Galectin-3 contributes to pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis, and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

Icodextrin-induced acute generalized exanthematous pustulosis in a patient with peritoneal dialysis.

Icodextrin has been widely prescribed for peritoneal dialysis (PD) patients with inadequate ultrafiltration, but icodextrin induced acute generalized exanthematous pustulosis (AGEP) has been not well recognized in clinical practice. We described a young-aged female with IgA nephropathy and end stage kidney disease under continuous automated peritoneal dialysis. She developed skin erythema with exfoliation over the groin 7th day after initiation of icodextrin based PD dialysate. Initially, her scaling skin lesion with pinhead-sized pustules affected the bilateral inguinal folds, and then it extended to general trunk accompanied by pruritus. She was admitted because of deterioration of skin lesion on 14th day of icodextrin exposure. She was afebrile and physical examination was notable for widespread erythematous papules with pruritus extending over her groins and trunk. Pertinent laboratory examination showed leukocytosis of 18 970 cells/µL with neutrophile count of 17 642 cells/µL (92.3%), and c-reactive-protein: 3.39 mg/dL. Skin biopsy revealed multifocal sub corneal abscess with papillary dermal edema, and upper-dermal neutrophilia with perivascular accentuation, consistent with the diagnosis of AGEP. After discontinuation of PD, she underwent temporary high-flux haemodialysis with treatment of steroid and antihistamine. Her dermatologic lesion resolved without any skin sequalae completely within 4 days, and she underwent icodextrin-free peritoneal dialysis at 17th day. This case highlighted the fact that icodextrin-induced AGEP should be early recognized to avoid inappropriate management.

'Aquaporin-omics': mechanisms of aquaporin-2 loss in polyuric disorders.

Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin-2 (AQP2) from collecting duct principal cells, explaining the associated polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium-induced NDI, unilateral ureteral obstruction, endotoxin-induced NDI) or proteomics (hypokalaemia-associated NDI, hypercalcaemia-associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress-sensor proteins, namely death receptors and stress-sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. KEY POINTS: Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin-2 (AQP2) protein is a common feature. Investigations of acquired NDI using transcriptomics (RNA-seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss. Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling. These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression.

Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain.

Mutations in the Kelch-like 3 (KLHL3) gene are the most common cause of inherited pseudohypoaldosteronism type II (PHAII) featuring thiazide-sensitive hypertension and hyperkalemic metabolic acidosis. Although Klhl3R528H/+ knock-in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense KLHL3 mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed Klhl3 KI mice harboring a nonsense W523X mutation (corresponding to the human KLHL3 W470X mutation). Both heterozygous and homozygous Klhl3W523X/+ KI mice exhibited typical PHAII with low-renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of Klhl3 mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1/4-Spak/Osr1-N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p-)Spak, total Ncc, and p-Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk-mediated Ncc pathway. In vitro studies showed that the human KLHL3 W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense Klhl3W523X/+ mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK-mediated Na+ -Cl- co-transporter reiterated the in vivo pathogenic role of nonsense KLHL3 mutations in PHAII.

Early Molecular Events Mediating Loss of Aquaporin-2 during Ureteral Obstruction in Rats.

BACKGROUND: Ureteral obstruction is marked by disappearance of the vasopressin-dependent water channel aquaporin-2 (AQP2) in the renal collecting duct and polyuria upon reversal. Most studies of unilateral ureteral obstruction (UUO) models have examined late time points, obscuring the early signals that trigger loss of AQP2. METHODS: We performed RNA-Seq on microdissected rat cortical collecting ducts (CCDs) to identify early signaling pathways after establishment of UUO. RESULTS: Vasopressin V2 receptor (AVPR2) mRNA was decreased 3 hours after UUO, identifying one cause of AQP2 loss. Collecting duct principal cell differentiation markers were lost, including many not regulated by vasopressin. Immediate early genes in CCDs were widely induced 3 hours after UUO, including Myc, Atf3, and Fos (confirmed at the protein level). Simultaneously, expression of NF-κB signaling response genes known to repress Aqp2 increased. RNA-Seq for CCDs at an even earlier time point (30 minutes) showed widespread mRNA loss, indicating a "stunned" profile. Immunocytochemical labeling of markers of mRNA-degrading P-bodies DDX6 and 4E-T indicated an increase in P-body formation within 30 minutes. CONCLUSIONS: Immediately after establishment of UUO, collecting ducts manifest a stunned state with broad disappearance of mRNAs. Within 3 hours, there is upregulation of immediate early and inflammatory genes and disappearance of the V2 vasopressin receptor, resulting in loss of AQP2 (confirmed by lipopolysaccharide administration). The inflammatory response seen rapidly after UUO establishment may be relevant to both UUO-induced polyuria and long-term development of fibrosis in UUO kidneys.

A young man with secondary adrenal insufficiency due to empty sella syndrome.

BACKGROUND: Empty sella syndrome is characterized by a constellation of symptoms that encompass various systems, and includes endocrine, neurologic, ophthalmologic, and psychiatric presentations. We here report a case of a young man presenting with severe hyponatremia due to empty sella syndrome and focus on changes in electrolytes during corticosteroid supplementation. CASE REPORT: A 36-year-old man presented with general weakness, poor appetite, and dizziness for 4 days. Physical assessment revealed lower limbs nonpitting oedema. Pertinent laboratory data showed severe hyponatremia (sodium 108 mmol/L). Endocrine work-up revealed low cortisol levels at 1.17 µg/dL (reference: 4.82-19.5 µg/dL) and inappropriately normal adrenocorticotropic hormone levels at 12.4 pg/mL (reference: 0.1-46.0 pg/mL), indicating secondary adrenal insufficiency. Brain magnetic resonance imaging confirmed the diagnosis of empty sella syndrome. He developed delirium and agitation one day after cortisol supplementation with a sodium correction rate of 10 mmol/L/day, while hypokalaemia (potassium 3.4 mmol/L) also developed. The symptoms improved after lowering the serum sodium level. This patient was eventually discharged after 12 days of hospitalization when the serum sodium and potassium levels were 139 mmol/L and 3.5 mmol/L, respectively. CONCLUSION: Herein, we address the importance of timely diagnosis of empty sella syndrome in patients with hyponatremia and highlight the close monitoring of the changes in electrolytes during corticosteroid replacement.

Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

The Kelch-like 3 ( KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII-causing mutations in BTB domain of KLHL3 in vivo have not been investigated. We generated and analyzed Klhl3 knock-in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3M131V/+ KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with-no-lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20-related proline/alanine-rich kinase/oxidative stress response kinase 1-N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold-labeling electron microscopy. In microdissected renal tubules, Klhl3M131V/+ KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3M131V/+ KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.-Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.

RNA-Seq and protein mass spectrometry in microdissected kidney tubules reveal signaling processes initiating lithium-induced nephrogenic diabetes insipidus.

Lithium salts, used for treating bipolar disorder, frequently induce nephrogenic diabetes insipidus (NDI) thereby limiting therapeutic success. NDI is associated with loss of expression of the gene coding for the molecular water channel, aquaporin-2, in the renal collecting duct (CD). Here, we use systems biology methods in a well-established rat model of lithium-induced NDI to identify signaling pathways activated at the onset of polyuria. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts (CCDs) of rats after 72 hours without or with initiation of lithium chloride administration. Transcriptome-wide changes in mRNA abundances were mapped to gene sets associated with curated canonical signaling pathways, showing evidence for activation of NF-κB signaling with induction of genes coding for multiple chemokines and most components of the Major Histocompatibility Complex Class I antigen-presenting complex. Administration of anti-inflammatory doses of dexamethasone to lithium chloride-treated rats countered the loss of aquaporin-2. RNA-Seq also confirmed prior evidence of a shift from quiescence into the cell cycle with arrest. Time course studies demonstrated an early (12 hour) increase in multiple immediate early response genes including several transcription factors. Protein mass spectrometry in microdissected CCDs provided corroborative evidence and identified decreased abundance of several anti-oxidant proteins. Thus, in the context of prior observations, our study can be best explained by a model in which lithium increases ERK activation leading to induction of NF-κB signaling and an inflammatory-like response that represses Aqp2 transcription.

Hypoparathyroidism concomitant with macrothrombocytopenia in an elderly woman with 22q11.2 deletion syndrome.

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.

Inward-rectifying potassium channelopathies: new insights into disorders of sodium and potassium homeostasis.

Inward-rectifying potassium (Kir) channels allow more inward than outward potassium flux when channels are open in mammalian cells. At physiological resting membrane potentials, however, they predominantly mediate outward potassium flux and play important roles in regulating the resting membrane potential in diverse cell types and potassium secretion in the kidneys. Mutations of Kir channels cause human hereditary diseases collectively called Kir channelopathies, many of which are characterized by disorders of sodium and potassium homeostasis. Studies on these genetic Kir channelopathies have shed light on novel pathophysiological mechanisms, including renal sodium and potassium handling, potassium shifting in skeletal muscles, and aldosterone production in the adrenal glands. Here, we review several recent advances in Kir channels and their clinical implications in sodium and potassium homeostasis.

Hyponatremia is a surrogate marker of poor outcome in peritoneal dialysis-related peritonitis.

BACKGROUND: Hyponatremia is known to be a marker of poor prognosis in many clinical conditions. The association between hyponatremia and clinical outcomes in peritoneal dialysis-related peritonitis (PDRP) has not been studied. We evaluated the association between hyponatremia and clinical parameters of patients with PDRP. METHODS: We conducted a retrospective analysis of medical records of patients with PDRP admitted to a medical center in the period 2004-2011. Patients with serum Na+ <130 mEq/L and ≥ 130 mEq/L at admission were divided into hyponatremic and normonatremic groups, respectively. The demographic and laboratory characteristics, pathogens of peritonitis, length of hospital stay and mortality rate were analyzed. RESULTS: Hyponatremia occurred in 27% (27/99) patients with PDRP. Gram-negative bacilli were the major pathogen responsible for 78% (21/27) PDRP in hyponatremic group while gram-positive cocci were found in 75% (41/55) PDRP in normonatremic groups. There was no significant difference in age, duration of dialysis, PD catheter removal rate and technique failure between two groups. Hyponatremic group had significantly higher serum CRP (p <0.001), lower serum albumin (p < 0.001) and phosphate (p < 0.05). Of note, serum Na+ level was positively correlated with serum albumin (p < 0.001), phosphate (p < 0.04) levels, and subjective global assessment (SGA) score (p < 0.001). Moreover, the length of hospital stay was longer and in-hospital mortality rate was higher in hyponatremic group (p < 0.001). Using a multivariable logistic regression, we showed that hyponatremia at admission is an independent predictor of in-hospital mortality (OR 76.89 95% CI 3.39-1741.67, p < 0.05) and long hospital stay (OR 5.37, 95% CI 1.58- 18.19, p < 0.05). CONCLUSIONS: In uremic patients with PDRP, hyponatremia at admission associated with a high frequency of gram negative bacilli infection, low serum albumin and phosphate levels, low SGA score, and poor prognosis with long hospital stay and high mortality rate.

R1933X mutation in the MYH9 gene in May-Hegglin anomaly mimicking idiopathic thrombocytopenic purpura.

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.

Identification and characterization of a novel CASR mutation causing familial hypocalciuric hypercalcemia.

Context: Although 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. Objective: A 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. Design: Sanger 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. Results: This 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. Conclusion: This novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+ corrected by therapeutic calcimimetics.

Acute prolonged neurotoxicity associated with recommended doses of ertapenem in 2 patients with advanced renal failure.

Ertapenem, a novel carbapenem with long-acting antimicrobial activity, is predominantly eliminated by the kidneys. Acute prolonged neurotoxicity associated with recommended doses of ertapenem in patients with advanced renal failure not yet on dialysis has not been reported. Two patients with Stage 5 chronic kidney disease (CKD) developed progressive hallucinations, asterixis, myoclonic jerks, and cognitive impairment after receiving the recommended dose reduction for CKD of ertapenem (500 mg/d) for 4 days (Case 1: acute cholecystitis) and 5 days (Case 2: arteriovenous fistula infection). Exhaustive diagnostic workups were non-revealing. Plasma ertapenem level measured 24 h after the last dose in Patient 2 was 53.7 mg/l, much higher than the therapeutic MIC90 (2 mg/l). Despite the cessation of ertapenem and initiation of high-flux hemodialysis, their neurologic manifestations lasted for 2 weeks. The structural and pharmacokinetic characteristics of ertapenem such as its high lipophilicity, central nervous penetration, and volume of distribution contributed to sustained neurotoxicity even with significant reduction in plasma ertapenem levels by high-flux hemodialysis. Although ertapenem 500 mg/d has been recommended in patients with glomerular filtration rate less than 30 ml/min/1.73 m2, our 2 cases highlight that this dosage might be excessive for patients with Stage 5 CKD, especially those not yet on dialysis.

Acute kidney disease following COVID-19 vaccination: a single-center retrospective study.

Background: Rare 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. Methods: This 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. Results: Twenty-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). Conclusion: Besides 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.

Machine Learning to Identify Genetic Salt-Losing Tubulopathies in Hypokalemic Patients.

Introduction: Clinically distinguishing patients with the inherited salt-losing tubulopathies (SLTs), Gitelman or Bartter syndrome (GS or BS) from other causes of hypokalemia (LK) patients is difficult, and genotyping is costly. We decided to identify clinical characteristics that differentiate SLTs from LK. Methods: A total of 66 hypokalemic patients with possible SLTs were recruited to a prospective observational cohort study at the University College London Renal Tubular Clinic, London. All patients were genotyped for pathogenic variants in genes which cause SLTs; 39 patients had pathogenic variants in genes causing SLTs. We obtained similar data sets from cohorts in Taipei and Kobe, as follows: the combined data set comprised 419 patients; 291 had genetically confirmed SLT. London and Taipei data sets were combined to train machine learning (ML) algorithms, which were then tested on the Kobe data set. Results: Single biochemical variables (e.g., plasma renin) were significantly, but inconsistently, different between SLTs and LK in all cohorts. A decision table algorithm using serum bicarbonate and urinary sodium excretion (FENa) achieved a classification accuracy of 74%. This was superior to all the single biochemical variables identified previously. Conclusion: ML algorithms can differentiate true SLT in the context of a specialist clinic with some accuracy. However, based on routine biochemistry, the accuracy is insufficient to make genotyping redundant.

Role of vitamin D in insulin resistance.

Vitamin D is characterized as a regulator of homeostasis of bone and mineral metabolism, but it can also provide nonskeletal actions because vitamin D receptors have been found in various tissues including the brain, prostate, breast, colon, pancreas, and immune cells. Bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation are all biological functions of vitamin D. Vitamin D may play an important role in modifying the risk of cardiometabolic outcomes, including diabetes mellitus (DM), hypertension, and cardiovascular disease. The incidence of type 2 DM is increasing worldwide and results from a lack of insulin or inadequate insulin secretion following increases in insulin resistance. Therefore, it has been proposed that vitamin D deficiency plays an important role in insulin resistance resulting in diabetes. The potential role of vitamin D deficiency in insulin resistance has been proposed to be associated with inherited gene polymorphisms including vitamin D-binding protein, vitamin D receptor, and vitamin D 1 alpha-hydroxylase gene. Other roles have been proposed to involve immunoregulatory function by activating innate and adaptive immunity and cytokine release, activating inflammation by upregulation of nuclear factor κB and inducing tumor necrosis factor α, and other molecular actions to maintain glucose homeostasis and mediate insulin sensitivity by a low calcium status, obesity, or by elevating serum levels of parathyroid hormone. These effects of vitamin D deficiency, either acting in concert or alone, all serve to increase insulin resistance. Although there is evidence to support a relationship between vitamin D status and insulin resistance, the underlying mechanism requires further exploration. The purpose of this paper was to review the current information available concerning the role of vitamin D in insulin resistance.

Insulin resistance in patients with chronic kidney disease.

Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.