Complement-Mediated Thrombotic Microangiopathy with 10 Years of Stable Renal Function After a Year-Long Treatment with Eculizumab with Coincidental Polycystic Kidney Disease.

BACKGROUND Complement-mediated thrombotic microangiopathy (cTMA), is a genetic disease that results when an unchecked alternative complement pathway is triggered by an external factor, resulting in endothelial cell injury with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, though other organ systems may be involved. CASE REPORT A 5-year-old girl presented with non-bloody diarrhea, hemolysis, renal failure, and thrombocytopenia. She was negative for Shiga toxin. She was diagnosed with cTMA, and this diagnosis was confirmed later by a mutation in the complement factor H (CFH) gene. The patient was started on eculizumab 8 weeks after onset of symptoms. A month later, she was able to stop hemodialysis. Eculizumab was given for a year, and then, because of clinical remission, was stopped. At the time of stopping hemodialysis, serum creatinine was 2.07 mg/dL; at the end of eculizumab therapy, it was 1.23 mg/dL. Now, 10 years later, it is 1.10 mg/dL. Glomerular filtration rate by Schwartz equation was 52 mL/min/1.73 m² after eculizumab and 60 mL/min/1.73 m² currently. The cTMA lab parameters normalized after 2 doses of eculizumab and have remained normal for 10 years. Two years ago, on routine ultrasound, renal cysts were noted. Recent genetic testing re-confirmed the CFH mutation and additionally showed a polycystic kidney disease (PKD1) mutation. Notably, there is no family history of either. Currently, the patient has mild proteinuria. CONCLUSIONS Instead of lifelong eculizumab treatment, we successfully managed the patient's condition with a year of eculizumab and intensive followup on sixty occasions over a decade. This approach can work if there are no relapses. Genetic tests revealed mutations for cTMA and autosomal dominant polycystic kidney disease (ADPKD)/PKD1 in the same patient. These have not been reported before, to the best of our knowledge.

A Rare Complication of Peritoneal Dialysis (PD) Catheter: Perforation of Sigmoid Colon by Migrating Tip of Peritoneal Dialysis Catheter.

BACKGROUND Peritoneal dialysis (PD) has benefits over hemodialysis (HD), including the ability of daily performance at home without interfering with important activities such as school attendance in children. However, there are risks and complications associated with it. This is the third pediatric case report of a dormant PD catheter tip perforating the colon and protruding through the anus, but without peritonitis, as would be highly expected. CASE REPORT A 12-year-old male with ESRD secondary to obstructive uropathy received a pre-emptive deceased donor kidney transplant that failed within a few days due to thrombosis secondary to factor V Leiden deficiency. Transplant nephrectomy was performed and several months later he was started on PD. Subsequently, due to multiple episodes of catheter drain failure, the modality was switched to HD with a plan to remove the PD catheter later. Two months after discontinuing PD, he presented to the Emergency Department with the catheter tip protruding through the anus and he was asymptomatic. Abdominal X-ray (AXR) and CT scans were performed. The PD catheter was removed and the colon was repaired by proctosigmoidoscopy and laparotomy. Five years later, he continues to be on HD by preference, with arteriovenous fistula (AVF), without any complications of perforation. CONCLUSIONS There are 2 cases previously reported in children with colonic perforation by the tip of a PD catheter without signs and symptoms of peritonitis, but those patients were on immunosuppression after kidney transplant. Our patient is unique because he was not on immunosuppression.

Uric Acid Control in Advanced Chronic Kidney Disease in a Southeastern US Urban Cohort.

OBJECTIVES: Uric acid (UA) control may be insufficient in chronic kidney disease (CKD) patients in the current era. It is unclear, however, whether this is the result of environmental effects, patient anthropometrics or insufficient dosing of medical therapy (allopurinol). METHODS: We have collected data on multiple clinical and laboratory parameters of 114 CKD clinic patients attending the nephrology clinic of the University of Mississippi Medical Center with an estimated glomerular filtration rate <45 mL · min-1 · 1.73 m2. We assessed the correlates of UA levels and the allopurinol doses along with achieved serum UA and urine pH. RESULTS: The cohort consisted of middle-aged to elderly patients with a mean (± standard deviation) age of 62.1 (11.6) years; 45.6% were female, 68.4% were African American and 47.4% had a history of gout. The mean UA level was 7.7 (2.49) mg/dL (range 3.1-16), allopurinol dose was 192 (99) mg/day (range 50-450) and estimated glomerular filtration rate was 23.8 (11.3) mL · min-1 · 1.73 m2. While the overall serum bicarbonate level was 25 (3.2) mEq/L, urine pH was <6 in 60.5% of the cohort. Significant univariate correlates of the administered doses of allopurinol were weight (r 0.317, P = 0.001), body mass index (BMI; r 0.313, P = 0.001), and female sex (r -0.198; P = 0.035). Achieved UA levels correlated directly with BMI (r 0.201, r = 0.036) but inversely with the allopurinol dose (r -0.196; P = 0.036). During logistic regression analysis with stepwise selection, only weight (ß 0.313, P = 0.001) and sex (ß -0.190, P = 0.039) proved to be predictive of the allopurinol dose; as for the achieved UA level, only BMI (ß 0.271, P = 0.006) and the allopurinol dose (ß -0.258; P = 0.009) had a significant effect. CONCLUSIONS: In patients with advanced CKD, conventional dosing recommendations for allopurinol are unlikely to suffice in reaching target serum UA goals. In our cohort, larger-than-usual allopurinol doses were well tolerated.

Adverse effects of chronic nicotine exposure on the kidney: Potential human health implications of experimental findings
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With the increasing popularity of E-cigarettes, chronic exposure to nicotine (NIC) is emerging as a novel risk factor for the kidney. NIC increases oxidative stress in the kidneys, which impairs the viability and function of renal tubular and endothelial cells, alters renal hemodynamics, and compromises overall kidney function. Moreover, long-term NIC exposure increases the risk of development and progression of chronic kidney diseases and may escalate the impact of coexisting morbidities such as obesity-associated renal disease, hypertension, renal transplant status, or the toxicity of various anticancer agents. In this review, we summarize experimental findings describing increased renal risk of chronic NIC exposure and explore therapeutic interventions to alleviate adverse effects of NIC.
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Chronic Nicotine Exposure Reduces Antioxidant Function of Simvastatin in Renal Proximal Tubule Cells.

BACKGROUND/AIM: We have previously reported that simvastatin exhibits antioxidant properties via extracellular signal-regulated kinase (ERK)/cAMP-response element binding (CREB) protein-dependent induction of heme oxygenase-1 (HO1) and chronic nicotine exposure inhibits ERK/CREB signaling in renal proximal tubule cells (through p66shc). Herein, whether nicotine dampens simvastatin-dependent HO1 induction was determined. MATERIALS AND METHODS: Renal proximal tubule (NRK52E) cells were pre-treated with 200 µM nicotine for 24 h followed by 10 µM simvastatin. Promoter activity of HO1 and manganese superoxide dismutase (MnSOD) and activation of CREB and ERK (via ELK1) were determined in luciferase reporter assays. CREB and p66shc were modulated via genetic means. RESULTS: Nicotine suppressed simvastatin-dependent activation of HO1 and MnSOD promoters and activity of CREB and ELK1 via p66shc. Overexpression of CREB or knockdown of p66shc restored simvastatin-dependent induction of HO1 and MnSOD in the presence of nicotine. CONCLUSION: Antioxidant efficiency of simvastatin might be significantly lessened in smokers/E-cigarette users.

Targeted surgical parathyroidectomy in end-stage renal disease patients and long-term metabolic control: A single-center experience in the current era.

BACKGROUND: The long-term results of surgical parathyroidectomy (PTX) in end-stage renal disease (ESRD) patients are less well known in the modern era of newer activated vitamin-D analogs, calcimimetics and intraoperative monitoring of parathyroid hormone (PTH). METHODS: We performed a retrospective chart review of all ESRD patients undergoing PTX at the University of Mississippi Medical Center between January 2005 and August 2011, with follow-up data as available up to 4 years. All PTXs were performed with intraoperative second-generation PTH monitoring and targeted gland size reduction. RESULTS: The cohort (N = 37) was relatively young with a mean (±SD) age of 48.4 ± 13.9. 94.6% of the subjects were African American and 59.5% female. Preoperatively, 45.9% received cinacalcet (CNC) at a mean dose of 63.5 ± 20.9 mg. The size of the largest removed glands measured 1.7 ± 0.8 cm and almost all (94.6%) glands had hyperplasia on histology. The mean length of inpatient stay was 5.5 ± 2.4 days. Preoperative calcium/phosphorus measured 9.6 ± 1.2/6.6 ± 1.7 mg/dL with PTH concentrations of 1589 ± 827 pg/mL. Postoperative PTH values measured 145.4 ± 119.2 pg/mL. Preoperative PTH strongly correlated (P < 0.0001) with both alkaline phosphatase (ALP) levels (r: 0.596) and the number of inpatient days (r: 0.545), but not with CNC administration. Independent predictors for the duration of hospitalization were preoperative ALP (beta 0.469; P = 0.001) and age (beta -0.401; P = 0.005) (R2 0.45); for postoperative hypocalcemia, age (beta: -0.321; P = 0.006) and preoperative PTH (beta: 0.431; P = 0.036) were significant in linear regression models with stepwise selection. CONCLUSION: Gland-sparing PTX achieved acceptable control of ESRD-associated hyperparathyroidism in most patients from a socioeconomically challenged, underserved population of the United States.

Age-dependent sensitivity of the mouse kidney to chronic nicotine exposure.

BackgroundMany adolescents are exposed to nicotine via smoking, e-cigarette use, or second-hand smoke. Nicotine-induced renal oxidative stress and its long-term consequences may be higher in adolescents than in adults because of intrinsic factors in the adolescent kidney.MethodsAdolescent and adult male C57Bl/6J mice were subjected to 2 or 200 µg/ml nicotine, which closely emulates passive or active smoking, respectively, for 4 weeks. Extent of nicotine exposure (cotinine content), oxidative stress (HNE), renal function (creatinine), tubular injury (KIM-1), and pretreatment renal levels of select pro-oxidant (p66shc) and antioxidant (Nrf2/MnSOD) genes were determined. Impact of p66shc overexpression or Nrf2/MnSOD knockdown on low-/high-dose nicotine-induced oxidative stress was determined in cultured renal proximal tubule cells.ResultsDespite similar plasma/renal cotinine levels, renal HNE and KIM-1 contents were higher in adolescents compared with those in adults, whereas renal function was unaltered after passive or active smoking-equivalent nicotine exposure. Pretreatment levels of p66shc were higher, whereas Nrf2/MnSOD levels were lower in the adolescent kidney. In agreement with this, overexpression of p66shc or knockdown of Nrf2/MnSOD augmented nicotine-induced ROS production in renal proximal tubule cells.ConclusionChronic nicotine exposure incites higher oxidative stress in the adolescent than in adult kidney because of a pre-existent pro-oxidant milieu.

Nicotine Exposure Augments Renal Toxicity of 5-aza-cytidine Through p66shc: Prevention by Resveratrol.

BACKGROUND/AIM: We have shown that either chronic nicotine (NIC) exposure or 5-aza-cytidine (AZA) augments oxidative stress-dependent injury through stimulating p66shc in renal cells. Hence, NIC could exacerbate adverse effects of AZA while antioxidants such as resveratrol (RES) could prevent it. MATERIALS AND METHODS: Renal proximal tubule cells (NRK52E) were treated with 20 µM RES prior to 200 µM NIC plus 100 nM AZA and cell injury (LDH release) was determined. Reporter luciferase assays determined p66shc activation and RES-induced antioxidant responses. Genetic manipulations identified the mechanism of RES action. RESULTS: NIC exacerbated AZA-dependent injury via augmenting p66shc transcription. While RES suppressed NIC+AZA-mediated injury, -surprisingly-it further enhanced activity of the p66shc promoter. RES protected cells via the cytoplasmic p66shc/Nrf2/heme oxygenase-1 (HO-1) axis. CONCLUSION: RES can protect the kidney from adverse effects of NIC in patients undergoing anticancer therapy.

Resveratrol Attenuates Nicotine-mediated Oxidative Injury by Inducing Manganese Superoxide Dismutase in Renal Proximal Tubule Cells.

BACKGROUND/AIM: Nicotine (NIC) exposure - via smoking and the increasingly popular E-cigarettes- increases oxidative stress and hence, renal risk in smokers. Resveratrol (RES) may help ameliorate this risk by mounting anti-oxidant responses in the kidney. MATERIALS AND METHODS: Renal proximal tubule cells (NRK52E) were treated with vehicle or 20 µM RES prior to treatment with 200 µM NIC and generation of reactive oxygen species (ROS) as well as cell viability was determined. RES-induced antioxidant responses were determined in reporter luciferase assays. Gene silencing was used to determine mechanism of RES action. RESULTS: RES protected NRK52E cells from NIC-induced oxidative injury. RES activated the promoter of the anti-oxidant manganese superoxide dismutase (MnSOD) gene via activation of the forkhead box O (FoxO3a) transcription factor. Silencing of MnSOD abolished the protective effects of RES on NIC-associated oxidative injury. CONCLUSION: RES may provide protection to the kidney from the adverse effects of NIC in smokers.

p66shc-mediated toxicity of high-dose alfa-tocopherol in renal proximal tubule cells

α-Tocopherol (TOC) is a widely used supplement known for its role as an antioxidant. Previously, we have shown that TOC elicits adaptive responses by upregulating the ERK/CREB/HO-1 pathway, which depends on its concentration in cultured renal proximal tubule cells (RPTCs). This suggests that high-dose TOC (hTOC) may elicit adverse effects via inflicting oxidative stress. Since the pro-oxidant p66shc is a major mediator of oxidant injury in various models of renal toxicants, we tested the hypothesis that hTOC elicits renal toxicity through activation of p66shc and consequent oxidative stress. RPTCs (NRK52E) were treated with high-dose TOC (hTOC; 400 nM) in cells where expression or mitochondrial cytochrome c-binding of p66shc was manipulated by genetic means. Intracellular production of reactive oxygen species (ROS), mitochondrial depolarization, and cell viability was also determined. Additionally, activation of the pro-survival ERK/CREB/HO-1 signaling and the p66shc promoter was determined via reporter luciferase assays. hTOC decreased cell viability via increasing ROS-dependent mitochondrial depolarization and suppressing the pro-survival ERK/CREB/HO-1 pathway via transcriptional activation of p66shc. Conversely, either knockdown of p66shc, mutation of its mitochondrial cytochrome c-binding site, or overexpression of ERK or HO-1 ameliorated adverse effects of hTOC and restored the pro-survival signaling. The pro-oxidant p66shc plays dual role in toxicity of high-dose TOC: it provokes oxidative stress and suppresses adaptive responses (AU)

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p66shc-mediated toxicity of high-dose α-tocopherol in renal proximal tubule cells.

α-Tocopherol (TOC) is a widely used supplement known for its role as an antioxidant. Previously, we have shown that TOC elicits adaptive responses by upregulating the ERK/CREB/HO-1 pathway, which depends on its concentration in cultured renal proximal tubule cells (RPTCs). This suggests that high-dose TOC (hTOC) may elicit adverse effects via inflicting oxidative stress. Since the pro-oxidant p66shc is a major mediator of oxidant injury in various models of renal toxicants, we tested the hypothesis that hTOC elicits renal toxicity through activation of p66shc and consequent oxidative stress. RPTCs (NRK52E) were treated with high-dose TOC (hTOC; 400 nM) in cells where expression or mitochondrial cytochrome c-binding of p66shc was manipulated by genetic means. Intracellular production of reactive oxygen species (ROS), mitochondrial depolarization, and cell viability was also determined. Additionally, activation of the pro-survival ERK/CREB/HO-1 signaling and the p66shc promoter was determined via reporter luciferase assays. hTOC decreased cell viability via increasing ROS-dependent mitochondrial depolarization and suppressing the pro-survival ERK/CREB/HO-1 pathway via transcriptional activation of p66shc. Conversely, either knockdown of p66shc, mutation of its mitochondrial cytochrome c-binding site, or overexpression of ERK or HO-1 ameliorated adverse effects of hTOC and restored the pro-survival signaling. The pro-oxidant p66shc plays dual role in toxicity of high-dose TOC: it provokes oxidative stress and suppresses adaptive responses.

Peritoneal Dialysis in Class 2-3 Obesity-A Single-Center Experience.

Extreme obesity may hamper successful peritoneal dialysis (PD) delivery. Among our PD patients, we have identified 15 markedly obese (class 2-3 obesity: body mass index [BMI] ≥35kg/m2) and 20 lean (BMI: 20-25kg/m2) dialysis patients and reviewed multiple clinical, laboratory and dialysis-related parameters. Extreme outliers of obesity (BMI > 40; 6 subjects) received detailed review. Although weight (P < 0.0001) and BMI (P < 0.0001) differed significantly, weekly Kt/V (obese versus lean: 2.05 ± 0.51 versus 2 ± 0.36), creatinine clearance (86.8 ± 44.8 versus 70 ± 30.4L/1.73m2) or residual renal functions were not statistically different. Total daily PD exchange volumes were similar (11.2 ± 2.5L versus 10.4 ± 2.5L, P = 0.378). Serum albumin, calcium, phosphorus, hemoglobin and parathyroid hormone levels did not differ, either. Analogous results have been obtained for extremely obese subjects (BMI 44.3 ± 4.2kg/m2; range: 40.2-51.6). Our study shows only limited effect of class ≥2 obesity for successful PD in this predominantly African American cohort.

Clinical Utility of Potassium-Sparing Diuretics to Maintain Normal Serum Potassium in Peritoneal Dialysis Patients.

♦ BACKGROUND: Hypokalemia is a vexing problem in end-stage renal disease patients on peritoneal dialysis (PD), and oral potassium supplements (OPS) have limited palatability. Potassium-sparing diuretics (KSD) (spironolactone, amiloride) may be effective in these patients. ♦ METHODS: We performed a cross-sectional review of 75 current or past (vintage > 6 months) PD patients with regard to serum potassium (K+), OPS, and KSD utilization. We reviewed charts for multiple clinical and laboratory variables, including dialysis adequacy, residual renal function, nutritional status and co-existing medical therapy. ♦ RESULTS: The cohort was middle-aged with a mean age of 49.2 years (standard deviation [SD] = 14.7) and overweight with a body mass index of 29.5 (6.7) kg/m2. Of all the participants, 57.3% were female, 73.3% African-American, and 48% diabetic with an overall PD vintage of 28.2 (24.3) months at the time of enrollment. Weekly Kt/V was 2.12 (0.43), creatinine clearance was 73.5 (33.6) L/week/1.73 m2 with total daily exchange volume of 10.8 (2.7) L. Residual urine output (RUO) measured at 440 (494) mL (anuric 30.6%). Three-month averaged serum K+ measured at 4 (0.5) mmol/L with 36% of the participants receiving K+ supplements (median: 20 [0;20] mmol/day) and 41.3% KSD (spironolactone dose: 25 - 200 mg/day; amiloride dose: 5 - 10 mg/day). Serum K+ correlated positively with weekly Kt/V (r = 0.239; p = 0.039), PD vintage (r = 0.272; p = 0.018) but not with PD modality, daily exchange volume, RUO, or KSD use. However, KSD use was associated with decreased use of OPS (r = -0.646; p < 0.0001). ♦ CONCLUSIONS: Potassium-sparing diuretics were effective in this cohort of PD patients and decreased the need for OPS utilization.

Coenzyme Q10 protects renal proximal tubule cells against nicotine-induced apoptosis through induction of p66shc-dependent antioxidant responses.

Chronic nicotine exposure (via smoking, E-cigarettes) increases oxidative stress in the kidney that sensitizes it to additional injury in experimental models and in the renal patient. The pro-apoptotic p66shc protein-via serine36 phosphorylation that facilitates its mitochondrial translocation and therein cytochrome c binding-generates oxidative stress that leads to injury of renal proximal tubule cells during chronic nicotine exposure. Coenzyme Q10-a clinically safe antioxidant-has been used against nicotine/smoke extract-associated oxidative stress in various non-renal cells. This study explored the anti-oxidant/anti-apoptotic effect of Coenzyme Q10 on nicotine-induced oxidative stress and its impact on p66shc in cultured rat renal proximal tubule cells (NRK52E). We studied the anti-oxidant effect of 10 µM Coenzyme Q10 using various mutants of the p66shc gene and also determined the induction of selected anti-oxidant entities (antioxidant response element, promoter of the manganese superoxide dismutase gene) in reporter luciferase assay during oxidative stress induced by 200 µM nicotine. Our studies revealed that Coenzyme Q10 strongly inhibits nicotine-mediated production of reactive oxygen species and consequent apoptosis that requires serine36 phosphorylation but not mitochondrial translocation/cytochrome c binding of p66shc. While both nicotine and Coenzyme Q10 stimulates the p66shc promoter, only nicotine exposure results in mitochondrial translocation of p66shc. In contrast, the Coenzyme Q10-stimulated and non-mitochondrial p66shc activates the anti-oxidant manganese superoxide dismutase promoter via the antioxidant response elements and hence, rescues cells from nicotine-induced oxidative stress and consequent apoptosis.

The pro-oxidant gene p66shc increases nicotine exposure-induced lipotoxic oxidative stress in renal proximal tubule cells.

Nicotine (NIC) exposure augments free fatty acid (FFA) deposition and oxidative stress, with a concomitant increase in the expression of the pro-oxidant p66shc. In addition, a decrease in the antioxidant manganese superoxide dismutase (MnSOD) has been observed in the kidneys of mice fed a high­fat diet. The present study aimed to determine whether the pro­oxidant p66shc mediates NIC­dependent increases in renal oxidative stress by augmenting the production of reactive oxygen species (ROS) and suppressing the FFA­induced antioxidant response in cultured NRK52E renal proximal tubule cells. Briefly, NRK52E renal proximal tubule cells were treated with 200 µM NIC, 100 µM oleic acid (OA), or a combination of NIC and OA. The expression levels of p66shc and MnSOD were modulated according to genetic methods. ROS production and cell injury, in the form of lactate dehydrogenase release, were subsequently detected. Promoter activity of p66shc and MnSOD, as well as forkhead box (FOXO)­dependent transcription, was investigated using reporter luciferase assays. The results demonstrated that NIC exacerbated OA­mediated intracellular ROS production and cell injury through the transcriptional activation of p66shc. NIC also suppressed OA­mediated induction of the antioxidant MnSOD promoter activity through p66shc­dependent inactivation of FOXO activity. Overexpression of p66shc and knockdown of MnSOD had the same effect as treatment with NIC on OA­mediated lipotoxicity. These data may be used to generate a therapeutic means to ameliorate renal lipotoxicity in obese smokers.

Simvastatin Inhibits Epithelial-to-Mesenchymal Transition Through Induction of HO-1 in Cultured Renal Proximal Tubule Cells.

BACKGROUND/AIM: Studies have shown that simvastatin (SIM) inhibits epithelial-mesenchymal transition (EMT), a key step in fibrosis, and activates the anti-fibrotic heme oxygenase-1 (HO-1) gene in renal proximal tubule cells independent of its lipid-lowering. We tested the hypothesis that SIM inhibits EMT via HO-1-dependent suppression of reactive oxygen species (ROS) release. MATERIALS AND METHODS: Renal proximal tubule cells were treated with either 10 µM SIM or 10 ng/ml transforming growth factor-ß1 (TGFß1) or with their combination and promoter activity of the alpha-smooth muscle actin (α-SMA) gene, stress fiber formation (markers of EMT), as well as ROS production were determined. HO-1 was manipulated via genetic and pharmacologic means. RESULTS: SIM prevented TGFß1-dependent EMT and ROS production. Inhibition/knockdown of HO-1 reversed, while induction/overexpression of HO-1 emulated beneficial effects of SIM. CONCLUSION: SIM, via HO-1, suppresses TGFß1-dependent ROS production and, hence, EMT. Further evaluation of the anti-fibrotic nature of SIM in the kidney would be useful in the treatment of chronic kidney disease.

Prenatal Nicotine Exposure Augments Renal Oxidative Stress in Embryos of Pregnant Rats with Reduced Uterine Perfusion Pressure.

BACKGROUND/AIM: Both maternal nicotine (NIC) exposure and placental insufficiency increase oxidative stress in the fetal kidney ensuing fetal programming of renal diseases in adult life. Their combined effects, however, are unknown. We tested the hypothesis that maternal NIC exposure exacerbates renal oxidative stress and injury in fetuses of pregnant rats with placental insufficiency. MATERIALS AND METHODS: Fourteen-day-pregnant rats were subjected to sham operation or reduced uterine perfusion pressure (RUPP) that received either nicotine (20 µg/ml in 1% saccharine) or vehicle (1% saccharine) in their drinking water. At gestational age of 21 days, male fetuses were collected by C-section and sacrificed: plasma and renal cotinine content, extent of renal oxidative stress (4-hydroxynonenal [HNE] and HO-1) and injury (KIM-1) were determined together with the weight of the fetal kidney and fetus. RESULTS: Prenatal NIC exposure resulted in cotinine accumulation in the plasma and kidney of the fetuses, augmented RUPP-associated increase in renal HNE content and HO-1 expression as well as KIM-1 expression. NIC also enhanced RUPP-induced reduction in fetal and fetal kidney weight. CONCLUSION: Prenatal NIC exposure augments the existing renal risk in the growth-restricted fetus, which may contribute to worsening in fetal programming of renal disease.

Nicotine Enhances High-Fat Diet-Induced Oxidative Stress in the Kidney.

INTRODUCTION: Life expectancy of an obese smoker is 13 years less than a normal weight smoker, which could be linked to the increased renal risk imposed by smoking. Both smoking-through nicotine (NIC)-and obesity-by free fatty acid overload-provoke oxidative stress in the kidney, which ultimately results in development of chronic kidney injury. Their combined renal risk, however, is virtually unknown. We tested the hypothesis that chronic NIC exposure worsens renal oxidative stress in mice on high-fat diet (HFD) by altering the balance between expression of pro-oxidant and antioxidant genes. METHODS: Nine-week-old male C57Bl/6J mice consumed normal diet (ND) or HFD and received either NIC (200 µg/ml) or vehicle (2% saccharine) in their drinking water. Body weight, plasma clinical parameters, renal lipid deposition, markers of renal oxidative stress and injury, as well as renal expression of the pro-oxidant p66shc and the antioxidant MnSOD were determined after 12 weeks. RESULTS: NIC significantly augmented levels of circulating free fatty acid, as well as lipid deposition, oxidative stress and sublethal injury in the kidneys of mice on HFD. In addition, NIC exposure suppressed HFD-mediated induction of MnSOD while increased expression of p66shc in the kidney. CONCLUSIONS: Tobacco smoking or the increasingly popular E-cigarettes-via NIC exposure-could worsen obesity-associated lipotoxicity in the kidney. Hence, our findings could help to develop strategies that mitigate adverse effects of NIC on the obese kidney. IMPLICATIONS: Life expectancy of an obese smoker is 13 years less than a normal weight smoker, which could be linked to the increased renal risk imposed by smoking. NIC-the main component of tobacco smoke, E-cigarettes and replacement therapies-links smoking to renal injury via oxidative stress, which could superimpose renal oxidative stress caused by obesity. Our results substantiate this scenario using a mouse model of diet induced obesity and NIC exposure and imply the augmented long-term renal risk in obese smokers. Also, our study may help to develop strategies that mitigate adverse effects of NIC on the obese kidney.

Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells.

BACKGROUND: Statins elicit antioxidant effects independently of their lipid-lowering properties. Heme oxygenase-1 (HO-1) induction may be a part of these pleiotropic effects, which are insufficiently described in the kidney. We hypothesize that simvastatin (SIM) transcriptionally activates HO-1 that protects renal proximal tubule cells from lipotoxic injury. METHODS: Impact of SIM on 100 µmol/l oleic acid (OA)-mediated reactive oxygen species (ROS) production and consequent oxidative stress (4-hydroxynonenal (HNE) content) as well as cell injury/apoptosis (lactate dehydrogenase (LDH) release, caspase-3 activation) were determined in cultured renal proximal tubule (NRK52E) cells. Effect of SIM on the HO-1 promoter and its enhancer elements (antioxidant response element (ARE), CCAAT, AP1, and cAMP response element (CRE)) was also determined in reporter luciferase assays. Dominant-negative (dnMEK, M1CREB) and pharmacologic (H89) approaches were used to inhibit activation of extracellular signal regulated kinase (ERK), CREB, and protein kinase A (PKA), respectively. RESULTS: SIM dose-dependently activated the HO-1 promoter that was essential for protection against OA-dependent ROS production/oxidative stress and LDH release/caspase-3 activation. We found that the HO-1 promoter was induced through ERK and PKA-dependent activation of the CRE by SIM. CONCLUSION: SIM may protect the kidney from adverse effects of circulating fatty acids by upregulating the antioxidant HO-1, aside from its well-described lipid-lowering effects.

Successful Peritoneal Dialysis in Large-Weight Subjects: Clinical Features and Comparisons with Normal-Weight Subjects.

Peritoneal dialysis (PD) obviates the need for temporary vascular access in end-stage renal disease; however, extremely heavy weight has been viewed as a relative contraindication to PD.We performed a cross-sectional review of multiple clinical and laboratory variables for 75 current or past PD patients (vintage > 6 months), comparing dialysis adequacy parameters for those with a large body weight (>100 kg, LWS group) and with a normal body weight (<75 kg, NWS group).In the LWS group (n = 17), mean weight was 117.2 ± 15.7 kg, and mean body mass index (BMI) was 37.2 ± 6.3 kg/m2; in the NWS group (n = 33), mean weight was 63.2 ± 9.2 kg, and mean BMI was 25.3 ± 4.5 kg/m2. Despite the marked differences in weight and BMI between the groups (both p < 0.0001), achieved Kt/V was adequate, although marginally less, in large subjects (1.96 ± 0.29 for the LWS group vs. 2.22 ± 0.47 for the NWS group, p = 0.022), and weekly global creatinine clearance was significantly better in the LWS group (92.5 ± 43.5 L/1.73 m2 vs. 62.2 ± 27.5 L/1.73 m2, p = 0.016). The total daily exchange volume was approximately 30% higher in the LWS group (12.8 ± 2.5 L vs. 9.9 ± 2.2 L, p < 0.0001). Residual creatinine clearance (p = 0.224) and residual urine output (p = 0.125) were similar and did not seem to influence the results. Compared with their LWS counterparts, members of the NWS group were more likely to have higher iron saturation (p = 0.053) and serum ferritin (p = 0.004), but lower achieved hemoglobin (p = 0.055).Successful PD is feasible in larger-weight individuals; however, given the retrospective nature of the present study, prospective trials are needed to confirm that observation.