Improvement Of Renal Dysfunction Research Articles

#3635 THERAPEUTIC STRATEGIES TARGETING RAGE IMPROVES RENAL OUTCOME IN LUPUS NEPHRITIS

Abstract Background and Aims Lupus nephritis (LN) occurs in up to 60% of patients with systemic lupus erythematosus (SLE). Despite of current development of immunosuppressant agents, LN still impairs the survival and quality of life in SLE patients. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that belongs to the immunoglobulin superfamily, which is strongly associated with innate immune system. In the present study, we examined whether RAGE is involved in the development of LN. Further, we explored the therapeutic impact of DNA-aptamer directed against RAGE on lupus-related kidney injury. Method [Protocol 1] RAGE expression in kidneys and urinary RAGE excretion (uRAGE) were determined at 8, 12, 16, 18, 20-week-old by real-time PCR and ELISA, respectively in MRL/lpr, SLE-prone mice. [Protocol 2] LN was induced by peritoneally injecting pristane in wild type and RAGE globally knockout mice. [Protocol 3] MRL/lpr mice were subcutaneously administrated with DNA-aptamer raised against RAGE (RAGE-apt) or Control-aptamer (Ctrl-apt) for 10weeks. Results [Protocol 1] uRAGE, but not urinary protein excretion, was increased in 8-week-old MRL/lpr mice when compared to that of the control of MRL/MPJ mice. uRAGE is positively correlated with urinary NAG, a tubular injury marker, suggesting that uRAGE can predict the onset and the progression of LN. Immunofluorescence staining demonstrated that RAGE was upregulated in distal tubules but not in glomerulus in early stage, meanwhile RAGE started to be extensively expressed in nephron at late stage of LN. Not only tubules, but RAGE was also found in infiltrated macrophages in glomerulus. In proximal tubules (PTC), RAGE was co-localized with cathepsine D, a lysosomal aspartyl protease, and Rab7, a marker of late endocytosis, suggesting that PTC RAGE is involved in endosome-related protein degradation. [Protocol 2] Pristane-induced the increase in systolic blood pressure was reduced with improvement of renal dysfunction in RAGE knockouts. RAGE knockouts also showed less fibrosis with the decrease in macrophage infiltration when compared to wild type mice in pristane-induced lupus nephritis. [Protocol 3] Similar to RAGE knockouts, administration of RAGE-apt reduced systolic blood pressure and attenuated the renal dysfunction. RAGE-apt also ameliorated mesangial expansion, crescent formation, and macrophage infiltration into glomerulus in MRL/lpr mice. The level of pro-inflammatory cytokines gene expression including IL-6, TNF-a, and MCP-1 was reduced by RAGE-apt, but not Ctrl-apt, in MRL/lpr mice. Conclusion RAGE could be involved in the pathogenesis of LN, and RAGE-DNA aptamer might be one of the promising therapeutic strategies for preventing the development of LN.

PS-B08-8: THERAPEUTIC STRATEGIES TARGETING RAGE IMPROVES RENAL OUTCOME IN LUPUS NEPHRITIS

Introduction: Lupus nephritis (LN) is present in 60% of patients with systemic lupus erythematosus (SLE). Despite of current development of immunosuppressant agents, LN still impairs the survival and quality of life in SLE patients. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that belongs to the immunoglobulin superfamily, which is strongly associated with innate immune system. In the present study, we examined whether RAGE is involved in the development of LN. Further, we explored the therapeutic impact of DNA-aptamer directed against RAGE on lupus-related kidney injury. Methods: [Protocol 1] RAGE expression in kidneys and urinary RAGE excretion (uRAGE) were determined at 8, 12, 16, 18, 20-week-old by real-time PCR and ELISA, respectively in MRL/lpr, SLE-prone mice. [Protocol 2] LN was induced by peritoneally injecting pristane in wild type and RAGE globally knockout mice. [Protocol 3] MRL/lpr mice were subcutaneously administrated with DNA-aptamer raised against RAGE (RAGE-apt) or Control-aptamer (Ctrl-apt) for 10weeks. Results: [Protocol 1] uRAGE levels, but not urinary protein excretion, were significantly increased in 8-week-old MRL/lpr mice when compared to those in control MRL/MPJ mice, suggesting that uRAGE could be an early marker of LN.. Immunofluorescence staining demonstrated that RAGE was upregulated in distal tubules but not in glomerulus in 8-week-old mice. Glomerular RAGE expression was increased from 12-week-old with mesangial matrix expansion and formation of cellular crescents. RAGE expression was also found in endothelium and infiltrated macrophages in glomerulus while RAGE was merged with cathepsine D, a lysosomal aspartyl protease, and Rab7, a marker of late endocytosis in tubular epithelial cells. [Protocol 2] Pristane-induced increase in systolic blood pressure was reduced with improvement of renal dysfunction in RAGE knockouts. RAGE knockouts also showed less fibrosis with decrease in macrophage infiltration when compared to wild type mice in pristane-induced lupus nephritis. [Protocol 3] Administration of RAGE-apt ameliorated mesangial expansion, crescent formation, and macrophage infiltration into glomerulus in MRL/lpr mice. RAGE-apt, but not Ctrl-apt, reduced the level of pro-inflammatory cytokines gene expression including IL-6, TNF-α, and MCP-1 in renal cortex of MRL/lpr mice. Conclusion: RAGE could be involved in the pathogenesis of LN, and RAGE-DNA aptamer might be one of the promising therapeutic strategies for preventing the development of LN.

Metabolic Support for Elderly, Severe COVID-19 Patients With Acute Respiratory Failure: A Case Series

ObjectivesSevere COVID-19 (SvC19) is a syndrome of acute lung injury, respiratory failure, cytokine storm, distributive shock, multi-system organ failure and high mortality. SvC19 disproportionately impacts the elderly, who are also at risk for micronutrient deficiency. After observing a beneficial response to micronutrient repletion (MR) in a 69 year-old male with SvC19, we hypothesized that nutritional deficiencies were linked to the pathogenesis and that correcting them could be beneficial. In this report we detail a case series of 18 older patients with SvC19 treated with MR.MethodsAll patients had SvC19 requiring mechanical ventilation, elevated levels of CRP, D-dimer and neutrophil to lymphocyte ratio. MR consisted of daily parenteral ascorbate, thiamine, pyridoxine and multivitamins, as well as daily ergocalciferol, zinc and carnitine via nasogastric tube.ResultsThe average age was 63.3 years. Six patients were male, 12 female. Disease severity was comparable based on SOFA score. A partial response was observed in 10 of the 18 patients (55.5%). Six (33.3%) were able to wean off blood pressure support. Five (27.7%) had improvement in gas exchange. Four (22.2) were able to wean off ventilator support. Three patients (37.5%) showed improvement in renal dysfunction.ConclusionsMR shows potential promise as an adjunctive treatment for severe COVID-19, particularly in older patients or those with chronic illness in whom nutritional deficiencies are more probable.Funding SourcesNone

When a harmless procedure causes a life‐threatening problem: a case report of metformin‐associated lactic acidosis following a colonoscopy

Metformin is the preferred initial pharmacologic agent for the treatment of adults with type 2 diabetes mellitus. Although considered safe, it carries a potential life‐threatening risk of lactic acidosis. Metformin‐associated lactic acidosis is believed to be a consequence of metformin inhibition of the mitochondrial respiratory chain, and has a mortality ranging between 10–50%. However, its outcome is better than lactic acidosis of other cause with similarly severe acid‐base imbalance.In this article, we describe the case of a 72‐year‐old woman with type 2 diabetes mellitus, presenting to the emergency department with gastrointestinal symptoms associated with severe lactic acidosis (arterial pH 6.6 and lactate 17mmol/L) and acute kidney injury. Upon obtaining collateral history, the diagnosis of severe metformin‐associated lactic acidosis following a colonoscopy preparation was made. The patient was admitted to the intensive care unit for organ support, being ultimately discharged home after one month in hospital. At discharge, she had full neurologic recovery, improvement of renal dysfunction and was under glycaemic control with insulin therapy.Metformin‐associated lactic acidosis’ mortality rate is about half that of the mortality rate seen in individuals with lactic acidosis of other cause. Despite current therapies being effective, preventive measures should always be primal. It is important to educate patients to discontinue this medication when appropriate and keep hydrated. Both upper and lower endoscopies should not be undertaken during the same day, as this further worsens dehydration. Other medications capable of impairing renal function should also be reviewed. Copyright ©

Gabapentin or pregabalin induced myoclonus: A case series and literature review

Gabapentin (GBP) and pregabalin (PGB) are FDA approved for adjunctive treatment of partial seizures and for treatment of post-herpetic neuralgia. Both drugs are primarily eliminated by renal excretion. However, PGB or GBP induced myoclonus has only been reported infrequently in case reports/series. It is not discussed with patients and its sudden occurrence can lead to anxiety because of “seizure-like” nature. In addition, first-contact physicians might treat it as seizures, leading to unnecessary tests and aggressive management. Medical records of patients who had myoclonus because of PGB or GBP seen by Neurology service between Jan & May 2017 in inpatient or outpatient setting at our tertiary care setting were reviewed. We identified six patients who were on either GBP or PGB or both who developed likely subcortical myoclonus in the setting of renal insufficiency and one patient who developed myoclonus independent of renal dysfunction. Our results indicate that myoclonus is commonly seen in patients in various clinical settings with or without renal insufficiency, and is independent of the severity of the renal failure. However, this is a reversible side effect of medication and it resolves either by discontinuing the medication, removing the medication with hemodialysis or by improvement of renal dysfunction. With a high index of suspicion, aggressive testing and treatment for other possible conditions like seizures (in non-epilepsy patients) or CNS infections can be avoided. In patients with renal failure and with decreased physiological renal clearance such as the elderly, GBP or PGB dose initiation and changes should be conservative.

BK Nephropathy in Renal Transplant Patients with Epididymo-Orchitis

: The patient was a 10-year-old male that was transplanted six months prior to this study. He was admitted because of epididymo-orchitis, pyuria, glucosuria, and rising blood urea nitrogen (BUN) and creatinine (Cr). BK viruria copy number was 50,000,000. In renal biopsy examination, acute cellular rejection was reported. The diagnosis was BK virus epididymo orchitis with BK allograft nephropathy. His treatment was started by discontinuation of tacrolimus and mycophenolate and starting of leflunomide and low dose prednisolone. After improvement of renal dysfunction and BK load, the treatment regimen was changed to cyclosporine and sirolimus. Renal function after the one-year follow up did not change and remained in a good condition.

Occurrence and improvement of renal dysfunction and serum potassium abnormality during administration of liposomal amphotericin B in patients with hematological disorders: A retrospective analysis

Liposomal amphotericin B (L-AMB) has the potential to cause two major adverse events, renal dysfunction and serum potassium abnormality; however, appropriate clinical management of these events remains unclear. We retrospectively analyzed data regarding 128 hematology patients who received L-AMB in our institute and examined the association between clinical characteristics and renal dysfunction or serum potassium abnormality. We found that the median weight-normalized dose of L-AMB was 2.69mg/kg and the median administration period was 16days. The overall occurrence rates of renal dysfunction and hypokalemia were 55.7% and 76.6%, respectively. Multivariate analysis revealed that pre-existing renal dysfunction (P=0.017) and concomitant use of nephrotoxic (P<0.0001) or antifungal drugs (P=0.012) were independent risk factors for renal dysfunction. A higher infusion volume did not mitigate the risk of renal dysfunction. Hypokalemia occurred significantly less often in men (P=0.028) and in patients who concomitantly used nephrotoxic drugs (P=0.013). Approximately 40% of the adverse events were improved at 30days after L-AMB termination and there was no significant association between these adverse events improvement and L-AMB dosage or infusion volume. Of note, hyperkalemia was observed in more patients who received allogeneic hematopoietic stem cell transplantation (P=0.0303) and concomitant treatment with nephrotoxic drugs (P=0.0281). These results suggest that imprudent reduction of L-AMB dose or redundant intravenous infusion may have minimal benefit for critical patients with suspected invasive fungal infection.

Effect of Paracentesis and Albumin on Non-azotemic Renal Dysfunction in Children With Cirrhosis

Background and Aim: Prevalence of renal dysfunction (RD) is unknown in cirrhotic children. Renal resistive index is a non-invasive tool to detect early RD before azotemia sets in. We aimed to detect RD in children with chronic liver disease by renal doppler ultrasonography (DU) and observe the effect of paracentesis and albumin infusion on renal resistive index Methods: Consecutive non-azotemic cirrhotics with normal glomerular filtration rate were prospectively enrolled. Decompensated patients underwent single time large volume paracentesis (LVP). Groups compared were decompensated albumin infusion group (AG) and non-albumin group (NAG) versus compensated cirrhotic group. Study flow is shown in Figure 1. Resistive indices were derived from bilateral renal artery velocity (upper, mid and lower poles) on DU by a single blinded sonologist. RD was defined as RI >0.7 from the average of all poles. All cases were followed up for 3 months for complications and mortality. Results: Compensated (n = 20) vs. decompensated (n = 20) group comparison showed age of presentation [10(7–18) vs 11(6–18) years, P = 0.8], PELD score [15(9–21) vs. 35(13–54) P < 0.001], prevalence of baseline RD [0% vs. 55%, P < 0.001]. Table 1 shows the comparison of AG vs. NAG. Both groups were similar in terms of etiology, PELD score and baseline RI. RI at 48 h and D7 significantly improved from baseline in AG. At follow-up, 30% developed azotemia and 25% died among the decompensated cirrhotics. All these patients had RI >0.7. None of the compensated patients developed azotemia in 3 months.Table 1Comparison of Decompensated Group With Large Volume Paracentesis (Albumin and Non-albumin Infusion Groups).AG (n = 10)NAG (n = 10)PEtiology • Autoimmune liver diseaseN = 4N = 5 • Budd-chiari syndromeN = 2N = 2– • Wilson diseaseN = 4N = 4PELD score34 (13–51)37 (26–54)0.50Baseline RI0.71 (0.46–0.78)aIn AG intergroup comparisons, statistical significance was seen with baseline RI vs. 48h (P=0.001), day 7 (P=0.001), day 30 (n=0.06), day 90 (n=0.97). No statistical significance was seen with in the NAG intergroup comparison.0.68 (0.50–0.82)0.0848 h after LVP0.67 (0.50–0.73)0.65 (0.53–0.75)0.43Day 7 of LVP0.64 (0.51–0.73)0.61 (0.55–0.78)0.43Day 30 of LVP0.59 (0.51–0.75) (n = 9)0.57 (0.53–0.64) (n = 9)0.86Day 90 of LVP0.59 (0.52–0.61) (n = 6)0.58 (0.52–0.60) (n = 9)0.38Development of abnormal GFRbAbnormal GFR defined as GFR <60mL/min/1.73m2 by Schwartz formula. in 3 months5 (50%)3 (30%)–Development of azotemiacAzotemia defined rise in serum creatinine ≥ 2 times the baseline value or >1mg/dL irrespective of age at any point of time on follow-up. RI: resistive index; LVP: large volume paracentesis; GFR: glomerular filtration rate; AG: albumin group; NAG: non-albumin group; PELD: pediatric end-stage liver disease. in 3 months4 (40%)2 (20%)–Mortality in 3 months4 (40%)1 (10%)–a In AG intergroup comparisons, statistical significance was seen with baseline RI vs. 48 h (P = 0.001), day 7 (P = 0.001), day 30 (n = 0.06), day 90 (n = 0.97). No statistical significance was seen with in the NAG intergroup comparison.b Abnormal GFR defined as GFR <60 mL/min/1.73 m2 by Schwartz formula.c Azotemia defined rise in serum creatinine ≥ 2 times the baseline value or > 1 mg/dL irrespective of age at any point of time on follow-up. RI: resistive index; LVP: large volume paracentesis; GFR: glomerular filtration rate; AG: albumin group; NAG: non-albumin group; PELD: pediatric end-stage liver disease. Open table in a new tab Conclusions: LVP overall improves the RI in cirrhotics. Those receiving albumin infusion have significant but transient improvement in renal dysfunction. A significant proportion of patients with RI develop azotemia in follow-up. Hence resistive index is reliable method to detect impending azotemia in cirrhotics. The authors have none to declare.

The Use of Everolimus for Renal-Transplant Patients with Nephrotoxicity by Calcineurin Inhibitors in our Center: Case Report

Introduction: Long-term renal-transplantation outcomes are reportedly impaired by acute and chronic nephrotoxicity caused by calcineurin inhibitors (CNI), while recent renal transplant results have improved remarkably due to progress in the development of immunosuppressive drugs. Everolimus (EVL) belongs to a novel class of immunosuppressive agents, known as mammalian target of rapamycin (mTOR) inhibitor or proliferation signal inhibitor, which allow dose reduction or even complete withdrawal of CNI. mTOR inhibitor, such as EVL appear to exacerbate pre-existing proteinuria and may ameliorate nephrotoxicity caused by CNI. We describe herein one patient showing histological improvement of CNI nephrotoxicity with EVL. Patient: A 53-year-old, female underwent her third living-donor transplantation. We used cyclosporine (CsA), mycophenolate mofetil (MMF), prednisolone (PSL) and basiliximab. Diuresis was obtained immediately, but on post-operative day 3 (POD 3), urine volume decreased and renal function gradually deteriorated. On POD 14, renal biopsy (BTx) revealed CsA-induced nephrotoxicity. Renal function improved with a reduction in the CsA dose, and the patient was subsequently discharged on POD 30 with a serum creatinine level (S-Cr) 1.07 (mg/dL). Acute r rejection occurred three times, but each time renal function was improved by anti-rejection therapy, and subsequently stabilized with S-Cr levels in the 1.4-1.6 range. S-Cr suddenly rose to 4.03 on POD 293. Histopathological examination showed CsA nephrotoxicity. Although we reduced the CsA dose, her renal function remained unstable. We changed CsA to EVL on POD 341, and renal function subsequently stabilized. On POD 420, her S-Cr level was 1.17, and BTx showed amelioration of nephrotoxicity findings. Conclusion: In this patient, we obtained improvement of renal dysfunction caused by CsA nephrotoxicity without rejection by switching CsA to EVL (EVL +MMF+PSL). EVL can be safely used as an alternative to CsA, and it is anticipated that EVL+MMF+PSL will become one of the choices for immunosuppressive therapy in the future.

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease.

Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in people with chronic kidney disease (CKD) for which no evidence-based treatment currently exists. Recently, a group of anti-hyperglycemic agents used in the treatment of Type 2 diabetes, termed incretin-based therapies, have come under scrutiny for their putative glucose-independent effects on cardiac function. In the present study, the actions of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of incretin-based therapy in preventing HFpEF induced by chronic renal impairment were investigated. Sham-operated and subtotally-nephrectomized rats were randomized to receive the DPP-4 inhibitors, linagliptin or sitagliptin for seven weeks before assessment of cardiac and renal structure and function. Analysis of pressure-volume loops revealed that both linagliptin and sitagliptin prevented the development of cardiac diastolic dysfunction, with cardiac collagen I synthesis also being reduced by DPP-4 inhibition. These attenuating cardiac effects occurred without change in renal function or structure where, in the doses administered, neither linagliptin nor sitagliptin affected GFR decline, proteinuria, renal fibrosis or the increased urinary excretion of biomarkers of renal toxicity. The beneficial cardiac effects of DPP-4 inhibition, in the absence of a concurrent improvement in renal dysfunction, raise the possibility that these agents may confer cardiovascular advantages in the CKD population.

Study on the safety and efficacy of tocilizumab, an anti-IL-6 receptor antibody, in patients with rheumatoid arthritis complicated with AA amyloidosis

Objectives: Although treatment of rheumatoid arthritis (RA) has progressed by the use of biologics, amyloid A (AA) amyloidosis is still an intractable complication in patients with RA. In the present study, safety and efficacy of 1-year treatment with an anti-IL-6 receptor antibody tocilizumab (TCZ) on RA and AA amyloidosis were estimated.Methods: TCZ (8 mg/kg every 4 weeks) was administered to five RA patients complicated with AA amyloidosis. The primary end point was improvement in renal dysfunction and the secondary end point was CDAI at 1 year after the treatment.Results: An improvement in the renal dysfunction, including urinary protein secretion, was found, in four patients including two patients who were refractory to etanercept, with a remarkable decrease of SAA concentration, and the progression of organ dysfunction was prevented at 1 year in all patients treated with TCZ. The mean clinical disease activity index decreased from 33.9 to 4.7 (p = 0.012) in five patients treated with TCZ for 1 year. Three non-serious adverse events were observed in two patients.Conclusions: TCZ ameliorates renal dysfunction in RA patients complicated with AA amyloidosis who are refractory to conventional therapies, thereby suggesting that TCZ has a potential to regulate AA amyloidosis.

Renal biopsy in patients aged 80 years and older: a single-center experience in Japan

There is a paucity of data on renal biopsy in a large number of the very elderly (age ≥ 80 years) worldwide. Clinicopathological features in 73 patients aged ≥ 80 years were evaluated and compared with control groups of 172 patients aged 60 - 61 years and 128 patients aged 70 - 71 years. The common indications for biopsy in the very elderly were nephrotic syndrome (NS), followed by proteinuria without NS and/or hematuria, and acute kidney injury (AKI). Histological diagnoses were considered to potentially modify treatment in 57 cases (78.1%): the most frequent diagnosis was membranous nephropathy, followed by minimal change disease, and various other diseases. There were no biopsy procedure-related serious complications. Clinical assessment of treatments was evaluated in 38 of 54 patients with AKI and/or NS. Improvement in renal dysfunction or NS was observed in 24 of 30 (80%) patients who received immunosuppressive therapy. There were statistically significant differences in the disease spectrum between the very elderly and control groups. This is the first report of renal biopsy findings in a relatively large number of Japanese very elderly patients. Histological observations are useful aids in estimating the prognosis and therapy selection for renal disorders, even in the very elderly.

PTU-016 Albumin restores renal blood flow (RBF) autoregulation in patients with refractory ascites and acute-on-chronic liver failure (ACLF) through stabilisation of endothelial function

IntroductionHaemodynamic alterations in liver failure are associated with endothelial dysfunction, a pro-inflammatory state and sympathetic activation which lead to disturbed RBF autoregulation and renal failure. Albumin is a multifunctional protein...

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.

Improvement in renal dysfunction and symptoms after laparoscopic adrenalectomy in a patient with pheochromocytoma complicated by renal dysfunction

A 70-year-old patient who was undergoing treatment for diabetes mellitus and chronic hepatitis was admitted to our hospital for evaluation of a tumor in the left adrenal gland (50 x 45 mm) and renal failure. On the basis of the patient's increased serum concentrations of catecholamines and other metabolites and the results of positron emission tomography (PET), the patient was diagnosed with a pheochromocytoma; iodinated metaiodobenzylguanidine ([(131)I]MIBG) scintigraphy was insufficient to establish this diagnosis. Subsequently, he underwent surgery for tumor resection. Histological examination suggested the tumor to be a malignant pheochromocytoma. After left adrenalectomy was performed, the elevated catecholamine and metabolite concentrations and the blood pressure were restored to normal, and the patient's symptoms of severe headaches and vertigo reduced. Furthermore, his renal function improved (Cr 2.0-1.2 mg/dl). Our patient exhibited a rare condition of pheochromocytoma complicated by renal failure, which was successfully treated with laparoscopic surgery.

Improvement of Renal Dysfunction by Conversion From Calcineurin Inhibitors to Sirolimus After Heart Transplantation

Chronic renal dysfunction is a common occurrence after heart transplantation in patients treated with calcineurin inhibitors (CIs). We evaluated the renal-sparing effects of converting stable heart transplant patients with renal dysfunction from a CI to sirolimus. Beginning in 2000, heart transplant patients with renal dysfunction were converted from a CI to sirolimus. CI was abruptly discontinued and sirolimus added at 5 mg twice a day for 2 days and then 2 mg daily. The treatment goal was a 24-hour level of 6 to 12 ng/ml. All patients were also managed with mycophenolate mofetil (MMF) at 1,000 mg twice daily. Eighty from a total of 235 cardiac transplant patients were converted to sirolimus. The average time post-transplant for conversion was 4.78 years (range 3 days to 16 years). The average age at transplant was 55.43 years (range 15 to 70). At a mean of 304 days post-conversion, the mean serum creatinine (sCr) decreased from 2.04 +/- 0.57 mg/dl pre-conversion to 1.64 +/- 0.48 mg/dl (p < 0.001). In patients whose sCr was <2.5 mg/dl before conversion, the mean SCr level decreased from 1.81 +/- 0.39 to 1.62 +/- 0.5 mg/dl post-conversion (p = 0.01), with no patient developing end-stage renal disease (ESRD). Four patients with sCr > or =2.5 developed ESRD requiring dialysis despite conversion. In the remaining 15 patients with sCr > or =2.5 mg/dl, the sCr decreased from 2.85 +/- 0.29 to 1.73 +/- 0.43 mg/dl (p = 0.001). Conversion to sirolimus from CI is safe and has a renal-sparing effect in the management of heart transplant patients with chronic renal dysfunction. Based on these results, sirolimus has a role as a first-line immunosuppressive agent in heart transplant patients with renal dysfunction.

Predictors of improvement in renal function after calcineurin inhibitor withdrawal for post-liver transplant renal dysfunction

Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined. Retrospective analysis of 33 post-transplant patients with creatinine clearance (CrCl) below 50 mL/min who were changed from CNI to either MMF or AZA. Following CNI withdrawal patients were divided into two groups: those with improved CrCl after switching and those without, to identify the variables associated with improved renal function. Variables associated with improved CrCl were: absence of hypertension or diabetes, shorter time between transplantation and switch, deterioration in CrCl in months prior to switch and treatment with MMF (compared with AZA). Our findings suggest CNI withdrawal should be targeted to a subgroup of patients whose renal function is most likely to improve.

Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning.

We determined whether endothelial nitric oxide synthase (eNOS) plays an important role in the renal protective effect of ischemic preconditioning (IP) against the ischemia/reperfusion-induced acute renal failure (ARF) by using eNOS-deficient (eNOS(-/-)) and wild-type (eNOS(+/+)) mice. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. IP, which consists of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed prior to 45-min ischemia. In eNOS(+/+) mice, IP treatment markedly attenuated the ischemia/reperfusion-induced renal dysfunction and significantly improved histological renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Constitutive nitric oxide synthase activity in the kidney without IP was markedly decreased 6 h after reperfusion, but this decreased response was not observed in eNOS(+/+) mice with IP treatment. The improvement of renal dysfunction in eNOS(+/+) mice with IP treatment was abolished by pretreatment with N(G)-nitro-l-arginine, a nonselective NOS inhibitor, whereas aminoguanidine, an inducible NOS inhibitor, had no effect. Finally, no protective effects of IP on ischemia/reperfusion-induced renal dysfunction and histological damage were observed in eNOS(-/-) mice. These findings strongly support the view that eNOS-mediated NO production plays a pivotal role in the protective effect of IP on ischemia/reperfusion-induced ARF.

PROTECTION OF ISCHEMIC RENAL INJURY BY RENAL ISCHEMIC PRECONDITIONING: POSSIBLE ROLE OF NITRIC OXIDE

P52 Aims: Ischemic preconditioning, a phenomenon induced by brief ischemia and reperfusion periods, renders an organ tolerant to subsequent prolonged ischemia. This study evaluated different schedules of preconditioning the kidney to assess the role of nitric oxide (NO) and determine the effects of preconditioning on kidney transplantation. Methods: Ischemic preconditioning, which consists of three cycles of 2-minute ischemia followed by 5-minute reperfusion, was performed prior to 45-minute ischemia.. Results: Ischemic preconditioning significantly improved the renal dysfunction induced by 45-minute ischemia followed by 24-hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45-minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning. The levels of renal antioxidant enzymes were significantly improved by ischemic preconditioning as compared to ischemia/reperfusion rats. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor. Conclusions: Ischemic preconditioning has a protective effect on renal structure and function and these findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion -induced acute renal failure is closely related to the renal nitric oxide production.

Role of nitric oxide in the renal protective effects of ischemic preconditioning.

Possible involvement of nitric oxide (NO) in the protective effect of ischemic preconditioning against the ischemia/reperfusion-induced acute renal failure was investigated. Ischemic preconditioning, which consists of three cycles of 2-minute ischemia followed by 5-minute reperfusion, was performed prior to 45-minute ischemia. Ischemic preconditioning significantly improved the renal dysfunction induced by 45-minute ischemia followed by 24-hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45-minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning, and these increases correlated with changes in endothelial NO synthase (eNOS) protein expression in renal tissues. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG-nitro-L-arginine, a nonselective NOS inhibitor, but not with aminoguanidine, an inducible NOS inhibitor. In addition, increment of endothelin-1 (ET-1) content in the kidney after the reperfusion was markedly suppressed by ischemic preconditioning treatment. These findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion -induced acute renal failure is closely related to the renal nitric oxide production following the increase in eNOS expression after the reperfusion and that the suppressive effect of ischemic preconditioning on the ischemia/reperfusion -induced renal ET-1 overproduction may be partly involved in the ameliorating effect of ischemic preconditioning.