Immunogenicity of COVID-19 Vaccination in Patients With End-Stage Renal Disease Undergoing Maintenance Hemodialysis: The Efficacy of a Mix-and-Match Strategy.

BACKGROUND: The objective of this study was to evaluate the immunogenicity of coronavirus disease 2019 (COVID-19) vaccination in patients with end-stage renal disease (ESRD) on hemodialysis. METHODS: ESRD patients at the hemodialysis center of a tertiary-care university-affiliated hospital and healthy employees at the clinical laboratory center were prospectively recruited between March and June 2021. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody analysis, blood samples were collected serially on days 0, 14, 28, and 56 after the first vaccine dose, and on days 7 and 50 after the second dose. Antibodies against the SARS-CoV-2 spike protein were quantified, and SARS-CoV-2 neutralizing antibodies were measured in the serum and plasma. RESULTS: Thirty-one ESRD patients and 55 healthy employees were regularly monitored. Twenty-five (80.6%) ESRD patients on hemodialysis received a mix-and-match strategy with ChAdOx1-BNT162b2 (AZ-Pf group) and six (19.4%) received two doses of ChAdOx1 (AZ-AZ group). ESRD patients on hemodialysis showed lower binding antibody titers and neutralizing antibody activities compared to healthy participants following the first vaccination with ChAdOx1. After the second dose, AZ-Pf group had higher immunogenicity than healthy people on days 7 and 50. The binding antibody titer and neutralizing antibody activities on days 7 and 50 were significantly higher in the AZ-Pf group than in the AZ-AZ group. CONCLUSION: ESRD patients on hemodialysis receiving the mix-and-match strategy (ChAdOx1-BNT162b2) have COVID-19 vaccine immunogenicity comparable to healthy individuals receiving two doses of ChAdOx1. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04871945.

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy.

BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. METHODS: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. RESULTS: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1ß was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicin nephropathy. CONCLUSION: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

The Cut-off Values of Surrogate Measures for Insulin Sensitivity in a Healthy Population in Korea according to the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010.

BACKGROUND: This study aimed to identify the gender-specific characteristics of the surrogate measures of insulin resistance and to establish valid cut-off values for metabolic abnormalities in a representative sample in Korea. METHODS: Data were collected from the datasets of the Korean National Health and Nutrition Examination Survey between 2007 and 2010. The total number of eligible participants was 10,997. We used three measures of insulin resistance: the homeostasis model assessment-insulin resistance (HOMA-IR), McAuley index, and triglyceride and glucose (TyG) index. The estimated cut-off values were determined using the highest score of the Youden index. RESULTS: The area under the curve (AUC) of the HOMA-IR, McAuley index, and TyG index were 0.737 (95% confidence interval [CI], 0.725-0.750), 0.861 (95% CI, 0.853-0.870), and 0.877 (95% CI, 0.868-0.885), respectively. The cut-off values of the HOMA-IR were 2.20 in men, 2.55 in premenopausal women, and 2.03 in postmenopausal women, and those of the McAuley index were 6.4 in men and 6.6 in premenopausal and postmenopausal women. For the TyG index, the cut-off values were 4.76 in men and 4.71 in premenopausal and postmenopausal women. CONCLUSION: In conclusion, the present study provides the valid cut-off values of the indirect surrogate measures of insulin sensitivity. These values may be used as reference for insulin sensitivity in a clinical setting and may provide a simple and supplementary method for identifying populations at risk of insulin resistance.

Alteration of Tight Junction Protein Expression in Dahl Salt-Sensitive Rat Kidney.

BACKGROUND/AIMS: Altered pressure natriuresis is an important mechanism of hypertension, but it remains elusive at the molecular level. We hypothesized that in the kidney, tight junctions (TJs) may have a role in pressure natriuresis because paracellular NaCl transport affects interstitial hydrostatic pressure. METHODS: To assess the association of salt-sensitive hypertension with altered renal TJ protein expression, Dahl salt-sensitive (SS) and salt-resistant (SR) rats were put on an 8% NaCl-containing rodent diet for 4 weeks. Systolic blood pressure (SBP) and urine NaCl excretion were measured weekly, and kidneys were harvested for immunoblotting and quantitative PCR analysis at the end of the animal experiments. RESULTS: SBP was significantly higher in SS rats than in SR rats during the first to fourth weeks of the animal experiments. During the first and second week, urinary NaCl excretion was significantly lower in SS rats as compared with SR rats. However, the difference between the two groups vanished at the third and fourth weeks. In the kidney, claudin-4 protein and mRNA were significantly increased in SS rats as compared with SR rats. On the other hand, occludin protein and mRNA were significantly decreased in SS rats as compared with SR rats. The expression of claudin-2, claudin-7, and claudin-8 did not vary significantly between the two groups. CONCLUSIONS: In SS rats, SS hypertension was associated with differential changes in renal TJ protein expression. Both upregulation of claudin-4 and downregulation of occludin might increase paracellular NaCl transport in the kidney, resulting in impaired pressure natriuresis in SS rats.

Effects of high intensity aerobic exercise on treadmill on maximum-expiratory lung capacity of elderly women.

[Purpose] The aim of this study was to examine whether a systematic high intensity aerobic exercise on treadmill was effective in improving pulmonary function. [Subjects and Methods] The subjects of this study were 22 healthy elderly women over 65 years of age who were attending the Senior Welfare Center and Social Welfare Center programs in B city. For the pulmonary function test, a spirometry (Pony FX, COSMED Inc., Italy) was used. The item for measurement of pulmonary function in elderly women was maximum-effort expiratory spirogram (MES). The pulmonary function test was performed 3 times, and its mean value was used for analysis. After a 15 minute warm-up stretching, high intensity aerobic exercise was performed for 20 minutes as a main exercise, followed by 15 minutes of cool-down stretching. Exercise was performed three days a week for 12 weeks. [Results] Among items of maximum-effort expiratory spirogram, a significant difference after exercise was demonstrated in forced vital capacity, forced expiratory volume in 1 second. Two factors were improved after exercise. [Conclusion] The results demonstrated that high intensity aerobic exercise on the treadmill has a positive effect on the pulmonary function of elderly women.

Evaluation of Urinary Indices for Albuminuria and Proteinuria in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS: Either protein-to-creatinine ratio (PCR) or albumin-to-creatinine ratio (ACR) can be adopted for estimation of proteinuria in patients with chronic kidney disease (CKD). Estimated protein excretion rate (ePER) and estimated albumin excretion rate (eAER) may be superior to ACR and PCR. Reports show that urine albumin-to-protein ratio (APR) may be useful in detecting tubular proteinuria, but should be compared with urine protein electrophoresis (PEP). METHODS: Both 24-h urine and spot urine were collected from 77 stable CKD patients for measurement of albumin, protein, and creatinine, and PEP. Based on MDRD and CKD-EPI equations, ePERMDRD, ePERCKD-EPI, eAERMDRD and eAERCKD-EPI were calculated to estimate daily proteinuria and albuminuria. Glomerular CKD was defined by clinical and/or pathological evidence. RESULTS: ACR correlated significantly with PCR. However, microalbuminuria was present in patients without pathologic proteinuria. Twenty-four-hour urine albumin correlated better with eAERMDRD and eAERCKD-EPI than ACR, and 24-h urine protein correlated better with ePERMDRD and ePERCKD-EPI than PCR. APR significantly but not well correlated with the albumin fraction in urine PEP. The albumin fraction obtained from urine PEP was significantly higher in patients with glomerulopathy than those with non-glomerular CKD, whereas there were no differences in APR between groups. In contrast with APR, the albumin fraction in urine PEP was independently associated with glomerular CKD. CONCLUSIONS: Both PCR and ACR are useful in evaluation of proteinuria. In quantifying daily proteinuria and albuminuria, ePER and eAER are superior to PCR and ACR, respectively. Compared with APR, urine PEP is more useful in diagnosing glomerular proteinuria.

A J-Shaped Association Between Serum Uric Acid Level and Allograft Outcomes After Living Donor Kidney Transplantation.

Hyperuricemia following kidney transplantation (KT) may contribute to a decline in allograft renal function, but be affected by KT-related confounding factors. Some studies have even suggested that a reduction in serum uric acid (UA) is associated with poor patient outcomes. Thus, we retrospectively analyzed the impact of serum UA on allograft outcomes in 281 KT recipients. KT recipients were divided into five groups according to serum UA level (mg/dL): Group I (n = 46), ≤ 5; Group II (n = 62), > 5 and ≤ 6; Group III (n = 70), > 6 and ≤ 7; Group IV (n = 53), > 7 and ≤ 8; Group V (n = 50), > 8. Regression analysis showed that serum UA level was significantly associated with future allograft function. In a Kaplan-Meier analysis, the dialysis-free survival of Group II recipients was better than that of the other groups (Group I, 140 ± 5 months; Group II, 208 ± 7 months; Group III, 148 ± 4 months; Group IV, 185 ± 12 months; Group V, 164 ± 11 months; P = 0.0164). In Cox proportional hazard models adjusting for estimated glomerular filtration rate, the relative risk of allograft loss still tended to be elevated in Group I (HR=3.417, 95% CI 1.138-10.258) and Group V (HR=2.793, 95% CI 1.108-7.041), using Group II as the reference. Our results suggest that there is a J-shaped association between serum UA levels and allograft outcomes in living donor KT recipients.

Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney.

Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser-scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan cotreatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

The risk of hyponatremia with desmopressin use for nocturnal polyuria.

BACKGROUND: Desmopressin is used for treating nocturnal polyuria, but hyponatremia is an associated concern in the elderly due to impaired urinary dilution. This study was undertaken to characterize hyponatremia occurring in adults using desmopressin for nocturnal polyuria. METHODS: Data from 172 patients who were prescribed desmopressin for nocturnal polyuria at a urology clinic from September 2010 through February 2013 were retrospectively analyzed. Demographic and laboratory parameters were investigated to examine the risk factors for desmopressin-associated hyponatremia. RESULTS: The average follow-up serum sodium measured 21 ± 22 days after using desmopressin was 138 ± 5 mmol/l. Hyponatremia (<135 mmol/l) was found in 24 patients (14%), and it was severe in 7 (<126 mmol/l). In the hyponatremic patients, serum sodium decreased by 11 ± 6 mmol/l. Patients with hyponatremia were older than those with normonatremia (78 ± 7 vs. 68 ± 9 years, p < 0.0001). The presence of either hyponatremia-predisposing comorbidities or concurrent medications was associated with hyponatremia. Patients with hyponatremia had lower basal hemoglobin (11 ± 2 vs. 13 ± 2 g/dl, p < 0.001) and serum sodium (139 ± 2 vs. 140 ± 2 mmol/l, p < 0.05) than those with normonatremia. Multivariate logistic regression after adjustment for basal serum sodium showed that advanced age (OR 1.15; 95% CI 1.03-1.27) and lower hemoglobin level (OR 0.64; 95% CI 0.43-0.94) were independently associated with hyponatremia. CONCLUSION: Hyponatremia is not infrequently associated with desmopressin use. Those with advanced age (≥65 years) and lower hemoglobin are at risk of desmopressin-associated hyponatremia and need to be carefully monitored.

Association between a change in donor kidney function and long-term allograft outcomes in kidney transplant recipients.

Reserve capacity of donated kidney may be an important determinant of allograft survival in kidney transplantation (KT). Here, we investigate change in estimated glomerular filtration rate of donor kidney (ΔeGFR(Donor)) over 30 days after KT as a predictor of the allograft function. A total of 222 recipients were divided into two groups according to ΔeGFR(Donor) as follows: Group I (n = 110), ΔeGFR(Donor) ≥ -25%; Group II (n = 112), ΔeGFR(Donor) < -25%. Three years after KT, Group I had a higher eGFR(Recipient) than Group II (55 ± 21 vs. 47 ± 22 mL/min/1.73 m2, P < 0.05). However, no differences in eGFR(Recipient) were detected between the two groups after 10 years. Linear regression analysis showed that ΔeGFR(Donor) was significantly associated with the eGFR(Recipient) at 3 years post-transplantation, but not at 10 years post-transplantation. In Kaplan-Meier analysis, Group I had a greater dialysis-free survival rate than Group II at the 10-year follow-up (84% vs. 76%, P < 0.05). However, no difference in overall survival rate between groups was detected. In the multivariate-adjusted Cox proportional-hazard model, ΔeGFR(Donor) was independently associated with future allograft loss (hazard ratio 0.973; 95% confidence interval 0.949-0.999). These results suggest that larger recovery of donor kidney function after KT donation is associated with better short/intermediate-term allograft outcomes. Follow-up assessment of donor kidney function may be useful to monitor KT recipients at risk for allograft loss.

Prognostic Significance of 1-Year Serum Albumin Levels Within the Normal Range After Kidney Transplantation.

Hypoalbuminemia is associated with poor outcomes in kidney transplantation (KT). However, what level is optimal in serum albumin is not clear for the long-term prognosis. To determine whether the long-term outcomes are different even between the normal ranges of serum albumin after KT, we analyzed data from 404 renal allograft recipients whose 1-year post-transplant serum albumin levels were within the normal limits (3.5-5.5 g/dL). During a follow-up of 122 ± 56 months, 97 graft losses, 20 patient deaths, and 50 cardiovascular (CV) events occurred. Based on 1-year serum albumin levels, the patients were divided into high normal (≥4.6 g/dL, n = 209) and low normal (<4.6 g/dL, n = 195) groups. Kaplan-Meier analyses revealed that the low normal group had poorer allograft survival (P = 0.01), patient survival (P < 0.001), and CV event-free survival (P < 0.001) than the high normal group. Cox regression analysis confirmed that 1-year serum albumin was inversely associated with the risk of graft loss (hazard ratio [HR] 0.414, 95% confidence interval [CI] 0.200-0.856), patient death (HR 0.097, 95% CI 0.019-0.484), and CV events (HR 0.228, 95% CI 0.074-0.702). In conclusion, a relatively low 1-year post-transplant serum albumin level within the normal limits (<4.6 g/dL) significantly predicts poor long-term outcomes.

Effects of dietary salt restriction on renal progression and interstitial fibrosis in adriamycin nephrosis.

BACKGROUND/AIMS: Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. METHODS: Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg), and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1), and uninephrectomized rats were studied for 6 weeks (experiment 2). RESULTS: In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin-induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and α-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-α, IκB-α, gp91(phox), p47(phox), and p67(phox) mRNA was blocked by salt restriction. CONCLUSION: Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-κB activation.

Investigation of the myopic outcomes of the newer intraocular lens power calculation formulas in Korean patients with long eyes.

This study investigated the underlying causes of the myopic outcomes of the optic-based newer formulas (Barrett Universal II, EVO 2.0, Kane, Hoffer-QST and PEARL-DGS) in long Korean eyes with Alcon TFNT intraocular lens (IOL) implantation. Postoperative data from 3100 randomly selected eyes of 3100 patients were analyzed to compare the reference back-calculated effective lens positions (ELPs) based on the Haigis formula using conventional axial length (AL) and Cooke-modified AL (CMAL) with the predicted ELP of each single- and triple-optimized Haigis formula applied to AL- and CMAL. Contrary to the AL-applied Haigis formula, the predicted ELP curve of the CMAL-applied, single-optimized Haigis formula, simulating the methods of the newer formulas, exhibited a significant upward deviation from the back-calculated ELP in long eyes. The relationship between the AL and anterior chamber depth in our long-eyed population differed from that in the base population of the PEARL-DGS formula. The myopic outcomes in long eyes appeared to stem from the substantial overestimation of the postoperative IOL position with AL modification, leading to the implantation of inappropriately higher-powered IOLs. This discrepancy may be attributed to the ethnic differences in ocular biometrics, particularly the relatively smaller anterior segment in East Asian patients with long AL.

Comparison of the formula accuracy for calculating multifocal intraocular lens power: a single center retrospective study in Korean patients.

This study evaluated the accuracy of newer formulas (Barrett Universal II, EVO 2.0, Kane, Hoffer QST, and PEARL-DGS) and the Haigis formula in Korean patients with the Alcon TFNT multifocal intraocular lens. In total, 3100 randomly selected eyes of 3100 patients were retrospectively reviewed. After constant optimization, the standard deviation (SD) of the prediction error was assessed for the entire group, and the root mean square error was compared for short and long axial length (AL) subgroup analysis. The Cooke-modified AL (CMAL) was experimentally applied to the Haigis formula. All the newer formulas performed well, but they did not significantly outperform the Haigis formula. In addition, all the newer formulas exhibited significant myopic outcomes (- 0.23 to - 0.29 diopters) in long eyes. Application of the CMAL to the Haigis formula with single constant optimization produced similar behavior and higher correlation with the newer formulas. The CMAL-applied triple-optimized Haigis formula yielded a substantially smaller SD, even superior to the Barrett and Hoffer QST formulas. The AL modification algorithms such as the CMAL used in newer formulas to cope with optical biometry's overestimation of the AL in long eyes seemed to overcompensate, particularly in the long eyes of the East Asian population.

Association between Relative Thrombocytosis and Microalbuminuria in Adults with Mild Fasting Hyperglycemia.

An elevated platelet count may contribute to significant thrombotic events and pose a risk for diabetic microvascular complications. Albuminuria, one of the hallmarks of diabetes, is thought to be a risk factor for endothelial dysfunction. In this study, we investigated the association between relative thrombocytosis and an increased urine albumin-to-creatinine ratio in healthy adult participants. Using multivariate analyses on data from the Korea National Health and Nutrition Examination Survey V-VI, 12,525 eligible native Koreans aged ≥ 20 were categorized into platelet count quintiles by sex. The highest platelet count quintile included younger, more obese participants with elevated white blood cell counts, poor lipid profiles, and a better estimated glomerular filtration rate. Restricted cubic spline regression analysis revealed significant associations between platelet count and fasting blood glucose, glycated hemoglobin, and urine albumin-to-creatinine ratio. Adjusted logistic regression models indicated that heightened fasting blood glucose and platelet count were linked to risk of microalbuminuria (fasting blood glucose, odds ratio = 1.026, 95%CI = 1.011-1.042; platelet count, odds ratio = 1.004, 95%CI = 1.002-1.006). Particularly, an increased platelet count was notably associated with microalbuminuria progression in subjects with impaired fasting glucose. These findings suggest that an elevated platelet count, even below diagnostic thrombocytosis levels, independently correlates with an increased risk of vascular endothelial dysfunction in patients with impaired fasting glucose.

Effect of low muscle mass on total mortality related to metabolic disease in chronic kidney disease patients.

Low muscle mass is a risk factor for mortality in patients with chronic kidney disease (CKD). However, it is not clear to what extent low muscle mass contributes to this risk, either independently or in combination with metabolic abnormalities and frailty. This study used data from the National Health and Nutrition Examination Survey 1999-2006 and 2011-2018. Low muscle mass was defined as Appendicular Skeletal Mass Index < 7 kg/m2 in men or < 5.5 kg/m2 in women. The follow-up duration was from the first anthropometric and clinical measurements to death or the last follow-up. This study enrolled 2072 patients with CKD. Low muscle mass was associated with a lower risk of metabolic abnormalities, but was associated with an elevated mortality risk. Conversely, central obesity was associated with a higher likelihood of metabolic abnormalities and frailty, yet showed no significant association with mortality risk. Subsequently conducted mediation analysis indicated that the effect of low muscle mass on mortality was direct, not mediated by frailty and metabolic abnormalities. In spite of the inverse relationship between low muscle mass and metabolic abnormalities, low muscle mass are directly associated with an increased risk of all-cause mortality. Low muscle mass may directly contribute to mortality in patients with CKD, independent of metabolic abnormalities and frailty in these patients.

Acute and chronic effects of dietary sodium restriction on renal tubulointerstitial fibrosis in cisplatin-treated rats.

BACKGROUND: Renal interstitial fibrosis is a major complication of cisplatin (CP) treatment, and increased sodium intake may accelerate its progression by stimulating transforming growth factor (TGF)-ß/Smad signaling. However, it is not clear whether a low-sodium diet has beneficial effects on the development of interstitial fibrosis because it activates the renin-angiotensin-aldosterone system. Here, we tested whether the TGF-ß/Smad signaling pathway is stimulated in CP-treated rats, and whether the development of tubulointerstitial fibrosis in CP nephropathy can be checked by dietary sodium restriction. METHODS: Male Sprague Dawley rats were randomly divided into controls, CP treatment and CP treatment with low-sodium diet. The acute experiment lasted 7 days with a single intraperitoneal injection (6 mg/kg) of CP, and the chronic experiment involved weekly injections (2 mg/kg) for 7 weeks. RESULTS: In both sets of experiments, CP treatment produced pronounced tubulointerstitial injury, increased infiltration of ED1-positive cells and increased expression of monocyte chemotactic protein-1 (MCP-1), α-smooth muscle actin (SMA), TGF-ß1, phosphorylated Smad3, fibronectin and collagen III proteins. In the acute experiment, the increases in expression of osteopontin, MCP-1, α-SMA, TGF-ß and collagen III were significantly reduced by dietary sodium restriction. In the chronic experiment, however, none of the measurements were improved by a low-sodium diet. Examination of CP-treated rat kidneys revealed de novo vimentin expression in tubular epithelial cells and invasion of α-SMA-positive tubular epithelial cells through the basement membrane into the interstitium. CONCLUSIONS: The pro-fibrotic effect of TGF-ß in CP nephropathy appears to be associated with the epithelial-mesenchymal transition and is ameliorated by dietary sodium restriction only during the acute phase.

Effect of mycophenolic acid on cyclosporin A-induced fibronectin expression in rat mesangial cells.

This study was undertaken to determine if mycophenolic acid (MPA) inhibits the profibrotic action of cyclosporin A (CsA) and, if so, to determine the molecular mechanisms involved. The effect of MPA treatment on CsA-induced signaling through the transforming growth factor-ß (TGF-ß)/Smad pathway was evaluated by immunoblot analysis in cultured primary rat mesangial cells. Treatment of cells with 1 µmol/l MPA did not significantly decrease the CsA-induced expression of TGF-ß(1), but partially reversed the increases in Smad3 phosphorylation and fibronectin (FBN) production, and increased Smad7 expression. These results suggest that MPA may ameliorate CsA-induced FBN production by modulating the Smad signaling pathway. This study provides evidence that MPA can attenuate CsA-induced renal injury after kidney transplantation.

Fractional excretion of uric acid as a predictor for saline responsiveness in long-term kidney transplant patients.

BACKGROUND/AIMS: Subclinical hypovolemia may contribute to allograft dysfunction in long-term kidney transplant (KT) patients. In order to predict responsiveness to saline hydration, indices for tubular transport were investigated. METHODS: Fifty-four clinically euvolemic long-term KT patients with recently aggravated azotemia were given intravenous hydration as follows: 0.9% saline 5 ml/kg over 1 h, followed by 0.9% saline 1 ml/kg/h over 12 h and 1 liter of 0.45% saline over the next 24 h. Serum and urine data were collected and analyzed to assess responses. RESULTS: In all patients, saline hydration relieved azotemia, as shown by blood urea nitrogen (46.9 ± 17.2 vs. 39.3 ± 15.4 mg/dl; p < 0.01) and serum creatinine levels (2.9 ± 1.1 vs. 2.5 ± 1.1 mg/dl; p < 0.01) on day 0 versus day 2. In 38 patients, serum creatinine did not increase in the following month (70% responders). Compared with the nonresponders, the responders had a higher urine-to-plasma creatinine ratio and lower fractional excretion of sodium, uric acid and urea at admission. Multivariate logistic regression analysis revealed that responsiveness to saline hydration was independently associated with lower fractional excretion of uric acid. CONCLUSION: Subclinical hypovolemia should be considered in long-term KT patients with azotemia of unexplainable causes. Fractional excretion of uric acid may predict responsiveness to saline hydration.

Bilateral renal cortical necrosis following binge drinking.

Renal cortical necrosis (RCN) is a rare cause of acute kidney injury secondary to ischemic necrosis of the renal cortex. Acute tubular necrosis after binge drinking is usually attributed to volume depletion, idiosyncratic reaction to alcohol, rhabdomyolysis or a combination with non-steroidal anti-inflammatory drugs. Binge drinking itself as a cause of RCN has not yet been reported. We report a case of a 25-year-old Asian male who developed bilateral RCN following binge drinking.