Attenuation of glycerol-induced acute kidney injury by previous partial hepatectomy: role of hepatocyte growth factor/c-met axis in tubular protection.

BACKGROUND/AIMS: Previous partial hepatectomy (HPTX) can attenuate glycerol-induced acute kidney injury (Gly-AKI). The aim of this study was to explore the pathophysiological mechanisms and the role of hepatocyte growth factor (HGF) in kidney protection. METHODS: Rats were subjected to HPTX 24 h before glycerol administration. Renal function, acute tubular necrosis, apoptosis, leukocyte infiltration, and the expression of HGF, c-met, monocyte chemoattractant protein-1, interleukin-1beta, and heme oxygenase-1 were evaluated 24 h after glycerol injection. The regenerative response was analyzed from 6 to 72 h after glycerol injection (BrdU incorporation). In a separate series of experiments, Gly-AKI+HPTX rats were treated with anti-HGF antibody. RESULTS: Gly-AKI+HPTX rats showed an increased expression of renal HGF and c-met as well as an improved creatinine clearance and reduced acute tubular necrosis and apoptosis, cytokine expression, and leukocyte infiltration. The regenerative response was less intense 24 and 72 h after glycerol administration in this group. The anti-HGF treatment disclosed an important role of HGF in the reduction of tubular injury, particularly apoptosis. Overexpression of heme oxygenase-1 was observed in Gly-AKI+HPTX rats, but was not associated with HPTX-induced renal protection. CONCLUSION: We conclude that Gly-AKI+HPTX rats have a reduced susceptibility to renal injury instead of an increased regenerative response and that endogenous HGF overexpression is responsible for suppression of tubular apoptosis.

Angiotensin II and endothelin in the renal cortex during the evolution of glycerol-induced acute tubular necrosis.

Hypertonic glycerol injection is one of the most frequently used models of experimental acute renal failure. Late structural changes such as interstitial fibrosis in the renal cortex and tubular atrophy have been detected after severe acute tubular necrosis (ATN). The aim of this study was to investigate the expression of angiotensin II (AII) and endothelin during the evolution of the ATN induced by glycerol and their relationships with the late structural changes observed in the kidneys. Forty-nine male Wistar rats were injected with a 50% glycerol solution, 8 mL/kg, divided into equal amounts, each administered into one hind leg, and 18 with 0.15 M NaCl solution. Blood and urine samples were collected 1, 5, 30, and 60 days after the injections to quantify sodium and creatinine; the animals were killed and the kidneys removed for histologic and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining in the cortical tubulointerstitium. Glycerol-injected rats presented a transitory increase in plasma creatinine levels and in fractional sodium excretion. The immunohistochemical studies showed increased AII and endothelin staining in the renal cortex from rats killed 5 days after glycerol injection (p<0.001) compared with control that persisted until day 60. The animals killed on days 30 and 60 also presented chronic lesions (fibrosis, tubular dilatation, and atrophy) in the renal cortex, despite the recovery of renal function. AII and endothelin may have contributed to the development of renal fibrosis in these rats.

Interstitial alterations in renal cortex in acute tubular necrosis (ATN) post-renal transplantation and in patients with ATN not related to renal transplant.

BACKGROUND: Abnormalities of renal function with long-term implications can persist after acute tubular necrosis (ATN), probably because of permanent loss of nephrons. Residual areas of fibrosis are also observed in the renal cortex post-ATN. In this study, we investigate the interstitial alterations post-ATN using histological and immunohistochemical methods. METHODS: We studied 11 patients with ATN of different etiologies and 19 patients with ATN post-renal transplantation. Eleven patients with ATN post-renal transplantation and one with ATN not related to renal transplantation were submitted to more than one biopsy because of delayed renal function recovery. The immunohistochemical studies were performed using alpha-smooth muscle-actin (alpha-SM-actin), endothelin, nuclear factor-kappaB (NF-kappaB), Jun-N-terminal kinase (p-JNK) and fibronectin antibodies. We also analyzed the urinary content of transforming growth factor-beta (TGF-beta) during the acute phase of ATN. RESULTS: The immunohistochemical studies showed increased alpha-SM-actin, fibronectin, endothelin, p-JNK and NF-kappaB staining in the tubulointerstitium area from the renal cortex of all patients when compared with controls (p < 0.001), and these increase persisted in the patients submitted to sequential biopsies. One of the patients with ATN without renal transplant and six patients with ATN post-renal transplant developed chronic renal failure. There was a significant increase of TGF-beta excretion in the urine of patients with acute renal failure (p < 0.01) compared with control. CONCLUSIONS: Our data show that the enhancement of renal TGF-beta production and the persistent increase of myofibroblasts, fibronectin, endothelin, p-JNK and NF-kappaB in renal cortex tubulointerstitium post-ATN may explain the impaired recovery of renal function observed in patients post-ATN frequently observed in patients with ATN post-renal transplant.

Acute renal failure in experimental envenomation with Africanized bee venom.

Human victims of multiple bee or wasp stings have been reported and develop severe clinical signs and symptoms. Acute renal failure (ARF), usually due to acute tubular necrosis (ATN) was a frequent complication. The pathogenetic mechanisms of ATN occurring in these accidents are still unclear. In the present study, female Wistar rats weighing 150-200 g were injected intravenously with Africanized bee venom at a dose of 0.4 microL/100 g body weight, and the kidney was observed under light and transmission electron microscopy and in immunohistochemical studies. The animals were divided into two groups: an Early group studied 3 to 8 hours after inoculation, and a Late group studied 24 to 30 hours after inoculation. The animals showed ATN mainly in the cortex and outer medulla with cast formation. After 24 hours, frequent mitotic figures were found in the tubular epithelium. Immunohistochemical studies revealed the presence of myoglobin and muscle actin in the tubular casts. Under electron microscopy, proximal tubule segments showed increasing intracytoplasmic vacuoles and attenuation of the brush border and of the basolateral infolding. This segment and the thick ascending limb of Henle's loop showed hydropic degeneration. Dead cells with apoptosis or necrosis due to cellular disintegration resulted in tubular basement membrane denudation. In the Late group, figures of intracytoplasmic myelin could be observed, some of them containing mitochondrial fragments. These changes are likely to be due to interactive effects of venom components, mainly mellitin and enzymes such as phospholipases, both acting on biological membranes. The ATN found was probably due to multiple causes, mainly a direct action of the venom on tubular cells, myoglobinuria, and perhaps ischemic mechanisms.

Peculiar electrolytic and hormonal abnormalities in acute renal failure due to leptospirosis.

Hypokalemia in leptospirosis acute renal failure (ARF) was studied in nine patients with severe leptospirosis ARF and five patients with moderate leptospirosis ARF and compared with five patients with severe acute tubular necrosis (ATN) and eight healthy individuals. Urinary volumes of both the severe and moderate leptospirosis groups were higher than those of the severe ATN group. Leptospirosis groups had serum potassium levels lower than those found in the healthy and severe ATN groups. Serum sodium levels were lower in the severe leptospirosis group than in the moderate leptospirosis, the severe ATN, and the healthy groups. There was a positive correlation between the fractional excretion of sodium and potassium in the severe leptospirosis group as well as between serum creatinine and potassium levels in the pooled leptospirosis groups. Urinary pH in the severe and moderate leptospirosis groups was lower than in the severe ATN group. Aldosterone levels were higher in the severe leptospirosis group than in the healthy individuals. Cortisol levels were higher in the leptospirosis groups than in the healthy subjects. These results strongly suggest that hypokalemia in leptospirosis ARF is due to renal potassium wasting potentialized by aldosterone and cortisol, requiring that special attention is given to potassium replacement as well as to volume repletion in the treatment of leptospirosis ARF.