Prevalence of albuminuria and cardiovascular risk profile in a referred cohort of patients with type 2 diabetes: an Asian perspective.

BACKGROUND: Microalbuminuria (MA) is a risk marker for diabetic nephropathy and cardiovascular (CV) disease (CVD) in patients with diabetes. This study aimed to describe the prevalence of albuminuria, CV risk factors, and treatments for renal and CV protection in an Asian population with type 2 diabetes. METHODS: This cross-sectional study conducted in eight Asian countries enrolled normotensive/hypertensive adults with type 2 diabetes without known proteinuria and/or non-diabetic kidney disease. Exclusion criteria were type 1 diabetes, menstruation, pregnancy, and acute fever. A single random urinary albumin/creatinine test was carried out in all patients. RESULTS: Of 8,561 patients, 14% had diabetic retinopathy, and 17% and 21% had history of CV disease and smoking, respectively. Normoalbuminuria was seen in 44%, MA in 44%, and macroalbuminuria in 12%. Target glycosylated hemoglobin (HbA1c) (<7%) was reached in only 37% of 3,834 patients with available values. Diabetes was managed by diet alone in 6%, while others received oral hypoglycemic drugs and/or insulin. In total, 75% did not reach target blood pressure (BP) of

A comparison of valsartan and captopril in patients with essential hypertension in Indonesia.

Adult Indonesian outpatients were randomised to receive either valsartan 80 mg once daily or captopril 25 mg twice daily for 8 weeks. The main criterion for tolerability was the incidence of adverse events. The primary efficacy variable was the change in mean sitting diastolic blood pressure (SDBP) from baseline to endpoint. No valsartan patients experienced dry cough, which was reported by 22 captopril patients (21.6%). Both drugs reduced mean SDBP and SSBP, with a trend in favour of valsartan. The percentage of valsartan patients whose BP normalised was higher than in captopril patients at week 4 (37% and 22%) and week 8 (45% and 34%), the difference being statistically significant at week 4 (p < 0.05). Valsartan 80 mg once daily is as effective as captopril 25 mg twice daily in reducing blood pressure in Indonesian patients, and has a better tolerability profile in respect of dry cough.

Control of monocyte influx in glomerulonephritis in transplanted kidneys in the rat.

Induction of anti-Thy-1 nephritis in different strains of inbred rats results in phenotypically different types of renal diseases. In Wistar and Lewis (LEW) rats, a transient influx of ED1+ macrophages occurs 24 hours after injection of anti-Thy-1 antibodies, whereas this does not occur in F344 rats. The present experiments were designed to investigate the role of the kidney in the regulation of the monocyte influx in this model. To dissociate the role of the immune system from local intrarenal factors in the control of monocyte influx, anti-Thy-1 nephritis was induced in LEW rats with an F344 kidney transplant and in F344 rats with a LEW kidney allograft. Acute rejection episodes were prevented by treatment with an anti-CD4 monoclonal antibody. Control rats received a syngeneic kidney graft. Monocyte influx after injection of anti-Thy-1 antibodies was found in the glomeruli of both LEW and F344 kidneys removed from LEW recipients, whereas there was no demonstrable monocyte influx after infusion of anti-Thy-1 antibodies in either LEW or F344 kidneys removed from F344 recipients. Monocyte infiltration correlated with the subsequent expansion of the mesangial extracellular matrix. The inability to attract monocytes was not due to the lack of glomerular expression of chemokines, because F344 and LEW glomeruli demonstrated a similar expression of monocyte chemoattractant protein-1 (MCP-1). Differences in the ability to activate the complement system were excluded. We conclude that the immune system controls the glomerular influx of monocytes and that the reaction of the mesangial cells is probably controlled by combinations of cytokines produced during the inflammatory process.

Increased urinary excretion of monocyte chemoattractant protein-1 during acute renal allograft rejection.

BACKGROUND: Acute rejection is characterized histologically by infiltration of the interstitium by mononuclear cells. Monocyte chemoattractant protein 1 (MCP-1) has recently been identified as a monocyte chemotactic factor. This study examined the possible role of MCP-1 in renal transplantation. METHODS: The concentration of MCP-1 in urine and serum of 19 renal transplant patients was investigated using an inhibition radioimmunoassay. The patients were divided into a non-rejection (NRj) and a rejection (Rj) group. Normal healthy volunteers were included as controls. Immunoperoxidase staining for MCP-1 and CD14, as a marker for macrophages, was performed in renal biopsies of transplant patients with rejection and six biopsies from histologically normal kidneys, as controls. The size of urinary MCP-1 was determined by gel filtration chromatography and in a number of fractions assessed for monocyte chemotactic activity using a modified Boyden chamber assay. RESULTS: Urinary excretion of MCP-1 in the Rj group ranged between 250 ng/mmol Cr and 3148 ng/mmol Cr with a median of 612 ng/mmol Cr. This is significantly higher than the results in the NRj group, ranging between 47 ng/mmol Cr and 288 ng/mmol Cr with a median of 229 ng/mmol Cr. In the normal control group, urinary MCP-1 levels ranged between 38 ng/mmol Cr and 74 ng/mmol Cr with a median of 50 ng/mmol Cr. The fractional excretion of MCP-1, calculated on the basis of MCP-1 and creatinine clearances, was found also to be significantly higher in the Rj group as compared to the NRj group. However, there was no significant difference in the serum levels of MCP-1 between the Rj, NRj, and normal control group. The intensity of MCP-1 staining in tubular epithelial cells and the degree of CD14+ cells in the interstitium was significantly higher in renal allograft biopsies than in the normal kidneys. In addition, MCP-1 isolated from urine of renal transplant patients with rejection was filtered with apparent molecular weight of 13 kDa and 11 kDa. Both sizes are chemotactically active for monocytes. CONCLUSIONS: These data suggest that urinary excretion of MCP-1 can be used as a marker for the episodes of acute rejection. The increase of urinary excretion of MCP-1 most likely is the result of local production by tubular epithelia cells. MCP-1 produced locally may, at least in part, be responsible for the influx of macrophages into the interstitium during rejection.

Regulation and production of IL-8 by human proximal tubular epithelial cells in vitro.

A number of inflammatory kidney diseases are associated with interstitial nephritis and influx of leucocytes in the renal interstitium. Potentially the influx of neutrophils in the interstitium may be induced by the chemotactic cytokine IL-8. In the present study we have analysed the production of IL-8 by cultured human proximal tubular epithelial cells (PTEC) in response to a number of proinflammatory cytokines. Primary cell lines of proximal tubular epithelium obtained from ten different kidneys, and cultured under serum-free conditions, were found to produce IL-8 to different degrees from not detectable levels up to 10.8 +/- 1.5 ng IL-8 per 1 x 10(5) cells in 72 h. Gel filtration chromatography of PTEC supernatant indicated that the size of IL-8 of PTEC is 15.1 and 8.1 kD, and is chemotactically active for polymorphonuclear neutrophils (PMN). Addition of 0.5 ng/ml rIL-1 alpha or 1000 U/ml recombinant tumour necrosis factor-alpha (rTNF-alpha) to the culture media of PTEC induced an up-regulation of IL-8 production up to 6.3-fold and 3.0-fold, respectively. The up-regulation by IL-1 alpha and TNF-alpha was dose- and time-dependent. In contrast, 500 U/ml recombinant interferon-gamma (rIFN-gamma) down-regulated the production of IL-8 3.4-fold. Northern blot analysis showed that IL-1 alpha and TNF-alpha increased the expression of IL-8 mRNA, whereas IFN-gamma reduced IL-8 mRNA expression. Taken together, these experiments indicate that human PTEC are a potential source of IL-8 in the kidney, and that IL-8 produced in the proximal tubule can be induced by various proinflammatory cytokines.

Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cells.

Impairment of renal function in various types of glomerular disease is associated with tubulointerstitial changes. The mechanism of mononuclear cell infiltration in the interstitium is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a monocyte-specific chemotactic factor. We analyzed the presence of MCP-1 in renal biopsies from patients with various forms of glomerular disease and demonstrated that MCP-1 expression is increased in renal tubular epithelial cells during disease. Further analysis showed that various cell lines of human proximal tubular epithelial cells (PTEC) produce MCP-1 in culture under serum-free conditions and that the production is inhibited by cycloheximide. IL-1 alpha and TNF-alpha enhanced the production by each cell line in a dose- and time-dependent manner as measured by radioimmunoassay. Northern blot analysis demonstrated that IL-1 alpha and TNF-alpha markedly enhanced the expression of MCP-1 mRNA. Taken together these observations support the notion that MCP-1 is synthesized de novo by PTEC. MCP-1 produced by PTEC is found to be 13 kD by gel filtration chromatography. It is chemotactically active for monocytes. We conclude that in various types of glomerular disease, MCP-1 expression in tubular epithelial cells is associated with up-regulation of MCP-1 production by PTEC. These findings raise the possibility that macrophages may accumulate in renal interstitium as a consequence of MCP-1 production by PTEC.

Monocyte chemoattractant protein-1 in normal and diseased human kidneys: an immunohistochemical analysis.

We conducted an immunohistochemical analysis to investigate the presence of monocyte chemoattractant protein-1 (MCP-1) in normal and diseased human kidneys and the correlation with infiltration of macrophages. A total of 50 renal biopsies were classified according to pathologic diagnosis. The distribution as well as the intensity of MCP-1 staining, and infiltration by CD68+ macrophages were evaluated in diseased versus normal kidneys. Weak staining of MCP-1 was detected in normal renal tissue, especially in tubular epithelial cells. Significant alterations in MCP-1 staining were observed in a number of diseases, in which the intensity of MCP-1 staining rather than the distribution of MCP-1-positive cells was higher. In membranous nephropathy, IgA nephropathy, and glomerulosclerosis, an association was found between the intensity of MCP-1 staining in tubular epithelial cells and interstitial infiltration of macrophages. The glomeruli in membranous nephropathy showed a stronger intensity of MCP-1 staining particularly in the glomerular visceral epithelial cells. The glomerular MCP-1 staining did not correlate significantly with the number of macrophages in the glomeruli. In conclusion, we describe increased cellular staining for MCP-1 in diseased human renal tissue, especially by tubular epithelial cells. Our observations suggest, complementary to in vitro and in vivo observations made by us and others, that specific roles may be played by MCP-1 in physiological and inflammatory processes in the kidney.

Glomerular filtration rate measurement by "single-shot" injection of inulin.

In 14 ADPKD patients the total body clearance and the urinary clearance of inulin using the constant infusion method were compared with the "single-shot" technique. Triplicate measurements of both clearances by each infusion method were obtained in 12 out of 14 patients. A high correlation was found between the total body clearance and the urinary clearance for both the constant infusion method (r = 0.96) and the single injection technique (r = 0.96). The coefficient of variation for the total body clearance of inulin was significantly lower for the constant infusion method and the single injection technique (7.8% and 7.1%) than for the urinary clearance of inulin (11.3% vs. 9.7%, P < 0.05). A constant overestimation of the urinary clearance by the total body clearance was observed with both methods (constant infusion method 8.3 ml.min-1 x 1.73 m-2 and single injection technique 13.4 ml.min-1 x 1.73 m-2). No concentration-dependent clearance was present. Determination of plasma inulin, especially at low levels, showed substantial interference by glucose. We conclude that, taking into account a constant overestimate of urinary clearance by the total body clearance of inulin, the single injection total body clearance possesses the best reproducibility and shows a good agreement with the conventional urinary clearance, which can be calculated by: GFR = TBCLss-13.1 ml.min-1 x 1.73 m-2 (in the range of 28 to 124 ml.min-1 x 1.73 m-2).