L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

Role of Renal Replacement Therapy During the Peri-Transplant Period of Heart Transplantation.

BACKGROUND Heart transplantation (HT) is the most useful treatment modality for heart failure. Although several studies have reported the impact of acute kidney injury (AKI) on clinical outcomes after transplantation, little is known about the impact of peri-transplant renal replacement therapy (RRT) on clinical outcomes. We compared the clinical outcomes according to RRT use status among patients with AKI during the peri-transplant period. MATERIAL AND METHODS The medical records of 21 patients who underwent HT from January 2006 to May 2019 were reviewed. We assessed the heart failure cause, comorbidities, immunosuppressant type, requirement for extracorporeal membrane oxygenation, AKI incidence, and cardiac and renal functions over time. The patients were divided into 3 groups: those without AKI (non-AKI group, n=6), those who underwent perioperative RRT (RRT group, n=10), and those who did not undergo RRT (non-RRT group, n=5). RESULTS The most common cause of HT was dilated cardiomyopathy (52.4%). Fifteen patients (71.4%) experienced AKI during the peri-transplant period. Among them, 9 (90%) in the RRT group underwent continuous RRT and only 1 (10%) underwent intermittent hemodialysis. Until 6 months after HT, the renal function of the RRT group was worse than that of the non-RRT group (estimated glomerular filtration rate 44.2 vs. 69.2 mL/min/1.73 m2, P=0.015), but the differences dissipated by 9 months. Finally, all patients, even in the RRT group, withdrew from dialysis. CONCLUSIONS RRT during the peri-transplant period in HT may be a good bridge therapy for renal function recovery in patients with cardiorenal AKI.

Mechanical thromboprophylaxis is sufficient to prevent the lower extremity deep vein thrombosis after kidney transplantation.

PURPOSE: Deep vein thrombosis (DVT) is a severe and common complication that occurs after the major operation. Despite the commonality of DVT there is limited data on the incidence of DVT after kidney transplantation (KT). Furthermore, most studies have been retrospective in design and were conducted in western countries. The aim of this study was to evaluate the incidence of lower extremity DVT with mechanical thromboprophylaxis within 1 month of KT in Korea. METHODS: A total of 187 consecutive patients who underwent KT were included in this study. Patients used a graduated elastic stocking (n = 93) or an intermittent pneumatic compression device (n = 94) to prevent DVT. The frequency of DVT during the first month after KT was evaluated using serial color duplex ultrasound on postoperative days 7 ± 2, 14 ± 2, and 28 ± 3. All patients were tested for eight thrombophilic factors before KT. RESULTS: DVT occurred in four patients (2.1%) during the first month after KT. All DVT developed in the graduated elastic stocking group. Interestingly, none of the patients had the factor V Leiden mutation or the prothrombin gene 20210A mutation. CONCLUSION: The incidence of DVT in this study was relatively lower than that of western populations. We did not encounter a factor V Leiden mutation or a prothrombin gene 20210A mutation in our study population. These findings suggest that inherited thrombophilic risk factors may be partially responsible for the difference in DVT incidence rates between different nationalities and/or ethnicities.

Pretransplant IFN-γ ELISPOT assay as a potential screening test to select immunosuppression protocols for patients receiving basiliximab induction therapy.

The use of basiliximab induction therapy has increased in standard immunological risk patients. The objective of this study was to identify whether pretransplant donor-reactive interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assay results were associated with post-transplant clinical outcomes in patients receiving basiliximab induction therapy and whether this could be helpful for choosing an efficacious immunosuppressive regimen. In 154 living donor renal transplant recipients who received basiliximab induction therapy without desensitization, we determined pretransplant ELISPOT frequencies and correlated the results with clinical outcomes based on the use of calcineurin inhibitors (tacrolimus [TAC] or cyclosporine [CSA]). The ELISPOT (+) patients had higher rate of post-transplant biopsy-proven acute rejection (AR) than ELISPOT (-) patients (P = 0.001) regardless of immunosuppressive regimen. In the logistic and multivariate regression analysis, ELISPOT was the only significant correlate of AR (P = 0.002), and the patients with increased ELISPOT results and CSA therapy were associated with AR. Our results suggest that the pretransplant ELISPOT (+) may assess the risk of poor post-transplant outcomes in patients with basiliximab induction.

Hyperglycemic hyperosmolar syndrome caused by steroid therapy in a patient with lupus nephritis.

A 51-yr-old female was referred to our outpatient clinic for the evaluation of generalized edema. She had been diagnosed with idiopathic thrombocytopenic purpura (ITP). She had taken no medicine. Except for the ITP, she had no history of systemic disease. She was diagnosed with systemic lupus erythematosus. Immunosuppressions consisting of high-dose steroid were started. When preparing the patient for discharge, a generalized myoclonic seizure occurred at the 47th day of admission. At that time, the laboratory and neurology studies showed hyperglycemic hyperosmolar syndrome. Brain MRI and EEG showed brain atrophy without other lesion. The seizure stopped after the blood sugar and serum osmolarity declined below the upper normal limit. The patient became asymptomatic and she was discharged 10 weeks after admission under maintenance therapy with prednisolone, insulin glargine and nateglinide. The patient remained asymptomatic under maintenance therapy with deflazacort and without insulin or medication for blood sugar control.

Comparison of clinical outcomes by different renal replacement therapy in patients with end-stage renal disease secondary to lupus nephritis.

BACKGROUND/AIMS: Many studies have compared patients with systemic lupus erythematosus (SLE) on renal replacement therapy (RRT) with non-lupus patients. However, few data are available on the long-term outcome of patients with end-stage renal disease (ESRD) secondary to SLE who are managed by different types of RRTs. METHODS: We conducted a retrospective multicenter study on 59 patients with ESRD who underwent maintenance RRT between 1990 and 2007 for SLE. Of these patients, 28 underwent hemodialysis (HD), 14 underwent peritoneal dialysis (PD), and 17 patients received kidney transplantation (KT). We analyzed the clinical outcomes in these patients to determine the best treatment modality. RESULTS: The mean follow-up period was 5 ± 3 years in the HD group, 5 ± 3 years in the PD group, and 10 ± 5 years in the KT group (p = 0.005). Disease flare-up was more common in the HD group than in the KT group (p = 0.012). Infection was more common in the PD and HD groups than in the KT group (HD vs. KT, p = 0.027; PD vs. KT, p = 0.033). Cardiovascular complications were more common in the HD group than in the other groups (p = 0.049). Orthopedic complications were more common in the PD group than in the other groups (p = 0.028). Bleeding was more common in the HD group than in the other groups (p = 0.026). Patient survival was greater in the KT group than in the HD group (p = 0.029). Technique survival was lower in the PD group than in the HD group (p = 0.019). CONCLUSIONS: Among patients with ESRD secondary to SLE, KT had better patient survival and lower complication rates than HD and lower complication rates than PD. The prognosis between the HD and PD groups was similar. We conclude that if KT is not a viable treatment option, any alternative treatment should take into account the patient's general condition and preference.

Distinct macrophage phenotypes contribute to kidney injury and repair.

The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.

Aldosterone-induced TGF-beta1 expression is regulated by mitogen-activated protein kinases and activator protein-1 in mesangial cells.

Aldosterone has been shown to stimulate renal TGF-beta(1) expression. However, the mechanisms for aldosterone-induced TGF-beta(1) expression have not been clearly determined in mesangial cells. We examined the role of extracellular-signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) in the aldosterone-induced TGF-beta(1) expression in rat mesangial cells. TGF-beta(1) protein in the conditioned medium released from rat mesangial cells was measured by sandwich ELISA, TGF-beta(1) mRNA expression was analyzed by Northern blotting, AP-1 DNA binding activity was measured by EMSA and the ERK1/2, JNK activity was analyzed by western blotting. Aldosterone significantly stimulated TGF-beta(1) protein production and TGF-beta(1) mRNA expression in mesangial cells in a dose-dependent manner. Aldosterone significantly increased AP-1 DNA binding activity in mesangial cells. Pre-treatment of cells with AP-1 inhibitor, curcumin, blocked aldosterone-induced AP-1 DNA binding activity as well as aldosterone-induced TGF-beta(1) production. Aldosterone increased phosphorylation of ERK1/2 and JNK in mesangial cells. Pre-treatment of cells with ERK1/2 inhibitor, PD98059, or JNK inhibitor, SP600125 significantly inhibited aldosterone-induced ERK1/2 and JNK activity and subsequently TGF-beta(1) production, respectively. We conclude that aldosterone-induced TGF-beta(1) expression in mesangial cells is regulated by the ERK1/2, JNK and AP-1 intracellular signaling pathways.

Development of anuria after appendectomy in a patient with a distal ureteral stone in a single kidney.

The development of anuria after appendectomy is usually related to complications associated with appendicitis or with the surgical sequelae of appendectomy. We report an unusual case of anuria after appendectomy in a 20-year-old woman. The patient was transferred to our hospital due to a sudden cessation of urine output just after appendectomy. We initially suspected that the anuria was caused by a complication of surgery. However, a review of her medical history and an abdominal computed tomography (CT) scan revealed that a distal ureteral stone in a single kidney had caused the anuria. There are few cases in the literature regarding a distal ureteral stone in a single kidney. This case indicates the importance of radiological evaluation in the differential diagnosis of acute appendicitis, especially in patients with unilateral renal agenesis.

Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal.

AIM: To examine whether the reversibility of chronic cyclosporine A (CsA) nephrotoxicity is associated with apoptotic cell death and its regulatory factors. METHODS: Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administering CsA (15 mg/kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay and the expression of pro-apoptotic [transforming growth factor-beta 1 (TGF-beta 1) and Fas] and anti-apoptotic [epidermal growth factors (EGF) and Bcl-2] factors. RESULTS: Discontinuation of CsA induced significant decreases in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells was correlated with the tubulointerstitial fibrosis score (r=0.919, P<0.01). Upregulation of TGF-beta and Fas expression in CsA-treated rat kidneys was decreased significantly after withdrawal of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels. CONCLUSION: CsA withdrawal is associated with a decrease in apoptotic cell death and with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity.