Sang Ju Lee

Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.

Vascular Endothelial Growth Factor Inhibition by dRK6 Causes Endothelial Apoptosis, Fibrosis, and Inflammation in the Heart via the Akt/eNOS Axis in db/db Mice

OBJECTIVE Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes. RESEARCH DESIGN AND METHODS We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db/db and db/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db/db-dRK6 and db/m-dRK6) or were untreated. RESULTS Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1α expression were significantly increased. No such changes were found in the other groups, including the db/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress. CONCLUSIONS Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.

Pretreatment with paricalcitol attenuates inflammation in ischemia–reperfusion injury via the up-regulation of cyclooxygenase-2 and prostaglandin E2

BACKGROUND The effect of paricalcitol on renal ischemia-reperfusion injury (IRI) has not been investigated. We examined whether paricalcitol is effective in preventing inflammation in a mouse model of IRI, and evaluated the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways as a protective mechanism of paricalcitol. METHODS Paricalcitol (0.3 μg/kg) was administered to male C57BL/6 mice 24 h before IRI. Bilateral kidneys were subjected to 23 min of ischemia, and mice were killed 72 h after IRI. The effects of paricalcitol on renal IRI were evaluated in terms of renal function, tubular necrosis, apoptotic cell death, inflammatory cell infiltration and inflammatory cytokines. The effects of paricalcitol on COX-2, PGE2 and its receptors were investigated. RESULTS Paricalcitol pretreatment improved renal function (decreased blood urea nitrogen and serum creatinine levels), tubular necrosis and apoptotic cell death in IRI-mice kidneys. The infiltration of inflammatory cells (T cells and macrophages), and the production of proinflammatory cytokines (RANTES, tumor necrosis factor-α, interleukin-1β and interferon-γ) were reduced in paricalcitol-treated mice with IRI. Paricalcitol up-regulated COX-2 expression, PGE2 synthesis and mRNA expression of receptor subtype EP4 in post-ischemic renal tissue. The cotreatment of a selective COX-2 inhibitor with paricalcitol restored functional injury and tubular necrosis in paricalcitol-treated mice with IRI. CONCLUSIONS Our study demonstrates that paricalcitol pretreatment prevents renal IRI via the inhibition of renal inflammation, and the up-regulation of COX-2 and PGE2 is one of the protective mechanisms of paricalcitol in renal IRI.

Late Referral to a Nephrologist Increases the Risk of Uremia-Related Cardiac Hypertrophy in Patients on Hemodialysis

Background: The prognosis and outcome of patients with end-stage renal disease are related to the quality of predialysis care and the timing of referral. Late referral (LR) has been correlated with more frequent hospital admissions, malnutrition and cardiovascular mortality after hemodilaysis (HD) is started. Methods: We investigated the effects of LR on cardiac hypertrophy, uremia-related metabolic risk factors and mortality in patients on HD. A baseline echocardiography was performed in 119 patients on HD, 67 of whom were early referrals (ER, referred more than 3 months before the start of HD) and 52 were LR (referred less than 3 months before the start of HD; median (range): 22.5 (4–120) vs. 1.0 (0–3) months, respectively). Results: The survival curves showed a higher mortality rate in the LR patients than in the ER patients (log rank, p = 0.004). More patients in the LR group died of cardiovascular disease compared to the ER patients (p = 0.04). The plasma levels of albumin were significantly lower (p < 0.05), and the intact parathyroid hormone (iPTH) and log C-reactive protein (log CRP) were significantly higher in the LR patients compared to the ER patients (p < 0.05 and p < 0.001, respectively). The LR patients, especially nonsurvivors, showed greater impairment of systolic cardiac function and more concentric left ventricular hypertrophy (LVH) than ER patients, as determined by interventricular septal thickness (p < 0.001), left ventricular posterior wall thickness (p < 0.001), relative wall thickness (p = 0.02), and the left ventricular mass index (LVMi, p < 0.001). Interestingly, the duration of the pre-HD treatment, after referral, was positively associated with the plasma albumin (r = 0.229; p = 0.01) and negatively associated with the log CRP (r = –0.350; p < 0.001), iPTH (r = –0.309; p = 0.001) and LVMi (r = –0.268; p = 0.004). Multiple linear regression analysis also demonstrated that the log CRP and iPTH as well as the LR were independently associated with LVMi in the HD patients (p < 0.05). Conclusions: The results of this study demonstrated that the LR HD patients were at an increased risk for more cardiovascular related mortality, severe concentric LVH and systolic dysfunction accompanied by inflammatory and malnutrition indices, as well as with increased iPTH levels. In the LR patients, the more severe LVH associated with severe inflammatory indices, as well as the higher iPTH levels, may be one of the causes of LR-related mortality.

Rifampin-associated tubulointersititial nephritis and Fanconi syndrome presenting as hypokalemic paralysis

BackgroundRifampin is one of the most important drugs in first-line therapies for tuberculosis. The renal toxicity of rifampin has been reported sporadically and acute tubulointerstitial nephritis (ATIN) is a frequent histological finding. We describe for the first time a case of ATIN and Fanconi syndrome presenting as hypokalemic paralysis, associated with the use of rifampin.Case presentationA 42-year-old man was admitted with sudden-onset lower extremity paralysis and mild renal insufficiency. He had been treated for pulmonary tuberculosis with isoniazid, rifampin, and ethambutol for 2 months. Laboratory tests revealed proteinuria, profound hypokalemia, hyperchloremic metabolic acidosis with a normal anion gap, positive urine anion gap, hypophosphatemia with hyperphosphaturia, hypouricemia with hyperuricosuria, glycosuria with normal serum glucose level, generalized aminoaciduria, and β2-microglobulinuria. A kidney biopsy revealed findings typical of ATIN and focal granular deposits of immunoglubulin A and complement 3 in the glomeruli and tubules. Electron microscopy showed epithelial foot process effacement and electron-dense deposits in the subendothelial and mesangial spaces. Cessation of rifampin resolved the patient’s clinical presentation of Fanconi syndrome, and improved his renal function and proteinuria.ConclusionThis case demonstrates that rifampin therapy can be associated with Fanconi syndrome presenting as hypokalemic paralysis, which is a manifestation of ATIN. Kidney function and the markers of proximal tubular injury should be carefully monitored in patients receiving rifampin.

Safety and Efficacy of a Quinolone-Based Regimen for Treatment of Tuberculosis in Renal Transplant Recipients

BACKGROUND Rifampin (RFP) is a first-line antituberculosis drug, but it increases the risk of acute rejection (AR) in transplant recipients. This study evaluated whether quinolone (QNL) can replace RFP in renal transplant recipients with tuberculosis. METHODS One hundred nine patients with active tuberculosis were included. Patients consisted of RFP (n = 91) and QNL (n = 18) groups based on the initial treatment regimen. Patients with RFP-associated adverse effects were subdivided into RFP-maintenance (RFP-M; n = 18) and QNL-conversion (QNL-C; n = 8) groups. Clinical outcomes were compared between groups. RESULTS The incidence of AR was higher in the RFP group than in the QNL group (24.2% vs 5.6%). The QNL group showed significantly higher 10-year graft survival rates than the RFP group (88.1% vs 66.5%; P = .022). The QNL-C group showed significantly higher 10-year graft survival rates than the RFP-M group (87.5% vs 27.8%; P = .011). The rate of complete functional recovery after AR was higher in the QNL-C group than in the RFP-M group (50% vs 22.2%). CONCLUSIONS A QNL-based regimen may be safe and effective for treatment of tuberculosis and may lower the risk of graft failure in renal transplant recipients.

Decisive Indicator for Gastrointestinal Workup in Anemic Patients with Nondialysis Chronic Kidney Disease

Background: Anemia and iron deficiency are universal problems in patients with chronic kidney disease (CKD). However, decisive indicator to guide the further gastrointestinal (GI) workup has not been determined. Methods: We included 104 anemic patients with nondialysis-dependent CKD stages 3-5 (38 patients at stage 3, 26 patients at stage 4, and 40 patients at stage 5). Hemoglobin, serum ferritin, transferrin saturation (TSAT), mean corpuscular volume (MCV), and corrected reticulocyte count data were assessed to evaluate diagnostic utility for bleeding-related GI lesions, which were identified by esophagogastroduodenoscopy and colonoscopy. Results: Bleeding-related GI lesions were found in 55 (52.9%) patients, and patients with stage 5 CKD had a higher prevalence of gastric lesions than patients with CKD stage 3 or 4 (all p < 0.05). The areas under the receiver operating characteristic curves used to predict bleeding-related lesions were 0.69 for TSAT (p = 0.002) and 0.61 for serum ferritin (p = 0.085). The sensitivity and specificity of a cutoff value for TSAT < 20% were 0.59 and 0.74, respectively. Hemoglobin, MCV, and corrected reticulocyte levels had no significant diagnostic utility. On multivariable logistic regression, the chance of GI lesions increased by 6% for each 1% reduction in TSAT and increased 4.1-fold for patients with CKD stage 5 (all p < 0.05). Conclusions: TSAT is a useful indicator for determining the GI workup in anemic patients with nondialysis-dependent CKD stages 3-5. Stage 5 CKD is independently associated with bleeding-related lesions and TSAT should be used cautiously in these patients.

Status of Initiating Pattern of Hemodialysis: A Multi-center Study

This study was to evaluate the status of initiating pattern of hemodialysis (HD). Five hundred-three patients in 8 University Hospitals were included. Presentation mode (planned vs. unplanned), and access type (central venous catheters [CVC] vs. permanent access) at initiation of HD were evaluated, and the influence of predialysis care on determining the mode of HD and access type was also assessed. Most patients started unplanned HD (81.9%) and the most common initial access type was CVC (86.3%). The main reason for unplanned HD and high rate of CVC use was patient-related factors such as refusal of permanent access creation and failure to attend scheduled clinic appointments. Predialysis care was performed in 57.9% of patients and only 24.1% of these patients started planned HD and 18.9% used permanent accesses initially. Only a minority of patients initiated planned HD with permanent accesses in spite of predialysis care. To overcome this, efforts to improve the quality of predialysis care are needed.

Unresolved subclinical hypothyroidism is independently associated with progression of chronic kidney disease.

Background and Aim: Patients with chronic kidney disease (CKD) often have subclinical hypothyroidism. However, few reports have investigated changes in the status of subclinical hypothyroidism in CKD patients and its clinical significance in CKD progression. Methods: We included 168 patients with nondialysis-dependent CKD stages 2-4. The normalization of subclinical hypothyroidism during follow-up was assessed, and the association between transitions in subclinical hypothyroid status and the rate of decline of the estimated glomerular filtration rate (eGFR) was investigated. Results: At baseline, 127 patients were euthyroid and 41 (24.4%) patients were diagnosed with subclinical hypothyroidism. Of these 41 patients, 21 (51.2%) spontaneously resolved to euthyroid during follow-up. The rate of eGFR decline of patients with resolved subclinical hypothyroidism was similar to that of euthyroid patients. The patients with unresolved subclinical hypothyroidism showed a steeper renal function decline than patients with euthyroidism or resolved subclinical hypothyroidism (all p < 0.05). The progression to end-stage renal disease was more frequent in those with unresolved subclinical hypothyroidism than in those who were euthyroid (p = 0.006). In multivariate linear regression for rate of eGFR decrease, unresolved subclinical hypothyroidism (β = -5.77, p = 0.001), baseline renal function (β = -0.12, p < 0.001) and level of proteinuria (β = -2.36, p = 0.015) were independently associated with the rate of renal function decline. Conclusions: Half of the CKD patients with subclinical hypothyroidism did not resolve to euthyroidism, and this lack of resolution was independently associated with rapid renal function decline.

Use of Blood Tests to Predict Upper Gastrointestinal Lesions in Patients With Chronic Kidney Disease

Objective Anemia and iron deficiency are common complications in patients with chronic kidney disease (CKD). However, information about the diagnostic indicators of bleeding-related upper gastrointestinal (GI) tract lesions is sparse and few studies have investigated anemic upper GI tract lesions. Methods We included 165 anemic patients with non–dialysis-dependent CKD stages 3 to 5 (44 patients at stage 3, 52 patients at stage 4, and 69 patients at stage 5). Transferrin saturation (TSAT), serum ferritin, mean corpuscular volume, and corrected reticulocyte count data were collected to evaluate their diagnostic use for bleeding-related upper GI tract lesions, which were identified by esophagogastroduodenoscopy. Results Bleeding-related GI tract lesions were found in 57 patients (34.5%). The area under the receiver-operating characteristic curve used to predict bleeding-related lesions was 0.63 for TSAT (P = 0.007), and the best cutoff value was 19.7% (sensitivity, 0.53; specificity, 0.76). The combination of cutoffs TSAT less than 20% or serum ferritin less than 100 ng/mL produced a 17% increment in sensitivity compared with that of TSAT less than 20% alone. The corrected reticulocyte levels and mean corpuscular volume had no significant diagnostic use. In patients with CKD stage 5, the sensitivity of TSAT or its combination with serum ferritin less than 100 ng/mL was significantly lower than in patients with CKD stage 3 (all P < 0.05). Conclusions Transferrin saturation is a significant predictor of anemic lesions in the upper GI tract, and serum ferritin can increase the sensitivity of TSAT. However, these indicators should be used with caution in patients with CKD stage 5 because their sensitivity is poor in this context.