Serum hepatocyte growth factor levels in patients with chronic renal disease--effect of GFR and pathogenesis.

Hepatocyte growth factor (HGF) is a growth-promoting peptide that appears to act in a renotropic and nephroprotective manner during acute renal damage. Recent studies suggest that HGF is also of importance in chronic renal diseases. The serum HGF level is correlated with serum creatinine, and it has been suggested that glomerular and tubular diseases affect serum HGF differently. In the present study. levels of serum HGF were determined and correlated to glomerular filtration rate (GFR) in 118 patients with various chronic renal diseases. GFR was determined by 99mTc-DTPA clearance, and the GFR values were evenly distributed in the interval 5-155 mL/min/1.73 m2. Serum HGF levels increased slightly with decreasing GFR: the Pearson correlation coefficient being 0.49 (p<0.0001). In 21 additional patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis, there was a more marked increase in the serum levels of HGF. The effect of glomerular and tubular diseases on serum HGF was examined by comparing the HGF levels in two groups of patients with similar GFR values: 57 patients with mainly glomerular disorders (diabetic nephropathy with micro- or macroalbuminuria or glomerulonephritis) and 14 patients with mainly tubular disorders (polycystic kidney disease). There was no significant difference between the HGF levels of the two groups (p=0.30). In conclusion: Serum HGF levels are correlated with GFR (for GFR > or = 5 mL/min/1.73 m2) in patients with chronic renal diseases, and glomerular and tubular disorders seem to affect the HGF level similarly.     

Serum hepatocyte growth factor levels in patients with chronic renal disease - effect of GFR and pathogenesis

Hepatocyte growth factor (HGF) is a growth-promoting peptide that appears to act in a renotropic and nephroprotective manner during acute renal damage. Recent studies suggest that HGF is also of importance in chronic renal diseases. The serum HGF level is correlated with serum creatinine, and it has been suggested that glomerular and tubular diseases affect serum HGF differently. In the present study, levels of serum HGF were determined and correlated to glomerular filtration rate (GFR) in 118 patients with various chronic renal diseases. GFR was determined by 99m Tc-DTPA clearance, and the GFR values were evenly distributed in the interval 5-155 mL/min/1.73 m 2 . Serum HGF levels increased slightly with decreasing GFR; the Pearson correlation coefficient being 0.49 (p < 0.0001). In 21 additional patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis, there was a more marked increase in the serum levels of HGF. The effect of glomerular and tubular diseases on serum HGF was examined by comparing the HGF levels in two groups of patients with similar GFR values: 57 patients with mainly glomerular disorders (diabetic nephropathy with micro- or macroalbuminuria or glomerulonephritis) and 14 patients with mainly tubular disorders (polycystic kidney disease). There was no significant difference between the HGF levels of the two groups (p = 0.30). In conclusion: Serum HGF levels are correlated with GFR (for GFR &#85 5 mL/min/1.73 m 2 ) in patients with chronic renal diseases, and glomerular and tubular disorders seem to affect the HGF level similarly.     

Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity

Adult male Sprague-Dawley rats maintained on a low sodium diet were administered 100 mg of cyclosporine per kg b.wt. per day s.c. for 4 to 10 days. Serum urea nitrogen was significantly elevated by day 4 and continued to rise, whereas serum creatinine was not elevated above control until day 10. Morphologic examination of perfusion-fixed kidneys from cyclosporine-treated rats revealed focal areas of tubular atrophy and interstitial fibrosis in the outer cortex and a generalized increase in interstitial cells in the outer medulla. No areas of acute tubular necrosis were identified. The effect of this dose of cyclosporine on renal hemodynamics was examined in conscious restrained rats. Renal blood flow, measured by microsphere injection, was 70% of control after four daily doses and remained near this level after eight daily doses. The glomerular filtration rate, measured by iodothalamate clearance, was 70% of control after four doses but fell to 34% of control after eight doses. [3H]Thymidine incorporation into renal DNA was used as a sensitive index of renal cell proliferation after cyclosporine administration (100 mg/kg/day). [3H]Thymidine incorporation was increased over control 3-fold in the outer cortex, 7-fold in the inner cortex and 11-fold in the medullary-papillary regions of the kidney after eight daily doses of cyclosporine. Histoautoradiographic examination of renal sections revealed an increase in the number of labeled nuclei in all three regions of the kidney from rats treated with cyclosporine. Morphometric analysis demonstrated that the majority of proliferating cells were located in the interstitium and not in renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure.

To determine the timing and location of renal cell regeneration after ischemic injury to the kidney and to assess whether exogenous epidermal growth factor (EGF) enhances this regenerative repair process to accelerate recovery of renal function, experiments were undertaken in rats undergoing 30 min of bilateral renal artery clamp ischemia followed by reperfusion for varying time intervals. Renal cell regeneration, as reflected by incorporation of radiolabeled thymidine within the kidney, began between 24 to 48 h and reached a peak at 72 h after renal ischemia. As demonstrated by histoautoradiography, renal thymidine incorporation was essentially confined to tubule cells. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that the majority of labeled cells were found in renal cortex, but some labeled cells were also located in the inner stripe of the outer medulla, suggesting that injury to medullary thick ascending limbs also occurs in this ischemic model. Exogenous EGF administration produced increases in renal thymidine incorporation compared with non-treated animals at 24, 48, and 72 h after ischemic injury. This accelerated DNA replicative process was associated with significantly lower peak blood urea nitrogen (BUN) and serum creatinine levels, averaging 63 +/- 20 and 3.1 +/- 0.4 mg/dl in EGF-treated ischemic rats compared with 149 +/- 20 and 5.1 +/- 0.1 mg/dl, respectively, in nontreated ischemic rats, and was also associated with a return to near normal BUN and serum creatinine levels in EGF-treated animals approximately 4 d earlier than that observed in nontreated animals. This report is the first demonstration that EGF accelerates the repair process of a visceral organ after an injurious insult.     

Aminoaciduria as a marker of acute renal transplant rejection--a patient study

Over 12 months, urine samples were systematically collected from 40 children who underwent renal transplantation for the treatment of end-stage renal disease. Sequential determinations of the excretion of individual amino acids relative to that of creatinine were carried out on 15 subjects. Nine of these (including three who sustained episodes of acute rejection) retained a native kidney in-situ, while in six patients (including three who underwent an episode of acute rejection) both native kidneys had been removed. In both subgroups, the amino acid/creatinine ratios of early morning urine samples were higher shortly before clinical manifestations of acute rejection became evident than in patients who, following renal transplantation, had stable kidney function, chronic graft rejection, or acute tubular necrosis, with one exception: a patient with one native kidney in-situ in whom acute tubular necrosis developed immediately after transplantation. The amino acids showing the greatest increase included Thr, Ser, Gly, and Ala. These values fell dramatically immediately prior to the clinical episode of acute rejection, with Thr, Ala, and Phe showing the most consistent changes. These alterations in urinary amino acid excretion occurred several days before changes in urinary protein excretion or the serum concentrations of urea and creatinine, and may have a role to play in the monitoring of renal transplant recipients.     

Behaviour of serum and urinary lysozyme after renal transplantation (author's transl)]

The behaviour of serum and urinary lysozyme was investigated before and after renal transplantation in 20 patients. The mean postoperative observation time was 67.8 (10 to 212) days. In 11 patients with reversible olig-anuria due to prolonged preoperative ischaemia, lysozymuria lasted for a period of 17 days after surgery, whereas in 8 patients with immediate transplant function lysozymuria disappeared 7 days after transplantation. Serum lysozyme concentrations were markedly elevated before transplantation in all patients. In patients with transplant failure due to ischaemia, normalization of serum lysozyme levels was achieved 28 days after surgery; patients with immediate function showed normal serum lysozyme levels already 7 days after transplantation. Prolonged lysozymuria was also noticed in 2 cases with irreversible ischaemic transplant failure, in 1 case with recurrence of glomerulonephritis and in 1 further case with acute pyelonephritis in the transplant. In 7 cases with an acute renal rejection crisis, lysozymuria was evident 0.7 days before clinical diagnosis of rejection. Serum lysozyme levels showed a strong correlation with serum correlation with serum creatinine concentrations. Therefore, lysozymuria in renal transplant patients indicates tubular transplant damage of varied aetiology. Elevated serum lysozyme levels, on the other hand, seem to reflect a reduced glomerular filtration rate.     

Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury

Context. A broad range of drugs and chemicals are capable of evoking acute kidney injury, which is conventionally determined by rising serum creatinine concentrations. However there are important limitations to this approach, and there has been interest in alternative biomarkers that might provide a more sensitive and rapid means of detecting acute kidney injury. Most of the available clinical data have thus far been ascertained in patients requiring critical care or with acute sepsis. However, if a sensitive indicator of acute kidney injury were developed, then this could provide a significantly improved means of detecting the effects of acute drug or toxin exposure. Objective. To review the available data concerning potential biomarkers of acute kidney injury and to assess their relative strengths and weaknesses in comparison to existing methods based on serum creatinine concentrations. A large number of possible biomarkers have been proposed. Evidence for individual biomarkers is reviewed with a particular emphasis on those with potential application in clinical toxicology. Where available, comparative data are presented. Methods. There were 236 papers identified using Medline, Embase, and Google Scholar databases, of which 52 were considered directly relevant. Creatinine. Creatinine is subject to glomerular filtration and, to a lesser extent tubular secretion. Serum concentrations are an insensitive marker of acute kidney injury, and the speed of an increase from baseline depends on the magnitude of the acute injury and pre-existing kidney functional reserve. A wide range of inter-individual concentrations means that single time-point determinations are difficult to interpret, and acute kidney injury may not manifest as a detectable increase in serum creatinine concentrations until at least 24–48 h after the primary insult. Kidney enzymes. Enzymes are often localised to specific anatomical locations, and acute injury may cause a detectable increase in urinary activity due to up-regulated activity or leakage due to cell membrane disruption. Key examples include gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase (GST), and N-acetyl-glucosaminidase (NAG), which are found predominantly in the proximal tubule and urinary enzyme activity increases after acute exposure to heavy metals and other nephrotoxins .Neutrophil gelatinase-associated lipocalin. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed by renal tubular epithelium, and a rise in urinary concentrations may provide an indicator of acute renal injury caused by any one of a broad range of provoking factors that is detectable before a rise in serum creatinine concentrations. Cystatin C. Serum and urinary cystatin C concentrations are closely related to kidney function and, for example, in acute tubular necrosis allow better prediction of the need for renal replacement therapy than serum creatinine concentrations. Kidney injury molecule 1. Kidney injury molecule 1 (KIM-1) is expressed in the proximal tubule in the setting of acute ischaemia. For example, urinary KIM-1 concentrations becomes detectable within 24 h of acute tubular necrosis. Urinary KIM-1 expression may be detected after exposure to a variety of nephrotoxic agents, even when serum creatinine concentrations do not increase, and this has been accepted by regulatory authorities as a sensitive biomarker of acute kidney injury during early drug development. Conclusions. Novel biomarkers appear capable of offering a more sensitive means of detecting acute kidney injury than existing approaches. Certain of these allow discrimination between the various mechanisms and anatomical site of acute injury. Ultimately, clinical assessment might incorporate a panel of different biomarkers, each informing on the integrated aspects of glomerular, tubular and interstitial function. Presence of biomarkers may in some cases detect mild or transient renal dysfunction that is presently undetected, and the clinical relevance needs further exploration. Whilst many potentially useful biomarkers have been proposed, comparatively few clinical data exist to support their validity in routine practice. Further prospective clinical studies are required to examine the validity of biomarkers after acute drug or toxin exposure, and to establish whether they might offer improved clinical outcomes in the setting of clinical toxicology.     

Regulation of dedifferentiation and redifferentiation in renal proximal tubular cells by the epidermal growth factor receptor

Repair of injured renal epithelium is thought to be mediated by surviving renal proximal tubular cells (RPTC) that must dedifferentiate to allow the proliferation and migration necessary for epithelial regeneration. RPTC then redifferentiate to restore tubular structure and function. Current models suggest that epidermal growth factor receptor (EGFR) activation is required for dedifferentiation characterized by enhanced vimentin expression, decreased N-cadherin expression, spindle morphology, and loss of apical-basal polarity after injury. Because an in vitro model of RPTC redifferentiation has not been reported, and the mechanism(s) of redifferentiation has not been determined, we used rabbit RPTC in primary cultures to address these issues. H2O2 induced the dedifferentiated phenotype that persisted >48 h; redifferentiation occurred spontaneously in the absence of exogenous growth factors after 72 to 120 h. Phosphorylation of two tyrosine residues of EGFR increased 12 to 24 h, peaked at 24 h, and declined to basal levels by 48 h after injury. EGFR inhibition during dedifferentiation restored epithelial morphology and apical-basal polarity, and it decreased vimentin expression to control levels 24 h later. In contrast, exogenous epidermal growth factor addition increased vimentin expression and potentiated spindle morphology. p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta receptor inhibitors did not affect redifferentiation after H2O2 injury. Similar results were observed in a mechanical injury model. These experiments represent a new model for the investigation of RPTC redifferentiation after acute injury and identify a key regulator of redifferentiation: EGFR, independent of p38 MAPK and the TGF-beta receptor.     

The effect of furosemide infusion on serum epidermal growth factor concentration after acute lung injury.

Acute lung injury and its more severe form, acute respiratory distress syndrome, are clinical syndromes of progressive hypoxemia and ventilation-perfusion mismatch with decreasing pulmonary compliance in the absence of congestive heart failure. Epidermal growth factor is involved in the pathogenesis of airway inflammation as well as a proinflammatory effect in other tissues. Furosemide has been shown to improve pulmonary gas exchange and intrapulmonary shunt by a nondiuretic mechanism in animal models of acute respiratory distress syndrome. The current study was undertaken to clarify whether furosemide attenuates the inflammatory response by changing the epidermal growth factor level in patients with acute lung injury. A prospective, randomized clinical trial involving 30 patients with acute lung injury was designed and conducted over 7 days. The measured outcomes included hemodynamics, acute physiology and chronic health evaluation (APACHE II) scores, and oxygenation. The serum specimens were analyzed with enzyme-linked immunoassay (ELISA) for epidermal growth factor at baseline, then 3 and 7 days after acute lung injury. The ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FIO2) improved in the furosemide-treated group within 24 hours (from 180 to 264; P = .01). The mean arterial pressure and heart rate was greater in this group than in the control group (that received no furosemide) on day 7 (P = .027). The mean arterial pressure increased and the heart rate decreased over time in the treatment group, but not significantly. Serum epidermal growth factor levels also were not significantly different between the furosemide treatment group and the control group (P > .05). Continuous furosemide infusion improves oxygenation and hemodynamics in patients with acute lung injury, but not through a change in the serum epidermal growth factor level. Further study is needed to determine the exact mechanism of furosemide action in patients with acute lung injury and acute respiratory distress syndrome.     

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

We have recently reported that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA is induced in the rat kidney after acute ischemic injury. The present studies were designed to investigate whether bioactive HB-EGF protein is also produced in response to renal injury induced by either ischemia/reperfusion or aminoglycosides. Heparin-binding proteins were purified from kidney homogenates by heparin affinity column chromatography using elution with a 0.2-2.0 M gradient of NaCl. A single peak of proteins that eluted at 1.0-1.2 M NaCl was detected in the postischemic kidney within 6 h of injury. This eluate fraction stimulated DNA synthesis in quiescent Balb/c3T3, RIE, and NRK-52E cell lines, all of which are responsive to the epidermal growth factor family of mitogenic proteins. The EGF receptor of A431 cells was also tyrosine phosphorylated by this eluate peak. Furthermore, immunoblotting with a polyclonal antibody against rat HB-EGF indicated that the eluate peak contained immunoreactive proteins of 22 and 29 kD mol wt, consistent with the reported sizes of the secreted form and membrane anchored form of HB-EGF, respectively. Immunohistochemical studies revealed that HB-EGF was produced predominantly in distal tubules in kidneys injured either by ischemia/reperfusion or aminoglycoside administration. We also found that during metanephric development immunoreactive HB-EGF was detected in the ureteric bud as early as E14.5 and persisted in structures arising from the ureteric bud throughout embryogenesis. These results suggest that in response to acute injury, HB-EGF is produced predominantly in distal tubules and that endogenous HB-EGF may be an important growth factor involved in renal epithelial cell repair, proliferation, and regeneration in the early stages of recovery after acute renal injury, as well as in nephrogenesis.     

Physiological concentrations of human epidermal growth factor in biological fluids: use of a sensitive enzyme immunoassay

A sandwich enzyme immunoassay for epidermal growth factor (EGF) has been developed which measures EGF concentrations in serum, urine, saliva, gastric and pancreatic juices without pretreatment. Sensitivity for human EGF is 500 fg/tube. Serum EGF concentration in normal males and females is 780 and 604 pg/ml, respectively. Urinary human EGF is 51.3 ng/mg creatinine for males, and 68.3 ng/mg creatinine for females. The difference is not significant, and no correlation between serum and urinary concentrations exists, but serum concentration changes with age. The highest concentration is seen up to 9 years of age, suggesting that EGF promotes cell proliferation during growth.     

Raised concentrations of the carboxy terminal propeptide of type IV (basement membrane) procollagen (NC1) in serum and urine of patients with glomerulonephritis

Type IV collagen is a major component of the glomerular and tubular basement membrane. We used a specific radioimmunoassay to determine (mean +/- SD) the concentration of carboxy terminal non-collagenous fragment (NC1) of type IV procollagen in the serum (normal 6.0 +/- 1.2 ng ml-1) and urine (normal 1.5 +/- 2.0 ng ml-1) of 142 patients with various kidney diseases. The 15 patients with active glomerulonephritis displayed (ANOVA, Scheffé test) significantly elevated NCl values in their serum (14 +/- 8.2 ng ml-1) as compared with the 32 patients with chronic interstitial nephritis (7.8 +/- 3.0 ng ml-1), the 17 patients with various other chronic kidney diseases (8.1 +/- 2.4 ng ml-1) and the 23 ambulatory kidney transplant patients (9.1 +/- 1.7 ng ml-1). The highest serum NCl concentrations were found in nine patients with membranoproliferative glomerulonephritis (16 +/- 9.4 ng ml-1). Sequential serum NCl concentrations in the one patient with active Goodpasture's syndrome were marginally elevated (less than 11 ng ml-1). Serum NCl did not increase with acute interstitial rejection episodes in six kidney transplant patients. The highest urinary NCl concentrations were found in seven patients with minimal change glomerulonephritis (7.5 +/- 3.2 ng ml-1). No correlation was found between serum NCl and serum creatinine, NCl and creatinine clearance, or renal NCl clearance and creatinine clearance. There was a significant correlation between serum NCl and proteinuria. Serum and urinary NCl concentrations were elevated independently from renal function, thus indicating intrinsic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Variation of serum and urinary neutrophil gelatinase associated lipocalin (NGAL) after strenuous physical exercise

Abstract Background: Strenuous exercise may trigger acute complications, such as exertional rhabdomyolysis and gastrointestinal complaint. As less is known about the potential renal impairment after long distance running, we assessed creatinine and neutrophil gelatinase associated lipocalin (NGAL) in serum (sNGAL) and urine (uNGAL) before and after an ultramarathon. Methods: The study population consisted of 16 trained male athletes who ran a 60 km ultramarathon. Blood and spot urine samples were collected 20 min before and immediately after the run. Creatinine was assessed by Jaffe assay on Beckman Coulter AU5800 and renal function was expressed as estimated glomerular filtration rate (eGFR) by MDRD formula. NGAL was measured by fully-automated immunoassay NGAL Test? on AU 5800. Results: Serum and urinary creatinine increased significantly by 38% and 78%, respectively. The eGFR contextually decreased by 31%. sNGAL, uNGAL and uNGAL/creatinine ratio increased by 1.6-fold, 7.7-fold and 2.9-fold. In six of 16 athletes (38%), the acute post-exercise increase of serum creatinine met the criteria of acute kidney injury. No significant relationship was found between pre-exercise, post-exercise values and post-exercise variation of sNGAL, uNGAL and uNGAL/creatinine ratio. A significant correlation was found between pre- and post-exercise changes of serum creatinine and sNGAL, but not with either uNGAL or uNGAL/creatinine ratio. Conclusions: The acute variations of serum creatinine and uNGAL attest that renal impairment is likely to develop after long distance running. The uNGAL seems more independent from creatinine variation and extra-renal sources, and thereby more reliable for monitoring the renal involvement in these types of kidney impairment.     

骨髓间充质干细胞修复损伤肾小管上皮细胞：可能与可行？

背景：研究表明骨髓间充质干细胞在急性肾损伤后能够通过直接分化为肾小管上皮细胞而促进肾功能的恢复,其修复肾脏的作用机制尚不清楚,能否直接分化为肾小管上皮细胞,目前仍有争议。目的：观察骨髓间充质干细胞输注后急性肾衰竭小鼠肾功能改变,外源性骨髓间充质干细胞在肾组织的分布以及是否向肾小管上皮细胞分化。方法：骨髓间充质干细胞来源于绿色荧光蛋白转基因小鼠。8～10周龄的健康雌性昆白小鼠90只随机随机分为3组。急性肾衰竭组和骨髓间充质干细胞组注射顺铂建立急性肾衰竭模型,骨髓间充质干细胞组在建模后24h经尾静脉输注绿色荧光蛋白转基因小鼠的骨髓间充质干细胞悬液。正常对照组不进行任何干预。建模后第1,4,7,14,28天测定血尿素氮和血肌酐,观察肾组织病理变化,荧光显微镜下观察绿色荧光蛋白阳性的骨髓间充质干细胞在肾组织的分布,共聚焦显微镜下观察骨髓间充质干细胞向肾小管上皮细胞的分化情况。结果与结论：骨髓间充质干细胞组顺铂注射4～14d后,尿素氮、肌酐值比急性肾衰竭组明显降低（P〈0.01或P〈0.05）。骨髓间充质干细胞组第4天肾组织中可见绿色荧光的绿色荧光蛋白细胞,分布在外髓质区肾小管,第7天仍可见少量荧光细胞,同时表达肾小管上皮特异性的功能蛋白megalin。结果提示骨髓间充质干细胞在损伤肾脏可直接分化为肾小管上皮细胞,并改善急性肾衰竭小鼠的肾功能。     

Bone marrow-derived cells mobilized by granulocyte-colony stimulating factor facilitate vascular regeneration in mouse kidney after ischemia/reperfusion injury

Bone marrow-derived cells (BMDC) play crucial roles in tissue regeneration. Granulocyte-colony stimulating factor (G-CSF) mobilizes BMDC and may facilitate the repair of kidney tissues after ischemia/reperfusion (I/R) injury. The tissue protective action of resveratrol, an antioxidant, might modify the regenerating potential of BMDC in I/R renal injury. This study examined whether G-CSF and/or resveratrol affect the recruitment of BMDC into vascular endothelial cells and renal tubular cells and the kidney function after I/R injury. I/R renal injury was induced in female mice that had been lethally irradiated and transplanted with male bone marrow cells. The mice were given saline, resveratrol or G-CSF, daily for 7 days. Non-irradiated and non-bone-marrow-transplanted female mice, which underwent the same kidney injury, were included as control. White blood cell (WBC) count and serum creatinine were monitored. Immunohistologic evaluation for renal tubular cells (cytokeratin) and endothelial cells (factor VIII-related antigen), and fluorescence in situ hybridization for mouse Y chromosome were performed. Although WBC was significantly higher in the G-CSF group, there was no significant difference in creatinine levels among all groups. Factor VIII-related antigen-positive cells with a Y-chromosome signal were identified in the capillary wall between renal tubuli and most frequently seen in the G-CSF group (p < 0.0001). Resveratrol did not affect kidney recovery in this model. No cytokeratin-positive renal tubular cells having a Y-chromosome signal were identified. In conclusion, BMDC are recruited into endothelial cell in I/R renal injury without apparent renal tubular cell regeneration, and G-CSF facilitates the endothelial cell regeneration.     

Acute Renal Failure after Folate: NaKATPase in Isolated Rat Renal Tubule

Abstract. Using refinements of quantitative histochemistry, i.e. oil-well technique, enzymatic Pi analysis and NADP/ NADPH cycling, the activity of NaKATPase (E.C. 3.6.1.3), an enzyme involved in transmembrane ion transport, was measured in single dissected segments of the proximal and distal tubule of male rats 10 min., 30 min., 60 h and 14 days after folate administration (250 mg/kg body weight). 10 min. after injection the onset of acute renal failure was already apparent by an increase in blood urea of 45 per cent and cessation of urine flow. 60 h after folate the rats became polyuric. The kidney wet weight rose by 40 per cent in a few minutes after the injection due to universal tubular dilatation. During the first hours numerous folate casts were localized, mainly in the thick ascending iimb of Henle's loops. In addition precipitates were found intracellularly in the distal part of the proximal convoluted tubules. The straight portion of the proximal tubules was free of precipitates. 10 min. after the injection tubular segments containing folate material did not show Na K ATPase activity, whereas the folate free tubular segments revealed a residual activity of 30 per cent. Only 15 per cent of the tubules within one lyophilized section had collapsed proximal portions with control activity values. However, the less collapsed segments of the distal tubules revealed a loss of Na K ATPase activity of 55 per cent. Thus folate seems to affect the distal tubule first of all. 60 h after folate administration, when kidney growth reached its maximum, the whole nephron lost its Na K ATPase activity. No tubular cell degeneration or necrosis could be detected during the development stage or the sustained phase of renal failure. After addition of folate to renal homogenate, Na K ATPase exhibited activation (+ 35 per cent) and inhibition (–42 per cent and more) of activity plotted against folate concentration. A careful evaluation of the available evidence led to the conclusion that the acute renal failure induced by folate differs markedly from other models by a directly altered tubular cell metabolism in the development stage of oliguria. Acute tubular obstruction may initiate oliguria. However it seems unlikely that tubular obstruction will be the unique pathogenic factor for this syndrome, especially for the development of the tremendous kidney growth. The inhibition of tubular Na K ATPase activity after folate may indicate an impaired tubular active reabsorption capacity which would be involved in the acute renal failure. The most important finding is that glomerular filtration does not seem to be a primary factor in the development of oliguria after folate administration.     

Hepatocyte growth factor modulates the hepatic acute-phase response in thermally injured rats

OBJECTIVE: Hepatocyte growth factor (HGF) has been shown to modulate the acute-phase response in vitro. The specific in vivo role of HGF in this multifactorial response, however, remains unknown. This study examines the effects of exogenous HGF on the acute-phase response in thermally injured rats. DESIGN: Prospective, randomized, laboratory study. SETTINGS: Shriners Hospital for Children and University of Texas Medical Branch laboratories. SUBJECTS: Fifty-six male Sprague-Dawley rats (weight range, 300-325 g). INTERVENTION: Animals received a 60% total body surface area third-degree scald burn and were randomly divided to receive either 400 microg/kg/day i.v. HGF or saline (control). MEASUREMENTS AND MAIN RESULTS: Serum acute-phase proteins, cytokines, and insulin-like growth factor (IGF)-I concentrations, as well as liver weight, protein and triglyceride content, IGF-I concentrations, and cytokine gene expression were measured 1, 2, 5, or 7 days after burn. Serum albumin was increased on days 2, 5, and 7 after burn, and transferrin was increased on day 7 after burn in HGF-treated rats compared with controls (p<.05). HGF increased alpha2-macroglobulin concentrations on postburn days 2, 5, and 7 compared with controls (p<.05). Serum interleukin-6 and tumor necrosis factor-alpha were significantly higher within 2 days of burn in rats treated with HGF (p<.05). HGF increased the hepatic gene expression of tumor necrosis factor-alpha compared with controls (p<.05). Serum IGF-I decreased in rats receiving HGF 1, 2, and 5 days after burn, whereas liver IGF-I concentrations were higher on days 1 and 7 after burn compared with controls (p<.05). Hepatic protein concentrations were higher in the HGF group compared with controls on postburn days 1, 2, and 7, with a concomitant increase in total liver weight (p<.05). HGF exerted a strong mitogenic effect on hepatocytes 1 and 2 days after thermal injury compared with controls (p<.05). CONCLUSIONS: These findings suggest that HGF modulates the acute-phase response in vivo after burn and causes changes in liver morphology.     

Tissue lipid peroxidation and antioxidant status in patients with adenocarcinoma of the breast

BACKGROUND: The results obtained for serum cystatin C, which has been proposed as a novel marker of glomerular filtration rate (GFR), in kidney and liver transplant are still very limited. In our study, the relationship between serum cystatin C and creatinine in kidney and liver transplant patients was investigated. METHODS: Serum cystatin C and creatinine concentrations were determined in 182 samples from 52 kidney transplant patients and 71 samples from 28 liver transplant patients at 1-9870 days post-transplantation time. Eighty-seven serum samples from 66 patients with different types of chronic kidney disease were also analysed. RESULTS: The serum creatinine (r=-0.517, p<0.001) and cystatin C (r=-0.409, p<0.001) concentrations were negatively correlated with the post-transplantation time in the kidney transplant patients. In the liver transplant patients, the correlation between these variables is not statistically significant. The creatinine/cystatin C ratio in the liver transplant group is significantly lower than in the other group of patients (p<0.001). This ratio in the kidney transplant patients groups is significantly lower than in the kidney disease group (p<0.001). In the kidney transplant patients the creatinine/cystatin C ratio and the post-transplantation time were negatively correlated (r=-0.523, p<0.001); however, in the liver transplant patients the correlation between these variables was not significant. CONCLUSIONS: In the groups of kidney disease and kidney transplant patients, as renal function decreases, there is an increase in the creatinine/cystatin C ratio. This may be due to the fact that, since creatinine is eliminated by glomerular filtration and tubular secretion, as renal function is impaired, its serum concentration increases to a greater extent than that of cystatin C, which is only eliminated by glomerular filtration. In the liver transplant patients, the creatinine/cystatin C ratio is lower than in the other groups. This may be due to better preserved renal function, lower muscular mass and a reduced rate of creatine formation and creatinine production in some of these patients. The serum cystatin C would be a better GFR marker than the widely used creatinine in liver transplant patients.     

Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease.

Chronic renal disease (CRD) is generally thought to be incurable, except through renal transplantation, and the number of patients with CRD is on the increase. Glomerulosclerosis and tubulointerstitial fibrosis represent the morphological equivalent of end-stage CRD. In this study, we demonstrated the preventive effect of hepatocyte growth factor (HGF) on the progression of renal dysfunction and fibrosis, using a spontaneous mouse model for CRD (ICGN strain). The mice progressively developed glomerular sclerotic injury, tubular atrophy, and renal dysfunction until they were 17 wk of age. When recombinant HGF was injected into these mice during a 4-wk-period (from weeks 14-17 after birth), DNA synthesis of tubular epithelial cells was found to be 4.4-fold higher than in mice without HGF injection, thereby suggesting tubular parenchymal expansion promoted by HGF. Notably, HGF suppressed the expression of transforming growth factor-beta and of platelet-derived growth factor as well as myofibroblast formation in the affected kidney. Consequently, the onset of tubulointerstitial fibrosis was almost completely inhibited by HGF, while HGF attenuated the progression of glomerulosclerosis, both leading to preventing manifestation of renal dysfunction. From our results, supplement therapy with HGF may be taken into consideration as a novel option for prevention and treatment of CRD.     

Kidney protection by pretreatment with free radical scavengers and allopurinol: renal function at recirculation after warm ischaemia in rabbits

Renal function and morphology were studied before and after 60 min of renal ischaemia and contralateral nephrectomy in five groups of rabbits. The animals were pretreated with superoxide dismutase, catalase, allopurinol or mannitol. One group was not pretreated and served as a control. A moderate transient increase in serum creatinine concentration was observed in the control rabbits, while a significantly less pronounced increase was noted after pretreatment with superoxide dismutase, catalase and mannitol. Pretreatment with allopurinol did not significantly reduce the postoperative increase in serum creatinine and sodium excretion, but the urine osmolality returned to normal more rapidly than in the control group. The appearance under the light microscope of kidney tissue taken from surviving rabbits was found to be normal irrespective of pretreatment. Severe tubular necrosis was observed in the kidneys from rabbits that died during the observation period.