Roberto Silva Costa

Protective Effect of Quercetin on the Evolution of Cisplatin-Induced Acute Tubular Necrosis

Background: The mechanism of cisplatin-induced nephrotoxicity is unknown, but has been associated with renal lipid peroxidation. The bioflavonoid quercetin may be a potential alternative to reduce cisplatin-induced nephrotoxicity. The aim of this study was to evaluate the effect of quercetin on the evolution of cisplatin-induced acute tubular necrosis. Methods: One hundred and three male Wistar rats were injected with cisplatin (5 mg/kg, i.p.), 43 of them received quercetin (50 mg/kg, by gavage) before cisplatin injection. Blood and urine were collected 5 and 20 days after the injection for the determination of plasma creatinine, urine volume and osmolality. The kidneys were removed for the determination of renal malondialdehyde (MDA) and for histological and immunohistochemical studies. The renal expression of fibronectin, α-smooth muscle actin, vimentin, Jun N-terminal kinase, nuclear factor-ĸB, and macrophages during the evolution of the acute tubular necrosis induced by cisplatin and the histological changes observed in the kidneys were analyzed. Results: Cisplatin-treated rats presented a transitory increase in plasma creatinine levels, tubular cell necrosis and increased immunostaining for vimentin, α-SM-actin, fibronectin, ED1, NF-ĸB, and p-JNK in the renal cortex and outer medulla. These alterations were less intense in animals treated with quercetin. Conclusion: Quercetin treatment attenuated the functional, histological and immunohistochemical alterations induced by cisplatin.

NEPHROTOXICITY ATTRIBUTED TO MEGLUMINE ANTIMONIATE (GLUCANTIME) IN THE TREATMENT OF GENERALIZED CUTANEOUS LEISHMANIASIS

BACKGROUND Pentavalent antimonials have became of basic importance for the treatment of leishmaniasis. Their most severe side effects have been reported to be increased hepatic enzyme levels and electrocardiographic abnormalities. Nephrotoxicity has been rarely related. OBSERVATIONS We report a case of generalized cutaneous leishmaniasis involving a 50-year old male patient who was submitted to treatment with meglumine antimoniate (Glucantime). He developed acute renal failure (ARF) due to acute tubular necrosis (ATN), followed by death after receiving a total of 53 ampoules of Glucantime. CONCLUSIONS The treatment with Glucantime was responsible by ARF diagnosed in this patient. The previous urine osmolarity and serum creatinine levels were normal and the autopsy showed ATN. It should be pointed out if ARF may also be explained by massive deposits of immunocomplexes by leishmania antibodies and antigens due to the antigenic break by the antimonial compound, since our patient presented countless lesions covering the entire tegument, similar to the Hexheimer phenomenon, but at the autopsy no glomerular alterations were seen.

Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage

BACKGROUND Cisplatin (CP)-induced renal damage is associated with inflammation. Hydrogen sulphide (H2S) is involved in models of inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by CP. METHODS The rats were injected with CP (5 mg/kg, i.p.) or PAG (5 mg/kg twice a day, i.p.) for 4 days, starting 1 h before CP injection. Control rats were injected with 0.15 M NaCl or PAG only. Blood and urine samples were collected 5 days after saline or CP injections for renal function evaluation. The kidneys were removed for tumour necrosis factor (TNF)-α quantification, histological, immunohistochemical and Western blot analysis. The cystathionine γ-lyase (CSE) activity and expression were assessed. The direct toxicity of H(2)S in renal tubular cells was evaluated by the incubation of these cells with NaHS, a donor of H2S. RESULTS CP-treated rats presented increases in plasma creatinine levels and in sodium and potassium fractional excretions associated with tubulointerstitial lesions in the outer medulla. Increased expression of TNF-α, macrophages, neutrophils and T lymphocytes, associated with increased H2S formation rate and CSE expression, were also observed in the outer medulla from CP-injected rats. All these alterations were reduced by treatment with PAG. A direct toxicity of NaHS for renal tubular epithelial cells was not observed. CONCLUSIONS Treatment with PAG reduces the renal damage induced by CP. This effect seems to be related to the H2S formation and the restriction of the inflammation in the kidneys from PAG + CP-treated rats.

Sodium bicarbonate treatment reduces renal injury, renal production of transforming growth Factor-β, and urinary transforming growth Factor-β excretion in rats with doxorubicin-induced nephropathy

The aim of this study is to investigate the effect of sodium bicarbonate on doxorubicin-injected rats. Thirty female Wistar rats were injected with doxorubicin (3.5 mg/kg of body weight, intravenously) and 30 rats with 0.15 mol/L of sodium chloride solution (group C). Fifteen days later, we replaced the drinking water with a 0.15-mol/L sodium bicarbonate solution for 10 of the animals injected with doxorubicin (group AD-B). Three months after the beginning of treatment, urine samples were collected to quantify albumin, creatinine, and transforming growth factor-beta (TGF-beta). The rats were killed, and the kidneys were removed for histological, morphometric, immunohistochemical, and RNA studies. All doxorubicin-injected animals showed structural renal changes. However, these alterations were less intense in rats treated with doxorubicin plus sodium bicarbonate (P < 0.05). The percentage of glomerulosclerosis was 0.11% +/- 0.08% in group C, 14.7% +/- 12.8% in group AD (rats treated with doxorubicin only), and 4.38% +/- 1.9% in group AD-B, and the percentage of tubulointerstitial damage was 0. 01% +/- 0.03% in group C, 54.6% +/- 20.3% in group AD, and 16.6% +/- 10.3% in group AD-B. The immunostaining for TGF-beta in the renal cortex and glomeruli was more intense in the animals injected with doxorubicin only. A greater renal cortical TGF-beta messenger RNA content was observed in the animals injected with only doxorubicin that did not receive sodium bicarbonate (P < 0.05). These animals also presented a greater rate of urinary TGF-beta excretion reported as picograms of TGF-beta per milligram of urinary creatinine (P < 0.05), which was 202 +/- 11 pg/mg in group C, 1, 103 +/- 580 pg/mg in group AD, and 299 +/- 128 pg/mg in group AD-B. However, albuminuria was more intense in the sodium bicarbonate-treated animals (P < 0.05). The animals from group AD also showed higher immunostaining scores for vimentin and albumin in tubule cells (P < 0.05). In conclusion, treatment with sodium bicarbonate reduces structural renal damage, albumin reabsorption, and renal TGF-beta production in rats with doxorubicin-induced nephropathy.

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 Henles 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.

Inhibition of Nuclear Factor-κB Activation Attenuates Tubulointerstitial Nephritis Induced by Gentamicin

Background: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-ĸB (NF-ĸB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-ĸB inhibitor. Methods: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. Results: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-ĸB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. Conclusions: These data show that inhibition of NF-ĸB activation attenuates tubulointerstitial nephritis induced by gentamicin.

Rhabdomyonecrosis experimentally induced in Wistar rats by Africanized bee venom

Damage is reported to skeletal muscle experimentally induced in Wistar rats by Africanized bee venom (ABV). Rhabdomyonecrosis was demonstrated indirectly by increased serum levels of the enzymes aspartate-aminotransferase and total creatine kinase, and directly by necrosis and inflammation observed by standard light microscopy of skeletal muscle. To our knowledge, this is the first report of a systemic damaging effect of ABV on skeletal muscle of experimentally envenomated rats. These data appear to reproduce experimentally some of the findings reported in cases of human envenomation due to multiple Africanized bee stings.

Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage.

AIMS Cisplatin (CP) promotes increased production of reactive oxygen species, which can activate p38 mitogen activated protein kinases (p38 MAPKs) leading to apoptosis and increased expression of proinflammatory mediators that intensify the cytotoxic effects of CP. We investigated the effect of the treatment with SB203580, a p38 MAPKs inhibitor, on oxidative stress, on the oxidation-associated signal, p38 MAPK and on apoptosis in CP-injected rats, starting after the beginning of the renal damage. MAIN METHODS Rats (n=21) were injected with CP (5 mg/kg, i.p.) and 3 and 4 days after some of them (n=8) were treated with SB203580 (0.5 mg/kg, i.p.). Controls (n=6) received saline (i.p.). Two or five days after saline or CP injections, plasma creatinine, urinary volume, sodium and potassium fractional excretions, blood urea nitrogen and urinary lipid peroxidation were measured. The kidneys were removed for histological, apoptosis, immunohistochemical and Western blot studies. KEY FINDINGS CP caused abnormalities in kidney functions and structure associated with raised urinary peroxidation levels and higher number of apoptotic cells in the outer medulla. The immunostaining studies showed increased numbers of macrophages/monocytes and p-p38 MAPKs positive cells in the renal outer medulla. The increase of p-p38 MAPKs expression was confirmed by Western blot analysis. All of these alterations were attenuated by treatment with SB203580. SIGNIFICANCE These data suggest that the beneficial effect of SB203580 on CP-induced renal damage might be related, in part, to the blockade of p38 MAPK activation with reduction of the inflammatory process, oxidative stress and apoptotic cell death.

Facial leontiasis ossea : a rare presentation of hyperparathyroidism secondary to chronic renal insufficiency

The term renal osteodystrophy is often used in a generic sense to include skeletal disorders of patients with chronic renal failure due to secondary hyperparathyroidism. The prevalence of this condition among patients on hemodialysis is considerably high. However, extreme forms such as facial leontiasis ossea are very rare, only 2 well-characterized cases having been reported thus far in the literature. In the present article we report the case of a female patient who developed hyperparathyroidism secondary to end-stage renal disease which was manifested as facial leontiasis ossea and culminated in dysphagia and respiratory difficulties caused by excess bone tissue growth.

Star fruit: simultaneous neurotoxic and nephrotoxic effects in people with previously normal renal function

Patients with renal failure not yet on dialysis (stages 3–5) or on dialysis treatment are susceptible to intoxication from eating star fruit (Figure ​(Figure1).1). In these patients, star fruit may cause mild to severe neurotoxicity including hiccups, vomiting, asthenia, mental confusion, seizures, coma and death [1–3]. However, there are anecdotal reports of individuals with normal renal function who became intoxicated as a result of eating or drinking a large amount of star fruit, and intractable and persistent hiccups are usually the main symptom. Fig. 1 Star fruit (Averrhoa carambola) or carambola has been cultivated in Malaysia, Southern China, Taiwan, India and Brazil. It is rather popular in the Philippines and Queensland, Australia and moderately so in some of the South Pacific Islands, particularly ... Star fruit nephrotoxicity in people with normal renal function is rarely reported and it is never associated with signs of neurotoxicity. There is only prior one study of such cases, which reported on two cases of acute renal failure (ARF) due to acute oxalate nephropathy in patients with previous normal renal function [4]. In the current study, we present five patients with previously normal renal function who became intoxicated from eating star fruit or drinking star fruit juice and presented simultaneously nephrotoxic and neurotoxic effects.