[Study on the role of the tubule in renal vasoconstriction induced by cyclosporine]. / Papel del túbulo en la vasoconstricción renal inducida por ciclosporina.

INTRODUCTION: Cyclosporine (CyA) has proved to induce cell apoptosis on cultured proximal tubule cells. However, there is no much data about the in vivo functional consequences of this injury or the long time observed CyA-induced renal vasoconstriction. MATERIAL AND METHODS: In a swine model of subacute CyA nephrotoxicity (10 mg/ Kg. dx 15 days), we performed a right nephrectomy, followed by left renal artery, vein and ureter catheterisati8n. After inducing water diuresis, three clearance periods of 15 minutes were performed before and after a furosemide 1 mg/kg infusion. Plasma and urine electrolytes, blood gas, acid excretion, plasma renin activity and aldosterone concentration, GFR, RPF, RBF, intra-renal vascular resistances, glomerular filtration pressure, distal Cl- delivery, water clearance and TTKG were measured or estimated on 7 control and 7 treated animals. Right kidney was processed for NaKATPase activity and immunostaining. RESULTS: Treated animals presented detaching proximal cells, luminal blebbing and loss of tight junctions. Cortical but not medullar sodium pump was internalised and partially inactive. Treated animals showed much lower fractional excretions of Na+, with significantly higher distal fractional reabsorption of Cl. Distal shift in fluid load resulted in a significant rise in renal O2 consumption, and modifications in the global renal estequiometry of Na+ transport/O2 uptake. Several consequences followed this situation: preglomerular resistances increased 3 times with only minor changes in postglomerular resistances and renal blood and plasma flow were significantly reduced. Furosemide partially reversed these effects. A slight increase in fractional filtration prevented GFR differences to become statistically significant. CONCLUSION: subacute CyA treatment even al doses not modifying GFR, may cause proximal tubule Na+ transport impairment, resulting in increased rates of distal delivery and absorption of fluid load. Renal uptake of O2 may be increased and tubule glomerular feedback should be expected to be activated. Absence of changes of GFR with furosemide is an early sign of CyA renal damage.

Papel del túbulo en la vasoconstricción renal inducida por ciclosporina / Study of the role of the tubule in renal vasoconstriction induced by cyclosporine

Introducción: Ciclosporina es el primero de una familia de potentes inmunosupresores con capacidad anticalcineurínica que, sin embargo, presentan como limitación terapéutica una nefrotoxicidad que puede aparecer desde periodos tempranos. Los primeros datos funcionales sugerían la existencia de vasoconstricción renal, si bien estudios posteriores han mostrado un efecto tóxico directo de ciclosporina sobre el túbulo proximal. Materiales y Métodos: En este artículo se presenta un modelo porcino de nefrotoxicidad por ciclosporina a medio plazo, analizándose los cambios hemodinámicos intrarrenales y las funciones tubulares, así como la relación entre ambos. Resultados: Ciclosporina produce específicamente una internalización e inactivación de la Na+, K+-ATPasa basolateral del túbulo proximal, determinando el desplazamiento axial de la carga filtrada hacia regiones distales (asa de Henle), con transportes activos más intensos y no modificados por ciclosporina. El resultado es un aumento en la reabsorción fraccional distal de cloro que condiciona un estímulo del “feed-back” túbulo glomerular, vasoconstricción aferente pero no eferente, aumento de las resistencias renales y caída de la presión intraglomerular. Furosemida restaura parcialmente la situación basal. La consecuencia inmediata es un aumento en el consumo de O2 por unidad de sodio trasportado. A nivel del túbulo colector no se observan cambios en la secreción de agua libre, pero la secreción de K+ parece limitada, y no se corrige al aumentar la oferta distal de sodio con furosemida, ni con aldosterona, cuyos valores fueron más altos en los animales tratados con ciclosporina. Conclusión: En resumen, el efecto vasoconstrictor de ciclosporina sobre el riñón se debe en parte a una retroalimentación túbulo glomerular activada por el desplazamiento de solutos filtrados de sus sitios de reabsorción proximal a otros sitos más distales. Las dietas con alto contenido en sodio pueden aumentar el efecto deletéreo de ciclosporina sobre el filtrado glomerular

Introduction: Cyclosporine (CyA) has proved to induce cell apoptosis on cultured proximal tubule cells. However, there is no much data about the in vivo functional consequences of this injury or the long time observed CyA-induced renal vasoconstriction. Material and Methods: In a swine model of subacute CyA nephrotoxicity (10 mg/ Kg. d x 15 days), we performed a right nephrectomy, followed by left renal artery, vein and ureter catheterisation. After inducing water diuresis, three clearance periods of 15 minutes were performed before and after a furosemide 1 mg/kg infusion. Plasma and urine electrolytes, blood gas, acid excretion, plasma renin activity and aldosterone concentration, GFR, RPF, RBF, intra-renal vascular resistances, glomerular filtration pressure, distal Cl- delivery, water clearance and TTKG were measured or estimated on 7 control and 7 treated animals. Right kidney was processed for NaKATPase activity and immunostaining. Results: Treated animals presented detaching proximal cells, luminal blebbing and loss of tight junctions. Cortical but not medullar sodium pump was internalised and partially inactive. Treated animals showed much lower fractional excretions of Na+, with significantly higher distal fractional reabsorption of Cl-. Distal shift in fluid load resulted in a significant rise in renal O2 consumption, and modifications in the global renal estequiometry of Na+ transport/O2 uptake. Several consequences followed this situation: preglomerular resistances increased 3 times with only minor changes in postglomerular resistances and renal blood and plasma flow were significantly reduced. Furosemide partially reversed these effects. A slight increase in fractional filtration prevented GFR differences to become statistically significant. Conclusión: subacute CyA treatment even al doses not modifying GFR, may cause proximal tubule Na+ transport impairment, resulting in increased rates of distal delivery and absorption of fluid load. Renal uptake of O2 may be increased and tubule glomerular feedback should be expected to be activated. Absence of changes of GFR with furosemide is an early sign of CyA renal damage