Aldosterone and the kidney.

The mineralocorticoid aldosterone is a key regulator of blood pressure, fluid and electrolyte homeostasis, and acts via the mineralocorticoid receptor (MR). In recent years, an increasing number of studies revealed deleterious effects of aldosterone via its receptor. Especially in patients with primary hyperaldosteronism (PHA) a significant higher risk of developing cardiovascular comorbidities and comortalities was reported. Also renal insufficiency is clearly increased in patients with PHA indicating a role of aldosterone and the MR in the pathogenesis of renal injury. It has been shown that aldosterone in combination with an elevated salt intake, leads to renal inflammation, fibrosis, podocyte injury, and mesangial cell proliferation. This review focuses on the current knowledge of aldosterone effects in the kidney and highlights this topic from 2 perspectives: from clinical medicine and from experimental studies.

Primary hyperaldosteronism.

Primary hyperaldosteronism (PHA) is regarded as a rare disease with prevalence rates of 0.5 to 2% within the hypertensive population. Recent studies using more detailed screening procedures in small hypertensive cohorts have suggested that PHA may be more common than previously thought (3-18%). Since a validated and cost-effective routine screening protocol for this entity is not established, many clinicians are reluctant to consider PHA as an underlying cause for a patient's high blood pressure. The insufficient perception of PHA may have fatal consequences since most patients are curable by an operation and missing the diagnosis often leads to significant and irreversible end-organ damage. This review focuses on the diagnosis of PHA and gives a rational and cost-effective flow chart for routine screening and differential diagnosis of PHA in hypertensive patients.

Effect of immunosuppressive and other drugs on the cortisol-cortisone shuttle in human kidney and liver.

BACKGROUND: Impaired 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) has been suggested in patients with hypertension or renal disease, where it may contribute to sodium retention and hypertension. 11beta-HSD1, which is expressed predominantly in liver and adipose tissue, influences glucose homeostasis and fat distribution by altering intracellular cortisol (F) concentrations. We tested immunosuppressive drugs that cause hypertension, and substances that interfere with steroidogenesis or influence glucose homeostasis for their ability to influence the inhibition of 11beta-HSD isozymes. METHODS: For inhibition experiments, we used microsomes prepared from unaffected parts of human liver segments and resected human kidney cortex because of hepatocarcinoma or renal cell cancer. The inhibitory potency of several compounds was evaluated in concentrations from 10(-9)-10(-5) mol/l. RESULTS: Only sirolimus, but not cyclosporine A, tacrolimus, mycophenolate mofetil, or azathioprine showed a slight inhibition of 11beta-HSD2 activity. None of the drugs that inhibit steroidogenesis (suramine, mitotane, etomidate, and aminogluthethimide) or steroid metabolism (rifampicine) influenced 11beta-HSDs, nor did ginsenoides Re, Rc, and Rb1. Among sulfonylureas, only gliclazide decreased significantly 11beta-HSD1 activity. CONCLUSIONS: Increased blood pressure due to immunosuppressive drugs is probably not caused by direct inhibition of 11beta-HSD2. An additional glucose lowering effect of sulfonylurea gliclazide may be due to its ability to inhibit 11beta-HSD1.

The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease.

Glomerular-derived proteins may activate tubular cells to express the macrophage-directed chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Macrophages at interstitial sites have a central role in directing renal scarring. We have prospectively assessed the relationship between albuminuria, urinary MCP-1/CCL2, interstitial macrophage infiltration, in situ damage, and clinical outcomes in a large group of patients with chronic kidney disease. We studied 215 patients and quantified albumin-creatinine ratio (ACR), urinary MCP-1/CCL2, interstitial macrophage numbers, and in situ damage. ACR correlated with urinary MCP-1/CCL2 (correlation 0.499; P<0.001), interstitial macrophage numbers (correlation 0.481; P<0.001), and index of chronic damage (correlation 0.363; P<0.001). Macrophage numbers closely correlated with in situ damage (correlation 0.755; P<0.001). By multivariate analysis ACR, urinary MCP-1/CCL2, and interstitial macrophage numbers were interdependent. By Kaplan-Meier survival analysis albuminuria, urinary MCP-1/CCL2, interstitial macrophages, and chronic damage predict the outcome. ACR, macrophage numbers, chronic damage, and creatinine independently predicted renal survival. The association of ACR with other variables was strongest in patients with less advanced disease states. There is a close association between albuminuria, urinary MCP-1/CCL2, and interstitial macrophage infiltration with in situ damage and clinical outcomes. These findings support the hypothesis that albuminuria triggers tubular MCP-1/CCL2 expression with subsequent macrophage infiltration. These processes may represent the dominant pathway for the progression of renal injury before the establishment of advanced renal scarring.

Blood components influence cytokine induction by bacterial substances.

While some studies clearly demonstrated transfer of cytokine-inducing substances (CIS) through dialysis membranes, other authors were unable to reproduce such a transfer. This inconsistency may have been caused by marked differences in experimental design. We performed a systematic evaluation of cytokine induction in whole blood and from separated peripheral blood mononuclear cells (PBMC) using either purified lipopolysaccharide (LPS) or culture supernatants from various bacterial strains. An in vitro hemodialysis circuit with whole blood in the blood compartment was employed; the dialysate was contaminated with sterile filtrates from Pseudomonas aeruginosa cultures. Addition of plasma samples from the blood side to PBMC readily induced interleukin (IL)-1beta and IL-6 after contamination of the dialysate, while the same samples failed to induce cytokine production in whole blood. In experiments using direct incubation, purified P. aeruginosa LPS induced more IL-1beta and IL-6 in whole blood compared to PBMC. In contrast, bacterial filtrates from Escherichia coli, Enterobacter cloacae and especially P. aeruginosa induced significantly less cytokines in whole blood compared to PBMC. Addition of erythrocytes but not granulocytes decreased cytokine induction by bacterial filtrates as well as by LPS, probably by adsorption of these substances. The addition of 30% plasma increased cytokine induction by LPS but decreased cytokine induction by P. aeruginosas filtrates. Our results suggest that cellular and plasmatic components of whole blood interact with bacterial CIS altering their pyrogenic activity. The detection of CIS depends on the test system used; whole blood cultures are not as sensitive for the detection of CIS from bacterial filtrates as PBMC cultures.

High-level sensitivity of quantitative pp65 cytomegalovirus (CMV) antigenemia assay for diagnosis of CMV disease in AIDS patients and follow-up.

Cytomegalovirus (CMV) antigenemia was evaluated in 174 patients positive for human immunodeficiency virus. Antigenemia could be detected in 96.7% of patients with CMV disease, 76.9% of patients suffering from a relapse of the disease, and 11.4% of asymptomatic patients with CD4 levels of < 100 cells per microliter. No antigenemia was detected in patients with CD4 levels of 250 to 500 cells per microliter. Specificity and the positive predictive value for CMV disease were increased only if more than 5 positive cells per slide were considered. However, CMV disease may also occur in patients with low-grade antigenemia.