Hoon Suk Park

The Oxford classification as a predictor of prognosis in patients with IgA nephropathy.

BACKGROUND In 2009, the Oxford classification was developed as a pathological classification system for immunoglobulin A nephropathy (IgAN) to predict the risk of disease progression. The aim of this retrospective study was to evaluate the clinical and pathologic relevance of the Oxford classification in Korean patients with a pathologic diagnosis of IgAN. PATIENTS AND METHODS We reviewed the renal pathology archives from January 2000 to December 2006 at Seoul St Marys Hospital in Korea and identified 273 patients, who were diagnosed as having IgAN. We enrolled 197 patients who were available for further clinicopathologic analysis. All cases of IgAN were categorized according to the WHO classification, the semiquantitative classification and the Oxford classification. These pathologic classifications were compared. The clinical and laboratory findings at the time of biopsy were compared with those at the end of the follow-up according to the Oxford classification. RESULTS When three pathologic classifications were compared, M1, S1, E1, T1 or T2 were associated with a higher score in the activity index. S1, T1 or T2 were associated with a higher score in the chronicity index and a higher grade in the WHO classification. The clinical and laboratory findings were compared according to the Oxford classification. At the time of biopsy, the proteinuria in patients with M1 was more than that of M0 (P = 0.035). At the end of follow-up, the number of antihypertensive drugs taken among patients with M1 was greater than that of patients with M0 (P = 0.001). At the time of biopsy, the proteinuria of patients with S1 was greater than that of S0 patients (P = 0.009). At the end of follow-up, the number of patients who received immunosuppressants was increased as the grade of T increased (P = 0.000). At the end point of the follow-up, the estimated glomerular filtration rate (eGFR) decreased as the grade of T increased (P = 0.008). The time-average proteinuria after adjusting the initial proteinuria increased significantly with increasing degree of T (P = 0.000). Levels of tubular atrophy/interstitial fibrosis were predictive for survival from end-stage renal disease or of having a 50% reduction of eGFR. CONCLUSION The pathologic variables of the Oxford classification correlated significantly with other classifications (the WHO classification and the semiquantitative classification). The Oxford classification is a simple method for predicting renal outcome and differentiating between active and chronic lesions. We suggest that the Oxford classification offers an advantage for determining treatment policy for patients with IgAN.

Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice

Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.

Clinical usefulness of BK virus plasma quantitative PCR to prevent BK virus associated nephropathy

The present study investigated the clinical usefulness of plasma real‐time polymerase chain reaction (PCR) (plasma‐PCR) in the prevention of BK virus‐associated nephropathy (BKVAN). First, we investigated the diagnostic value of plasma BK‐PCR, urine BK‐PCR, and urine cytology for the prediction of BKVAN retrospectively. Then we designed a prospective study of regular plasma‐PCR monitoring and pre‐emptive immunosuppression (IS) reduction based on the result. In the retrospective cohort, the prevalence of BKVAN was 3.7% (14/379) and the positive rate of decoy cells, urine‐PCR (>1 × 1010 copies/ml), and plasma‐PCR (>1 × 104 copies/ml) was 18.6%, 11.1%, and 5.5%, respectively. Plasma‐PCR was superior to urine‐PCR or urine cytology in specificity and positive predictive value for detection of BKVAN. In prospective study, regular monitoring of plasma‐PCR detected significant BKV viremia in 8.3% (12/145) and BKVAN in 1 patient (0.6%). After IS reduction, BKV viremia was eliminated in 91.6% (11/12) within 103 days (25–254). In patients with viremia, the frequency of acute rejection did not increase and allograft function did not differ significantly compared with those in patients without viremia during the first year post‐transplant (P > 0.05, in both). Plasma‐PCR is useful to predict an increased risk for BKVAN, and regular monitoring is effective to prevent the development of BKVAN.

Comparison of Clinical Outcome between High and Low Baseline Anti-ABO Antibody Titers in ABO-Incompatible Kidney Transplantation

High baseline anti-ABO antibody titer is still an important obstacle for successful ABO-incompatible kidney transplantation (ABO IKT). This study aims to investigate the clinical outcome of ABO IKT in patients with a high baseline titer in comparison with patients with a low baseline titer. Fourteen patients who received ABO IKT at our center were classified as the high-titer group (≥1:256, n = 8) or the low-titer group (≤1:128, n = 6). We used a protocol composed of rituximab, plasmapheresis, and intravenous immunoglobulin (RTX/PP/IVIG). We compared the intensity of preparation, complications, and clinical outcome between the two groups. The high-titer group required more sessions of pretransplant (10.5 ± 3.5 vs. 6.0 ± 1.3 times, p = 0.01) and posttransplant (1.6 ± 1.8 vs. 0 ± 0 times) PP/IVIG than the low-titer group did. All patients from both groups showed immediate recovery of graft function. The antibody titer and allograft function in the high-titer group were stable and did not differ significantly from those of the low-titer group up to 1 year after kidney transplantation. There was no antibody-mediated rejection in either group during follow-up, but three cases of acute cellular rejection developed in the high-titer group. The high-titer group showed two cases of opportunistic viral infection (herpes gingivitis and cytomegalovirus viremia) and one case of graft loss due to postoperative bleeding. ABO IKT can be safely performed even in patients with a high baseline anti-ABO antibody titer, but the risk for infection and bleeding should be considered before transplantation.

Concomitant increase in muscle strength and bone mineral density with decreasing IL-6 levels after combination therapy with alendronate and calcitriol in postmenopausal women.

ObjectiveThe aims of this study were to assess changes in muscle mass and strength according to changes in bone mineral density (BMD) after alendronate-calcitriol therapy and to assess subsequent changes in common biomarkers for osteoporosis and sarcopenia to establish a common strategy against these coexisting conditions. MethodsThirty-eight women with osteopenia and without conditions affecting calcium metabolism, inflammatory cytokines, acute and chronic medical conditions, and regular endurance exercise completed the study. Appendicular lean mass and BMD were measured, and relative skeletal mass index was determined. Grip strength was measured with a JAMAR hand dynamometer. Serum interleukin-6 (IL-6), protein carbonyl, and parathyroid hormone (PTH) were measured as biomarkers related to bone and muscle mass before and after a 6-month combination therapy with alendronate (5 mg) and calcitriol (0.5 &mgr;g). ResultsBaseline serum IL-6 showed significant negative correlations with lumbar BMD and handgrip strength (r = −0.458, P = 0.01, and left hand; r = −0.387, P = 0.03, respectively), whereas serum 25-hydroxy vitamin D level was 13.97 (5.65) ng/mL, compatible with vitamin D insufficiency and inversely correlated with PTH level (r = −0.481, P = 0.005). The observation of secondary hyperparathyroidism in association with 25-hydroxy vitamin D deficiency was absent, in contrast with previous reports. After treatment, the mean IL-6 level decreased by 56.5% (8.9%) (P = 0.0032), lumbar BMD increased by 2.62% (2.87%; P = 0.0002), and average handgrip strength increased by 33.52% (8.34%; P = 0.0001). Posttherapy IL-6 level was not significantly correlated with posttherapy BMD and handgrip strength (r = 0.06, P = 0.76, and r = 0.156, P = 0.45, respectively). However, the degree of IL-6 changed by treatment displayed a significant negative correlation with initial lumbar BMD and a positive correlation with PTH levels. ConclusionsImprovement not only in lumbar BMD but also in handgrip strength (a representative parameter for sarcopenia) has been observed with 6 months of alendronate-calcitriol combination therapy. Initial IL-6 levels display an inverse relationship with pretreatment lumbar BMD and handgrip strength. The degree of change in IL-6 levels induced by the combination therapy is correlated with the initial degree of the catabolic status of the bone, indicated by markers such as PTH and the severity of lumbar BMD derangements.

Increased interleukin-17 producing effector memory T cells in the end-stage renal disease patients

Patients with end-stage renal disease (ESRD) exhibit immune dysregulation, but the precise immunological profile and the effect of hemodialysis (HD) on it has not been investigated fully. Thirty-eight ESRD patients (22 on HD and 16 in pre-dialysis) and 24 healthy volunteers were included. We compared the T cell immune profiles as in these patients. Among the effector T cell subset, the percentages of Th17 and Th2 cells were significantly higher in the ESRD group than in the healthy controls (P<0.05). The percentage of Th1 cells did not differ significantly between these groups. The percentages of Th1, Th2 and Th17 cells did not differ significantly (P>0.05) between the two subgroups within the ESRD group. The CCR4(-)CCR6(+)/CD4(+) T cell percentage was also significantly higher in the ESRD group. The naïve T cell (T(naïve)) percentage was significantly lower in the ESRD group, and the difference between patients and controls was greater in the pre-dialysis patients than in the HD patients (P<0.05, for each comparison). By contrast, the percentages of central memory T cells (T(CM)) and effector memory T (T(EM)) cells were significantly higher in the ESRD group. Interleukin-17 production by T(EM) cells was significantly higher in the ESRD group. The severity of uremia was related negatively to the T(naïve) cell percentage but positively to the T(CM) and T(EM) cell percentages. The percentages of T(EM) and CD45RA(+) T effector memory subsets of CD8(+) T cells were significantly higher in the ESRD group (P<0.05). The result of this study showed significantly altered T cell-associated immunity and that it could not be corrected with hemodialysis.

Clinical significance of the ratio between FOXP3 positive regulatory T cell and interleukin-17 secreting cell in renal allograft biopsies with acute T-cell-mediated rejection.

The aim of this study is to investigate the clinical significance of the ratio between interleukin‐17 (IL‐17) secreting cell and FOXP3‐positive regulatory T cell (FOXP3+ Treg) infiltration in renal allograft tissues with acute T‐cell‐mediated rejection (ATCMR). Fifty‐six patients with biopsy‐proven ATCMR were included. Infiltration of FOXP3+ Treg and IL‐17‐secreting cells was evaluated with immunostaining for FOXP3 or IL‐17 on the biopsy specimens, and the patients were divided into the FOXP3 high group (Log FOXP3/IL‐17 > 0·45) or the IL‐17 high group (Log FOXP3/IL‐17 < 0·45). We compared the allograft function, severity of tissue injury, and clinical outcome between the two groups. In the IL‐17 high group, allograft function was significantly decreased compared with the FOXP3 high group (P < 0·05). The severity of interstitial and tubular injury in the IL‐17 high group was higher than the FOXP3 high group (P < 0·05). The proportions of steroid‐resistant rejection, incomplete recovery and recurrent ATCMR were higher in the IL‐17 high group than in the FOXP3 high group (all indicators, P < 0·05). The IL‐17 high group showed lower 1‐year (54% versus 90%, P < 0·05) and 5‐year (38% versus 85%, P < 0·05) allograft survival rates compared with the FOXP3 high group. Multivariate analysis revealed that the FOXP3/IL‐17 ratio was a significant predictor for allograft outcome. The FOXP3/IL‐17 ratio is a useful indicator for representing the severity of tissue injury, allograft dysfunction and for predicting the clinical outcome of ATCMR.

Higher infiltration by Th17 cells compared with regulatory T cells is associated with severe acute T-cell-mediated graft rejection

The aim of this study was to evaluate whether the Th17 and Treg cell infiltration into allograft tissue is associated with the severity of allograft dysfunction and tissue injury in acute T cell-mediated rejection (ATCMR). Seventy-one allograft tissues with biopsy-proven ATCMR were included. The biopsy specimens were immunostained for FOXP3 and IL-17. The allograft function was assessed at biopsy by measuring serum creatinine (Scr) concentration, and by applying the modified diet in renal disease (MDRD) formula, which provides the estimated glomerular filtration rate (eGFR). The severity of allograft tissue injury was assessed by calculating tissue injury scores using the Banff classification. The average numbers of infiltrating Treg and Th17 cells were 11.6 ± 12.2 cells/mm2 and 5.6 ± 8.0 cells/mm2, respectively. The average Treg/Th17 ratio was 5.6 ± 8.2. The Treg/Th17 ratio was significantly associated with allograft function (Scr and MDRD eGFR) and with the severity of interstitial injury and tubular injury (P < 0.05, all parameters). In separate analyses of the number of infiltrating Treg and Th17 cells, Th17 cell infiltration was significantly associated with allograft function and the severity of tissue injury. By contrast, Treg cell infiltration was not significantly associated with allograft dysfunction or the severity of tissue injury. The results of this study show that higher infiltration of Th17 cell compared with Treg cell is significantly associated with the severity of allograft dysfunction and tissue injury.

Aquagenic Urticaria: A Report of Two Cases

Aquagenic urticaria is a rare form of physical urticaria, in which contact with water evokes wheals. A 19-year-old man and a 4-year-old boy complained of recurrent episodes of urticaria. Urticaria appeared while taking a bath or a shower, in the rain, or in a swimming pool. Well-defined pin head to small pea-sized wheals surrounded by variable sized erythema were provoked by contact with water on the face, neck, and trunk, regardless of its temperature or source. Results from a physical examination and a baseline laboratory evaluation were within normal limits. Treatment of the 19-year-old man with 180 mg fexofenadine daily was successful to prevent the wheals and erythema. Treatment with 5 ml ketotifen syrup bid per day resulted in improvement of symptoms in the 4-year-old boy.

Comparison of the palindrome vs. step-tip tunneled hemodialysis catheter: a prospective randomized trial.

Numerous designs for tunneled hemodialysis catheter have been developed in an effort to improve catheter function and survival. In this prospective randomized controlled study, 97 patients were randomized into the palindrome catheter group (PC, n = 47) and step‐tip catheter group (SC, n = 50). Demographic characteristics were not different between the two groups. The effective blood flow rates at different pump speeds were comparable between the two groups. The recirculation was low within acceptable range in both types of catheter, and hemodialysis adequacy was not different between the two groups. However, when arterial and venous blood lines were reversed, while the recirculation was significantly increased in SC, it was not increased at all in PC. The catheter dysfunction‐free survival rate was significantly higher in PC than in SC (78.9% vs. 54.4% at 2 months, p = 0.008). The overall catheter survival rate was also higher in PC than in SC (90.6% vs. 68.8% at 2 months, p = 0.015). We conclude that both catheters are equally effective on the adequate hemodialysis and low recirculation. However, the PCs have advantages over the SCs in terms of lower catheter dysfunction rate, lower recirculation with reversed blood lines, higher short‐term catheter survival rate.