limited kinds of cancer. The effect of anti-diabetic therapy (ADT) on carcinogenesis among diabetic patients is also unclear.Using population-based representative insurance claims data in Taiwan, 36,270 DM patients and 145,080 comparison subjects without DM were identified from claims from 2005 to 2010. The association between the top ten leading causes of cancer-related death in Taiwan and DM was evaluated. Whether ADT altered the risk of developing cancer was also investigated.Incidence of cancer at any site was significantly higher in patients with DM than in those without (p

Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na(+)-Cl(-) cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 (D561A/+) mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 (-/-)) and Spak knockout (Spak (-/-)) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 (D561A/+), KSP-Osr1 (-/-), and Spak (-/-) mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 (D561A/+) and Wnk4 (D561A/+).KSP-Osr1 (-/-) mice while phosphorylated Ncc normalized in Wnk4 (D561A/+).Spak (-/-) mice. Furthermore, Wnk4 (D561A/+).KSP-Osr1 (-/-) mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 (D561A/+).Spak (-/-) mice exhibited normal responses. Wnk4(D561A/+).Spak (-/-).KSP-Osr1 (-/-) triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.

The NaCl cotransporter (NCC) is essential for sodium reabsorption at the distal convoluted tubules (DCT), and its phosphorylation increases its transport activity and apical membrane localization. Although insulin has been reported to increase sodium reabsorption in the kidney, the linkage between insulin and NCC phosphorylation has not yet been investigated. This study examined whether insulin regulates NCC phosphorylation. In cultured mpkDCT cells, insulin increased phosphorylation of STE20/SPS1-related proline-alanine-rich kinase (SPAK) and NCC in a dose-dependent manner. This insulin-induced phosphorylation of NCC was suppressed in WNK4 and SPAK knockdown cells. In addition, Ly294002, a PI3K inhibitor, decreased the insulin effect on SPAK and NCC phosphorylation, indicating that insulin induces phosphorylation of SPAK and NCC through PI3K and WNK4 in mpkDCT cells. Moreover, acute insulin administration to mice increased phosphorylation of oxidative stress-responsive kinase-1 (OSR1), SPAK and NCC in the kidney. Time-course experiments in mpkDCT cells and mice suggested that SPAK is upstream of NCC in this insulin-induced NCC phosphorylation mechanism, which was confirmed by the lack of insulin-induced NCC phosphorylation in SPAK knockout mice. Moreover, insulin administration to WNK4 hypomorphic mice did not increase phosphorylation of OSR1, SPAK and NCC in the kidney, suggesting that WNK4 is also involved in the insulin-induced OSR1, SPAK and NCC phosphorylation mechanism in vivo. The present results demonstrated that insulin is a potent regulator of NCC phosphorylation in the kidney, and that WNK4 and SPAK are involved in this mechanism of NCC phosphorylation by insulin.

The fundamental mechanisms by which a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Excess dietary salt intake acts as a risk factor for autoimmune diseases; however, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high salt intake on autoimmune diabetes, nonobese diabetic (NOD) mice were fed a high-salt diet (HSD) or a normal-salt diet (NSD) from6 to 12 weeks of age and monitored for diabetes development. Our results revealed that the HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T-cell- autonomous manner when compared with the NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T-cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared with HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T-cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T-cell pathogenicity is a central player linking high-salt-intake influences to immunopathophysiology of diabetogenesis in NODmice. [ABSTRACT FROM AUTHOR]