• Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector.

      Luo, Xiaoyan; Hall, Gentzon; Li, Songtao; Bird, Andrew; Lavin, Peter J; Winn, Michelle P; Kemper, Alex R; Brown, Talmage T; Koeberl, Dwight D; Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA. (2011-11)
      Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-associated virus serotype 2 (AAV2) vector encoding human G6Pase was pseudotyped with four serotypes, AAV2, AAV7, AAV8, and AAV9, and we evaluated efficacy in 12-day-old G6pase (-/-) mice. Hypoglycemia during fasting (plasma glucose <100 mg/dl) was prevented for >6 months by the dsAAV2/7, dsAAV2/8, and dsAAV2/9 vectors. Prolonged fasting for 8 hours revealed normalization of blood glucose following dsAAV2/9 vector administration at the higher dose. The glycogen content of kidney was reduced by >65% with both the dsAAV2/7 and dsAAV2/9 vectors, and renal glycogen content was stably reduced between 7 and 12 months of age for the dsAAV2/9 vector-treated mice. Every vector-treated group had significantly reduced glycogen content in the liver, in comparison with untreated G6pase (-/-) mice. G6Pase was expressed in many renal epithelial cells of with the dsAAV2/9 vector for up to 12 months. Albuminuria and renal fibrosis were reduced by the dsAAV2/9 vector. Hepatorenal correction in G6pase (-/-) mice demonstrates the potential of AAV vectors for the correction of inherited diseases of metabolism.
    • Identification of the optimal donor quality scoring system and measure of early renal function in kidney transplantation.

      Moore, Jason; Ramakrishna, Satish; Tan, Kay; Cockwell, Paul; Eardley, Kevin; Little, Mark A; Rylance, Paul; Shivakumar, Kunigal; Suresh, Vijayan; Tomlinson, Kerry; et al. (Transplantation, 2009-02-27)
      The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction.
    • Immune profile and Epstein-Barr virus infection in acute interstitial nephritis: an immunohistochemical study in 78 patients.

      Mansur, Abdurrezagh; Little, Mark A; Oh, Weng Chin; Jacques, Steven; Nightingale, Peter; Howie, Alexander J; Savage, Caroline O S; Renal Immunobiology, University of Birmingham, College of Medical and Dental Sciences, London, UK. (Nephron. Clinical practice, 2011)
      Acute interstitial nephritis (AIN) is a common cause of acute kidney injury and is characterised by a dense interstitial cellular infiltrate, which has not been well defined. Previous studies have demonstrated a correlation between Epstein-Barr virus (EBV) infection and AIN. The purpose of our study was to define the nature of the interstitial immune infiltrate and to investigate the possibility of renal infection with EBV.
    • Traumatic parenchymal laceration in a horseshoe kidney.

      Stunell, H; Grainger, R; Torreggiani, Wc; Department of Radiology, Adelaide & Meath Hospital, Tallaght, Dublin, Ireland. (2011-03)
      An 18-year-old man was transferred to the authors' institution after a motor vehicle collision in which he was a restrained front seat passenger. The referring hospital performed contrast-enhanced computed tomography which revealed a previously undiagnosed horseshoe kidney with a laceration of the right lower pole moiety. On transfer, he was pale and mildly tachycardic but normotensive.
    • TRPC6 enhances angiotensin II-induced albuminuria.

      Eckel, Jason; Lavin, Peter J; Finch, Elizabeth A; Mukerji, Nirvan; Burch, Jarrett; Gbadegesin, Rasheed; Wu, Guanghong; Bowling, Brandy; Byrd, Alison; Hall, Gentzon; et al. (2011-03)
      Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.