Mehul Dixit

Managing Henoch-Schonlein purpura in children with fish oil and ACE inhibitor therapy.

Background:  Henoch–Schonlein purpura (HSP) is a vasculitic syndrome with palpable purpura and renal involvement. The treatment for HSP with persistent renal disease remains controversial. The kidney biopsy in HSP shows IgA deposits and fish‐oil therapy has proven to be promising in halting the progression of IgA nephropathy.

Hyponatremic hypertensive syndrome (HHS) in an 18-month old-child presenting as malignant hypertension: a case report

BackgroundThe combination of hyponatremia and renovascular hypertension is called hyponatremic hypertensive syndrome (HHS). Malignant hypertension as a presentation has been reported in adults with HHS but is rare in children.Case presentationAn eighteen month-old male presented with drowsiness, sudden onset status epilepticus and blood pressure of 210/160. The electrolytes on admission revealed sodium of 120 mEq/L and potassium of 2.1 mEq/L. The peripheral renin activity (PRA) was 172 ng/ml/min (normal 3–11 ng/ml/min) and serum aldosterone level was 91 ng/dl (normal 4 to 16 ng/dl). Patient underwent angioplasty with no success, followed by surgical correction. Two years since the diagnosis, the blood pressure is controlled with labetolol and amlodipine (at less than sixth of the pre-operative dosages). The PRA is 2.4 ng/ml/min and aldosterone 15.5 ng/dl. The child not only had three renal arteries on left but all of them were stenosed which to best of our knowledge has not been described.ConclusionAs uncommon as HHS with malignant hypertension may be in adults it is under-reported in children and purpose of the case report is to raise its awareness.

Nephropathic cystinosis associated with cardiomyopathy: a 27-year clinical follow-up.

BackgroundNephropathic cystinosis is an autosomal recessive disease resulting from intracellular accumulation of cystine leading to multiple organ failure.Case reportWe describe the clinical course of a patient managed from the age of six until his death at the age of 33 years. He underwent multiple surgery, including two renal transplants, developed transplant renal artery stenosis that was managed medically, and progressive heart failure at the age of 33 years. His death from a ruptured pseudoaneurysm associated with a restrictive cardiomyopathy is noteworthy. A limited cardiac autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell, along with 1000-fold higher tissue cystine content of the left ventricular myocardium compared to patients without cystinosis, suggesting the possibility of direct cystine mediated metabolic injury.

AMBULATORY BLOOD PRESSURE AND HEART RATE IN ADOLESCENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS

There is little information regarding ambulatory blood pressure in adolescents with insulin-dependent diabetes. Twenty-four-hour ambulatory blood pressure and heart rate was studied in 28 normotensive adolescents with insulin-dependent diabetes mellitus (IDDM) and normoalbuminuria, and adolescent controls. Ambulatory heart rate was higher during day and night (P = .001) in the IDDM patients, with normal mean diurnal variation of heart rate and blood pressure. Duration of diabetes related to diastolic ambulatory blood pressure (r = 0.69, P = .0001) and diastolic blood pressure burden (r = 0.61, P = .0001) independent of age, gender, height, body mass index, metabolic control, and albumin excretion rate. The ambulatory blood pressure monitor was well accepted in patients and controls. Ambulatory blood pressure monitoring in adolescents detects early changes in relation to duration of insulin-dependent diabetes.

Role of p66shc in Renal Toxicity of Oleic Acid

Background/Aims: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36-phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells. Methods: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells. Results: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity. Conclusion: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity.

Genomic organization of the KIAA0057 gene that encodes a TRAM-like protein and its exclusion as a polycystic kidney and hepatic disease 1 (PKHD1) candidate gene.

Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, 616ZRB, 703 South 19th Street, Birmingham, Alabama 35294, USA Institute for Human Genetics, University of Bonn, D53111 Bonn, Germany Department of Pediatrics, Rainbow Babies’ and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio 44106, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

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.

Serum beta2-microglobulin and immunoglobulin levels in young hemodialysis patients.

Abstract Amyloidosis is a complication of long-term hemodialysis treatment. The major histological feature of hemodialysis-associated amyloidosis (HAA) is the deposition of amyloid fibrils in the affected lesions, due, in part, to elevated serum β2-microglobulin (β2M) levels. In vitro studies reveal that serum immunoglobulin light and heavy chains co-deposit with β2M in tissues affected by HAA. Only one study of HAA has been performed in young dialysis patients. We therefore assessed risk factors for HAA in a group (n=30) of young (18.7±0.9 years) patients receiving chronic, uninterrupted hemodialysis using cellulose acetate membranes. All patients initiated dialysis before reaching 18 years of age. The pre-dialysis serum β2M level was 49.7±3.9 mg/l (normal 0–2.4 mg/l). Since serum albumin was normal (4.3±0.1 mg/dl) and serum protein/albumin was elevated (1.7±0.0, normal 1.2–1.5), indicating increased circulating protein, we assayed immunoglobulins in the same patients. The serum immunoglobulin levels (expressed as a percentage of the total level of serum proteins) were elevated (21.3±0.9%, normal 11.1%–21.0%). The Kt/v was 1.37±0.03, suggesting that the high levels of serum β2M and immunoglobulins were not due to inadequate dialysis in these patients. Patients with residual renal function (Kr) did display significantly lower serum levels of β2M (33.2±2.3, P=0.03). Furthermore, improved clearance of β2M correlated with higher values of Kr (r=0.914). In contrast, serum levels of immunoglobulin (22.6±3.7, P=0.5) were unaffected by Kr. In addition, there was no correlation between older age at onset of dialysis and serum levels of either β2M (r=0.107) or immunoglobulins (r=0.321). Finally, the length of time on dialysis had no effect on serum levels of either β2M (r=0.105) or immunoglobulins (r=0.092). Taken together, these results indicate that young hemodialysis patients may be at risk for HAA.

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.

Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting.

In the United States non-steroidal anti-inflammatory drugs (NSAID) are freely available over-the-counter. Because of the adverse effects on the kidneys and the popularity of these drugs, unregulated use of NSAIDs is an under recognized and potentially dangerous problem. Fifteen inpatients, mean age of 15.2 ± 2.3 years (five males, 10 females), were referred to nephrology for acute kidney injury. All patients admitted to taking ibuprofen and six also consumed naproxen. None of the patients had underlying renal diseases at the time of admission. Nine patients had proteinuria and 12 had hematuria (including one with gross hematuria). One patient had nephrotic syndrome but the condition resolved spontaneously without steroids and has remained in remission for four years. Two patients required dialysis. Only one of the dialyzed patients required steroid therapy for recovery of renal function. The mean duration of hospitalization was 7.4 ± 5.5 days. The serum creatinine peaked at 4.09 ± 4.24 (range 1.2-15.3) mg/dL. All patients recovered renal function with normalization of serum creatinine to 0.71 ± 0.15 mg/dL. The estimated GFR (glomerular filtration rate) at peak of renal failure was 38.2 ± 20.5 mL/min but did improve to a baseline of 134 ± 26.2 mL/min (range 89-177, p < 0.01). However, the duration from onset to normalization of serum creatinine was 37 ± 42 days indicating that majority of patients had abnormal renal function for a prolonged period. In conclusion, NSAIDs pose a significant risk of renal failure for significant duration and as an entity may be under recognized.