Changes to blood parameters after postparturient hemoglobinuria in 11 Holstein-Friesian cows.

This study reviewed a case series of 11 Holstein-Friesian (HF) cows with postpartum hemoglobinuria (PPH) from one dairy herd. The first clinical signs of PPH appeared in the animals during the second or third lactation, between 21 and 30 days after calving. The clinical signs, including depression, diminished appetite, a dark red to brown color in the urine, pale mucous membranes, and a decrease in milk yields were observed in these 11 animals. Three of the cows developed jaundice of the mucous membranes and five had dry, parched feces. PPH was confirmed on laboratory test results of blood and urine samples. Anemia, serum hypophosphatemia (Pi = 0.79 mmoL/L), and increased liver function analytes (total bilirubin, total protein, and urea concentrations) were observed in all animals. Animals were treated with intravenous phosphorus supplementations for the first 2 days after clinical signs were noted, and then oral supplementations were administered. After the clinical signs resolved and the treatments were discontinued, the animals still had mild anemia; however, the phosphorus concentration increased to 1.40 mmoL/L. Gamma-glutamyltransferase activity increased compared with activities measured before treatments and total bilirubin concentrations decreased slightly; however, the concentrations were still more than twice the upper limit of the normal RI. These animals were diagnosed with liver damage that had developed over the course of PPH, indicating the need for the further monitoring and treatment of cows during the postparturient period, even if clinical signs are no longer present.

Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside.

With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.

Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis.

Hemoglobinuria is associated with kidney injury in various hemolytic pathologies. Currently, there is no treatment available and its pathophysiology is not completely understood. Here we studied the potential detrimental effects of hemoglobin (Hb) exposure to the distal nephron (DN). Involvement of the DN in Hb kidney injury was suggested by the induction of renal hepcidin synthesis (p < 0.001) in mice repeatedly injected with intravenous Hb. Moreover, the hepcidin induction was associated with a decline in urinary kidney injury markers 24p3/NGAL and KIM1, suggesting a role for hepcidin in protection against Hb kidney injury. We demonstrated that uptake of Hb in the mouse cortical collecting duct cells (mCCDcl1) is mediated by multi-protein ligand receptor 24p3R, as indicated by a significant 90% reduction in Hb uptake (p < 0.001) after 24p3R silencing. Moreover, incubation of mCCDcl1 cells with Hb or hemin for 4 or 24 h resulted in hepcidin synthesis and increased mRNA expression of markers for oxidative, inflammatory and ER stress, but no cell death as indicated by apoptosis staining. A protective role for cellular hepcidin against Hb-induced injury was demonstrated by aggravation of oxidative, inflammatory and ER stress after 4 h Hb or hemin incubation in hepcidin silenced mCCDcl1 cells. Hepcidin silencing potentiated hemin-mediated cell death that could be diminished by co-incubation of Nec-1, suggesting that endogenous hepcidin prevents necroptosis. Combined, these results demonstrate that renal hepcidin synthesis protects the DN against hemin and hemoglobin-mediated injury.

Correlation of BACH1 and Hemoglobin E/Beta-Thalassemia Globin Expression.

OBJECTIVE: The diverse clinical phenotype of hemoglobin E (HbE)/ß-thalassemia has not only confounded clinicians in matters of patient management but has also led scientists to investigate the complex mechanisms involved in maintaining the delicate red cell environment where, even with apparent similarities of α- and ß-globin genotypes, the phenotype tells a different story. The BTB and CNC homology 1 (BACH1) protein is known to regulate α- and ß-globin gene transcriptions during the terminal differentiation of erythroid cells. With the mutations involved in HbE/ß-thalassemia disorder, we studied the role of BACH1 in compensating for the globin chain imbalance, albeit for fine-tuning purposes. MATERIALS AND METHODS: A total of 47 HbE/ß-thalassemia samples were analyzed using real-time quantitative polymerase chain reaction and correlated with age, sex, red blood cell parameters, globin gene expressions, and some clinical data. RESULTS: The BACH1 expression among the ß-thalassemia intermedia patients varied by up to 2-log differences and was positively correlated to age; α-, ß-, and γ-globin gene expression level; and heme oxygenase 1 protein. BACH1 was also negatively correlated to reticulocyte level and had a significant correlation with splenectomy. CONCLUSION: This study indicates that the expression of BACH1 could be elevated as a compensatory mechanism to decrease the globin chain imbalance as well as to reduce the oxidative stress found in HbE/ß-thalassemia.

The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup.

The in vivo Pig-a assay uses flow cytometry to measure phenotypic variants for antibody binding to cell surface glycosylphosphatidylinositol (GPI)-anchored proteins. There is good evidence suggesting that the absence of antibody binding is the result of a mutation in the endogenous X-linked Pig-a gene, which forms the rationale for the assay. Although the assay has been performed with several types of hematopoietic cells and in a variety of mammalian species, including humans, currently it is optimized only for measuring CD59-deficient (presumed Pig-a mutant) erythrocytes in the peripheral blood of rats. An expert workgroup formed by the International Workshop on Genotoxicity Testing considered the state of assay development and the potential of the assay for regulatory use. Consensus was reached on what is known about the Pig-a assay and how it should be conducted, and recommendations were made on additional data and refinements that would help to further enhance the assay for use in hazard identification and risk assessment.

The presence of CD55- and/or CD59-deficient erythrocytic populations in patients with rheumatic diseases reflects an immune-mediated bone-marrow derived phenomenon.

BACKGROUND: Complement has the potential to provoke severe impairment to host tissues, as shown in autoimmune diseases where complement activation has been associated with diminished CD55 and/or CD59 expression on peripheral blood cell membranes. The aim of this study was to evaluate the presence of CD55- and/or CD59-deficient erythrocytic populations in patients with different rheumatic diseases and to investigate possible correlations with clinical or laboratory parameters. MATERIAL AND METHODS: CD55 and CD59 expression was evaluated in erythrocytes of 113 patients with rheumatic diseases, 121 normal individuals, and 10 patients with paroxysmal nocturnal hemoglobinuria (PNH) using the Sephacryl gel microtyping system. Ham and sucrose tests were also performed. RESULTS: Interestingly, the majority of patients (104/113, 92%) demonstrated CD55- and/or CD59-deficient erythrocytes: 47 (41.6%) with concomitant deficiency of CD55 and CD59, 50 (44.2%) with isolated deficiency of CD55, and 6 (6.2%) with isolated deficiency of CD59. In normal individuals, only 2 (1%) had concomitant CD55/CD59 negativity and 3 (2%) had isolated CD55 or CD59 deficiency. All PNH patients exhibited simultaneous CD55/CD59 deficiency. Positive Ham and sucrose tests were found only in PNH patients. There was no association between the CD55- and/or CD59-deficient erythrocytes and hemocytopenias or undergoing treatment. However, CD55 expression significantly influenced hemoglobin values (F=6.092, p=0.015). CONCLUSIONS: This study provides evidence supporting the presence of erythrocytes with CD55 and/or CD59 deficiency in patients with rheumatic diseases. Moreover, CD55 deficiency on red cells influences hemoglobin concentration. Further studies using molecular techniques will clarify the exact pathophysiological mechanisms of this deficiency.

Hemoglobin H disease in Guangxi province, Southern China: clinical review of 357 patients.

The clinical characteristics of 357 patients with hemoglobin H (HbH) disease from the Guangxi province of Southern China were studied. One hundred and ninety-one (53.3%) patients were diagnosed with HbH-Constant Spring, 19 were diagnosed with HbH Westmead. Ten patients were shown to have coinherited HbH-Constant Spring/QS with a ß-thalassemia mutation. Coinheritance of the ß-thalassemia gene does not alleviate anemia (8.2 ± 2.3 vs. 7.6 ± 1.7 g/dl, p = 0.276), or influence age at diagnosis (20.2 ± 19.6 vs. 12.9 ± 11.0 years, p = 0.276). Ferritin levels were significantly higher in the group of patients with the nondeletional form of the disease (475 ± 719 vs. 249 ± 264 ng/ml, p = 0.005).

A longitudinal study of urinary dipstick parameters in wild chimpanzees (Pan troglodytes verus) in Côte d'Ivoire.

We performed 796 dip-stick tests on urine from 100 wild West African chimpanzees (Pan troglodytes verus) from 4 habituated groups in the tropical rain forest of Taï National Park, Cote d'Ivoire, to establish reference values for health monitoring. Specific gravity was also measured on 359 urine samples from 62 chimpanzees. The effect of age, sex, group, month, estrus, pregnancy, meat consumption, and acute respiratory disease on pH, leucocytes, protein, blood, hemoglobin, and glucose was examined using ordinal logistic regression. The presence of nitrite, ketones, bilirubin, and urobilinogen in urine was also recorded. Outbreak of acute respiratory disease did not influence any of the urinary parameters. Thirty-seven percent of the samples had a pH <7 and the whole range of pH was found through the year, in all age groups, and in both sexes. Meat consumption lowered the urinary pH. Our results show that all pH levels must be considered normal for the West African chimpanzee subspecies P. troglodytes verus living in the rainforest. We also found a cluster of glucose-positive samples at a specific point in time which was not attributed to diabetes mellitus. These findings highlight that there are differences in normal physiological parameters among wild chimpanzees living in different habitats.

Estimation of a valuation function for a diabetes mellitus-specific preference-based measure of health: the Diabetes Utility Index.

Preference-based measures of health (PBMH) provide 'preference' or 'utility' weights that enable the calculation of QALYs for the economic evaluations of interventions. The Diabetes Utility Index (DUI) was developed as a brief, self-administered, diabetes mellitus-specific PBMH that can efficiently estimate patient-derived health state utilities. To describe the development of the valuation function for the DUI, and to report the validation results of the valuation function. Multi-Attribute Utility Theory (MAUT) was used as the framework to develop a valuation function for the DUI. Twenty of 768 possible health states of the DUI classified as anchor states, single-attribute level states including corner states, and marker states were selected and described for preference elicitation interviews. Visual analogue scale and standard gamble (SG) exercises were used to measure preferences from individuals with diabetes recruited from primary care and community settings in and around Morgantown, WV, USA for the 20 health states defined by combinations of DUI attributes and severity levels. Data collected in the interviews were used to develop a valuation function that calculates utilities for the DUI health states and calculates attribute-level utilities. A validation survey of the valuation function was conducted in collaboration with the West Virginia University (WVU) Diabetes Institute. A total of 100 individuals with diabetes were interviewed and their preferences for various DUI health states measured. From data generated in the interviews, a DUI valuation function was developed on a scale where 1.00 = perfect health (PH) and 0.00 = the all worse 'pits' state, and adjusted to yield utilities on the conventional scale 1.00 = PH and 0.00 = dead. A total of 396 patients with diabetes who received care at WVU clinics completed a DUI mail validation survey (response rate = 33%). Clinical data consisting of International Classification of Diseases, 9th edition, diagnosis codes and glycosylated haemoglobin (HbA(1c)) values for the respondents were merged with their responses to the DUI. The utilities calculated by the scoring function of the DUI compared favourably to cardinal SG utilities for three DUI health states for which both assessments were available. The DUI utility function slightly underestimated actual SG utilities for mild and moderate health states (mean absolute difference = 0.05). There was a small but significant correlation between DUI utility scores and average past year HbA(1c) values (r = -0.30; p < 0.001). Respondents with two or more complications had significantly lower DUI utilities than those with no complications (p < 0.001) or one complication (p = 0.015). Insulin users had significantly lower DUI utilities than non-users (p < 0.001), and those with HbA(1c) values <7% had significantly higher DUI utilities than those with HbA(1c) values of >or=7% (p < 0.001). No significant association was found between DUI scores and age or sex. These results show evidence of the feasibility and validity of the DUI. Further research is suggested to demonstrate the generalizability of these findings, to study the responsiveness of the DUI, and to examine the clinical meaningfulness of DUI change scores.

Structure and function comparison of Micropechis ikaheka snake venom phospholipase A2 isoenzymes.

Comparison of the crystal structures of three Micropechis ikaheka phospholipase A2 isoenzymes (MiPLA2, MiPLA3 and MiPLA4, which exhibit different levels of pharmacological effects) shows that their C-terminus (residues 110-124) is the most variable. M-Type receptor binding affinity of the isoenzymes has also been investigated and MiPLA4 binds to the rabbit M-type receptor with high affinity. Examination of surface charges of the isoenzymes reveals a trend of increase in positive charges with potency. The isoenzymes are shown to oligomerize in a concentration-dependent manner in a semi-denaturing gel. The C-termini of the medium (MiPLA4) and highly potent (MiPLA2) isoenzyme molecules cluster together, forming a highly exposed area. A BLAST search using the sequence of the most potent MiPLA2 results in high similarity to Staphylococcus aureus clotting factor A and cadherin 11. This might explain the myotoxicity, anticoagulant and hemoglobinuria effects of MiPLA2s.

Cardiovascular risk factors and probability for cardiovascular events in HIV-infected patients - part III: age differences.

OBJECTIVE: In recent years, concerns have been growing about an elevated rate of cardiovascular diseases in HIV-infected patients due to side effects of antiretroviral therapy. The present study analyses the cardiovascular risk profile and the probability of cardiovascular events with regard to the age of HIV-infected patients. METHODS: Cardiovascular risk factors of 309 HIV-infected adults were analysed. Patients were divided into four groups: 18-30 years (group 1), 31-40 years (group 2), 41-50 years (group 3), > 50 years (group 4). Overall 10-years probability for cardiovascular events was evaluated by the Framingham algorithm. RESULTS: Differences between the groups were detected in cardiovascular risk factors including changes in lipid- and glucose metabolism. Lipid values increased with elevated age, such as total cholesterol concentration (Mean +/- SEM in group 1 vs. group 4: 4.71 +/- 0.20 to 6.36 +/- 0.21 mmol/L, p < 0.05), LDL-cholesterol concentration (2.86 +/- 0.17 vs. 4.17 +/- 0.21 mmol/L, p < 0.05) and triglyceride concentration (1.56 +/- 0.14 vs. 3.48 +/- 0.40 mmol/L, p < 0.05). HDL-cholesterol concentration did not show a significant difference (1.15 +/- 0.03 mmol/L). Glucose concentration increased with elevated age in HIV-infected patients (5.28 +/- 0.19 vs. 6.46 +/- 0.24 mmHg, p < 0.05), but there was no significant difference in HbA1c - concentration, blood pressure and smoking rate between the groups. The overall 10-years probability for cardiovascular events was higher in group 1 (median: 1.9%) than in group 4 (20.5%; p < 0.01). CONCLUSIONS: The risk of cardiovascular events is related to the age in HIV-infected patients. Therefore, an increased duration of life due to a more effective antiretroviral therapy will have a significant impact on the rate of cardiovascular events in this patient population. In the future, further increase of cardiovascular events in HIV-infected patients may be expected.

Glycaemic control of diabetic patients in an urban primary health care setting in Sarawak: the Tanah Puteh Health Centre experience.

Achieving glycaemic goals in diabetics has always been a problem, especially in a developing country with inadequate facilities such as in Sarawak in Malaysia. There are no reported studies on the control of diabetes mellitus in a diabetic clinic in the primary health care setting in Sarawak. This paper describes the profile of 1031 patients treated in Klinik Kesihatan Tanah Puteh Health Centre. The mean age was 59 years, the mean BMI 27 kg/m2. There was a female preponderance and mainly type-2 diabetes. Mean HbA1c was 7.4%. Glycaemic control was optimal in 28% (HbA1c <6.5%), fair in 34% (HbA1c 6.5-7.5%) and poor in 38% (HbA1c >7.5%). Reasonable glycaemic control can be achieved in the primary health care setting in Sarawak.

Use of the GlucoWatch biographer in children with type 1 diabetes.

OBJECTIVE: To determine whether use of the GlucoWatch biographer improves glucose control in children and adolescents with type 1 diabetes. METHODS: Forty children in poor glucose control (glycohemoglobin [HbA1c] >8%) were randomized to diabetes management with or without glucose monitoring using the biographer. Conventional glucose monitoring was performed 4 times daily in both groups. Those randomized to the biographer group were asked to wear the device 4 times per week for 3 months (intervention phase) and to perform blood glucose monitoring if the biographer alerted them that glucose was < or =70 mg/dL (3.9 mmol/L) or > or =300 mg/dL (16.7 mmol/L). After 3 months, all patients received biographers and were followed for 6 months (observation phase). HbA1c values were determined at baseline and after 1, 3, 6, and 9 months. RESULTS: The median HbA1c was 8.6% and 8.9% (control versus biographer) at baseline and was significantly lower in the biographer group after 3 months (8.4% vs 9%). More hypoglycemia was detected when subjects were wearing the biographer, especially at night. No severe hypoglycemia occurred. During the observation phase, HbA1c values at 6 months were 8.5% and 8.3% and at 9 months were 8.6% and 8.4% in the control and biographer groups, respectively. Two children dropped out of the study, 1 because of skin irritation from using the device. CONCLUSIONS: The GlucoWatch biographer was well tolerated by children and adolescents and significantly improved glucose control compared with standard therapy. The use of the biographer with an alarm to detect nocturnal hypoglycemia has the potential to increase the safety of diabetes management in children.

Helicobacter pylori, gastrointestinal symptoms, and metabolic control in young type 1 diabetes mellitus patients.

OBJECTIVE: The role of Helicobacter pylori infection in metabolic control and gastrointestinal symptoms in type 1 diabetes mellitus (DM1) patients has been debated. The aim of this study was to investigate the prevalence of H pylori, of the more cytotoxic Cag-A-positive strains, and the effects of infection on gastrointestinal symptoms and metabolic control in young DM1 patients. Research Design and Methods. H pylori infection was investigated by using the 13C-urea breath test in 121 DM1 patients (65 males, 56 females; mean age: 15 +/- 6 years) and 147 matched controls. In positive patients, an assay for specific immunoglobulin G against Cag-A was performed. Glycosylated hemoglobin A, daily insulin requirement, and duration of illness were established; a questionnaire concerning the presence of dyspeptic symptoms was administered. RESULTS: No difference in H pylori infection rate between patients and controls was observed. Thirty-four (28.1%) of 121 patients and 43 (29.25%) of 147 controls were infected. Twenty-one patients and 24 controls were positive for Cag-A. Glycosylated hemoglobin A, daily insulin requirement, and duration of illness were not affected by infection nor by Cag-A status. Among gastrointestinal symptoms, only halitosis was related to H pylori infection, but this association disappeared after correction for age. Positive patients with halitosis showed a worse glycemic control than uninfected patients with halitosis. CONCLUSIONS: H pylori infection and Cag-A-positive strains do not affect metabolic control in DM1 patients. With regard to gastrointestinal symptoms studied, H pylori infection, when present in participants with halitosis, seems to predict a worse metabolic control than in H pylori-negative patients with halitosis.

The form of iron oxide deposits in thalassemic tissues varies between different groups of patients: a comparison between Thai beta-thalassemia/hemoglobin E patients and Australian beta-thalassemia patients.

Mössbauer spectra of 12 beta-thalassemia/hemoglobin E spleen samples from Thai patients who had not received multiple blood transfusions and chelation therapy and seven beta-thalassemia spleen samples from Australian patients who had received multiple blood transfusions and chelation therapy were recorded with sample temperatures of 78 K. Each spectrum was found to consist of a superposition of a relatively intense central doublet characteristic of high-spin Fe(III), a low intensity sextet of peaks due to magnetic hyperfine-field splitting, and occasionally a doublet that could be attributed to heme iron. A significant (P=0.01) difference (Kolmogorov-Smirnov statistic of 0.71) between the distributions of sextet signal intensity as a fraction (Fs) of the total non-heme iron Mössbauer spectral signal for the two groups of patients was detected. The distribution of Fs for the Thai beta-thalassemia/hemoglobin E spleens had a mean value of 0.128 (S.D. 0.035) while that for the Australian beta-thalassemia spleens had a mean of 0.27 (S.D. 0.12). No significant difference between the distributions of non-heme iron concentrations in the tissues for the two groups of patients was detected by atomic absorption spectrometry. This study shows that the Australian beta-thalassemia patients had a higher fraction of their non-heme spleen iron in a goethite-like form than the Thai beta-thalassemia/Hb E patients.

Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired, heme oxygenase-dependent resistance to renal injury.

Considerable attention is directed to a surprising biologic phenomenon wherein tissues exposed to one insult acquire resistance to another. We identify a novel example of acquired resistance to acute renal failure and a mechanism that contributes to such resistance. Nephrotoxic serum, administered to rats 24 h before the induction of glycerol-induced acute renal failure, reduces functional and structural injury that occurs in this model. Since heme oxygenase, the rate-limiting enzyme in heme degradation, protects against heme protein-induced renal injury, we questioned whether induction of heme oxygenase underlies the protection afforded by nephrotoxic serum. Kidney heme oxygenase (HO-1) mRNA was induced 6 h after nephrotoxic serum and renal tubules were identified as the site of expression of heme oxygenase protein. Induction of heme oxygenase was accompanied by increased renal content of ferritin but not by induction of other antioxidant enzymes. Inhibition of heme oxygenase prevented the protection afforded by nephrotoxic serum. Nephrotoxic serum did not protect against ischemic acute renal failure, a model in which heme oxygenase is not induced. Thus, nephrotoxic serum protects against glycerol-induced acute renal failure by inducing heme oxygenase in tubules. This study provides the first demonstration of resistance to tubular injury acquired from glomerular inflammation, uncovers a mechanism for such resistance, and exposes the dialogue that occurs between glomeruli and tubules.

Hemolysis on intravenous administration of a new calcium antagonist.

Hemolysis-inducing properties of the new calcium antagonist Ro 40-5967 administered intravenously to 39 healthy male subjects were investigated in a placebo-controlled study. The volunteers were randomized into five parallel groups of 9 subjects each: three groups, receiving infusions of 40 mg Ro 40-5967 in 60, 30, and 15 min, respectively; one group receiving 80 mg Ro 40-5967 in 30 min as two simultaneous doses of 40 mg in the cubital veins of both arms; and one group receiving 80 mg Ro 40-5967 in 30 min in one arm. Within each group, 3 subjects received placebo under randomized double-blind conditions. Plasma haptoglobin decreased by 67% after 3.5 h in 2 subjects who received 80 mg Ro 40-5967 in one arm (treatment schedule thereupon discontinued). Serum bilirubin levels also increased in a dose-dependent manner in all groups as compared with placebo. Other parameters of hemolysis remained unchanged; no hemoglobinuria was observed. The intravascular hemolysis observed on infusion limits the therapeutic application of Ro 40-5967 to oral use only.

Multifunctional roles of glycosyl-phosphatidylinositol lipids.

The results presented here indicate that GPI lipids are a structurally and functionally diverse molecular family. Despite new detailed information on the structures of GPI-anchored proteins, there is relatively scant information on the structure of free-GPI. Thus, little is known of the relationships between GPI structures and the mechanism of their biological effects. For example, there is no distinction at the structural level between hormone-sensitive free-GPI and those that serve as precursors for protein-GPI. Nor is there precise biochemical data on the mechanism and importance of free-GPI in hormone signaling, or the signaling roles that GPI anchors play in protein function. The T-cell activation cascade is an ideal system for studying both forms of GPI and their derivatives. The study of GPI molecules in T lymphocytes offers the exciting possibility of addressing questions on the structure, function, genesis, and regulation of both free- and protein-GPI molecules in a single cell type. The detection of multiple protein-GPI and free-GPI forms, and of hormone-sensitive GPI, provides the first approach to these issues. For the moment, the potential for biochemical signaling by intact GPI or its metabolites is enormous. If significant progress is to be made, the structures of hormone sensitive free-GPI must be elucidated. Only then can we precisely define the roles of these molecules in the regulation of cell metabolism and proliferation.

Tubular secretion of Tamm-Horsfall protein is decreased in type 1 (insulin-dependent) diabetic patients with diabetic nephropathy.

Signs of glomerular, proximal and distal tubular dysfunction as well as metabolic control were studied in type 1 diabetes mellitus. To that end, the urinary excretion rates of albumin, sodium, phosphate and Tamm-Horsfall protein as well as HbA1c levels were measured in 20 patients with different degrees of diabetic nephropathy (positive Albustix for several years). Eight diabetic patients with short duration of diabetes and without any diabetic complications and 10 apparently healthy subjects were studied for comparison. The HbA1c levels in the three groups were 8.6 +/- 1.2, 5.9 +/- 2.2 and 4.1 +/- 0.4%, respectively (mean +/- SD). Duration of diabetes in the two diabetic groups were 27 +/- 7 and 3 +/- 1 years, respectively. The urinary protein levels were measured by enzyme-linked immunoassays. The fractional clearance of sodium (1.9 +/- 1.9%; p < 0.001) and phosphate (27 +/- 11%; p < 0.01) were increased in patients with diabetic nephropathy compared to diabetic patients without nephropathy (0.6 +/- 0.2 and 16 +/- 4%) and healthy control subjects (0.6 +/- 0.1 and 16 +/- 4%, respectively). Tamm-Horsfall protein excretion rate was decreased in both diabetic groups (15.0x/3.1 and 37.9x/1.9 micrograms/min, geometric mean x/tolerance factor, p < 0.001 and p < 0.05, respectively) compared to the healthy subjects (63.8x/1.3 micrograms/min). Furthermore, patients with diabetic nephropathy had a lower excretion rate of Tamm-Horsfall protein (15.0x/3.1 micrograms/min) compared to patients without signs of nephropathy (37.9x/1.9 micrograms/min, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)