Glomerular macrophage is an indicator of early treatment response in diffuse proliferative lupus nephritis.

BACKGROUND: Patients with diffuse proliferative lupus nephritis (class IV) who responded to treatment within 6 months had better renal outcome than those who did not. Glomerular macrophage is known to be associated with poor renal outcome in glomerular diseases. OBJECTIVE: To evaluate association between glomerular macrophage number and early treatment response in lupus nephritis class IV patients. MATERIAL AND METHOD: Renal biopsies (n = 90, 86 females) diagnosed with lupus nephritis class IV were included in the study. The patients were divided into 2 groups (n = 45 each) according to response to treatment within 6 months. The treatment response group was defined as having decreased serum creatinine at least 25% from baseline and 24 hr urine protein or UPCR (urine protein creatinine ratio) < 1. The non-response group was defined as stable or increased serum creatinine and 24 hr urine protein or UPCR > or = 1. Immunohistochemistry for macrophage marker (CD68) was performed and the glomerular macrophages were counted on each biopsy. The relevant clinicopathologic data were collected. RESULTS: The glomerular macrophage number in response and non-response group was 4.5 +/- 2.5 and 6.2 +/- 4.5 respectively (p = 0.029). The glomerular macrophage number was conversely and inversely correlated with activity (r = 0.281, p = 0.007) and chronicity (r = -0.358, p < 0.001) index, respectively CONCLUSION: Lupus nephritis class IV patients who responded to treatment within 6 months had lower glomerular macrophages than those who did not. The glomerular macrophage number may be used to determine treatment response in lupus nephritis class IV patients.

Optimal Time for Recirculation with Ultrafiltration to Remove Disinfectant in Reused Dialyzer.

The practice of dialyzer reuse is common in developing countries. One essential technique for safe dialyzer reprocessing is to remove disinfectants properly to the recommended standards before treatment initiation, using dialysis machine recirculation with ultrafiltration. This study was conducted to identify the most effective time for carrying out this procedure, and the factors affecting it. We studied 420 high-flux dialyzers with three different membrane types: FB210U (cellulose triacetate), F80S (polysulfone), and Elisio-210HR (polyethersulfone) at four reused cycles (5th, 10th, 15th, and 19th). Peracetic acid was used as the disinfectant at a concentration of 0.16%. The total cell volume (TCV) and clot inspection grade of the reused dialyzer were recorded before the procedure. The optimal time for disinfectant removal was independently determined by two observers using the residual peroxide strip test of the ultrafiltrate. We observed that disinfectant removal was dependent on the recirculation time and became undetectable at 5 minutes. The type of dialyzer had a significant effect on the effective recirculation time (shortest for FB210U followed by Elisio-210HR and F80S; p < 0.001), but the reused number, TCV, and clot inspection grade did not. It is conceivable that the dialyzer membrane type might affect peracetic acid removal. In conclusion, the interval for carrying out dialysis machine recirculation with ultrafiltration depends on the dialyzer type, and 5 minutes is the optimal time for the operation. This result can be implemented to improve further practice in dialyzer reprocessing.

Medication Adherence, Complementary Medicine Usage and Progression of Diabetic Chronic Kidney Disease in Thais.

PURPOSE: Non-adherence to medication is receiving more attention as a significant problem common to management of chronic diseases including diabetes and chronic kidney disease (CKD). This study was designed to assess the medication adherence and self-medication in a cohort of Thai patients with diabetic kidney disease, and its association with clinical outcomes. PATIENTS AND METHODS: Non-dialysis patients with diabetic CKD visiting outpatient's clinics of Siriraj Hospital, the largest tertiary care in Thailand, were asked for participation. Self-administered questionnaire was given to assess medication adherence (the 6-item-medication-taking-behavior measure in Thai), complementary medicine usage, and personal information. Clinical, pharmaceutical, and relevant laboratory data (at current and the last visit of around 12 months) were abstracted from the medical records. RESULTS: Of the 220 participants eligible (54.1% male, mean age 71.3), 50.9%, 24.1%, and 25% were classified as high-, medium-, and low-medication adherence, respectively. Overall, 24.1% reported self-usage of at least one type of herbal or complementary medicines. The most commonly identified items were cordyceps, cod liver oil, Nan Fui Chao, and turmeric (6 each), with unidentified Thai herbal mixture in 11. On multivariate analysis, late-stage CKD (stage IV-V) was the only independent predictor for low adherence (odds ratio (OR), 5.54; 95% confidence interval (CI), 2.82-10.88). Low adherence was associated with higher blood pressure, lower estimated glomerular filtrate rate (eGFR), and more eGFR decline with greater risk of being rapid CKD progressor (annual eGFR drop >5 mL/min/1.73 m2) [OR, 1.15; 95% CI, 1.06-1.25]. CONCLUSION: Medication taking behavior was a frequently encountered problem in Thai diabetic CKD patients. Increased medication non-adherence was independently predicted by stages of increasing CKD severity, and it was associated with poorer hypertensive control and kidney outcome. Targeting interventions to improve medication adherence should be an important strategy to slow CKD progression among patients with diabetic CKD.

Prevalence of chronic kidney disease stages 3-5 in low- and middle-income countries in Asia: A systematic review and meta-analysis.

Chronic kidney disease (CKD) is a major public health problem in low- and middle-income countries (LMICs). Although CKD prevalence has been rapidly increasing in LMICs, particularly in Asia, quantitative studies on the current epidemiology of CKD in this region are limited. This study aimed to identify the prevalence of CKD stages 3-5 in LMICs in Asia, by subregion, country economy classification, identification of CKD, traditional and non-traditional risk factors. A systematic review and meta-analysis of observational studies was conducted through a literature search of seven electronic databases and grey literature search published until November 2021. The Newcastle-Ottawa quality assessment scale (NOS) was used to assess the risk of bias of each study. A random-effects model was used to estimate pooled prevalence. The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42019120519). Of 4,548 potentially relevant records, 110 studies with moderate and high quality were included with 4,760,147 subjects. The average prevalence (95% CI) of CKD stages 3-5 in 14 LMICs in Asia was 11.2% (9.3-13.2%). The prevalence of CKD stages 3-5 was varied among subregions and country economic classification. CKD prevalence was 8.6% (7.2-10.2%) in east Asia, 12.0% (7.7-17.0%) in south-east Asia, 13.1% (8.7-18.2%) in western Asia, and 13.5% (9.5-18.0%) in south Asia. CKD prevalence was 9.8% (8.3-11.5%) in upper-middle-income countries and 13.8% (9.9-18.3%) in lower-middle-income countries. Prevalence of CKD stage 3-5 in LMICs in Asia is comparable to global prevalence. High level of heterogeneity was observed. Study of factors and interventions that lead to the delay of CKD progression is needed.

Can we predict final outcome of internal medicine residents with in-training evaluation.

OBJECTIVE: To assess the predictive value of in-training evaluation for determining future success in the internal medicine board certifying examination. MATERIAL AND METHOD: Ninety-seven internal medicine residents from Faculty of Medicine Siriraj Hospital who undertake the Thai Board examination during the academic year 2006-2008 were enrolled. Correlation between the scores during internal medicine rotation and final scores in board examination were then examined. RESULTS: Significant positive linear correlation was found between scores from both written and clinical parts of board certifying examination and scores from the first-year summative written and clinical examinations and also the second-year formative written examination (r = 0.43-0.68, p < 0.001). Monthly evaluation by attending staffs was less well correlated (r = 0.29-0.36) and the evaluation by nurses or medical students demonstrated inverse relationship (r = -0.2, p = 0.27 and r = -0.13, p = 0.48). CONCLUSION: Some methods of in-training evaluation can predict successful outcome of board certifying examination. Multisource assessments cannot well extrapolate some aspects of professional competences and qualities.

Testosterone rapidly increases Ca2+-activated K+ currents causing hyperpolarization in human coronary artery endothelial cells.

Testosterone has endothelium-dependent vasodilatory effects on the coronary artery, with some reports suggesting endothelial ion channel involvement. This study employed the whole-cell patch clamp technique to investigate the effect of testosterone on ion channels in human coronary artery endothelial cells (HCAECs) and the mechanisms involved. We found that 0.03-3µM testosterone significantly induced a rapid, concentration-dependent increase in total HCAEC current (EC50, 71.96±1.66nM; maximum increase, 59.13±8.37%; mean±SEM). The testosterone-enhanced currents consisted of small- and large-conductance Ca2+-activated K+ currents (SKCa and BKCa currents), but not Cl- and nonselective cation currents. Either a non-permeant testosterone conjugate or the non-aromatizable androgen dihydrotestosterone (DHT) could increase HCAEC currents as well. The androgen receptor antagonist flutamide prevented this testosterone, testosterone conjugate, and DHT effect, while the estrogen receptor antagonist fulvestrant did not. Incubating HCAECs with pertussis toxin or protein kinase A inhibitor H-89 largely inhibited the testosterone effect, while pre-incubation with phospholipase C inhibitor U-73122, prostacyclin inhibitor indomethacin, nitric oxide synthase inhibitor L-NAME or cytochrome P450 inhibitor MS-PPOH, did not. Finally, testosterone application induced HCAEC hyperpolarization within minutes; this effect was prevented by SKCa and BKCa current inhibitors apamin and iberiotoxin. This is the first electrophysiological demonstration of androgen-induced KCa current increase, leading to hyperpolarization, in any endothelial cell, and the first report of SKCa as a testosterone target. Our data show that testosterone rapidly increased whole-cell HCAEC SKCa and BKCa currents via a surface androgen receptor, Gi/o protein, and protein kinase A. This mechanism may explain rapid testosterone-induced coronary vasodilation seen in vivo.

Abnormal kinetics of erythrocyte sodium lithium countertransport in patients with diabetic nephropathy in Thailand.

BACKGROUND: In essential hypertension and diabetic nephropathy, sodium-lithium counter transport (Na/Li CT) is an inherited marker for metabolic influences of cardiovascular risk. The kinetics of Na/Li CT are modified by two types of thiol group in the membrane. In choline medium, the type 1 thiol reacts with N-ethtyl maleimide (NEM) to cause a decrease in Km and increase Vmax/Km ratio. However in the presence of external Na or Li both the type 1 or type 2 thiols react so that both Km and Vmax are reduced. Low Km of Na/Li CT has been previously reported to be a major abnormality in diabetic nephropathy (DN) and can be used to identify diabetic patients who are at high risk for DN. A recent study showed that the type 1 thiol protein controlling the Km of Na/Li CT was a 33-kD protein and the gene for this protein is going to be cloned. OBJECTIVE: The authors sought to identify Na/Li CT kinetic abnormalities in Type 2 diabetes in Thai patients. MATERIAL AND METHOD: Erythrocyte Na/Li CT kinetics and their modulation by thiol proteins were measured in erythrocytes from 22 patients with Type 2 diabetes and 42 normal control subjects. RESULTS: The kinetics of Na/Li CT in untreated erythrocytes were similar Thiol protein alkylation with NEM generally caused both Vmax and Km to fall, but caused Km to rise in erythrocytes of diabetic patients, whose native Km was low. Thus, abnormalities in the regulation of Na/Li CT by key thiol proteins were found in about one-third of subjects with Type 2 diabetes in Thailand. CONCLUSION: Membrane abnormalities may indicate a common pathway of pathological mechanism found in essential hypertension and diabetic nephropathy and may be used as a phenotype for further genetic studies of this transporter.

Immunohistochemical study for the diagnosis of Alport's syndrome.

BACKGROUND: Alport's syndrome (AS) is the most common cause of inherited glomerular disease in Thailand. The majority of cases show X-linked inheritance, which is caused by mutations in the gene coding for the alpha5 chain of type IV collagen in the glomerular basement membrane (GBM) and epidermal basement membrane (EBM). Such mutation usually leads to a reduction in protein amount, thus, immunohistochemical studies have been considered in diagnostic evaluation. OBJECTIVE: To study the expression of alpha[IV] collagen chains in the skin as an alternative approach to diagnose AS. MATERIAL AND METHOD: Eleven unrelated probands with proven AS, 7 relatives with abnormal urinalysis, 4 suspected individuals, and 8 normal controls were enrolled. A punch skin biopsy and immunofluorescence staining of the tissue specimens for alpha1, alpha3 and alpha5[IV] collagen chains was performed. RESULTS: The alpha5[IV] chain was absent in the EBM in all male AS patients while a discontinuing pattern was observed in all females except one. The findings are specific for AS with a sensitivity of 91%. Studies in relatives and suspected individuals also confirmed the advantage of this approach as demonstrated by the absence and discontinuation of alpha5[IV] staining in all males and females, respectively. We also analyzed their expressions in the kidney tissue and demonstrated abnormal alpha3 and alpha5[IV] staining in five of six samples. CONCLUSION: Immunohistochemical study of the skin should be used as a screening method in patients suspected of AS, as it is much less invasive. Moreover, it is a useful adjunct to conventional examination of biopsied renal tissue.

An analysis of 3,555 cases of renal biopsy in Thailand.

BACKGROUND: The knowledge of the epidemiology of biopsied renal diseases provides useful information in clinical practice. There are several epidemiologic population-based studies of biopsy-proven nephropathies with detailed clinicopathologic correlations that could be different according to the country analyzed. OBJECTIVE: To identify the prevalence of primary and secondary glomerular diseases and to study the trend of the pattern changes of the glomerulopathy in Thailand. MATERIAL AND METHOD: A retrospective study of percutaneous renal biopsies during a 23-year period of 1982 to 2005 was performed. A total of 3,555 consecutive native kidney biopsies in adult patients between 12 and 84 years of age were analyzed for the prevalence and changes in the 5-year interval over the two decades. RESULTS: From the clinical trial of 3,275 patients, the ratio between primary and secondary glomerular diseases was 2:1 (2154:1121). The most common primary glomerular disease (2154 patients) were IgM nephropathy (n = 986, 45.8%) followed by IgA nephropathy (n = 386, 17.9%); membranous nephropathy (n = 341, 15.8%); diffuse endocapillary proliferative glomerulonephritis (n = 114, 5.3%) and diffuse crescentic glomerulonephritis (n = 71, 3.3%). Lupus nephritis was the most prevalent cause of secondary glomerulonephritis in the present study (n = 992, 88.5%). Examination of the 5-year interval along the study period revealed a significant increase in the prevalence of IgA nephropathy and diabetic nephropathy. Prevalence of focal and segmental glomerulosclerosis rose by five times over the last two decades in contrast to IgM nephropathy, which prevalence is decreasing. CONCLUSION: There is high prevalence of IgM nephropathy, IgA nephropathy, and lupus nephritis in Thailand which is different from other countries. It could be due to various races and altered environments. The information obtained from these results is an important contribution for the understanding of the prevalence in renal diseases in Thailand. It can be used as the baseline data for making efficient research into the appropriate and beneficial way of management in the future.

Effect of short-term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients.

OBJECTIVE: Hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease in chronic hemodialysis patients. This stratified randomized controlled trial was designed to measure the effect of high dose oral vitamin B6, vitamin B12, and folic acid on homocysteine levels, and to evaluate the effect on atherosclerosis as measured by Intima-Media Thickness (IMT) of carotid arteries. MATERIAL AND METHOD: Fifty-four chronic hemodialysis patients with hyperhomocysteinemia were randomized to receive oral 15 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 daily (treatment group) or oral 5 mg folic acid alone (control group) for 6 months. Homocysteine level and IMT were measured in both groups. RESULTS: At 6 months, homocysteine levels in the treatment group were significantly reduced from 27.94 +/- 8.54 to 22.71 +/- 3.68 mmol/l (p = 0.009) and were not significantly increased from 26.81 +/- 7.10 to 30.82 +/- 8.76 mmol/l in control group (p = 0.08). Mean difference between both groups was statistically significant (p = 0.002). There was no significant difference of IMT of carotid arteries, however, a tendency that the treatment group would have less thickness was observed (0.69 +/- 0.29 mm and 0.62 +/- 0.16 mm, p = 0.99). CONCLUSION: Treatment of hyperhomocysteinemia in chronic hemodialysis patients with daily oral 15 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for 6 months decreases homocysteine levels and tends to reduce IMT of carotid arteries. A long term study for the prevention of atherosclerosis is warranted.

Relationship between hyperhomocysteinemia and atherosclerosis in chronic hemodialysis patients.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor of coronary artery heart disease (CAHD) and atherosclerosis in a normal population. However, it is still controversial in end-stage kidney disease patients who underwent long-term dialysis. Carotid intima-media thickness (IMT) is the standard non-invasive measurement of atherosclerosis. The aims of the present study were to determine the homocysteine (Hcy) level, and to evaluate its role as a risk factor of atherosclerosis in hemodialysis (HD) patients. MATERIAL AND METHOD: Clinical data and blood chemistries were assayed in 62 HD patients. Atherosclerosis was defined by clinical presentations of CAHD, cerebrovascular or peripheral vascular diseases, or carotid plaque by ultrasound. IMT was also measured by ultrasound RESULTS: Plasma Hcy level in HD patients was significantly higher in HD patients than normal controls (28.3 +/- 8.3 vs 9.7 +/- 2.9 micromol/l, p < 0.001). Older age (p < 0.001), male sex (p = 0.05), longer duration of HD (p = 0.05), and higher plasma Hcy level (p = 0.01) correlated with atherosclerosis by univariate analysis, but plasma Hcy did not show significant correlation by multivariable analysis. There was also correlation between IMT and atherosclerosis in HD patients (p < 0.001) but no correlation was observed between plasma Hcy level and lMT. CONCLUSION: Hyperhomocysteinemia is not an independent factor in the genesis of atherosclerosis in HD patients. Advanced age plays a major role of hyperhomocysteinemia and IMT is a useful marker of atherosclerosis in these patients.

The urea transporter family (SLC14): physiological, pathological and structural aspects.

Urea transporters (UTs) belonging to the solute carrier 14 (SLC14) family comprise two genes with a total of eight isoforms in mammals, UT-A1 to -A6 encoded by SLC14A2 and UT-B1 to -B2 encoded by SLC14A1. Recent efforts have been directed toward understanding the molecular and cellular mechanisms involved in the regulation of UTs using transgenic mouse models and heterologous expression systems, leading to important new insights. Urea uptake by UT-A1 and UT-A3 in the kidney inner medullary collecting duct and by UT-B1 in the descending vasa recta for the countercurrent exchange system are chiefly responsible for medullary urea accumulation in the urinary concentration process. Vasopressin, an antidiuretic hormone, regulates UT-A isoforms via the phosphorylation and trafficking of the glycosylated transporters to the plasma membrane that occurs to maintain equilibrium with the exocytosis and ubiquitin-proteasome degradation pathways. UT-B isoforms are also important in several cellular functions, including urea nitrogen salvaging in the colon, nitric oxide pathway modulation in the hippocampus, and the normal cardiac conduction system. In addition, genomic linkage studies have revealed potential additional roles for SLC14A1 and SLC14A2 in hypertension and bladder carcinogenesis. The precise role of UT-A2 and presence of the urea recycling pathway in normal kidney are issues to be further explored. This review provides an update of these advances and their implications for our current understanding of the SLC14 UTs.

The SLC14 gene family of urea transporters.

Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Urea transporters mediate passive urea uptake that is inhibited by phloretin and urea analogues. Facilitated urea transporters are divided into two classes: (1) the renal tubular/testicular type of urea transporter, UT-A1 to -A5, encoded by alternative splicing of the SLC14A2 gene, and (2) the erythrocyte urea transporter UT-B1 encoded by the SLC14A1 gene. The primary structure of urea transporters is unique, consisting of two extended, hydrophobic, membrane-spanning domains and an extracellular glycosylated-connecting loop. UT-A1 is the result of a gene duplication of this two-halves-structure, and the duplicated portions are linked together by a large intracellular hydrophilic loop, carrying several putative protein kinase A (PKA) and -C (PKC) phosphorylation sites. UT-A1 is located in the apical membrane of the kidney inner medullary collecting duct cells, where it is stimulated acutely by cAMP-mediated phosphorylation in response to the antidiuretic hormone vasopressin. Vasopressin also up-regulates UT-A2 mRNA/protein expression in the descending thin limb of the loops of Henle. UT-A1 and UT-A2 are regulated independently and respond differently to changes in dietary protein content. UT-A3 and UT-A4 are located in the rat kidney medulla and UT-A5 in the mouse testis. The widely expressed UT-B participates in urea recycling in the descending vasa recta, as demonstrated by a relatively mild "urea-selective" urinary concentrating defect in transgenic UT-B null mice and individuals with the Jk(null) blood group.

Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis.

Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl(-)/HCO(3)(-) exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity.

Characterization of a highly polymorphic marker adjacent to the SLC4A1 gene and of kidney immunostaining in a family with distal renal tubular acidosis.

BACKGROUND: Mutations in the human SLC4A1 (AE1/band 3) gene are associated with hereditary spherocytic anaemia and with distal renal tubular acidosis (dRTA). The molecular diagnosis of AE1 mutations has been complicated by the absence of highly polymorphic genetic markers, and the pathogenic mechanisms of some dRTA-associated AE1 mutations remain unclear. Here, we characterized a polymorphic dinucleotide repeat close to the human AE1 gene and performed an immunocytochemical study of kidney tissue from a patient with inherited dRTA with a defined AE1 mutation. METHODS: One CA repeat region was identified in a phage P1-derived artificial chromosome (PAC) clone containing most of the human AE1 gene and the upstream flanking region. We determined its heterozygosity value in multiple populations by PCR analysis. Genotyping of one family with dominant dRTA identified the AE1 R589H mutation, and family member genotypes were compared with the CA repeat length. AE1 and vH(+)-ATPase polypeptides in kidney tissue from an AE1 R589H patient were examined by immunocytochemistry for the first time. RESULTS: This CA repeat, previously reported as D17S1183, is approximately 90 kb upstream of the AE1 gene and displayed considerable length polymorphism, with small racial differences, and a heterozygosity value of 0.56. The allele-specific length of this repeat confirmed co-segregation of the AE1 R589H mutation with the disease phenotype in a family with dominant dRTA. Immunostaining of the kidney cortex from one affected member with superimposed chronic pyelonephritis revealed vH(+)-ATPase-positive intercalated cells in which AE1 was undetectable, and proximal tubular epithelial cells with apparently enhanced apical vH(+)-ATPase staining. CONCLUSIONS: The highly polymorphic dinucleotide repeat adjacent to the human AE1 gene may be useful for future studies of disease association and haplotype analysis. Intercalated cells persist in the end-stage kidney of a patient with familial autosomal dominant dRTA associated with the AE1 R589H mutation. The absence of detectable AE1 polypeptide in those intercalated cells supports the genetic prediction that the AE1 R589H mutation indeed causes dominant dRTA.