Soon Hyo Kwon

Uremia induces functional incompetence of bone marrow-derived stromal cells

BACKGROUND Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. METHODS We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. RESULTS Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. CONCLUSION These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD.

Validation of the Oxford classification of IgA nephropathy: a single-center study in Korean adults.

Background/Aims The recently published Oxford classification of IgA nephropathy (IgAN) proposed a split system for histological grading, based on prognostic pathological features. This new classification system must be validated in a variety of cohorts. We investigated whether these pathological features were applicable to an adult Korean population. Methods In total, 69 adult Korean patients with IgAN were analyzed using the Oxford classification system at Soonchunhyang University Hospital, Seoul, Korea. All cases were categorized according to Lees classification. Renal biopsies from all patients were scored by a pathologist who was blinded to the clinical data for pathological variables. Inclusion criteria were age greater than 18 years and at least 36 months of follow-up. We excluded cases with secondary IgAN, diabetic nephropathy combined other glomerulopathies, less than 36 months of follow-up, and those that progressed rapidly. Results The median age of the patients was 34 years (range, 27 to 45). Mean arterial blood pressure was 97 ± 10 mmHg at the time of biopsy. The median follow-up period was 85 months (range, 60 to 114). Kaplan-Meier analysis showed significant prognostic predictions for M, E, and T lesions. A Cox proportional hazard regression analysis also revealed prognostic predictions for E and T lesions. Conclusions Using the Oxford classification in IgAN, E, and T lesions predicted renal outcome in Korean adults after taking clinical variables into account.

Risk factors for mortality in diabetic peritoneal dialysis patients

BACKGROUND It is well established that the survival rate of diabetic end-stage renal disease patients remains the lowest among all primary diagnoses probably because of higher prevalence of cardiovascular diseases (CVD) associated with diabetes. This study was designed to evaluate the impact of CVD and other risk factors individually or in combination on mortality in diabetic peritoneal dialysis (PD) patients. METHODS In a retrospective study, 213 incident PD patients [118 had diabetes mellitus (DM), 94 were female, mean age 55 ± 13 years] underwent initial assessment of nutritional status, comorbid disease (CMD) survey, residual renal function (RRF), dialysis adequacy and peritoneal transport characteristics at a mean of 9 days (range, 3-24 days) after start of PD and were then followed for 30 ± 24 months (range, 3-115 months). Of 213 patients, 154 patients were reassessed after a mean of 11 months (range, 6-19 months). Nutritional status was assessed by subjective global assessment and other methods. CMD was graded by Davies index and included DM, CVD, liver disease and respiratory disease. RESULTS On Kaplan-Meier analysis, patient survival was significantly lower in female DM patients compared to other groups. The 3-year patient survival rate was 46, 70, 82 and 83% for female DM, male DM, male non-DM and female non-DM, respectively (P = 0.003). On Cox proportional hazards multivariate analysis including all patients, old age, presence of CVD or protein-energy wasting (PEW), low serum albumin concentration and low RRF were independent predictors of mortality but not DM per se or female gender. In DM patients, old age, female gender, presence of CVD or PEW and low RRF were independent predictors of mortality while old age was the only risk factor in non-DM patients. After adjustment for age, gender and RRF, DM patients with both CVD and PEW had a risk of mortality that was 3.3 times that of DM patients without CVD and PEW. In DM patients without CVD and PEW, patient survival was not different from that of non-DM patients without CVD and PEW. CONCLUSIONS DM per se was not a risk factor for mortality in this group of PD patients. Instead, the higher mortality rate in diabetic PD patients, in particular among female patients, was mainly attributable to concurrent morbidity such as CVD and PEW, together with low RRF.

An Assessment of AKIN Criteria for Hospital-Acquired Acute Kidney Injury: A Prospective Observational Cohort Study

Background and Aims: The Acute Kidney Injury Network (AKIN) criteria assert a new definition for acute kidney injury (AKI). We investigated the incidence of hospital-acquired AKI, along with the clinical characteristics and outcomes in hospitalized patients according to AKIN stage. Methods: We performed a prospective, observational, single-center study. We monitored serum creatinine everyday for all patients using a hospital data survey system during the study period from September 2007 to February 2008. Results: Hospital-acquired AKI occurred in 1.2% of all hospitalized patients during the study period. Among patients with AKI, 29.2% were in stage 1, 36.5% were in stage 2 and 34.4% were in stage 3. A significantly higher rate of renal recovery was observed in patients with lower-stage injuries (71.4, 60.0, and 21.2% for stages 1, 2, and 3, respectively). Mortality for patients with stage 3 AKI (51.5%) was significantly higher than that for patients with stages 1 or 2 (p < 0.013). Independent risk factors for mortality in patients with AKI included malignancy, stage 3 AKI, diuretic use, and intensive care unit admission prior to AKI. Conclusions: Our findings support the utility of the AKIN criteria for hospital-acquired AKI, and demonstrate that stage 3 AKI poses a significant risk for poor patient and renal outcomes.

Subtle change of cystatin C, with or without acute kidney injury, associated with increased mortality in the intensive care unit ☆ ☆☆

PURPOSE Recent epidemiologic studies suggest a significant association between small increases in serum creatinine (sCr) and adverse outcomes. The Acute Kidney Injury Network (AKIN) sought to increase the sensitivity of the AKIN criteria for acute kidney injury (AKI) by recommending the use of small changes in sCr for the diagnosis of AKI. Several recent studies have reported that serum cystatin C (cysC) is more accurate than sCr as a surrogate for the glomerular filtration rate. This study was performed to determine whether small increases in cysC (≥0.3 mg/L within 48 hours) are associated with clinical outcomes in critically ill patients. MATERIALS AND METHODS This was a prospective study of 274 consecutive patients admitted to the intensive care unit. Clinical data, including urine output, sCr, cysC, and outcomes, were collected for up to 3 months. Kaplan-Meier curves were used to determine the 90-day survival rate. Mortality was adjusted according to the Cox proportional hazards model. RESULTS Acute kidney injury developed in 84 (30.7%) patients based on the AKIN criteria. Among these patients, 42 (50%) had stage 1; 8 (9.5%), stage 2; and 34 (40.4%), stage 3 disease. Fourteen patients with increased cysC did not have AKI by AKIN criteria. The overall 90-day mortality was 20.8%. When mortality was stratified by group, it was 5.7% for the no-AKI-without-cysC-increment group, 28.6% for the no-AKI-with-increased-cysC group, 33.3% for the AKIN stage 1 group, 62.5% for the AKIN stage 2 group, and 70.6% for the AKIN stage 3 group (P < .001). Kaplan-Meier curves were constructed for each group based on stage and 90-day survival. The Cox analysis showed that patients who met AKIN criteria and patients with increases of cysC without AKI had associated mortality. In addition, patients with increases in cysC without AKI had outcomes similar to the patients with stage 1 AKI. CONCLUSIONS Small increases of cysC were associated with increased mortality in intensive care unit patients independent of diagnosis of AKI by AKIN criteria.

Uremic Toxin p‐Cresol Induces Akt‐Pathway‐Selective Insulin Resistance in Bone Marrow‐Derived Mesenchymal Stem Cells

We reported a functional incompetence in mesenchymal stem cells (MSCs) under uremia, but the mechanisms have not been explored. To study the mechanisms of dysfunctional MSCs induced by uremia, we characterized insulin signaling in MSCs and investigated the effect of uremic toxin, p‐cresol, on the proangiogenic actions of insulin. In MSCs, insulin induced hypoxia‐inducible factor (HIF)−1α, vascular endothelial growth factor, and stromal cell‐derived factor 1α expressions via PI3K/Akt‐dependent pathway. MSCs treated with p‐cresol exhibited altered insulin signaling in a selective manner for insulin receptor substrate‐1/PI3K/Akt pathway, whereas ERK pathway remained active. The insulin‐induced increase of HIF‐1α was blunted by p‐cresol treatment. This Akt‐selective insulin resistance was also observed in MSCs isolated from chronic kidney disease (CKD) mice. In mice model of hindlimb ischemia, blood flow recovery, capillary density, and local production of angiogenic factors in the ischemic limb treated with CKD MSCs were significantly inferior to those promoted by control MSCs. However, modifying CKD MSCs by overexpression of HIF‐1α restored all of these changes. Taken together, these data suggest that p‐cresol contributes to insulin resistance in a selective manner for Akt pathway. This might be a biological explanation for the functional incompetence of MSCs under uremia through defects in the insulin‐induced elevation of HIF‐1α protein expression. Stem Cells 2014;32:2443–2453

Determination of Single-Kidney Glomerular Filtration Rate in Human Subjects by Using CT

PURPOSE To test the hypothesis that computed tomography (CT)-derived measurements of single-kidney glomerular filtration rate (GFR) obtained in human subjects with 64-section CT agree with those obtained with iothalamate clearance, a rigorous reference standard. MATERIALS AND METHODS The institutional review board approved this HIPAA-compliant study, and written informed consent was obtained. Ninety-six patients (age range, 51-73 years; 46 men, 50 women) with essential (n = 56) or renovascular (n = 40) hypertension were prospectively studied in controlled conditions (involving sodium intake and renin-angiotensin blockade). Single-kidney perfusion, volume, and GFR were measured by using multidetector CT time-attenuation curves and were compared with GFR measured by using iothalamate clearance, as assigned to the right and left kidney according to relative volumes. The reproducibility of CT GFR over a 3-month period (n = 21) was assessed in patients with renal artery stenosis who were undergoing stable medical treatment. Statistical analysis included the t test, Wilcoxon signed rank test, linear regression, and Bland-Altman analysis. RESULTS CT GFR values were similar to those of iothalamate clearance (mean ± standard deviation, 38.2 mL/min ± 18 vs 41.6 mL/min ± 17; P = .062). Stenotic kidney CT GFR in patients with renal artery stenosis was lower than contralateral kidney GFR or essential hypertension single-kidney GFR (mean, 23.1 mL/min ± 13 vs 36.9 mL/min ± 17 [P = .0008] and 45.2 mL/min ± 16 [P = .019], respectively), as was iothalamate clearance (mean, 26.9 mL/min ± 14 vs 38.5 mL/min ± 15 [P = .0004] and 49.0 mL/min ± 14 [P = .001], respectively). CT GFR correlated well with iothalamate GFR (linear regression, CT GFR = 0.88*iothalamate GFR, r(2) = 0.89, P < .0001), and Bland-Altman analysis was used to confirm the agreement. CT GFR was also moderately reproducible in medically treated patients with renal artery stenosis (concordance coefficient correlation, 0.835) but was unaffected by revascularization (mean, 25.3 mL/min ± 15.2 vs 30.3 mL/min ± 18.5; P = .097). CONCLUSION CT assessments of single-kidney GFR are reproducible and agree well with a reference standard. CT can be useful to obtain minimally invasive estimates of bilateral single-kidney function in human subjects.

Atherosclerotic Renal Artery Stenosis: Current Status

Atherosclerotic renal artery stenosis (ARAS) remains a major cause of secondary hypertension and kidney failure. Randomized prospective trials show that medical treatment should constitute the main therapeutic approach in ARAS. Regardless of intensive treatment and adequate blood pressure control, however, renal and extrarenal complications are not uncommon. Yet, the precise mechanisms, accurate detection, and optimal treatment in ARAS remain elusive. Strategies oriented to early detection and targeting these pathogenic pathways might prevent development of clinical end points. Here, we review the results of recent clinical trials, current understanding of the pathogenic mechanisms, novel imaging techniques to assess kidney damage in ARAS, and treatment options.

Reanalysis of membranoproliferative glomerulonephritis patients according to the new classification: a multicenter study

Background All types of membranoproliferative glomerulonephritis (MPGN) are progressive diseases with poor prognoses. Recently, a newly proposed classification of these diseases separated them into immune complex- and complement-mediated diseases. We investigated the frequency of C3 glomerulonephritis among previously diagnosed MPGN patients. Methods We conducted a retrospective study of patients diagnosed with MPGN at three tertiary care institutions between 2001 and 2010. We investigated the incidence of complement-mediated disease among patients diagnosed with MPGN. Progressive renal dysfunction was defined as a 50% reduction in the glomerular filtration rate or the need for renal replacement therapy. Results Among the 3,294 renal biopsy patients, 77 (2.3%) were diagnosed with MPGN; 31 cases were excluded, of which seven were diagnosed with systemic lupus nephritis, and the others were not followed for a minimum of 12 months after biopsy. Based on the new classification, complement-mediated MPGN was diagnosed in two patients (4.3%); only one patient developed progressive renal dysfunction. Among the immune complex-mediated MPGN patients, 17 patients developed progressive renal dysfunction. Serum albumin and creatinine levels at the time of MPGN diagnosis were risk factors of renal deterioration, after adjusting for low C3 levels and nephrotic syndrome. Conclusion Complement-mediated glomerulonephritis was present in 4.3% of patients previously diagnosed with MPGN.

Association between the hemodialysis adequacy and sexual dysfunction in chronic renal failure: a preliminary study

BackgroundThe core question of the study was whether adequately achieved HD affected the sexual dysfunction in women on hemodialysis (HD) with chronic renal failure (CRF).MethodsThirty-seven female patients on HD, including 18 women with adequate HD and 19 women with non-adequate HD, and 36 healthy controls were included in this study. Demographic and clinical variables, including the sexual hormones estradiol and testosterone, were recorded. Sexual function was assessed according to the Female Sexual Function Index (FSFI) and results were compared between groups. Adequate HD was defined as an average urea clearance of over 1.3 (Kt/V) over three consecutive months.ResultsAll domains of the FSFI questionnaire, with the exception of satisfaction, were higher in the control group than in the HD group. In comparing the adequate and non-adequate HD groups, there was no difference in any of the six domains of the FSDI questionnaire. Among the clinical variables, the number of menopausal women was higher in the HD group than in the control group (P = 0.023). Estradiol and testosterone levels were higher in the control group than in the HD group (P = 0.003, 0.027, respectively). The number of menopausal women and estradiol and testosterone levels showed no differences between the adequate and non-adequate HD groups. Correlation analysis between Kt/V and FSFI showed no significant relationship, but estrogen did show a significant relationship with FSFI (correlation coefficient = 0.399, P = 0.001).ConclusionsHD adequacy alone does not have a significant impact on sexual dysfunction. Other treatments options should be considered to treat sexual dysfunction in women with CRF.