Approaches and methods in gene therapy for kidney disease

Renal gene therapy may offer new strategies to treat diseases of native and transplanted kidneys. Several experimental techniques have been developed and employed using nonviral, viral, and cellular vectors. The most efficient vector for in vivo transfection appears to be adenovirus. Glomeruli, blood vessels, interstitial cells, and pyelum can be transfected with high efficiency. In addition, electroporation and microbubbles with ultrasound, both being enhanced naked plasmid techniques, offer good opportunities. Trapping of mesangial cells into the glomeruli as well as natural targeting of monocytes or macrophages to inflamed kidneys are elegant methods for site-specific delivery of genes. For gene therapy in kidney transplantation, hemagglutinating virus of Japan liposomes are efficient vectors for tubular transfection, whereas enhanced naked plasmid techniques are suitable for glomerular transfection. However, adenovirus offers the best opportunities in a renal transplantation setup because varying parameters of graft perfusion allows targeting of different cell types. In renal grafts, lymphocytes can be used for selective targeting to sites of inflammation. In conclusion, for both in vivo and ex vivo renal transfection, enhanced naked plasmids and adenovirus offer the best perspectives for effective clinical application. Moreover, the development of safer, nonimmunogenic vectors and the large-scale production could make clinical renal gene therapy a realistic possibility for the near future

Extracorporeal elimination in acute valproate intoxication

Severe poisoning with valproate may result in coma and death. The management of valproate intoxication is principally supportive. Valproate is scarcely excreted renally and is mainly protein bound and, therefore, not considered to be amenable for extracorporeal elimination. Despite these unfavourable pharmacokinetic properties, several case reports showed successful treatment of valproate intoxication with haemodialysis and/or haemoperfusion. We describe a male patient (57 years) after ingestion of 64 g of valproate. The patient was successfully treated with haemodialysis for 6 h. Haemodialysis was followed by continuous venovenous haemodiafiltration (CVVH-D) for 18 h to prevent a rebound phenomenon. This report confirms the benefit of haemodialysis in serious valproate overdose. A review of the literature shows that haemodialysis followed by CVVH-D is the treatment of choice in severe valproate intoxication

The role of angiotensin(1–7) in renal vasculature of the rat

Objective Angiotensin(1–7) is an active component of the renin–angiotensin–aldosterone system. Its exact role in renal vascular function is unclear. We therefore studied the effects of angiotensin(1–7) on the renal vasculature in vitro and in vivo.Methods Isolated small renal arteries were studied in an arteriograph system by constructing concentration–response curves to angiotensin II, without and with angiotensin(1–7). In isolated perfused kidneys, the response of angiotensin II on renal vascular resistance was measured without and with angiotensin(1–7). The influence of angiotensin(1–7) on angiotensin II-induced glomerular afferent and efferent constriction was assessed with intravital microscopy in vivo under anaesthesia. In freely moving rats, we studied the effect of angiotensin(1–7) on angiotensin II-induced reduction of renal blood flow with an electromagnetic flow probe.Results Angiotensin(1–7) alone had no effect on the renal vasculature in any of the experiments. In vitro, angiotensin(1–7) antagonized angiotensin-II-induced constriction of isolated renal arteries (9.71 ± 1.21 and 3.20 ± 0.57%, for control and angiotensin(1–7) pre-treated arteries, respectively; P < 0.0005). In isolated perfused kidneys, angiotensin(1–7) reduced the angiotensin II response (100 ± 16.6 versus 72.6 ± 15.6%, P < 0.05) and shifted the angiotensin II dose–response curve rightward (pEC50, 6.69 ± 0.19 and 6.26 ± 0.12 for control and angiotensin(1–7) pre-treated kidneys, respectively; P < 0.05). Angiotensin(1–7), however, was devoid of effects on angiotensin-II-induced constriction of glomerular afferent and efferent arterioles and on angiotensin-II-induced renal blood flow reduction in freely moving rats in vivo.Conclusion Angiotensin(1–7) antagonizes angiotensin II in renal vessels in vitro, but does not appear to have a major function in normal physiological regulation of renal vascular function in vivo

The role of angiotensin(1–7) in renal vasculature of the rat

Objective Angiotensin(1–7) is an active component of the renin–angiotensin–aldosterone system. Its exact role in renal vascular function is unclear. We therefore studied the effects of angiotensin(1–7) on the renal vasculature in vitro and in vivo.Methods Isolated small renal arteries were studied in an arteriograph system by constructing concentration–response curves to angiotensin II, without and with angiotensin(1–7). In isolated perfused kidneys, the response of angiotensin II on renal vascular resistance was measured without and with angiotensin(1–7). The influence of angiotensin(1–7) on angiotensin II-induced glomerular afferent and efferent constriction was assessed with intravital microscopy in vivo under anaesthesia. In freely moving rats, we studied the effect of angiotensin(1–7) on angiotensin II-induced reduction of renal blood flow with an electromagnetic flow probe.Results Angiotensin(1–7) alone had no effect on the renal vasculature in any of the experiments. In vitro, angiotensin(1–7) antagonized angiotensin-II-induced constriction of isolated renal arteries (9.71 ± 1.21 and 3.20 ± 0.57%, for control and angiotensin(1–7) pre-treated arteries, respectively; P < 0.0005). In isolated perfused kidneys, angiotensin(1–7) reduced the angiotensin II response (100 ± 16.6 versus 72.6 ± 15.6%, P < 0.05) and shifted the angiotensin II dose–response curve rightward (pEC50, 6.69 ± 0.19 and 6.26 ± 0.12 for control and angiotensin(1–7) pre-treated kidneys, respectively; P < 0.05). Angiotensin(1–7), however, was devoid of effects on angiotensin-II-induced constriction of glomerular afferent and efferent arterioles and on angiotensin-II-induced renal blood flow reduction in freely moving rats in vivo.Conclusion Angiotensin(1–7) antagonizes angiotensin II in renal vessels in vitro, but does not appear to have a major function in normal physiological regulation of renal vascular function in vivo

The role of angiotensin(1-7) in renal vasculature of the rat

Angiotensin(1-7) is an active component of the renin-angiotensin-aldosterone system. Its exact role in renal vascular function is unclear. We therefore studied the effects of angiotensin(1-7) on the renal vasculature in vitro and in vivo. Isolated small renal arteries were studied in an arteriograph system by constructing concentration-response curves to angiotensin II, without and with angiotensin(1-7). In isolated perfused kidneys, the response of angiotensin II on renal vascular resistance was measured without and with angiotensin(1-7). The influence of angiotensin(1-7) on angiotensin II-induced glomerular afferent and efferent constriction was assessed with intravital microscopy in vivo under anaesthesia. In freely moving rats, we studied the effect of angiotensin(1-7) on angiotensin II-induced reduction of renal blood flow with an electromagnetic flow probe. Angiotensin(1-7) alone had no effect on the renal vasculature in any of the experiments. In vitro, angiotensin(1-7) antagonized angiotensin-II-induced constriction of isolated renal arteries (9.71 +/- 1.21 and 3.20 +/- 0.57%, for control and angiotensin(1-7) pre-treated arteries, respectively; P <0.0005). In isolated perfused kidneys, angiotensin(1-7) reduced the angiotensin II response (100 +/- 16.6 versus 72.6 +/- 15.6%, P <0.05) and shifted the angiotensin II dose-response curve rightward (pEC50, 6.69 +/- 0.19 and 6.26 +/- 0.12 for control and angiotensin(1-7) pre-treated kidneys, respectively; P <0.05). Angiotensin(1-7), however, was devoid of effects on angiotensin-II-induced constriction of glomerular afferent and efferent arterioles and on angiotensin-II-induced renal blood flow reduction in freely moving rats in vivo. Angiotensin(1-7) antagonizes angiotensin II in renal vessels in vitro, but does not appear to have a major function in normal physiological regulation of renal vascular function in viv