Kallikrein protects against microalbuminuria in experimental type I diabetes.

Tissue kallikrein is the main kinin-forming enzyme in mammals, and differences in kinin levels are thought to be a contributing factor to diabetic nephropathy. Here, we determined the role of the kallikrein-kinin system in the pathogenesis of streptozotocin-induced diabetic nephropathy in wild-type and tissue kallikrein-knockout mice. All diabetic mice developed similar hyperglycemia, but the knockout mice had a significant two-fold increase in albuminuria compared to the wild-type mice before and after blood pressure elevation. Ezrin mRNA, a podocyte protein potentially implicated in albuminuria, was downregulated in the kidney of knockout mice. One month after induction of diabetes, the mRNAs of kininogen, tissue kallikrein, kinin B1, and B2 receptors were all increased up to two-fold in the kidney in both genotypes. Diabetes caused a 50% decrease in renal angiotensin-converting enzyme expression and a 20-fold increase in kidney injury molecule-1 reflecting tubular dysfunction, but there was no genotype difference. Our study found an early activation of the kallikrein-kinin system in the kidney and that this has a protective role against the development of diabetic nephropathy. The effect of tissue kallikrein deficiency on microalbuminuria in diabetic mice is similar to the effect of genetically high angiotensin-converting enzyme levels, suggesting that both observations, in part, result from a deficiency in kinins.

GDF15 triggers homeostatic proliferation of acid-secreting collecting duct cells.

Although adult kidney cells are quiescent, enlargement of specific populations of epithelial cells occurs during repair and adaptive processes. A prerequisite to the development of regenerative therapeutics is to identify the mechanisms and factors that control the size of specific populations of renal cells. Unfortunately, in most cases, it is unknown whether the growth of cell populations results from transdifferentiation or proliferation and whether proliferating cells derive from epithelial cells or from circulating or resident progenitors. In this study, the mechanisms underlying the enlargement of the acid-secreting cell population in the mouse kidney collecting duct in response to metabolic acidosis was investigated. Acidosis led to two phases of proliferation that preferentially affected the acid-secreting cells of the outer medullary collecting duct. All proliferating cells displayed polarized expression of functional markers. The first phase of proliferation, which started within 24 h and peaked at day 3, was dependent on the overexpression of growth differentiation factor 15 (GDF15) and cyclin D1 and was abolished when phosphatidylinositol-3 kinase and mammalian target of rapamycin were inhibited. During this phase, cells mostly divided along the tubular axis, contributing to tubule lengthening. The second phase of proliferation was independent of GDF15 but was associated with induction of cyclin D3. During this phase, cells divided transversely. In summary, acid-secreting cells proliferate as the collecting duct adapts to metabolic acidosis, and GDF15 seems to be an important determinant of collecting duct lengthening.

Tissue kallikrein deficiency aggravates cardiac remodelling and decreases survival after myocardial infarction in mice.

BACKGROUND: Tissue kallikrein (TK) is a major kinin-releasing enzyme present in arteries. TK is involved in cardioprotection in the setting of acute myocardial ischaemia but its role in post-ischaemic heart failure (HF), a major cause of delayed mortality after myocardial infarction (MI), is unknown. AIM: To determine whether TK deficiency in the mouse influences survival and cardiac remodelling after MI. METHODS: MI was induced in 10 week-old male TK-deficient mice and wild-type littermates. Survival was assessed up to 14 months. Cardiac morphological and functional parameters were serially measured by echocardiography. In another experiment, myocardial capillary density and NOS content were evaluated at 3 months. RESULTS: Infarct size was similar in both genotypes. MI resulted in severe cardiac dysfunction. Up to 12 months after MI, TK(-/-) mice displayed an increased mortality rate (P<0.05, relative risk of death=3.41) and aggravation of left ventricular hypertrophy and dilatation by comparison with TK(+/+) (+18% and +27% respectively, both P<0.05). NOS1 and NOS3 were abnormally regulated in the heart of TK(-/-) mice after MI. CONCLUSIONS: TK exerts a protective role in HF in mice. Coronary effects are probably involved. As partial genetic deficiency in TK activity occurs in humans, TK-deficient subjects may be at increased risk of mortality in HF.

Designing a Coding Data Warehouse to Support and Enhance Medical Act Coding.

Standards Data Warehouse has been implemented in many hospitals. It has enormous potential to improve performance measurement and health care quality. Accessing, organizing, and using these data to optimize clinical coding are evolving challenges for hospital systems. This paper describes development of a coding data warehouse based Entities-Attribute-Value (EAV) that we created by importing data from the clinical data warehouse (CDW) of public hospital. In particular, it focuses on design, implementation, and evaluation of the warehouse. Moreover, it defines the rules to convert a conceptual model of coding into an EAV logical model and his implementation using integrating biology and the bedside (i2b2). We evaluate it using data research mono and multi-criteria and then calculate the precision of our model. The result shows that, the coding data warehouse provides with good accuracy, an association of diagnostic code and medical act closer the patient's clinical landscape. Doctors without knowledge of coding rules could use this information to optimize and improve the diagnostic coding.

Design and Implementation of Big Data-Based Documents to Optimize Medical Coding.

Clinical information systems (CISs) in some hospitals streamline the data management from data warehouses. These warehouses contain heterogeneous information from all medical specialties that offer patient care services. It is increasingly difficult to manage large volumes of data in a specific clinical context such as quality coding of medical services. The document-based Not Only SQL (NO-SQL) model can provide an accessible, extensive and robust coding data management framework while maintaining certain flexibility. This paper focus on the design and implementation of a big data-coding warehouse, it also defines the rules to convert a conceptual model of coding into a document-oriented logical model. Using that model, we implemented, analyzed a big data-coding warehouse via the Mongodb database, and evaluated it using data research mono- and multi-criteria and then calculated the precision of our model.

Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias.

BACKGROUND: Small scale clinical trials suggested the feasibility and the efficacy of autologous myoblast transplantation to improve ventricular function after myocardial infarction. However, these trials were hampered by unexpected episodes of life-threatening ventricular tachyarrhythmias (VT). We investigated cardiac electrical stability after myoblast transplantation to the myocardium. METHODS AND RESULTS: Seven days after coronary ligation, Wistar rats were randomized into 3 groups: a control group receiving no further treatment, a vehicle group injected with culture medium into the infarcted myocardium, and a myoblast group injected with autologous myoblasts. Holter monitoring did not discriminate the myoblast from the vehicle groups. Programmed Electrical Stimulation (PES) was performed to evaluate further a cardiac substrate for arrhythmia susceptibility. The occurrence of sustained VT during PES was similar in control and vehicle groups (5/17 and 4/19 rats, respectively; p=0.50). In contrast, 13/20 rats (65%) from the myoblast group showed at least one episode of sustained VT during PES (p<0.05 and p<0.005 versus control and vehicle groups). As a further control group, rats injected with autologous bone marrow mononuclear cells into the infarcted myocardium did not show increased susceptibility to PES. CONCLUSIONS: In an infarcted rat model, myoblast transplantation but not bone marrow mononuclear cells or myocardial injection per se induces electrical ventricular instability. Because ventricular arrhythmias are life-threatening disorders, we suggest that such preclinical evaluation should be conducted for any new source of cells to be injected into the myocardium.

Constructing a Pre-Emptive System Based on a Multidimentional Matrix and Autocompletion to Improve Diagnostic Coding in Acute Care Hospitals.

Short-stay MSO (Medicine, Surgery, Obstetrics) hospitalization activities in public and private hospitals providing public services are funded through charges for the services provided (T2A in French). Coding must be well matched to the severity of the patient's condition, to ensure that appropriate funding is provided to the hospital. We propose the use of an autocompletion process and multidimensional matrix, to help physicians to improve the expression of information and to optimize clinical coding. With this approach, physicians without knowledge of the encoding rules begin from a rough concept, which is gradually refined through semantic proximity and uses information on the associated codes stemming of optimized knowledge bases of diagnosis code.

Using a snowflake data model and autocompletion to support diagnostic coding in acute care hospitals.

PURPOSE: Efficient and adequate coding is essential for all hospitals to optimize funding, follow activity, and perform epidemiological studies. OBJECTIVE: We propose an autocompletion method for optimizing diagnostic coding in acute care hospitals. METHODS: Using a terminology snowflake model integrating SNOMED 3.5 and ICD-10 codes, autocompletion algorithms generate a list of diagnostic expressions from partial input concepts. RESULTS: A general autocompletion component has been developed and tested on a set of inpatient summary reports. Concepts expressed as strings of three or four characters return a noisy list of diagnostic labels or codes. Concepts expressed as groups of strings return lists that are semantically close to the labels present in hospital reports. The most pertinent information lies in the length of the expressions entered. CONCLUSION: Autocompletion can be a complementary tool to existing coding support systems.

Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension.

The present study was intended to determine whether the long-term V2 receptor-mediated effects of vasopressin on sodium reabsorption in the renal collecting duct is an aggravating factor in salt-sensitive hypertension. Deoxycorticosterone acetate (DOCA)-salt hypertension was induced in uninephrectomized rats that had been chronically pretreated with a V2 agonist (dDAVP; 1-deamino-8D-arginine vasopressin; 0.6 microg/kg.d) or a V2 antagonist (SR121463, 3 mg/kg.d) or were untreated. Plasma osmolality and natremia were not significantly different in the groups. Blood pressure was significantly increased by dDAVP pretreatment (+11 mm Hg; P = 0.006), and this effect was exacerbated after DOCA-salt-induced hypertension (+17 mm Hg; P = 0.042). The dDAVP-treated rats had a lower hematocrit (40 +/- 2% vs. 47 +/- 1% and 45 +/- 2%) and markedly higher albuminuria (91 +/- 9 vs. 17 +/- 8 and 15 +/- 8 mg/d), mortality rate (50% vs. 0% and 0%), and cardiac and renal hypertrophy than the control and SR121463 groups. Histological renal lesions were worsened by V2 agonism and prevented by V2 antagonism. Renal mRNA expression of beta- and gamma-subunits of the epithelial sodium channel was significantly increased by dDAVP treatment (P < 0.05). These findings provide evidence that chronic stimulation of vasopressin V2 receptor raises basal blood pressure in rats and exacerbates the development of DOCA-salt hypertension, organ damage, and mortality. These effects could be due at least in part to the sustained stimulation of sodium reabsorption by epithelial sodium channel in the distal part of the nephron, which promotes sodium retention.

Profiles of the 2 INK4a gene products, p16 and p14ARF, in human reference urothelium and bladder carcinomas, according to pRb and p53 protein status.

The INK4a/ARF locus encodes 2 cell cycle regulatory proteins: p16 and p14(ARF). P16 inhibits the activities of cdks, which maintain the retinoblastoma protein (pRb) in its active hypophosphorylated state. P14(ARF) blocks MDM2-induced p53 degradation and transactivational silencing. In this study, we investigated the expression of p16 and p14(ARF) in reference human urothelium and in 51 urothelial carcinomas (UCs) of all stages and grades, by reverse transcription-polymerase chain reaction (RT-PCR). Patterns of p14(ARF) and p16 expression were compared with each other and then with patterns of p53 and pRb protein expression, respectively, as determined by immunohistochemistry. P14(ARF) and p16 mRNAs were present at low levels or were undetectable in reference urothelia and in most superficial tumors, whereas they were present at high levels in a subset of tumors of advanced stage and high grade. The expression profiles of these 2 mRNAs were correlated in all but 4 cases, indicating that the 2 INK4a products may have nonredundant functions. Forty-six of the 51 tumors (90%) presented changes to or a lack of activation of the p14(ARF)-p53 pathway and were p53 positive (n = 10), p14(ARF) negative (n = 23), or both p53 positive and p14(ARF) negative (n = 13), suggesting that these 2 components of the pathway may be altered or nonactivated. Markedly high levels of p16 mRNA (n = 5) were associated with the absence of pRb expression, with the exception of 1 case in which the p16 gene contained a deletion mutation. A lack of p16 mRNA or low levels of this mRNA were associated with pRb detection in all but 1 case. In invasive UCs, the p16-pRb pathway, the p14(ARF)-p53 pathway, or in many cases both pathways were altered or not activated, demonstrating the involvement of these pathways in invasive bladder tumorigenesis.

Determinants of continuance intention in a post-adoption satisfaction evaluation of a clinical information system.

PURPOSE: The evaluation of end-user satisfaction is an essential part of any clinical information system (CIS) project. The purpose of this study is to evaluate the determinants of CIS continuance intention in a late post-adoption phase at the Georges Pompidou University Hospital (HEGP) in Paris. METHODS: We designed an electronic survey instrument based on an IT post-adoption model (ITPAM) developed from three previous models, i.e., the Delone and McLean Information Success Model, the Davis TAM model and the Bhattacherjee information system continuance intention model. RESULTS: 419 questionnaires were collected from CIS users directly involved in patient care. The perceived CIS quality, usefulness and user satisfaction are significantly lower for medical professions than other professional groups. Continuance intention is very high within all professional subgroups. In a multiple regression analysis, the global satisfaction (R(2) = .780) was positively and significantly correlated with CIS quality, confirmation of expectations and perceived CIS usefulness. The continuance intention (R(2) = .392) was positively and significantly correlated with perceived CIS usefulness, confirmation of expectations and global satisfaction. CONCLUSION: In a late post-adoption CIS deployment phase, continuance intention does not significantly depend on individual end user characteristics but is significantly associated with the perceived CIS usefulness, confirmation of expectations and global satisfaction.

Antiangiogenic properties of viscum album extracts are associated with endothelial cytotoxicity.

BACKGROUND: Viscum album (VA) extracts are widely used in cancer therapy and are known to be cytotoxic to tumors and endothelial cells. Angiogenesis plays an important role in the growth, sustenance and metastasis of tumors. Inhibition of angiogenesis is now being explored as a new therapeutic avenue for cancer. MATERIALS AND METHODS: The cytotoxicity of VA extracts was analyzed by Annexin V labeling and propidium iodide uptake in EA-hy926 endothelial cells. The antiangiogenic effect was studied in vitro by treating the EA-hy926 cells in matrigel and subsequent analysis of vascular formation. Computer-assisted image analysis of vascular formation was analyzed to quantify the in vitro data. In vivo studies were performed by implanting matrigel +/- VA extracts in Balb/C mice that had been subjected to IP treatment with VA extracts. RESULTS: The combination of systemic and intra- matrigel treatment with the VA Qu Spez extract caused significant inhibition of angiogenesis. The VA P extract treatment showed insignificant change in vessel formation. CONCLUSION: These results may provide novel guidelines towards improved strategies using VA extracts based on the inhibition of angiogenesis of tumors.

Computerized morphometric analysis of microvasculature in non-small cell lung carcinoma.

Interactions between tumor cells and microvasculature are particularly critical. This computerized morphometric study was designed to analyze the distance between cancer cells and blood vessels and microvasculature organization in non-small cell lung carcinoma (NSCLC) comparing squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Seventy nine nests of tumor cells, located less than or more than 3 mm from the invading edge, with a similar surface area, and their surrounding stroma were analyzed. After immunolabeling with an antihuman CD34 monoclonal antibody, computerized morphometric analyses of microvascular density (MVD), distribution of microvessels within stroma, and fractions of carcinomatous cells over various distances from microvessels were performed. This analysis showed a significantly higher MVD score in ADC than in SCC, particularly close to the invading edge (382+/-57 in ADC <3 mm; 242+/-28 in SCC <3 mm, p=0.015). Moreover, a significantly higher proportion of cancer cells was situated more than 75 microm from microvessels in SCC than in ADC, regardless of their site in relation to the invading edge (for example, 25+/-5% in ADC <3 mm; 52+/-3% in SCC <3 mm, p=0.001).

Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures.

PURPOSE: It has been established that the immune system plays an important role in tumor rejection. There is also compelling evidence that immune responses can develop independently of secondary lymphoid organs in tertiary lymphoid structures. We studied the presence and the correlation of tertiary lymphoid structures with clinical outcome in non-small-cell lung cancer (NSCLC), as the prognostic value of these structures in patients with cancer had not yet been established. PATIENTS AND METHODS: This retrospective study was performed by immunohistochemistry on paraffin-embedded tissue specimens from 74 patients with early-stage NSCLC. RESULTS: Tertiary lymphoid structures were detected in some tumors but not in nontumoral lungs. Thus we called these structures tumor-induced bronchus-associated lymphoid tissue (Ti-BALT). As in lymph nodes, Ti-BALTs were composed of mature dendritic cell (DC)/T-cell clusters adjacent to B-cell follicles and had features of an ongoing immune response. Because the quantitative counting of Ti-BALT was difficult to achieve, we used mature DCs that homed exclusively in Ti-BALT as a specific marker of these structures. Univariate analysis showed that the density of mature DCs was highly associated with a favorable clinical outcome (overall, disease-specific, and disease-free survival), suggesting that Ti-BALT may participate in antitumoral immunity. The density of tumor-infiltrating lymphocytes, in particular, CD4(+) and T-bet(+) Th1 T cells, was profoundly decreased in tumors weakly infiltrated by mature DCs. CONCLUSION: The density of mature DCs was found to be a better predictor of clinical outcome than the other parameters tested. The number of tumor-infiltrating mature DCs may identify patients with early-stage NSCLC who have a high risk of relapse.

Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in adult rat offspring.

OBJECTIVE: Epidemiological and experimental studies have led to the hypothesis of fetal origin of adult diseases, suggesting that some adult diseases might be determined before birth by altered fetal development. We have previously demonstrated in the rat that in utero exposure to maternal diabetes impairs renal development leading to a reduction in nephron number. Little is known on the long-term consequences of in utero exposure to maternal diabetes. The aim of the study was to assess, in the rat, long-term effects of in utero exposure to maternal diabetes on blood pressure and renal function in adulthood. RESEARCH DESIGN AND METHODS: Diabetes was induced in Sprague-Dawley pregnant rats by streptozotocin on day 0 of gestation. Systolic blood pressure, plasma renin activity, and renal function were measured in the offspring from 1 to 18 months of age. High-salt diet experiments were performed at the prehypertensive stage, and the abundance of tubular sodium transporters was evaluated by Western blot analysis. Kidney tissues were processed for histopathology and glomerular computer-assisted histomorphometry. RESULTS AND CONCLUSIONS: We demonstrated that in utero exposure to maternal diabetes induces a salt-sensitive hypertension in the offspring associated with a decrease in renal function in adulthood. High-salt diet experiments show an alteration of renal sodium handling that may be explained by a fetal reprogramming of tubular functions in association or as a result of the inborn nephron deficit induced by in utero exposure to maternal diabetes.

Tissue kallikrein is involved in the cardioprotective effect of AT1-receptor blockade in acute myocardial ischemia.

Angiotensin-converting enzyme inhibitors limit infarct size in animal models of myocardial ischemia reperfusion injury. This effect has been shown to be due to inhibition of bradykinin degradation rather than inhibition of angiotensin II formation. The purpose of this study was to determine whether angiotensin AT1 receptor blockade by losartan or its active metabolite EXP3174 protects against myocardial ischemia-reperfusion injury in mice and whether this protection is mediated by the kallikrein kinin system. We subjected anesthetized mice to 30 min of coronary artery occlusion followed by 3 h of reperfusion and evaluated infarct size immediately after reperfusion. Losartan (Los) or EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] were administered 5 min before starting reperfusion at dosages determined by preliminary studies of blood pressure effect and inhibition of angiotensin pressor response. Compared with saline, both drugs significantly reduced myocardial infarct size by roughly 40% (P < 0.001). Pretreatment of mice with the selective AT2 receptor antagonist PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid] did not affect infarct size in the absence of losartan but abolished the reduction in infarct size provided by losartan. In tissue kallikrein gene-deficient mice (TK-/-), losartan no longer reduced infarct size. Pretreatment of wild-type mice with the B2 receptor antagonist icatibant reproduced the effect of TK deficiency. We conclude that AT1 receptor blockade provides cardioprotection against myocardial ischemia-reperfusion injury through stimulation of AT2 receptors. Kallikrein and B2 receptor are major determinants of this cardioprotective effect of losartan. Our results support the hypothesis of a coupling between AT2 receptors and kallikrein during AT1 receptor blockade, which plays a major role in cardioprotection.

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients.

Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.

Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure.

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.

Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation.

BACKGROUND: In the past it was widely assumed that hyaline afferent arteriolosclerosis was responsible for ischemic glomerulosclerosis in the aging and hypertensive kidney. However, glomerular lesions of focal segmental glomerulosclerosis are now recognized in essential hypertension. Experimentally, such lesions are associated with loss of autoregulation of blood flow and glomerular hyperperfusion, as well as initial glomerular hypertrophy. These observations challenge the notion of ischemia as a unitary explanation for glomerulosclerosis. METHODS: A morphometric study was performed on normal portions of eight kidneys removed for tumors in aging, normotensive patients. Measurements were made of 126 pairs of afferent arterioles and their associated glomeruli. In addition, the amount of extracellular matrix (ECM) in the immediate periglomerular region was quantitated. RESULTS: Afferent arterioles were divided into three types according to the presence or absence of hyaline deposits and whether these did or did not obstruct the lumen. Arterioles with nonobstructive hyaline deposits had lumens over twice as large as those without deposits (482 +/- 240 micro2 vs. 204 +/- 160 micro2, P=0.0000). Their associated glomeruli had significantly greater total capillary area, particularly the hilar capillaries (1276 +/- 797 micro2 vs. 667 +/- 492 micro2, P=0.002), but with larger individual capillaries elsewhere as well (P=0.03). Arterioles with obstructive deposits differed from those with nonobstructive deposits by their smaller lumens (P=0.001) and walls (P=0.004), with a higher proportion of ECM in the periglomerular region (P=0.001), all consistent with a later stage of lesion. Glomeruli were divided into four basic types: normal, hypertrophic, glomeruli with features of focal segmental glomerulosclerosis (FSGS-type), and ischemic. Compared to normal glomeruli, hypertrophic glomeruli were larger, with greater total capillary area (P=0.0005), particularly the hilar capillaries (P=0.0000), and larger capillaries in the remainder of the tuft (P=0.003), but showed no evident lesions. FSGS-type glomeruli were also larger, with larger hilar capillaries (P=0.0005), but showed an increase in ECM due to sclerotic lesions (P=0.004). The remaining capillaries showed an inverse relation with the amount of mesangial matrix, showing a spectrum of sizes from enlarged to shrunken. As anticipated, ischemic glomeruli were significantly smaller than normal ones in every parameter measured. There was a strong association between hypertrophic/FSGS-type glomeruli and hyaline arteriolosclerosis, found in 90.3% of such glomeruli, versus 29.1% for the remaining glomeruli (P=0.0001). The great majority of hyaline deposits were of the nonobstructive variety (86.2%), but some were obstructive (13.8%), particularly in FSGS-type glomeruli, consistent with a more advanced lesion. CONCLUSIONS: We believe we have demonstrated in the aging kidney of humans the morphologic correlates of loss of autoregulation, occurring on a focal basis, with afferent arteriolar dilatation and increase in glomerular capillary size and subsequent focal segmental glomerulosclerosis. Hyaline arteriolosclerosis of the nonobstructive sort is strongly associated with these changes and may play a role in their pathogenesis.

Diabetes-induced albuminuria: role of antidiuretic hormone as revealed by chronic V2 receptor antagonism in rats.

BACKGROUND: Vasopressin, an antidiuretic hormone, is elevated in diabetes mellitus (DM). The aim of this study was to evaluate whether the V(2) receptor-mediated actions of vasopressin contribute to the albuminuria of diabetes. METHODS: Fourteen adult male Wistar rats with streptozotocin-induced DM were treated over 9 weeks with a selective, non-peptide, orally active V(2) receptor antagonist (SR 121463) and were compared to 14 untreated diabetic rats (control). The dose of antagonist was adapted in order to maintain urine osmolality close to plasma osmolality, but not to induce the formation of hypoosmotic urine. Every second week, urine was collected in metabolic cages for two 24 h periods. RESULTS: Urinary albumin excretion (UAE) rose regularly and significantly with time in the untreated control group, whereas it did not rise in treated rats. Interestingly, a variable pattern of UAE increase over time was observed in different rats of the control group. Some rats exhibited pronounced progression of albuminuria with time, while others showed no or only a very modest rise. An a posteriori partition of the control group into 'progressors' and 'non-progressors' revealed that progressors had more intense urinary concentrating activity, higher creatinine clearance and larger relative glomerular mesangial area than the other subgroup. CONCLUSIONS: This study shows that V(2) receptor-mediated actions of vasopressin play a critical role in the albuminuria of diabetes. It also reveals that individual rats, like humans, seem to exhibit an unequal susceptibility to diabetic nephropathy, or at least to albuminuria, a factor considered to be one of its early manifestations.