Effect of proteinuria on the rapid kidney function decline in chronic kidney disease depends on the underlying disease: A post hoc analysis of the BRIGHTEN study.

AIMS: It is unclear whether the effect of proteinuria on rapid kidney function decline is equivalent among diabetic kidney disease (DKD), non-DKD with diabetes (NDKD+DM), and nephrosclerosis without diabetes (NS-DM), particularly in advanced chronic kidney disease patients. METHODS: In total, 1038 chronic kidney disease patients who participated in the BRIGHTEN study were included in the present study. A linear mixed effect model was applied to estimate the annual estimated glomerular filtration rate decline in each disease group. RESULTS: The prevalence of rapid decliners (rapid kidney function decline, defined as an eGFR loss of > 5 mL/min/1.73 m2/year) in the DKD group (44.6 %) was significantly higher compared with the NDKD+DM (27.9 %) and NS-DM (27.0 %) groups. By contrast, the prevalence of rapid decliners in different urine total protein to creatinine ratio (UPCR) categories (<0.5, 0.5 to < 1.0, 1.0 to < 3.5, and ≥ 3.5 g/g) were equivalent between the DKD and NS-DM groups. Moreover, the prevalence of a UPCR < 1.0 g/g in rapid decliners of the NS-DM group was more than double than in those of the DKD and NDKD+DM groups. CONCLUSIONS: The risk of rapid kidney function decline in NS-DM patients with low levels of proteinuria may be greater than initially predicted.

The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli.

Aging is both a natural and inevitable biological process. With advancing age, the kidneys undergo anatomical and physiological changes that are not only the consequences of normal organ senescence but also of specific diseases (such as atherosclerosis or diabetes) that occur with greater frequency in older individuals. Disentangling these two processes, one pathologic and the other physiologic, is difficult. In this review we concentrate on the glomerular structural and functional alterations that accompany natural aging. We also analyze how these changes affect the identification of individuals of advancing age as having chronic kidney disease (CKD) and how these changes can influence prognosis for adverse outcomes, including all-cause mortality, end-stage renal disease, cardiovascular events and mortality, and acute kidney injury. This review describes important shortcomings and deficiencies with our current approach and understanding of CKD in the older and elderly adult.

Net endogenous acid production is associated with a faster decline in GFR in African Americans.

Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24 h urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I(125)iothalamate glomerular filtration rate (iGFR) and time to end-stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein-to-creatinine ratio, and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate of 1.01 ml/min per 1.73 m(2) per year faster in the highest compared to the lowest quartile. However, in time-to-event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25 mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease.

Podocyte injury damages other podocytes.

Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.

Senile nephrosclerosis--does it explain the decline in glomerular filtration rate with aging?

Nephrosclerosis can be defined by the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis on renal biopsy. Chronic kidney disease is identified clinically by a reduction in glomerular filtration rate (GFR) and has been characterized histologically by nephrosclerosis. Many relatively healthy older adults have been diagnosed with chronic kidney disease because of a decline in GFR with normal aging. Recent data show that in healthy adults (living kidney donors), nephrosclerosis on renal biopsy does not associate with GFR independent of age. This may be explained by the decline in GFR and nephrosclerosis being universal with aging (i.e. senescence), by structural changes in the kidney other than nephrosclerosis impacting GFR, or by extrarenal factors affecting GFR decline with age. However, the argument that the age-related decline in GFR can be fully explained by the development of nephrosclerosis in a subset of older adults is not supported by existing data.

[Management of a patient in condition of preterminal chronic renal insufficiency as criterion for probability assessment of risk factors].

It was modified the instant method of Caplan-Meiyer (worked out for the characteristic of the patients revealing) for calculation of a new criterion--preservation of the patient in the condition pre terminal chronic renal insufficiency (CRI). It was determined 102,5; 112,5; 122,5; 132,5; 142,5; 152,5; 162,5; 172,5; 182,5; 192,5; 202,5; 212,5; 222,5; 232.5; 242,5-monthly preservation of the patient in the condition pre terminal CRI, which was formed: (98.0 +/- 1.1)%, (92.8 +/- 1.8)%, (85.6 +/- 2.1)%, (75.9 +/- 2.4)%, (62.8 +/- 2.7)%, (51.0 +/- 2.5)%, (39.9 +/- 2.4)%, (30.7 +/- 2.1)%, (22.9 +/- 1.9)%, (17.0 +/- 1.6)%, (11.8 +/- 1.5)%, (7.9 +/- 1.3)%, (4.6 +/- 1.1)%, (1.9 +/- 0.6)%. It was shown that size of this parameter changed considerably subject to the initial reason of CRI the patient sex, adequateness of the medical providing, from harmful habits (smoking) and the presence of accompanying pathologies (comorbidity coefficient).

Common charge-shift mutation Glu65Lys in K+ channel ß1-Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.

BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory ß1-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Naturally occurring genetic variants in human chromogranin A (CHGA) associated with hypertension as well as hypertensive renal disease.

Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 30-UTR. In chromaffin cell-transfected CHGA 30-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 30-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 30-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.

Systolic pressure, diastolic pressure, or pulse pressure as a cardiovascular risk factor in renal disease.

Chronic kidney disease is a leading global health problem with an increasing prevalence. Hypertension is present in most patients with chronic kidney disease, and hypertension-related nephrosclerosis is a top cause of progressive renal damage and end-stage renal disease. Systolic blood pressure (BP) and pulse pressure, together with nocturnal BP, are the most important factors favoring the progression of renal failure. Consequently, strict control of BP and other cardiovascular risk factors is required, including an adequate degree of suppression of the renin-angiotensin system in every patient.

Effects of Sustained-Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results.

TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI2 Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 µg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 µg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.

Adrenergic beta-1 receptor genetic variation predicts longitudinal rate of GFR decline in hypertensive nephrosclerosis.

BACKGROUND: End-stage renal disease (ESRD) due to hypertension is common and displays familial aggregation in African Americans, suggesting genetic risk factors, including adrenergic activity alterations which are noted in both hypertension and ESRD. METHODS: We analysed 554 hypertensive nephrosclerosis participants (without clinically significant proteinuria) from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) African American Study of Kidney Disease and Hypertension (AASK) cohort to determine whether decline in glomerular filtration rate (GFR) over approximately 3.8 years was predicted by common genetic variation within the adrenergic beta-1 (ADRB1) receptor at non-synonymous positions Ser49Gly and Arg389Gly. RESULTS: The polymorphism at Ser49Gly (though not Arg389Gly, in only partial linkage disequilibrium at r(2) = 0.18) predicted the chronic rate of GFR decline, with minimal decline in Gly(49)/Gly(49) (minor allele) homozygotes compared to Ser(49) carriers; concordant results were observed for haplotypes and diploid haplotype pairs at the locus. An independent replication study in 1244 subjects from the San Diego Veterans Affairs Hypertension Cohort confirmed that Gly(49)/Gly(49) homozygotes displayed the least rapid decline of eGFR over approximately 3.6 years. CONCLUSION: We conclude that GFR decline rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway, particularly at ADRB1. The results suggest novel strategies to approach the role of the adrenergic system in the risk and treatment of progressive renal disease.

Epithelial-to-mesenchymal transition in early transplant tubulointerstitial damage.

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation. Detection of EMT depended on the marker used; low levels of alpha-smooth muscle actin were found in 61% of biopsies, but the less specific marker S100 calcium binding protein-A4 (also known as Fsp1) suggested a higher incidence of EMT. The presence or development of TID did not correlate with EMT but instead significantly correlated with subclinical immune activity (P < 0.05). Among biopsies showing TID, microarray analysis revealed differential regulation of 127 genes at 1 mo and 67 genes at 3 mo compared with baseline; these genes were predominantly associated with fibrosis, tissue remodeling, and immune response. Of the 173 EMT-associated genes interrogated, however, only 8.1% showed an expression pattern consistent with EMT at 1 mo and 6.3% at 3 mo. The remainder were not differentially altered, or their changes in expression were opposite those expected to promote EMT. Quantitative reverse transcriptase-PCR revealed that the expression pattern of 12 EMT-associated genes was inconsistent over time, opposite that expected, or consistent with subclinical rejection or inflammation. In conclusion, EMT does not seem to play a significant role in the development of early allograft fibrosis.

Thrombotic thrombocytopenic purpura: the masquerader.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder with a mortality rate of up to 90% if left untreated, and is characterized by microvascular thrombi, mainly in small arteries and capillaries, thrombocytopenia, hemolysis, and neurological abnormalities. Malignant hypertension (HTN) is a clinical syndrome characterized by severe hypertension associated with end-organ damage; including encephalopathy, renal dysfunction, and retinal hemorrhage due to platelet aggregation in the microcirculation leading to thrombotic microangiopathy (TMA). These are similar to TTP. Malignant hypertension can cause endothelial injury and fibrinoid necrosis in the vessel wall which results in its clinical manifestations. Therefore, it is difficult to differentiate malignant hypertension from TTP. However, it is critical to differentiate these two entities, as early initiation of plasmapheresis in TTP can be life saving. TTP is considered a masquerader as it can present with few clinical features and, if the index of suspicion is not very high, lead to mortality.

Volume Ratio of Glomerular Tufts to Bowman Capsules and Renal Outcomes in Nephrosclerosis.

BACKGROUND: The concomitant appearance of glomerular collapse and enlargement is characteristic of the histological findings in nephrosclerosis. However, no previous study quantitatively examined the clinicopathological significance of this feature in patients with biopsy-proven nephrosclerosis. METHODS: Renal biopsy specimens and follow-up data from nephrosclerosis patients with estimated glomerular filtration rates >30 ml/min/1.73 m2 at diagnosis were retrospectively reviewed. Mean volumes for glomerular tufts (GV) and Bowman capsules (BV) were separately calculated, based on the measurement of all areas of glomerular tufts and Bowman capsules in a cross-section of biopsy specimens. The G/B ratio was defined as the ratio of GV to BV. The doubling of serum creatinine levels (DSC) and the initiation of renal replacement therapies (end-stage renal disease (ESRD)) were examined as renal outcome indices. RESULTS: A total of 67 patients with biopsy-proven nephrosclerosis were included. Clinicopathological findings at biopsy, other than GV, were comparable among all patients, irrespective of G/B ratio. Overall, 25 patients (37%) developed DSC and 9 (13%) developed ESRD during the median observation periods of 7.8 and 8.5 years, respectively. Renal survival curve analyses indicated a significantly worse prognosis for patients with a low G/B ratio, as compared with those with a high G/B ratio. Cox hazard analyses for DSC identified low G/B ratio as a significant predictor, but not low GV or BV. CONCLUSIONS: These results suggest that the quantitative evaluation of G/B ratio may detect subtle abnormalities in the glomerulus, indicating the subsequent renal outcomes of nephrosclerosis patients.

Amplified Association Between Blood Pressure and Albuminuria in Overweight Patients With Biopsy-Proven Hypertensive Nephrosclerosis.

BACKGROUND: An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis. METHODS: A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period. RESULTS: Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (ß = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years. CONCLUSIONS: Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.

Synergistic induction of osteopontin by aldosterone and inflammatory cytokines in mesangial cells.

Hypertensive nephrosclerosis is characterized by activation of the renin-angiotensin-aldosterone system in combination with an inflammatory response characterized by an infiltration of T-cells and mononuclear cells, which release proinflammatory cytokines like IL-1beta/TNFalpha. In various models of experimental hypertensive disease the chemokine osteopontin (OPN) enhances further leukocyte infiltration. Therefore, we investigated the induction of OPN expression in renal mesangial cells (MCs) by aldosterone and the inflammatory cytokines IL-1beta/TNFalpha. Incubation with aldosterone resulted in a time- and concentration-dependent increase in OPN mRNA and protein. OPN mRNA expression followed a biphasic time course with an early increase between 4 and 8 h and the second phase starting at 14 h. The early phase was independent of protein synthesis, indicating a direct effect of aldosterone. Aldosterone-mediated induction of OPN was prevented by spironolactone, indicative of a receptor-mediated aldosterone effect. The mineralocorticoid receptor (MR) was identified in MCs by RT-PCR and immunoprecipitation, and shown to interact with a putative aldosterone-response element of the OPN promoter. The proinflammatory cytokines IL-1beta and TNFalpha only marginally affected OPN expression in MCs. However, coincubation of aldosterone and the cytokines synergistically increased OPN mRNA and protein levels. Since the synergistic effect on OPN mRNA was inhibited by diphenyleneiodonium, we assume an involvement of reactive oxygen species (ROS). We conclude that the chemokine OPN is a target gene of aldosterone in renal MCs, which is activated via the MR, and that proinflammatory cytokines enhance aldosterone-dependent OPN expression. In vivo, this may result in further leukocyte infiltration aggravating hypertensive nephrosclerosis.

Estrogen and angiotensin II interactions determine cardio-renal damage in Dahl salt-sensitive rats with heart failure.

UNLABELLED: In women, the role of estrogen in the interrelationship between the progression of kidney and cardiac diseases is not fully understood. The present study attempted to elucidate the relationship between the process of cardiac remodeling and nephrosclerosis in ovariectomized Dahl salt-sensitive (DSS) rats with myocardial infarction (MI). METHODS: 60 DSS rats with MI produced by ligation of the left coronary artery were divided into 5 groups as follows: group 1: MI rats without ovariectomy (OVX); group 2: MI rats with OVX; group 3: MI and OVX rats with estradiol (E) (17beta-estradiol 15 mg/pellet/90 days subcutaneous pellet) supplementation; group 4: MI rats with OVX administered an angiotensin receptor antagonist (ARB), olmesartan, (2.5 mg/kg b.w. per day), and group 5: MI and OVX rats with E supplementation and administration of ARB in combination. Two weeks after ligation of the left coronary artery, OVX was carried out; this marked the start of the experiment. Body weight, systolic blood pressure (SBP), and urinary protein excretion were measured every 2 weeks for 12 weeks. Transthoracic echocardiogram was performed under anesthesia at 12 weeks. Blood samples for measurement of plasma renin activity, angiotensin (Ang) II, and aldosterone were obtained. At the end of the study, the heart and the kidney tissues were collected for light microscopic examination and evaluations of the expression of mRNA of angiotensin-converting enzyme and endothelial nitric oxide synthase (ecNOS). RESULTS: SBP in female DSS rats with MI and with or without OVX transiently increased at week 4 and then gradually decreased toward the end of the study. Administration of ARB reduced SBP significantly (p < 0.05) in rats with OVX independently of E supplementation. OVX significantly (p < 0.05) increased and E supplementation further increased (p < 0.01) urinary protein excretion. E supplementation plus ARB administration significantly decreased urinary protein excretion. OVX increased activity in renin-angiotensin-aldosterone system (RAS) and both E and ARB supplementation suppressed RAS (p < 0.05). Expression of ecNOS was decreased in the rats with OVX and this was reversed by E supplementation in the heart but not in the kidneys, although combined administration with ARB reversed it in the kidney (p < 0.01). Transthoracic echocardiogram showed decreased ejection fraction by OVX and it was reversed by E supplementation and administration of ARB. Pathological changes of the kidney showed that E supplementation produced thrombotic microangiopathic lesions in the glomeruli. These changes were reversed by concomitant administration of ARB. CONCLUSION: Although estrogen appears to protect the development of cardiac remodeling and heart failure, it promotes microangiopathy in the kidney due to thrombosis. Concomitant administration of estrogen and ARB might be effective for protection of the heart and the kidney in OVX DSS rats with CHF.

Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension.

OBJECTIVE: We examined the contribution of high blood pressure versus direct mineralocorticoid effects to the progression of kidney inflammation and fibrosis in established experimental deoxycorticosterone-acetate (DOCA)-salt hypertension. METHODS: Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. After 4 weeks of DOCA-salt hypertension, rats were either killed (n = 6), or treated with a non-hypotensive dose of spironolactone (n = 7) or triple therapy (hydrochlorothiazide, reserpine and hydralazine, n = 8) to normalize blood pressure or with vehicle (n = 19) for two further weeks. Mean arterial pressure (MAP) was measured intra-arterially. Glomerulosclerosis, interstitial fibrosis, macrophage infiltration and complement deposition were evaluated on kidney sections. Expression of collagens, chemokines and cytokines was measured by real-time PCR. RESULTS: MAP was elevated in DOCA rats, not affected by spironolactone and normalized by triple therapy. Glomerulosclerosis and interstitial fibrosis of DOCA rats were alleviated by spironolactone and triple therapy. Macrophage infiltration, complement C3 deposition and nitrotyrosine staining in the kidney were significantly reduced by spironolactone as well as triple therapy. The expression of collagens, chemokines, adhesion molecules and profibrotic cytokines in the kidney was elevated in hypertension and decreased by triple therapy but not significantly affected by spironolactone. CONCLUSION: Direct mineralocorticoid effects as well as high blood pressure per se contribute to inflammation and fibrosis of the kidney. Oxidative stress may mediate the direct mineralocorticoid effects on kidney inflammation.