Oral acyclovir induced hypokalemia and acute tubular necrosis a case report.

BACKGROUND: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously. CASE PRESENTATION: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L. CONCLUSIONS: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir.

Rhabdomyolysis observed at forensic autopsy: a series of 52 cases.

Rhabdomyolysis is characterized by skeletal muscle injury resulting in the release of intracellular proteins (such as myoglobin) and electrolytes into the blood circulation, which cause acute kidney injury, myoglobinuria and electrolyte imbalances. Clinical diagnosis of rhabdomyolysis is made on the basis of biochemical analysis; however, for forensic autopsies, biochemical data are often not available, and it is necessary to diagnose rhabdomyolysis via histopathological examinations. This study analyzed 52 cases with rhabdomyolysis and applied myoglobin immunohistochemistry to kidney, urine and blood samples. We found that blunt force injuries were the most common cause of rhabdomyolysis across all age groups, and drugs were the second most common cause. The drugs included ketamines, amphetamines, synthetic cathinones, entheogens, benzodiazepines, opioid analgesics, and anesthesia. Less than 60% of our cases had biochemical data, including myoglobin (92.5~416,978 ng/mL), creatine kinase (220~774,015 U/L), potassium (1.6~10.3 meq/L), calcium (2.7~29.2 mg/dL), and phosphorus (2.6~14.2 mg/dL). In the kidney tissue sections, we found that 95% of the rhabdomyolysis cases were positive for myoglobin immunohistochemistry and that 96% were associated with acute tubular necrosis. Our findings describe the features of fatal rhabdomyolysis in a large series and suggest that myoglobin immunohistochemistry can be used in post-mortem blood and urine cell blocks to detect myoglobin.

Targeting of regulated necrosis in kidney disease.

The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation-mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention.

A Case of Oxalate Nephropathy: When a Single Cause Is Not Crystal Clear.

Hyperoxaluria can result in oxalate nephropathy with intratubular calcium oxalate crystallization and acute tubular injury. Primary inherited enzymatic deficiency or secondary causes such as excessive dietary intake, enteric increased absorption, or high doses of vitamin C, which is metabolized to oxalate, may underlie hyperoxaluria and oxalate nephropathy. We report a case of acute kidney injury due to oxalate nephropathy in a patient using chelating therapy with oral ethylenediamine tetra acetic acid (EDTA), intravenous supplementation with vitamin C, and chronic diarrhea and discuss the potential kidney damage these factors can cause in particular settings. To our knowledge, this is the first report suggesting an association between oral EDTA and oxalate nephropathy.

An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis.

Diagnostic kidney biopsies sometimes yield clinically unsuspected diagnoses. We present a case of a 69-year-old woman with established ANCA-associated vasculitis (AAV) of 4 years duration who was in clinical remission following cytotoxic therapy and was on maintenance immunosuppression. She presented to the hospital with acute kidney injury (AKI), symptoms suggestive of a systemic vasculitis, and in addition had hypercalcemia, metabolic alkalosis. A relapse in the AAV was suspected but a diagnostic kidney biopsy showed acute tubular necrosis, patchy interstitial inflammation, and calcium phosphate deposits. It was found that the patient recently started consuming large doses of over-the-counter calcium-containing antacids and vitamin Dcontaining multivitamin supplements. Cessation of these drugs led to improvement of renal function to baseline. This case highlights several teaching points: (1) the kidney biopsy can prove to be critically important even in cases where there appears to be a more obvious clinical diagnosis, (2) AK due to calcium-alkali syndrome has characteristic histopathological changes, and (3) that the triad of hypercalcemia, metabolic alkalosis, and AKI is exclusively associated with the ingestion of excessive quantities of calcium-containing antacids. The physician should keep this in mind, and pro-actively seek pertinent medication history from the patient. A brief review of calcium-alkali syndrome is given.

Effects of Schizolobium parahyba extract on experimental Bothrops venom-induced acute kidney injury.

BACKGROUND: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. METHODOLOGY: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). PRINCIPAL FINDINGS: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. CONCLUSION: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.

Protective and therapeutic effects of licorice in rats with acute tubular necrosis.

OBJECTIVES: Various protective and therapeutic effects such as antioxidant, anti-inflammatory, anticancer, antihistaminic, and antibacterial effects have been depicted for licorice. However, its biological effects in the kidney are still not clear. Therefore, we aimed to investigate the efficiency of licorice in rats with gentamicin (GM)-induced acute tubular necrosis. DESIGN AND METHODS: Rats were randomized into the control group (only saline for 12 days), licorice group (licorice for 12 days), GM group (GM for 12 days), GM + licorice group, and licorice-treated GM group (licorice for 12 days after taking GM for 12 days). Blood urea, creatinine, and uric acid levels were measured and histopathological analyses of the kidneys were performed. The oxidative side of oxidant-antioxidant balance was evaluated by detecting lipid peroxidation (LPO) and total peroxide levels, and antioxidative side was determined by measuring total antioxidant capacity (TAC) and reduced glutathione (GSH) levels in plasma and kidney tissues. RESULTS: The oxidant-antioxidant balance seemed to be shifted to the oxidative side in the GM group when compared with the control and GM + licorice groups. In GM group, biochemical profiles showed a remarkable increase in blood uric acid, urea, and creatinine levels, and depletion of renal tissue and plasma TAC and GSH levels. In addition, histopathologic studies revealed severe acute tubular necrosis, congestion, and hyaline casts, verifying GM-induced nephrotoxicity. Licorice was effective in reduction of blood urea, creatinine, and uric acid levels, and also effective in decreasing the tubular necrosis score. Licorice treatment also significantly reduced LPO and total peroxide levels, and increased TAC and GSH levels in both renal tissue and blood. Moreover, these changes in rats subjected to the combined therapy (GM + licorice) were significantly less than those of GM group. CONCLUSIONS: Licorice ameliorates GM-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing LPO, and improving antioxidant defense.

Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia.

Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.

Ozone postconditioning in renal ischaemia-reperfusion model. Functional and morphological evidences.

BACKGROUND: Ischaemia-reperfusion is one of the main causes of kidney complications. The most frequent lesion is acute tubular necrosis. Ozone oxidative preconditioning exerts a modulatory effect of redox state of renal cells in models of ischaemia-reperfusion, by stimulating endogenous antioxidant mechanisms. Similar results have been obtained in more recent studies using ischaemic postconditioning. OBJECTIVES: To evaluate the effect of ozone oxidative postconditioning on renal function and morphology in an ischaemia-reperfusion rat model. METHODS: We used forty female Wistar rats weighing between 150g-200g randomly divided into 4 groups (negative control, positive control, oxygen and ozone). The groups: positive control, oxygen and ozone were subjected to 60 minutes of ischaemia and 10 days of reperfusion. During reperfusion, the oxygen group was given 26mg/kg body weight of oxygen, and the ozone group 0.5mg/kg body weight of ozone, rectally. At the end of the experiment urine and blood samples were taken for renal function tests and kidneys were removed for histological study. RESULTS: The ozone group showed no significant differences for filtration fraction and proteinuria compared to the negative control group. The glomerular filtrate rate, renal plasma flow and creatinine showed a slight improvement in comparison with oxygen and positive control groups. The ozone group showed significantly less overall histological damage than the positive control and oxygen groups. CONCLUSIONS: Ozone postconditioning showed to have a protective effect in preserving renal function and morphology.

[Aristolochic acid induces renal tubular injury and inhibits expression of bone morphogenetic protein-7 mRNA in renal tissue of rats].

OBJECTIVE: To investigate the pathogenic mechanism of aristolochic acid nephropathy (AAN) by observing the renal tubular injury and the change of the expression of bone morphogenetic protein-7 (BMP-7) mRNA in renal tissue of rats induced by aristolochic acid (AA), an active constituent in Caulis Aristolochiae Manshuriensis (CAM). METHODS: Forty-six male Wistar rats were randomly divided into normal control group (n=20) and AA-treated group (n=26). Rats in AA-treated group were intragastrically administered with AA 20 mg/(kg.d), and rats in control group were treated with equal volume of potable water. At the end of the 4th, 8th and 12th week of administration, the 24 h-urine was collected by metabolic cage for detecting the activity of N-acetyl-beta-D-glucosaminidase (NAG) and the blood samples were obtained from abdominal aorta for detecting serum creatinine (SCr). Pathological change and the degree of injury of the kidneys were observed by microscopy. The expression of proliferative cell nuclear antigen (PCNA) was detected by immunohistochemical method, and mRNA expression of bone morphogenetic protein-7 (BMP-7) in the renal tissue was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the normal control group, the activity of NAG and the ratio of SCr vs body weight were markedly increased in rats of the AA-treated group after treatment (P<0.05 and P<0.01). Pathological section of renal tissue showed that most renal tubules had cloudy swelling, and vacuolar degenerating in tubular epithelial cells, with brush border dropping off, and parts of tubular basement membrane were exposed. The degrees of injuries were aggravated depending on treating time. The tubulointerstitial injury (TI) parameter in rats of AA-treated group was higher than that of the normal control group. The positive expression of PCNA was observed in the damaged tubular cells. The proliferation index of PCNA was significantly increased after 4- and 8-week treatment (P<0.01), but was decreased after 12-week treatment (P<0.05). The mRNA expression of BMP-7 was markedly decreased in the AA-treated group compared with the normal control group after 4-week treatment (P<0.05), and decreased with the extension of treatment time. CONCLUSION: AA can induce injury of the renal tubules, impair the cell regeneration, and inhibit the expression of BMP-7 mRNA in renal tissue. This may be one of the pathogenic mechanisms of AAN.

[Wenyang Huoxue Recipe up-regulates the expression of angiopoietin-1 mRNA in rats with chronic aristolochic acid nephropathy].

OBJECTIVE: To investigate the effects of Wenyang Huoxue Recipe (WRHXR), a compound traditional Chinese herbal medicine for warming yang and promoting blood flow, on the expression of angiopoietin mRNA in rats with chronic aristolochic acid nephropathy induced by Caulis Aristolochia Manshuriensis (CAM) decoction, and to explore the protection mechanism of WYHXR against kidney damage. METHODS: Twenty-eight male SD rats were randomly divided into normal control group, CAM group and WYHXR-treated group. Rats in the normal control group (n=8) and CAM group (n=10) were intragastrically administered with normal saline 10 ml/(kg.d) or CAM decoction 10 ml/(kg.d) respectively. Rats in the WYHXR-treated group (n=10) were intragastrically administered with WYHXR 30 g/(kg.d) and CAM decoction 10 ml/(kg.d). The expressions of Ang-l and Ang-2 mRNAs were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) after 20-week treatment. RESULTS: Compared with the normal control group, the expression of Ang-l mRNA was significantly decreased, and the expression of Ang-2 mRNA was significantly increased in the CAM group (P<0.01). Compared with the CAM group, the expression of Ang-l mRNA was increased in the WYHXR-treated group (P<0.01). The expression of Ang-2 mRNA had no significant difference between the CAM group and the WYHXR-treated group (P>0.05). Renal pathology showed that renal damage in WYHXR-treated group was significantly reduced as compared with the CAM group. CONCLUSION: WYHXR can up-regulate the expression of Ang-l mRNA, which may be its action mechanism in protecting the kidneys.

[Protective effect of melatonin and sodium thiosulphate on histopathology and ultrastructure of the kidney in rats with acute paraquat poisoning]. / Efecto protector de la melatonina y el tiosulfato de sodio sobre la histopatología y la ultraestructura del riñon en ratas con intoxicación aguda por Paraquat.

Paraquat (PQ) toxicity produces severe injures in many major organs systems, including kidney, developing renal failure with fatal evolution in most of the cases. Several antidotes have been used in the treatment of paraquat intoxication without satisfactory results. The antioxidative effect of melatonin (MLT) and sodium thiosulphate (STS) on kidney in rats with acute intoxication by PQ was studied. Forty male Wistar rats were used, divided in 4 groups of 10 rats each. Group I, control, was injected intraperitoneally (ip) with 1 ml of saline solution; group II, received DL50 of PQ, ip; groups III and IV, DL50 of PQ, and simultaneously the first dose of MLT (15 mg/kg, ip) or STS (1,5 g/kg, i.p.) respectively. Thirty minutes later, groups III and IV received a second similar dose of MLT and TSS. After 24 hours, rats were sacrificed with pentobarbital, and kidneys were extracted for morphological study. Light and electronic microscopy observations showed in group II morphological changes of acute tubular necrosis in proximal tubule in group II, similar findings, with lesser magnitude, were observed in the animals treated with the antidotes, suggesting a partial protection. In conclusion, individual use of MLT and STS at the doses and time used partially prevent damage caused by paraquat to the cell. In consequence, more experiments with these drugs are necessary to considere them as specific treatments in cases of poisoning by paraquat.

Ocular lesions and experimental choline deficiency.

Previous studies have shown ocular haemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline-deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one of them were fed a choline-deficient diet and the rest was fed a choline-supplemented diet ad libitum. Animals from both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution light microscopy and the study of the retina as "rétine a plat". Kidneys were studied by light microscopy. Choline-supplemented rats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only choline-deficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras and ciliary and vitreous bodies. Correlations between ocular and renal lesion (r = 0.72, p < 0.0001, CI 95%: 0.48-0.86); ocular lesion and creatinine (r = 0.86, p < 0.0001, Cl 95%: 0.72-0.93) and ocular lesion and urea (r = 0.70, p < 0.0001, Cl 95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved.

Acute tubular necrosis associated with chromium picolinate-containing dietary supplement.

OBJECTIVE: To report a case of acute tubular necrosis associated with the use of a chromium picolinate-containing dietary supplement. CASE SUMMARY: A 24-year-old white male who had been ingesting a dietary supplement (Arsenal X) for 2 weeks during his workout sessions developed acute renal failure. Radiologic investigation showed the presence of a solitary right kidney, and an open renal biopsy confirmed features of acute tubular necrosis. He developed significant renal impairment that required hemodialysis. He was also treated with plasmapheresis and steroids, as a diagnosis of pulmonary-renal syndrome was entertained early in the disease course, which was subsequently ruled out. The patient ultimately recovered and, on outpatient visits, was noted to have normal renal function. DISCUSSION: The use of dietary supplements has become increasingly popular in the US, and these supplements are not subject to stringent premarketing testing or postmarketing surveillance. The main ingredients in the supplement discussed here were chromium picolinate, Sida cordifolia, synephrine, and guarana. An objective causality assessment using the Naranjo probability scale indicated a probable association between the use of this supplement and the development of acute renal failure in this patient. CONCLUSIONS: Current information regarding the beneficial effects of trivalent chromium is not very robust; therefore, use of this agent cannot be recommended at this time. This report serves as an important reminder to the public, as well as healthcare providers, of potential nephrotoxic reactions to dietary supplements.

Ocular lesions and experimental choline deficiency

Previous studies have shown ocular haemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline-deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one ofthem were fed a choline-deficient diet and the rest was fed a choline- supplemented diet ad libitum. Animalsfrom both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution lightmicroscopy and the study of the retina as “rétine a plat”. Kidneys were studied by light microscopy. Cholinesupplementedrats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only cholinedeficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras andciliary and vitreous bodies. Correlations between ocular and renal lesion (r=0.72, p<0.0001, CI 95%: 0.48-0.86); ocular lesion and creatinine (r=0.86, p<0.0001, CI 95%: 0.72-0.93) and ocular lesion and urea (r=0.70, p<0.0001, CI 95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved

Estudios previos han demostradohemorragia ocular en ratas deficientes en colina. El objetivo de este trabajo es profundizar en la relación entre las alteraciones oculares, renales y bioquímicas en ratas deficientes en colina. Cincuenta y una ratas Wistar macho recién destetadas fueron divididas en dos grupos: treinta y una fueron alimentadas con una dieta colino deficiente y el resto con colina suplementada ad-libitum. Los animales de ambos grupos fueron sacrificados entre el quinto y el octavo día. Se midió la concentración de urea, creatinina y homocisteína en sangre. Los ojos fueron estudiados por microscopía de luz, microscopía óptica de alta resolución y para el estudio de la retina como retina plana. Los riñones fueron estudiados por microscopía de luz. Las ratas suplementadas con colina no mostraron lesiones oculares o renales. Las colino deficientes que mostraron lesiones renales, necrosis tubular o cortical, no siempre tuvieron cambios oculares. No se encontraron cambios oculares en la única rata deficiente en colina sin lesión renal. Los cambios oculares consistieron principalmente en hemorragia enambas cámaras, cuerpo ciliar y vítreo. La correlación entre la lesión ocular y renal (r=0.72, p<0.0001, CI 95%:0.48-0.86), lesión ocular y creatinina (r=0.86, p<0.0001, CI 95%: 0.72-0.93) y lesión ocular y urea (r=0.70,p<0.0001, CI 95%: 0.44-0.85) fue positiva. La deficiencia de colina induce lesiones oculares luego del desarrollode la necrosis renal. La patología ocular podría ser debida a la inmadurez de los vasos oculares. El sistemahialoide, coroideo y retinal están involucrados

Ocular lesions and experimental choline deficiency

Previous studies have shown ocular haemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline-deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one ofthem were fed a choline-deficient diet and the rest was fed a choline- supplemented diet ad libitum. Animalsfrom both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution lightmicroscopy and the study of the retina as ¶rétine a plat÷. Kidneys were studied by light microscopy. Cholinesupplementedrats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only cholinedeficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras andciliary and vitreous bodies. Correlations between ocular and renal lesion (r=0.72, p<0.0001, CI 95%: 0.48-0.86); ocular lesion and creatinine (r=0.86, p<0.0001, CI 95%: 0.72-0.93) and ocular lesion and urea (r=0.70, p<0.0001, CI 95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved (AU)

Estudios previos han demostradohemorragia ocular en ratas deficientes en colina. El objetivo de este trabajo es profundizar en la relación entre las alteraciones oculares, renales y bioquímicas en ratas deficientes en colina. Cincuenta y una ratas Wistar macho recién destetadas fueron divididas en dos grupos: treinta y una fueron alimentadas con una dieta colino deficiente y el resto con colina suplementada ad-libitum. Los animales de ambos grupos fueron sacrificados entre el quinto y el octavo día. Se midió la concentración de urea, creatinina y homocisteína en sangre. Los ojos fueron estudiados por microscopía de luz, microscopía óptica de alta resolución y para el estudio de la retina como retina plana. Los riñones fueron estudiados por microscopía de luz. Las ratas suplementadas con colina no mostraron lesiones oculares o renales. Las colino deficientes que mostraron lesiones renales, necrosis tubular o cortical, no siempre tuvieron cambios oculares. No se encontraron cambios oculares en la única rata deficiente en colina sin lesión renal. Los cambios oculares consistieron principalmente en hemorragia enambas cámaras, cuerpo ciliar y vítreo. La correlación entre la lesión ocular y renal (r=0.72, p<0.0001, CI 95%:0.48-0.86), lesión ocular y creatinina (r=0.86, p<0.0001, CI 95%: 0.72-0.93) y lesión ocular y urea (r=0.70,p<0.0001, CI 95%: 0.44-0.85) fue positiva. La deficiencia de colina induce lesiones oculares luego del desarrollode la necrosis renal. La patología ocular podría ser debida a la inmadurez de los vasos oculares. El sistemahialoide, coroideo y retinal están involucrados (AU)

Ocular lesions and experimental choline deficiency

Previous studies have shown ocular haemorrhages in choline-deficient rats. The aim of this paper is to study further the relationship between ocular and renal lesions and biochemical alterations in rats fed a choline-deficient diet. Fifty one weanling male Wistar rats, were divided into two groups. Thirty one ofthem were fed a choline-deficient diet and the rest was fed a choline- supplemented diet ad libitum. Animalsfrom both groups were killed between the fifth and the eighth day. Urea, creatinine and homocysteine concentrations in blood were determined. Eyes were used for light microscopy study; high resolution lightmicroscopy and the study of the retina as ¶rétine a plat÷. Kidneys were studied by light microscopy. Cholinesupplementedrats did not show ocular or renal lesion. Choline-deficient rats that showed renal lesions, tubular or cortical necrosis, did not always have ocular changes. There were no ocular changes in the only cholinedeficient rat without renal lesion. The ocular changes consisted mainly in haemorrhage in both cameras andciliary and vitreous bodies. Correlations between ocular and renal lesion (r=0.72, p<0.0001, CI 95%: 0.48-0.86); ocular lesion and creatinine (r=0.86, p<0.0001, CI 95%: 0.72-0.93) and ocular lesion and urea (r=0.70, p<0.0001, CI 95%: 0.44-0.85) were positive. Choline-deficiency induces ocular haemorrhagic lesions after the development of renal necrosis. The ocular pathology could be due to the immaturity of the ocular vasculature at this age. The hyaloid, choroid and retinal system are involved (AU)

Estudios previos han demostradohemorragia ocular en ratas deficientes en colina. El objetivo de este trabajo es profundizar en la relación entre las alteraciones oculares, renales y bioquímicas en ratas deficientes en colina. Cincuenta y una ratas Wistar macho recién destetadas fueron divididas en dos grupos: treinta y una fueron alimentadas con una dieta colino deficiente y el resto con colina suplementada ad-libitum. Los animales de ambos grupos fueron sacrificados entre el quinto y el octavo día. Se midió la concentración de urea, creatinina y homocisteína en sangre. Los ojos fueron estudiados por microscopía de luz, microscopía óptica de alta resolución y para el estudio de la retina como retina plana. Los riñones fueron estudiados por microscopía de luz. Las ratas suplementadas con colina no mostraron lesiones oculares o renales. Las colino deficientes que mostraron lesiones renales, necrosis tubular o cortical, no siempre tuvieron cambios oculares. No se encontraron cambios oculares en la única rata deficiente en colina sin lesión renal. Los cambios oculares consistieron principalmente en hemorragia enambas cámaras, cuerpo ciliar y vítreo. La correlación entre la lesión ocular y renal (r=0.72, p<0.0001, CI 95%:0.48-0.86), lesión ocular y creatinina (r=0.86, p<0.0001, CI 95%: 0.72-0.93) y lesión ocular y urea (r=0.70,p<0.0001, CI 95%: 0.44-0.85) fue positiva. La deficiencia de colina induce lesiones oculares luego del desarrollode la necrosis renal. La patología ocular podría ser debida a la inmadurez de los vasos oculares. El sistemahialoide, coroideo y retinal están involucrados (AU)

[Peritubular capillary injury in Chinese herb guan-mu-tong-induced acute tubular necrosis].

OBJECTIVE: To explore the role and mechanisms of peritubular capillary (PTC) injury in the progression of Chinese Herb guan-mu-tong (GMT, aristolochiae manshuriensis kom) induced acute tubular necrosis (GMT-ATN). METHODS: Renal biopsy tissue from 4 cases of GMT-ATN and 5 cases of antibiotic induced ATN (A-ATN) were included in the study. Tubulointerstitial injury was semi-quantitatively assessed. Immunohistochemical SP method was applied to reveal PTC as well as the expression of vascular endothelial growth factor (VEGF). Ultra microstructure of endothelial cells and basement membrane of PTC was detected by electronic microscopy (EM). 5 cases of minor mesangioproliferative non-IgA glomerulonephritis were selected as a control group. RESULTS: The density of PTC was decreased significantly in GMT-ATN, as compared with the A-ATN and control group (211.08 +/- 56.15 vs 413.54 +/- 66.59, 536.62 +/- 68.38, P < 0.01). Dilated and deformed PTC lumina were noted in GMT-ATN with some endothelial cells and basement membrane partially disrupted. Most endothelial cells were found to be swollen with vacuoles dispersed in the cell plasma. The basement membrane was partially shrunk and thickened. The expression of VEGF in renal tubular epithelial cells (RTEC) was much less in the GMT-ATN than that in A-ATN group 2.1 (0-3.86)% vs [42.5 (31.33-60.25)%, P < 0.01], even though it was higher than that in the control group [23.1 (18.2-39.5)%, P < 0.01]; the expression was correlated with PTC density. Close correlation was also found between RTEC regeneration and PTC density, as well as VEGF expression (r = 0.880 and 0.802 respectively, P < 0.01). CONCLUSIONS: PTC was markedly injured in GMT-ATN; this could be one of the cause for the continuously progressing tubulointerstitial damage. The low expression of VEGF in RTEC might contribute to the PTC injury process.

Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model.

Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-beta has been consistently implicated. Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-beta-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 (x)/(/) 1.2 versus 20.5 (x)/(/) 1.3 mg/d; P < 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P < 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-beta activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-beta signaling in vivo. In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.

Molecular mechanisms of renal tissue repair in survival from acute renal tubule necrosis: role of ERK1/2 pathway.

Our earlier studies with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) showed that prior administration of a low priming dose of 15 mg/kg, i.p. to mice, given 72 hours before administration of a normally lethal dose of DCVC (75 mg/kg, i.p.) led to renal tubule necrosis, however sustained renal tubule regeneration was observed and these mice recovered from renal failure and survived. The objective of the present study was to investigate the role of extracellular signal-regulated kinase (ERK) pathway in this autoprotection model. Following the priming dose of DCVC, IL-6 protein and mRNA increased markedly as early as 1 hour after dosing, peaking at 3 hours with a 1.5-fold increase in plasma. Immunocytochemistry on kidney sections using specific antibodies against TGF-alpha, HB-EGF, EGFr, IGF-1Rbeta, Grb-2, and phospho-p44/42 MAP kinase (ERK1/2) revealed a significantly higher staining of these molecules 3 to 72 hours after dosing, indicating up regulation of the ERK pathway. Following a lethal dose of DCVC (75 mg/kg) the early increase in these signaling molecules was not sustained, being markedly reduced 24 and 36 hours after dosing, leading to inhibition of S-phase DNA synthesis, cell division and renal tubule repair. In contrast, prior treatment with a low dose of DCVC, followed by a high dose led to a sustained stimulation of the renal ERK pathway, renal tubule regeneration and recovery from acute renal failure. These results suggest that a sustained activation of the ERK1/2 pathway may be a key factor in enabling a continued renal tubule repair and hence protection from the progressive phase of DCVC-induced acute renal tubular necrosis in the mouse.