Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice

Jang, Hye Ryoun,Park, Ji Hyeon,Kwon, Ghee Young,Park, Jae Berm,Lee, Jung Eun,Kim, Dae Joong,Kim, Yoon-Goo,Kim, Sung Joo,Oh, Ha Young,Huh, Wooseong American Physiological Society 2016 American Journal of Physiology Vol.310 No.4

<P>Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-alpha and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required.</P>

B Cells Limit Repair after Ischemic Acute Kidney Injury

Jang, Hye Ryoun,Gandolfo, Maria Teresa,Ko, Gang Jee,Satpute, Shailesh R.,Racusen, Lorraine,Rabb, Hamid American Society of Nephrology 2010 Journal of the American Society of Nephrology Vol.21 No.4

Urinary Angiotensinogen Excretion and Intrarenal Angiotensinogen Expression in Minimal Change Disease Patients

( Hye Ryoun Jang ),( Ajin Jo ),( Ji Hyeon Park ),( Jung Eun Lee ),( Woo Seong Huh ),( Dae Joong Kim ),( Ha Young Oh ),( Yoon Goo Kim ) 대한신장학회 2011 Kidney Research and Clinical Practice Vol.30 No.6

Purpose: Urinary angiotensinogen (AGT) has been reported as an important marker reflecting the activity of intrarenal renin-angiotensin system (RAS) in chronic glomerulonephritis patients. We investigated urinary AGT excretion and intrarenal AGT expression in patients with minimal change disease (MCD). Methods: In 20 patients with biopsy-proven MCD, urinary and plasma AGT was measured using a sandwich ELISA and intrarenal AGT expression was measured with immunohistochemistry. Urine samples from normal healthy volunteers and patients with biopsy-proven thin basement membrane disease (TBM) were used as control groups. Results: MCD patients showed a wide range of natural logarithm of the urinary AGT/creatinine [ln (urinary AGT/Cr)] and the ln (urinary AGT/Cr) was higher in MCD patients compared with normal controls and TBM controls (normal control vs. TBM vs. MCD, 1.2±0.25 vs. 0.9±0.34 vs. 3.2±0.40). Intrarenal AGT expression was diverse in MCD patients (intrarenal AGT, arbitrary unit, 27.39-78.52 in TBM, 0.00-145.80 in MCD). Ln (urinary AGT/Cr) did not show a direct correlation with intrarenal AGT expression, plasma AGT, or urinary protein/creatinine ratio. Conclusion: Urinary AGT excretion and intrarenal AGT expression are enhanced in some MCD patients, suggesting that intrarenal RAS is activated in these patients.

Gitelman 증후군 환자에서 면역조직화학법으로 확인한 원위세관 sodium-chloride cotransporter (NCCT)의 결손

장혜련 ( Hye Ryoun Jang ),허남주 ( Nam Ju Heo ),손민정 ( Min Jung Son ),이재욱 ( Jay Wook Lee ),이정환 ( Jeong Hwan Lee ),전은실 ( Un Sil Jeon ),신성준 ( Sung Jun Shin ),나기영 ( Ki Young Na ),주권욱 ( Kwon Wook Joo ),이정상 ( Jun 대한내과학회 2005 대한내과학회지 Vol.69 No.6

목적 : Gitelman 증후군은 저포타시움혈증, 대사성 알칼리증, 고레닌혈증, 고알도스테론혈증, 요 중 칼슘 배설의 저하 및 저마그네슘혈증을 특징으로 하는 유전성 질환이다. 이는 원위세관 sodium-chloride cotransporter (NCCT)의 유전자 돌연변이에 의하여 발생하는 것으로 알려져 있으나 사람의 신조직에서 NCCT 결손이 증명된 바는 없었다. 방법 : 저자들은 임상적으로 Gitelman 증후군이 의심되는 환자에서 이뇨제를 이용한 신청소율 검사와 유전자 검사를 시행하였고, 이를 통하여 감별진단한 Gitelman 증후군 환자의 신조직에서 인간 NCCT에 대한 토끼 다클론 항체를 이용한 면역조직화학법을 시행하였다. 신세포암으로 신적출술을 시행 받은 환자의 정상 신조직과 전해질 이상이 없었던 사구체신염 환자의 신조직을 각각 정상 대조군과 질환 대조군으로 하였다. 결과 : 대상 환자는 저포타시움혈증과 대사성 알칼리증, 저마그네슘혈증 및 요 중 칼슘 배설의 저하를 보였다. Bartter 증후군과 감별을 위하여 furosemide 및 hydrochlorothiazide를 이용한 신청소율 검사를 시행하였다. 수분 부하를 시행한 기저치(86.1%)에 비해서 furosemide를 투여한 후 distal fractional chloride reabsorption이 감소하였으나(9.7%) hydrochlorothiazide 투여 후에는 변화가 없었다(81.4%). 유전자 검사 결과 SLC12A3 유전자의 돌연변이(S967F)가 발견되었다. 신조직에서 면역조직화학법을 시행한 결과 정상 및 질환 대조군에서는 원위세관 세포의 내강 막 쪽에 NCCT가 뚜렷이 염색되었으나, Gitelman 증후군에서는 원위세관 세포의 NCCT에 대한 면역 반응성이 관찰되지 않았다. 반면에 Na/K-ATPase, Na-K-2Cl cotransporter, calbindin-D28K는 대조군과 대상 환자의 신조직에서 모두 관찰되었다. 결론 : 기능적 검사로 진단된 Gitelman 증후군 환자의 신조직에서 NCCT의 결함을 면역조직화학법으로 확인하였다. Background : Gitelman`s syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. It is known to be caused by a mutation of SLC12A3 gene coding the sodium-chloride cotransporter (NCCT) in the distal tubule. The defect of NCCT in human renal tissues has not been investigated, and we tested whether the defect of NCCT can be detected in renal tissue of a patient with Gitelman`s syndrome by using immunohistochemistry. Methods : In an adult patient with Gitelman`s syndrome, blood and urine samples were collected for measurement of biochemical parameters. Renal clearance study and gene analysis were performed. Immunohistochemistry was performed on the renal tissue of the patient using a rabbit polyclonal antibody directed against a synthetic peptide corresponding to a portion in the amino terminal tail for human NCCT. Normal human renal tissues from surgical nephrectomy due to renal cell carcinoma and renal biopsy tissues from patients with glomerulonephritis but without any electrolyte disturbance were used as controls. Results : The patient had hypokalemic metabolic alkalosis, hypocalciuria and hypomagnesemia. Renal clearance study revealed a decrease in distal fractional chloride reabsorption after the administration of furosemide. SLC12A3 gene mutation (S967F) was found by direct sequencing method. Immunohistochemistry showed the absence of NCCT staining in the renal tissue of the patient. On the other hand, the immunostaining of other transporters was all positive in renal tissues from both Gitelman`s syndrome patients and controls. Conclusions : We report the absence of intact NCCT in the renal tissue of a Gitelman`s syndrome patient.(Korean J Med 69:642-650, 2005)

Role of T cells in ischemic acute kidney injury and repair

이경호,Hye Ryoun Jang 대한내과학회 2022 The Korean Journal of Internal Medicine Vol.37 No.3

Ischemic acute kidney injury (AKI) is a common medical problem with significant mortality and morbidity, affecting a large number of patients globally. Ischemic AKI is associated with intrarenal inflammation as well as systemic inflammation; thus, the innate and adaptive immune systems are implicated in the pathogenesis of ischemic AKI. Among various intrarenal immune cells, T cells play major roles in the injury process and in the repair mechanism affecting AKI to chronic kidney disease transition. Importantly, T cells also participate in distant organ crosstalk during AKI, which affects the overall outcomes. Therefore, targeting T cell-mediated pathways and T cell-based therapies have therapeutic promise for ischemic AKI. Here, we review the major populations of kidney T cells and their roles in ischemic AKI.

Electronic alerts based on clinical decision support system for post-contrast acute kidney injury

( Hojin Jeon ),( Hye Ryoun Jang ) 대한신장학회 2023 Kidney Research and Clinical Practice Vol.42 No.5

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation

Park, Ji Hyeon,Jang, Hye Ryoun,Kim, Do Hee,Kwon, Ghee Young,Lee, Jung Eun,Huh, Wooseong,Choi, Soo Jin,Oh, Wonil,Oh, Ha Young,Kim, Yoon-Goo American Physiological Society 2017 American Journal of Physiology Vol.313 No.4

<P>Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUGB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3. Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1. and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2 -fold higher than baseline levels) showed no renoprotective effects on day 6. Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AK.I. progression or alter the intrarenal inflammatory- micromilieu.</P>

Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Ko, Gang Jee,Jang, Hye Ryoun,Huang, Yanfei,Womer, Karl L.,Liu, Manchang,Higbee, Elizabeth,Xiao, Zuoxiang,Yagita, Hideo,Racusen, Lorraine,Hamad, Abdel Rahim A.,Rabb, Hamid American Society of Nephrology 2011 Journal of the American Society of Nephrology Vol.22 No.4

The impact of early and late acute rejection on graft survival in renal transplantation

( Eun Hee Koo ),( Hye Ryoun Jang ),( Jung Eun Lee ),( Jae Berm Park ),( Sung Joo Kim ),( Dae Joong Kim ),( Yoon Goo Kim ),( Ha Young Oh ),( Woo Seong Huh ) 대한신장학회 2015 Kidney Research and Clinical Practice Vol.34 No.3

Background: Advances in immunosuppression after kidney transplantation have decreased the influence of early acute rejection (EAR) on graft survival. Several studies have suggested that late acute rejection (LAR) has a poorer effect on longterm graft survival than EAR. We investigated whether the timing of acute rejection (AR) influences graft survival, and analyzed the risk factors for EAR and LAR. Methods: We performed a retrospective cohort study involving 709 patients who underwent kidney transplantation between 2000 and 2009 at the Samsung Medical Center, Seoul, Korea. Patients were divided into three groups: no AR, EAR, and LAR. EAR and LAR were defined as rejection before 1 year and after 1 year, respectively. Differences in graft survival between the three groups and risk factors of graft failure were analyzed. Results: Of the 709 patients, 198 (30%) had biopsy-proven AR [EAR¼152 patients (77%); LAR¼46 patients (23%)]. A total of 65 transplants were lost. The 5-year graft survival rates were 97%, 89%, and 85% for patients with no AR, EAR, and LAR, respectively. These differences were significant (Po0.001 for both by log-rank test). In time-dependent Cox regression analysis, EAR (hazards ratio, 3.37; 95% confidence interval, 1.90-5.99) and LAR (hazards ratio, 5.32; 95% confidence interval, 2.65- 10.69) were significantly related to graft failure. When we set LAR as standard and compared it with EAR, there was no statistical difference between EAR and LAR (P¼0.21). Conclusion: AR, regardless of its timing, significantly worsened graft survival. Treatments to reduce the incidence of AR and improve prognosis are needed.

Acute Renal Failure Following Off-pump Coronary Artery Bypass Surgery (OPCAB): Incidence, Risk Factors, and Outcomes

( Sun Moon Kim ),( Hye Ryoun Jang ),( Ran Hui Cha ),( Yon Su Kim ),( Curie Ahn ),( Jin Suk Han ),( Suhng Gwon Kim ),( Jung Sang Lee ),( Ki Bong Kim ),( Kwon Wook Joo ) 대한신장학회 2007 Kidney Research and Clinical Practice Vol.26 No.4

Purpose : Off-pump coronary artery bypass (OPCAB) is known to be associated with a lower risk acute renal failure (ARF) than on-pump method. However, little data is available on ARF in OPCAB. The aim of the present study was to identify the incidence, risk factors, and mortality of ARF OPCAB. Methods : Perioperative variables in medical records of 573 patients who had undergone OPCAB from Jan 2000 to June 2004 were evaluated. ARF was defined as a 50% increase in preoperative serum creatinine (over 1.4 mg/dL) within 72 hours after operation, or as the need for postoperative dialysis. Results : The incidence of ARF and ARF requiring dialysis were 9.8% and 2.6%, respectively. The independent risk factors for ARF after OPCAB were the perioperative use of an intra-aortic balloon pump (OR, 4.425; 95% CI, 2.342-8.403), high preoperative serum creatinine (OR 2.099; 95% CI, 1.422-3.098), diabetes (OR, 1.961; 95% CI, 1.078-3.571), and old age (OR, 1.479; 95% CI, 1.034-2.116). The in-hospital mortality rate was 53.3% for patients requiring dialysis, 19.6% for all ARF patients and 0.8% for patients without ARF (p<0.001). The 3-year cumulative mortality rate was 38.4 in all ARF patients and 5.2% in patients without ARF (p<0.001). Conclusion : ARF was not an uncommon complication in adults who underwent OPCAB. Perioperative hemodynamic instability, preoperative renal dysfunction, diabetes, and age could independently predict the development of ARF after OPCAB and the severity of ARF was related to higher in-hospital and long-term mortality rates.