Dong Wan Chae

Clinical implications of pathologic diagnosis and classification for diabetic nephropathy

AIMnThe usefulness of renal pathologic diagnosis in type II DM (diabetes mellitus) remains debate.nnnMETHODSnWe grouped the pathologic diagnoses as pure DN (diabetic nephropathy), NDRD (non-diabetic renal disease), and NDRD mixed with DN (Mixed). We classified pure DN as the criteria suggested by Tervaert. We compared the accuracy of clinical parameters to predict DN and usefulness of pathology to predict renal prognosis.nnnRESULTSnAmong 126 enrolled patients, there were 50 pure DN, 65 NDRN, and 11 Mixed. The sensitivity and specificity for predicting DN with the presence of retinopathy were 77.8-73.6% and, with a cut-off value of 7.5 years of diabetic duration, the sensitivity and specificity were 64.5-67.2%. ESRD (end stage renal disease) occurred in 44.0% of DN, 18.2% of Mixed, and 12.3% of NDRD (p<0.001). Among pure DN, Class IV showed the lowest estimated glomerular filtration rate (eGFR). We estimated the 5-year renal survival rate as 100.0% in Classes I and IIa, 75.0% in Class IIb, 66.7% in Class III, and 38.1% in Class IV (p=0.002).nnnCONCLUSIONSnNephropathy of type II DM was diverse and could not be completely predicted by clinical parameters. The renal pathologic diagnosis was a good predictor for renal prognosis in type II DM.

Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney

BackgroundThe inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model.MethodsRats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested.ResultsThe sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and −9 and Bax levels and decreased macrophage infiltration.ConclusionsIn rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.

KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease): design and methods

BackgroundThe progression and complications of chronic kidney disease should differ depending on the cause (C), glomerular filtration rate category (G), and albuminuria (A). The KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease), which is a prospective cohort study, enrolls subjects with chronic kidney disease stages 1 to 5 (predialysis).Methods/DesignNine nephrology centers in major university hospitals throughout Korea will enroll approximately 2,450 adults with chronic kidney disease over a 5-year period from 2011 to 2015. The participating individuals will be monitored for approximately 10xa0years until death or until end-stage renal disease occurs. The subjects will be classified into subgroups based on the following specific causes of chronic kidney disease: glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, and others. The eligible subjects will be evaluated at baseline for socio-demographic information, detailed personal/family history, office BP, quality of life, and health behaviors. After enrollment in the study, thorough assessments, including laboratory tests, cardiac evaluation and radiologic imaging, will be performed according to the standardized protocol. The biospecimen samples will be collected regularly. A renal event is defined by >50% decrease in estimated GFR (eGFR) from the baseline values, doubling of serum creatinine, or end-stage renal disease. The primary composite outcome consists of renal events, cardiovascular events, and death. As of September 2013, 1,470 adult chronic kidney disease subjects were enrolled in the study, including 543 subjects with glomerulonephritis, 317 with diabetic nephropathy, 294 with hypertensive nephropathy and 249 with polycystic kidney disease.DiscussionAs the first large-scale chronic kidney disease cohort study to be established and maintained longitudinally for up to 10xa0years, the KNOW-CKD will help to clarify the natural course, complication profiles, and risk factors of Asian populations with chronic kidney disease.Trial registrationNo. NCT01630486 at http://www.clinicaltrials.gov.

Trends in the prevalence of chronic kidney disease, other chronic diseases and health-related behaviors in an adult Korean population: data from the Korean National Health and Nutrition Examination Survey (KNHANES)

BACKGROUNDnChronic kidney disease (CKD) is an increasing public health problem. However, there have been limited data on the trend of CKD prevalence, along with the changes of health-related behaviors and other chronic diseases in an adult Korean population.nnnMETHODSnData from the Korean National Health and Nutrition Examination Survey in 2005 and 2007 were analyzed. The study subjects comprised 8400 participants aged ≥ 20 years with creatinine data. CKD was defined as estimated glomerular filtration rate (GFR) <60 mL/min/1.73m(2). GFR was estimated by the abbreviated Modification of Diet in Renal Disease equation.nnnRESULTSnThe CKD prevalence was significantly decreased from 2005 to 2007 (8.8 versus 7.2%; P = 0.010). The prevalence of hypertension was stable but that of diabetes was increased. The proportion of blood pressure (BP) <130/80 mmHg in the whole population, and HbA1c <7% in the diabetic participants was increased from 2005 to 2007. Participants in 2007 walked more than those in 2005. The proportion of current smoking and sodium/energy/protein excess was decreased from 2005 to 2007. In subgroup analysis, only hypertensive participants without diabetes revealed a decreasing trend of CKD.nnnCONCLUSIONSnThe CKD prevalence was decreased from 2005 to 2007. Since increased diabetes and improved diabetic control neutralized their impact on CKD, improved BP was the fundamental reason for the decrease. Various health-related behaviors may have indirectly affected the decrease of CKD through their effect in controlling BP and diabetes.

Management of patients with diabetes and CKD: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.

Hypoxia-Inducible Factor Activation Protects the Kidney from Gentamicin-Induced Acute Injury

Gentamicin nephrotoxicity is one of the most common causes of acute kidney injury (AKI). Hypoxia-inducible factor (HIF) is effective in protecting the kidney from ischemic and toxic injury. Increased expression of HIF-1α mRNA has been reported in rats with gentamicin-induced renal injury. We hypothesizd that we could study the role of HIF in gentamicin-induced AKI by modulating HIF activity. In this study, we investigated whether HIF activation had protective effects on gentamicin-induced renal tubule cell injury. Gentamicin-induced AKI was established in male Sprague-Dawley rats. Cobalt was continuously infused into the rats to activate HIF. HK-2 cells were pre-treated with cobalt or dimethyloxalylglycine (DMOG) to activate HIF and were then exposed to gentamicin. Cobalt or DMOG significantly increased HIF-1α expression in rat kidneys and HK-2 cells. In HK-2 cells, HIF inhibited gentamicin-induced reactive oxygen species (ROS) formation. HIF also protected these cells from apoptosis by reducing caspase-3 activity and the amount of cleaved caspase-3, and -9 proteins. Increased expression of HIF-1α reduced the number of gentamicin-induced apoptotic cells in rat kidneys and HK-2 cells. HIF activation improved the creatinine clearance and proteinuria in gentamicin-induced AKI. HIF activation also ameliorated the extent of histologic injury and reduced macrophage infiltration into the tubulointerstitium. In gentamicin-induced AKI, the activation of HIF by cobalt or DMOG attenuated renal dysfunction, proteinuria, and structural damage through a reduction of oxidative stress, inflammation, and apoptosis in renal tubular epithelial cells.

Additional role of urine output criterion in defining acute kidney injury

BACKGROUNDnDiagnosis of acute kidney injury (AKI) has been a major concern due to its association with increased morbidity and mortality. However, the clinical implication of the urine output criterion (UOCr) in diagnosing AKI has not been fully established.nnnMETHODSnWe assessed the incidence of AKI among 1625 critically ill patients and analysed the overall survival rates based on the serum creatinine criterion (CrCr) and UOCr, both of which have been defined by the AKI Network (AKIN).nnnRESULTSnWithin 7 days of admission, the risk rate of AKI was 57.0% and the rate determined by UOCr alone was 25.7%. AKI determined by the UOCr alone increased hazard ratios (HRs) for mortality; 1.81 (Stage 1), 2.96 (Stage 2) and 4.17 (Stage 3) compared to non-AKI. However, the difference in mortality between Stages 2 and 3 using the CrCr alone was not significant (P = 0.881). In patients with Stages 2 and 3 by the CrCr, the UOCr further separated the survival rates (P = 0.001 among the four UOCr stages). The diuretic dose did not alter the discriminative function of the UOCr for survival rates. However, 42.1% of non-AKI cases, as determined by the UOCr, were identified as AKI cases by the CrCr.nnnCONCLUSIONnAlthough some AKI cases were not identified by the UOCr alone, the UOCr has an additional role in AKI staging, regardless of diuretic use.

The Occurrence of Warfarin-Related Nephropathy and Effects on Renal and Patient Outcomes in Korean Patients

Background Warfarin-related nephropathy (WRN) is a recently described disease entity, in which excessive warfarinization (international normalized ratio (INR) >3.0) causes acute kidney injury. Previous reports regarding WRN included few Asian patients who might have differed from the western WRN patients in terms of genetic and environmental factors. Methods During the period of March 2003 to December 2011, the data about a total of 1297 patients who had serum creatinine (sCr) level measured within 1 week after INR >3.0 and within 6 months before INR >3.0 was analyzed through the retrospective review of electronic medical records of a single tertiary hospital in Korea. Result WRN developed in 19.3% of patients having excessive warfarinization. The incidence was higher in the chronic kidney disease (CKD) group than the non-CKD group. The risk of WRN increased as the basal serum albumin level decreased and was strongly associated with highest quartile serum AST level at post INR elevation and the presence of congestive heart failure. But the presence of atrial fibrillation was protective against the development of WRN. Neither the presence of CKD nor basal estimated glomerular filtration rate (eGFR) was an independent risk factor for WRN. Despite no difference in the basal sCr level, the sCr level was higher in patients with WRN than those without WRN after follow-up. The mortality rates were also higher in patients with WRN. Conclusions WRN developed in 19.3% of patients having excessive warfarinization. A lower basal serum albumin, highest quartile serum AST level at post INR elevation, and congestive heart failure were associated with the occurrence of WRN. The development of WRN adversely affected renal and patient outcomes.

Bilirubin attenuates the renal tubular injury by inhibition of oxidative stress and apoptosis

BackgroundBilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases. We investigated whether administration of BIL had a protective effect on cyclosporine (CsA)-induced nephropathy (CIN), and examined the effects of BIL on the oxidative stress and apoptosis.MethodsBIL was pretreated intraperitoneally three times for a week (60 mg/kg), and CsA was injected for 4 weeks (15 mg/kg/day, subcutaneous). Proximal tubular epithelial (HK2) cells were pretreated with 0.1mg/ml of BIL for 24 hours, and then treated with 20 μM of CsA for another 24 hours.ResultsCsA induced marked increases in urine kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) concentrations (Pu2009<u20090.05). BIL reduced urine Kim-1 in CIN (Pu2009<u20090.05), while urine NGAL exhibited a decreasing tendency. In CsA-treated rat kidneys, the protein expression of NOX4 and p22phox was reduced by BIL (Pu2009<u20090.05). BIL ameliorated CsA-induced arteriolopathy, tubulointerstitial fibrosis, tubular injury, and the apoptosis examined by TUNEL assay (Pu2009<u20090.01). In HK2 cells, BIL reduced intracellular reactive oxygen species in CsA-treated cells. CsA increased the protein expression of bax, cleaved caspase-9, caspase-3 and the activity of caspase-3; however, the anti-apoptotic bcl-2 protein was reduced. These changes were recovered by BIL (Pu2009<u20090.05).ConclusionsThe direct administration of BIL protected against CsA-induced tubular injury via inhibition of oxidative stress and apoptosis.

Erythropoietin improves long-term outcomes in patients with acute kidney injury after coronary artery bypass grafting.

Previous studies reported the beneficial effect of erythropoietin (EPO) in acute injuries. We followed patients with and without acute kidney injury (AKI) after coronary artery bypass grafting (CABG) and evaluated the effect of EPO on long-term outcome. We also assessed the efficacy of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a predictive marker of AKI. Seventy-one patients scheduled for elective CABG were randomly given either 300 U/kg of EPO or saline before CABG. The primary outcome was AKI, and the secondary outcome was the all-cause-mortality and composite of all-cause-mortality and end stage renal disease (ESRD). Twenty-one patients had AKI, 14 (66.7%) in the placebo group and 7 (33.3%) in the EPO group (P = 0.05). Also, uNGAL was higher in the patients with AKI than in those without AKI at baseline, 2, 4, 24, and 72 hr after CABG (P = 0.011). Among patients with AKI, 2-week creatinine (Cr) was not different from baseline Cr in the EPO group, but 2-week Cr was significantly higher than baseline Cr in the placebo group (P = 0.009). All-cause-mortality (P = 0.022) and the composite of all-cause-mortality and ESRD (P = 0.003) were reduced by EPO. EPO reduces all-cause-mortality and ESRD in patients with AKI, largely due to the beneficial effect of EPO on recovery after AKI.