Modular cis-regulatory logic of yellow gene expression in silkmoth larvae.

Colour patterns in butterflies and moths are crucial traits for adaptation. Previous investigations have highlighted genes responsible for pigmentation (ie yellow and ebony). However, the mechanisms by which these genes are regulated in lepidopteran insects remain poorly understood. To elucidate this, molecular studies involving dipterans have largely analysed the cis-regulatory regions of pigmentation genes and have revealed cis-regulatory modularity. Here, we used well-developed transgenic techniques in Bombyx mori and demonstrated that cis-regulatory modularity controls tissue-specific expression of the yellow gene. We first identified which body parts are regulated by the yellow gene via black pigmentation. We then isolated three discrete regulatory elements driving tissue-specific gene expression in three regions of B. mori larvae. Finally, we found that there is no apparent sequence conservation of cis-regulatory regions between B. mori and Drosophila melanogaster, and no expression driven by the regulatory regions of one species when introduced into the other species. Therefore, the trans-regulatory landscapes of the yellow gene differ significantly between the two taxa. The results of this study confirm that lepidopteran species use cis-regulatory modules to control gene expression related to pigmentation, and represent a powerful cadre of transgenic tools for studying evolutionary developmental mechanisms.

Genome size of Pachypsylla venusta (Hemiptera: Psyllidae) and the ploidy of its bacteriocyte, the symbiotic host cell that harbors intracellular mutualistic bacteria with the smallest cellular genome.

Psyllids harbor the primary symbiont, Carsonella ruddii (gamma-Proteobacteria), within the cytoplasm of specialized cells called bacteriocytes. Carsonella has the smallest known cellular genome (160 kb), lacking numerous genes that appear to be essential for bacterial life. This raises the question regarding the genetic mechanisms of the host which supports the survival of Carsonella. Our preceding analyses have indicated that some of the genes that are encoded in the psyllid genome and which are highly expressed in the bacteriocyte are of bacterial origin. This implies that psyllids acquired genes from bacteria by lateral gene transfer (LGT) and are using these genes to maintain the primary symbiont, Carsonella. To reveal the complete picture of LGT from symbiotic bacteria to the genome of psyllids, whole genome analysis of psyllids is essential. In order to assess the feasibility of whole genome analysis of the host psyllid, the genome size of the hackberry petiole gall psyllid, Pachypsylla venusta, was estimated. Feulgen image analysis densitometry and flow cytometry demonstrated that the haploid genome size of P. venusta is 0.74 pg (724 Mb), verifying the feasibility of whole genome analysis. Feulgen image analysis densitometry further revealed that bacteriocytes of P. venusta are invariably 16-ploid. This higher ploidy may be essential to facilitate the symbiotic relationship with bacteria, as it appears to be a feature common to insect bacteriocytes. These results provide a foundation for genomics-based research into host-symbiont interactions.

Caste-specific cytochrome P450 in the damp-wood termite Hodotermopsis sjostedti (Isoptera, Termopsidae).

Termites are eusocial insects with a well-defined caste system, which is an example of polyphenism. This polyphenism is based on hormonally controlled differential gene expression. In the damp-wood termite Hodotermopsis sjostedti, we induced differentiation into the soldier caste by using juvenile hormone analogue treatment. We then investigated specific gene expression, which appeared during the hormonal response and triggered caste differentiation, using fluorescent differential display. A candidate cDNA sequence with similarity to cytochromes P450, CYP6AM1, was characterized and its transcript shown to be repressed between 1 and 3 days after hormone treatment. CYP6AM1 was specifically expressed in the fat body of pseudergates and soldiers. The putative function of this P450 is discussed with respect to the caste differentiation system.

Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. A double-blind study among 4 doses.

BACKGROUND/AIMS: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. METHOD: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 microg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. RESULTS: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, -7.8% in the 1-microg group, -18.9% in the 1.5-microg group and -24.1% in the 2-microg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were -0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-microg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-microg group among the three calcitriol groups. CONCLUSION: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 microg per dialysis session.

Elimination study of silver in a hemodialyzed burn patient treated with silver sulfadiazine cream.

Silver sulfadiazine (SSD) cream is a potent agent for the treatment of burns. In a patient with end-stage renal disease, we observed a marked elevation in serum silver concentration in the course of 2 weeks of SSD cream therapy (200 g/d). Serum concentration of silver reached a maximum of 291 ng/mL in association with a rapid deterioration of mental status. SSD therapy was discontinued, and hemodialysis, hemofiltration, or plasma exchange was continually performed. Four months later, the patient died. At autopsy, profoundly elevated levels of silver were found in brain tissues of this patient (617.3, 823.7 ng/g wet tissue weight in the cerebrum and cerebellum, respectively). To determine the most efficient therapy to remove silver from serum, we compared hemodialysis (HD), hemofiltration (HF), and plasma exchange (PE). Both plasma exchange and hemofiltration were effective in decreasing serum silver, and their effects were additive. By contrast, HD was ineffective in reducing serum silver. This case illustrates that, on SSD cream therapy, burn patients with disturbed renal function are at risk of accumulating silver in serum and tissue to the level that may cause neuralgic decompensation. Removal of serum silver can best be effected by PE, particularly when combined with HF. In contrast, HD per se does not appear efficacious. None of these blood purification modalities improves deterioration of neurological status potentially attributable to silver deposition in brain tissues.

Expression of epidermal growth factor and its receptor in rabbits with ischaemic acute renal failure.

Urinary immunoreactive epidermal growth factor (EGF) levels decrease, and renal immunoreactive EGF levels increase in rats with ischaemic acute renal failure (ARF). We investigated the immunohistochemical localization of EGF and EGF receptor in rabbits with ischaemic ARF to clarify the significance of renal EGF. Male New Zealand White rabbits underwent right nephrectomy prior to a 60 min renal artery clamp. At 3, 6, 24, 48, 72 and 96 h after ischaemia, serum urea nitrogen and serum creatinine were determined. Guinea pig anti-rabbit EGF antibody and monoclonal anti-EGF receptor antibody were used for the primary incubation. EGF was immunolocalized to the ascending limb of Henle and the distal convoluted tubule in the normal right kidneys. However, in the post ischaemic left kidneys at 6, 24, 48 and 72 h, immunoreactivity of EGF was associated with proximal tubules. In the normal kidneys, antibody to EGF receptor reacted with distal tubules and collecting ducts. In the ischaemic kidneys, EGF receptor was localized in the basolateral membrane in the proximal tubules. The expression of EGF and EGF receptor in renal tubules may play an important role in repair following ischaemic renal damage.

The effects and pharmacokinetics of rhG-CSF in patients with chronic renal failure.

The pharmacokinetics and effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutrophils and immunological function were studied in 10 patients with end-stage renal failure. A single dose and 2-week consecutive dosing of 50 micrograms/m2 of rhG-CSF were drip infused intravenously, and plasma rhG-CSF levels, peripheral blood cell counts, coagulation, and neutrophil and immunological functions were determined during treatment. The mean half-life of rhG-CSF in patients (2.47 +/- 0.64 h) was prolonged to about twice that of healthy subjects, and hemodialysis did not affect the pharmacokinetics. A marked increase in neutrophils and a slight increase in lymphocytes were observed with the single and consecutive administration of rhG-CSF, but no significant changes were noted in other leukocyte fractions and erythrocyte and platelet counts. The neutrophil alkaline phosphatase value increased significantly following rhG-CSF administration, and other neutrophil functions were also ameliorated in several patients with neutrophil dysfunction. In consecutive administration, however, mild bone pain and increased serum alkaline phosphatase were observed in about half the patients, but neither accumulation of rhG-CSF nor antibody production was detected. From these results, it is concluded that rhG-CSF is safe and effective for the treatment of neutropenia and neutrophil dysfunction in patients with renal failure.

Plasma bradykinin levels during hemodialysis with PAN DX and polysulfone membranes with and without concurrent ACE inhibitor.

The effects of dialyzer membrane material and concurrent angiotensin converting enzyme (ACE) inhibitor on plasma bradykinin levels during hemodialysis were investigated by administration of 3 successive hemodialyses using a PAN DX membrane dialyzer and another 3 using a polysulfone membrane dialyzer with the order of the 2 sequences randomized, for 6 patients receiving concurrent treatment with ACE inhibitor and 6 others receiving no ACE inhibitor. With the PAN DX membrane dialyzer the plasma bradykinin concentration obtained from the dialyzer outlet was significantly higher than that from the inlet at 10 min, but not at 5 min after initiation of dialysis, whereas no significant difference between inlet and outlet bradykinin concentrations was observed at either time with the polysulfone membrane dialyzer. No significant difference was observed between the changes in plasma bradykinin concentration in cases involving concurrent ACE inhibitor and that in cases receiving no ACE inhibitor. The results suggest that the PAN DX membrane dialyzer stimulates bradykinin production, but also that its release of bradykinin is delayed, possibly because of adsorption and modified release of bradykinin by the PAN DX membrane, and that ACE inhibitor may have no significant effect on the change in plasma bradykinin levels.

Endothelin-1 and endothelin B type receptor are induced in mesangial proliferative nephritis in the rat.

We studied whether endothelin-1 (ET-1) and its receptor subtypes (ETAR, endothelin A type receptor; and ETBR, B type receptor) were up-regulated in the glomerulus of a rat model of mesangial proliferative glomerulonephritis induced by anti-thymocyte serum (anti-Thy-1 GN). A marked increase in preproET-1 mRNA could be demonstrated in glomerular RNA 3 and six days after disease induction (4.1- and 4.9-fold vs. day 0, respectively), corresponding to the time of mesangial cell proliferation, to the time of macrophage infiltration into glomeruli, and also to the time of increase in glomerular PDGF B-chain mRNA expression. The localization of ET-1 protein in the mesangial area and along the inner aspect of the glomerular capillary wall was also demonstrated by immunohistochemistry from day 3 and maximal at day 6. The major source of the cells expressing ET-1 in glomeruli appeared to be mesangial cells, glomerular endothelial cells and monocyte/macrophages. Furthermore, both gene and protein expression of ET-1 were associated with increased urinary excretion of ET-1. There was no increase in the plasma ET-1 immunoreactivity. Glomerular expression of ETBR mRNA increased in anti-Thy-1 GN (1.5-fold vs. day 0 at day 3 after disease induction, 3.6-fold at day 6 and 2.7-fold at day 10), but there was minimal change in ETAR mRNA expression. These results suggest that preproET-1 mRNA, which is induced in anti-Thy-1 GN, is linked primarily with ETBR mRNA expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of rHuEpo on cellular proliferation and endothelin-1 production in cultured endothelial cells.

BACKGROUND: Although elevation of blood pressure is considered to be the main adverse effect under rHuEpo therapy in haemodialysis patients, the precise mechanism remains obscure. The direct effect of rHuEpo on endothelial cells (EC) has been suggested as one of contributing factors of rHuEpo-induced hypertension. METHODS: EC were incubated with various concentrations of rHuEpo (0, 1000, 5000, 10,000 mU/ml) for up to 7 days, and cell numbers, DNA and protein synthesis by EC and supernatant concentrations of immunoreactive endothelin-1 (ET) were determined by haemocytometer, 3H-thymidine and 3H-leucine incorporation, and RIA, respectively. The effect of rHuEpo on EC proliferation was confirmed by anti-rHuEpo rabbit antiserum. The effect of cycloheximide or acinomycin D was also examined on the increase in ET production by rHuEpo. RESULTS: rHuEpo dose-dependently stimulated the proliferation of cultured EC, and this proliferative effect was inhibited by anti-rHuEpo rabbit antiserum. DNA and protein syntheses by EC were also increased by rHuEpo. The supernatant concentrations of ET cultured with rHuEpo at 5000 mU/ml or more showed significantly greater values than those without rHuEpo and the increase in ET in the supernatants of media containing 5000 mU/ml rHuEpo was inhibited by incubation with 0.2 microgram/ml actinomycin D or 10 micrograms/ml cycloheximide. Further, rHuEpo increased DNA synthesis by EC which had been cultured in E-BM medium containing 0.5 or 2% FBS for 3 h and which were recultured in E-BM medium containing 5% FBS for 15 h. CONCLUSIONS: rHuEpo directly stimulates EC proliferation as a competence factor, and it also accelerates endothelin-1 production in association with stimulation of DNA and protein syntheses by EC.

Current status of renal replacement therapy in Japan.

The study of the current status of renal replacement therapy in Japan is based on the analysis of data from the registry reports for regular dialysis therapy and kidney transplantation. The total number of patients receiving regular dialysis therapy was 123,926 at the end of 1992: 117,809 (95.1%) on hemodialysis and 6,117 (4.9%) on peritoneal dialysis. The primary diseases of newly accepted patients were chronic glomerulonephritis (42.2%), diabetic nephropathy (28.4%), nephrosclerosis (5.9%), polycystic kidney disease (2.7%), chronic pyelonephritis (1.6%), and others. The number of kidney transplant patients in Japan was 8,384 at the end of 1991: 6,154 (73.4%) received a living donor transplantation and 2,230 (26.9%) received a cadaver donor transplantation. Overall 5-year survival rates of dialysis patients were 60.4%: 69.7% for chronic glomerulonephritis, 41.7% for diabetic nephropathy, 39.6% for nephrosclerosis, 73.6% for diffuse polycystic kidney disease, and 66.6% for chronic pyelonephritis. The causes of death of dialysis patients were heart failure (31.1%), cerebrovascular accident (13.6%), infectious diseases (11.3%), malignancies (7.1%), cachexia/uremia (6.7%), myocardial infarction (5.8%), and others. The gross mortality rate of dialysis patients was increased in cases of less than 4 hours of the average length of each dialysis session, less than 4% and more than 9% of the average weight loss during each dialysis session, less than 1.0 of Kt/V, and less than 0.9 and more than 1.7 g/kg/d of protein catabolic rate. Overall 5-year patient and graft survival rates of kidney transplant patients since 1964 were 82.7% and 60.3%: 84.4% and 65.0% in living donor cases, and 77.4% and 46.2% in cadaver donor case, respectively. Those since 1983 were 90.1% and 68.2%: 91.3% and 72.6% in living donor cases, and 87.8% and 59.3%, respectively. Graft survival rates were superior in cases treated with combined steroid, cyclosporine and azathioprine or mizoribine, to those treated with other immuno-suppressive regimens, and they decreased as the number of HLA-A, -B and -DR increased.

Relative hypoparathyroidism in hemodialysis patients.

To clarify the incidence and contributing factors of hypoparathyroidism in a hemodialysis (HD) population, 224 patients undergoing maintenance HD were investigated. They were divided into 4 groups according to their high-sensitive parathyroid hormone levels: extra-high (EH) group > 420,000 pg/ml; high (H) group 20,000-420,000 pg/ml; moderate (M) group 4,500-20,000 pg/ml; low (L) group, < 4,500 pg/ml. In group L, a 25-mg/kg deferoxamine (DFO) infusion test was undertaken to estimate aluminum (Al) accumulation. The distribution in each group was 42, 35, 12, and 11% for groups L, M, H and EH, respectively. Group-L patients were relatively older than those of the other groups. Diabetes was seen in 20% of group-L patients, as opposed to no diabetes in groups H and EH. Among the 22 diabetics, 82% were in group L. 70% of group-L patients showed a less than 50-micrograms/l Al increment after the DFO infusion test. Bone mineral density (BMD) did not differ between the groups with relative hypoparathyroidism (RHP=L) and background-matched non-RHP, either at the initiation of HD or the recent period, and the changes in BMD were comparable between the 2 groups. These results suggest that a considerable number of HD patients show RHP. Diabetes, but not Al accumulation, was considered to be one of the predisposing factors of RHP. Though the outcome of RHP will be aplastic bone disease (ABD) in HD patients, the clinical significance of ABD has not been fully evaluated. Further studies are required to clarify the precise mechanisms of RHP and the significance of ABD.

Effects of membrane characteristics on cytokine production by mononuclear cells in regular haemodialysis patients.

To determine the relationship between haemodialysis and cytokine production, the effects of solute permeability and biocompatibility of dialysis membranes on cytokine production by mononuclear cells were evaluated. Eighteen stable haemodialysis patients were divided into three groups and underwent haemodialysis under the same conditions except for the dialysis membrane used. Endotoxin in dialysate remained at concentrations of 10 pg/ml or less throughout the study. Haemodialysis was performed for a total of 6 weeks. Group A used a regenerated cellulose low-flux membrane during the first 2 weeks, a regenerated cellulose high-flux membrane during the next 2 weeks and a polymethylmethacrylate (PMMA) high-flux membrane during the last 2-week period, while Group B used the regenerated low-flux cellulose membrane first, followed by the PMMA low-flux membrane and PMMA high-flux membrane. Group C used the same membrane throughout the 6-week study period. Peripheral mononuclear cells were sampled before, 30 min after the start and upon completion of the final dialysis session and incubated for 18 h in the presence and absence of lipopolysaccharide (LPS) stimulation. Tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-6 concentrations in the supernatant and cell lysate were determined. In all groups, cytokine production just before the final dialysis using each membrane was comparable regardless of the presence or absence of LPS stimulation. LPS-stimulated TNF-alpha production decreased significantly 30 min after the start of dialysis compared to the predialysis baseline. This change was not affected by the type of membrane used.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anticoagulant effect of a single bolus injection of parnaparin sodium (LHG) on a hemodialysis model in dogs].

Hemodialysis was performed on dogs, following intravenous bolus injections of LHG at dosage levels of 50, 100 and 200 IU/kg and heparin at the levels of 100 and 200 IU/kg. LHG exerted dose-dependent anticoagulant effects and prolonged the hemodialysis time, compared to heparin with similar anti-Xa activity. When LHG was administered, the half-life of plasma anti-Xa activity was longer than that of heparin at similar anti-Xa activity. LHG prolonged the activated partial thromboplastin time (APTT) linearly and dose-dependently. However, the prolongation was much less than that of heparin, and the anticoagulant activity of LHG continued even after the APTT returned to the value before LHG administration. When LHG was administered, whole blood Xa activated coagulation time (XCT) and plasma Xa activated coagulation time (PXCT) were prolonged in a significantly greater degree compared to APTT. Therefore, XCT and PXCT were considered to be appropriate parameters for monitoring LHG. In the groups administered with LHG at 100 and 200 IU/kg, where hemodialysis could be continued for 8 hr, the tissue factor pathway inhibitor (TFPI) activity in the plasma tended to show a sustained increase. These findings suggested the possibility that not only the antithrombin III dependency mechanism but also the TFPI mechanism contributed to a longer LHG hemodialysis duration compared to heparin administration.

Effect of dialysis membranes and ACE inhibitor on bradykinin levels during hemodialysis.

The effects of dialyzer membrane material and concurrent angiotensin converting enzyme (ACE) inhibitor on plasma bradykinin levels during hemodialysis were investigated. Six patients treated with an ACE inhibitor and 6 other patients not receiving an ACE inhibitor underwent three consecutive hemodialysis sessions with an AN-69 dialyzer and three sessions with a polysulfone dialyzer. The sequence of dialyzers (AN-69 followed by polysulfone or the reverse) was determined randomly. With the AN-69 membrane dialyzer, the plasma bradykinin level at the dialyzer outlet was significantly greater than that at the dialyzer inlet at 5 min but not at 10 min after initiation of dialysis, whereas no significant difference between inlet and outlet bradykinin concentrations was observed at either time with the polysulfone membrane dialyzer. The changes in plasma bradykinin level in patients with concurrent ACE inhibitor did not differ from those found in patients without ACE inhibitor. These results indicate that the AN-69 membrane stimulates bradykinin production at the initial stage of hemodialysis in patients with as well as without concurrent ACE inhibitor. Further study is necessary to clarify the exact role of ACE inhibitor in elevation of bradykinin levels during hemodialysis.

Immunochemical study of epidermal growth factor in rats with mercuric chloride-induced acute renal failure.

Urine contains high concentrations of epidermal growth factor (EGF), and EGF is a potent growth promoter for proximal tubular cells. In the present study, urinary and whole-kidney EGF levels were investigated in rats with mercuric chloride (HgCl2)-induced acute renal failure (ARF) using a specific radioimmunoassay for rat EGF to clarify changes in EGF after toxic injury. Male Wistar rats were given HgCl2 (2 mg/kg, subcutaneously) or saline. Serum urea nitrogen and creatinine levels were measured for 4 days after toxin administration. Forty-eight hours after toxic injury, urinary immunoreactive EGF levels in HgCl2-treated rats decreased significantly compared with control rats (1.62 +/- 0.15 versus 3.78 +/- 0.21 ng/mg creatinine; p < 0.01). Urinary immunoreactive EGF was at its lowest level 96 h after toxic injury (0.64 +/- 0.06 ng/mg creatinine; p < 0.001). Twenty-four hours after toxic injury, renal immunoreactive EGF levels increased significantly compared with control rats (22.04 +/- 2.12 versus 4.84 +/- 0.70 ng/g wet weight tissue; p < 0.001), and the increase persisted for as long as 48 h (13.36 +/- 1.61 ng/g wet weight tissue; p < 0.05). In summary, urinary immunoreactive EGF levels decreased and renal EGF levels increased in rats with HgCl2-induced ARF. These findings suggest that there is an impairment in the excretion of EGF in rats with HgCl2-induced ARF and that local paracrine production of EGF continues in ARF.

A multicenter study with once a week or once every two weeks high-dose subcutaneous administration of recombinant human erythropoietin in continuous ambulatory peritoneal dialysis.

OBJECTIVE: To investigate the effectiveness of administering relatively high doses of r-HuEPO subcutaneously once a week or once every 2 weeks in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Multicenter prospective analysis. The trial was divided into two phases: an initial 8-week phase (once a week dosing) followed by a 12-week maintenance phase (once every 2 weeks dosing). A response was defined as a change in hematocrit (Ht) of 3% or more. Results were analyzed using Sheffe's test, Mantel-Haenszel's test, and Dunnett's test. SETTING: Eleven renal units in Japan providing a CAPD program. PATIENTS: Forty-one CAPD patients with a Ht of 28% or less. RESULTS: After the initial 8 weeks, 13 (81.3%) of 16 patients showed a response to 6000 U (106.9 +/- 20.0 U/kg) subcutaneously (sc), once a week. Eleven (84.6%) of 13 in the 9000 U (166.5 +/- 27.7 U/kg) group and all 12 (100%) in the 12,000 U (210.7 +/- 42.1% U/kg) group also showed responses. At the end of both phases, that is, at 20 weeks, 7 (53.8%) of 13 patients in the 6000 U group with once every 2 weeks dosing, 7 (63.6%) of 11 in the 9000 U group, and 10 (90.9%) of 11 in the 12,000 U group maintained responses with the same dosing interval. There were no significant changes in mean blood pressure during the study period, and only 2 patients developed treatable hypertension with mild headache. CONCLUSION: Administration of relatively high doses of r-HuEPO to CAPD patients once a week or once every 2 weeks is safe and potentially an effective regimen for the correction of renal anemia.

Urinary epidermal growth factor levels in patients with acute renal failure.

To investigate the importance of epidermal growth factor (EGF) in patients with renal dysfunction, urinary human EGF (hEGF) levels were determined by radioimmunoassay in 16 patients with acute renal failure (ARF) and in 12 healthy controls. Seven patients with chronic renal failure also were studied. Urinary hEGF levels, corrected for urine creatinine concentrations, were significantly decreased in patients with ARF in the acute phase compared with normal control subjects (0.98 +/- 0.20 v 13.74 +/- 1.18 ng/mg creatinine, P < 0.001), and subsequently increased during the recovery phase (6.10 +/- 0.73 ng/mg creatinine, P < 0.001 v acute phase). A significant positive correlation existed between urinary hEGF levels and creatinine clearance in patients with ARF (r = 0.66, P < 0.001). Serum hEGF levels also were significantly lower in patients with ARF compared with normal control subjects (0.10 +/- 0.01 v 0.30 +/- 0.03 ng/mL, P < 0.001). No significant correlation was found between hEGF concentrations in serum and urine. In conclusion, measurement of urinary hEGF may be useful in the diagnosis of ARF and for following the recovery of the kidney after severe tubular injury.