Luis I. Juncos

Long-term enalapril and hydrochlorothiazide in radiation nephritis.

Radiation of the kidney often leads to renal failure. The contribution of arterial hypertension to the development of this complication is unclear. The aim of this study was to determine the renal effects of antihypertensive therapy in 1- and 2-kidney rat models of radiation nephritis. Five groups of Long Evans rats had X-irradiation of the left kidney. In groups 1 and 2, the right kidney was left undisturbed (2-kidney model). The rats in group 3, 4 and 5 underwent right nephrectomy 21 days before radiation (1-kidney model). Groups 1 and 3 received no drug treatment and served as controls for each model. Groups 2 and 4 had enalapril 50 mg/l in drinking water and group 5 hydrochlorothiazide (HCT) 200 mg/l, also in drinking water. Blood pressure increased significantly in both control groups and remained normal throughout the study in all treated groups. At the end of the study, mean urinary protein excretion was lower in the two enalapril-treated groups but not in HCT-treated animals. Groups 1 and 2 (2-kidney models) showed similar increments in plasma creatinine (PCreat), and, in both groups, the creatinine clearance (CCreat) dropped to the same extent. Among nephrectomized animals (1-kidney model), PCreat was lower and CCreat higher in the enalapril-treated group. Consistent with these findings, glomerular sclerosis was less severe in both enalapril-treated groups. We conclude that, in radiation nephritis, lowering blood pressure with enalapril exerts a beneficial effect on renal function and structure, whereas a similar reduction in blood pressure induced by HCT does not.

Statins reverse renal inflammation and endothelial dysfunction induced by chronic high salt intake

High salt intake (HS) is a risk factor for cardiovascular and kidney disease. Indeed, HS may promote blood-pressure-independent tissue injury via inflammatory factors. The lipid-lowering 3-hydroxy 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors exert beneficial lipid-independent effects, reducing the expression and synthesis of inflammatory factors. We hypothesized that HS impairs kidney structure and function in the absence of hypertension, and these changes are reversed by atorvastatin. Four groups of rats were treated for 6 wk in metabolic cages with their diets: normal salt (NS); HS, NS plus atorvastatin and HS plus atorvastatin. We measured basal and final body weight, urinary sodium and protein excretion (U(Prot)V), and systolic blood pressure (SBP). At the end of the experimental period, cholesterolemia, creatinine clearance, renal vascular reactivity, glomerular volume, cortical and glomerular endothelial nitric oxide synthase (eNOS), and transforming growth factor (TGF)-β1 expression were measured. We found no differences in SBP, body weight, and cholesterolemia. HS rats had increased creatinine clearence, U(Prot)V, and glomerular volume at the end of the study. Acetylcholine-induced vasodilatation decreased by 40.4% in HS rats (P < 0.05). HS decreased cortical and glomerular eNOS and caused mild glomerular sclerosis, interstitial mononuclear cell infiltration, and increased cortical expression of TGF-β1. All of these salt-induced changes were reversed by atorvastatin. We conclude that long-term HS induces inflammatory and hemodynamic changes in the kidney that are independent of SBP. Atorvastatin corrected all, suggesting that the nitric oxide-oxidative stress balance plays a significant role in the earlier stages of salt induced kidney damage.

Local and Systemic Cellular Immunity in Early Renal Artery Atherosclerosis

BACKGROUND AND OBJECTIVES Modern imaging techniques have increased the incidental detection of renal atherosclerotic disease (RAD). Because immune activation may hasten RAD progression, identifying cellular immune markers might provide clues to clinical activity. In this study, cellular immune markers were assessed in early RAD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Immune cell markers in peripheral blood of two groups of hypertensive patients with normal carotid and coronary arteries were evaluated: 28 patients had incidental RAD and 22 patients had normal renal arteries; 21 renal arteries obtained at necropsy from individuals with history of hypertension and tissue evidence of RAD were examined and matched with 21 individuals with normal renal arteries. Cell subpopulations were measured by flow cytometry in peripheral blood and direct cell count, respectively, using T and dendritic cells monoclonal antibodies. RESULTS Peripheral blood of RAD patients showed increased numbers of cells expressing CD3, CD4, CD83, and CD86. CD4 to CD8 ratio was 8.3 ± 1.4 (RAD) to 3.4 ± 0.9 (normal; P<0.001). No differences were found in CD25, CD8, and S100 among groups. Postmortem samples from RAD showed increased CD3+, CD4+, CD86+, and S100+ cells, whereas CD25+ and CD8+ were unmodified between groups. CD4+ to CD8+ ratio was higher in the RAD(PM) group. CONCLUSIONS These results are consistent with an increased expression of immune cell markers in early RAD. Additional studies will explore if they may potentially turn into treatment targets to prevent disease progression.

Anandamide inhibits transport-related oxygen consumption in the loop of Henle by activating CB1 receptors.

The energy required for active Na chloride reabsorption in the thick ascending limb (TAL) depends on oxygen consumption and oxidative phosphorylation (OXP). In other cells, Na transport is inhibited by the endogenous cannabinoid anandamide through the activation of the cannabinoid receptors (CB) type 1 and 2. However, it is unclear whether anandamide alters TAL transport and the mechanisms that could be involved. We hypothesized that anandamide inhibits TAL transport via activation of CB1 receptors and NO. For this, we measured oxygen consumption (Q(O(2))) in TAL suspensions to monitor the anandamide effects on transport and OXP. Anandamide reduced Q(O(2)) in a concentration-dependent manner. During Na-K-2Cl cotransport and Na/H exchange inhibition, anandamide did not inhibit TAL Q(O(2)). To test the role of the cannabinoid receptors, we used specific agonists and antagonists of CB1 and CB2 receptors. The CB1-selective agonist WIN55212-2 reduced Q(O(2)) in a concentration-dependent manner. Also, the CB1 receptor antagonist rimonabant blocked the effect of anandamide on Q(O(2)). In contrast, the CB2-selective agonist JHW-133 had no effect on Q(O(2)), while the CB2 receptor antagonist AM-630 failed to block the anandamide effects on Q(O(2)). To confirm these results, we measured CB1 and CB2 receptor expression and only CB1 expression was detected. Because CB1 receptors are strong nitric oxide synthase (NOS) stimulators and NO inhibits transport in TALs, we evaluated the role of NO. Anandamide stimulated NO production and the NOS inhibitor N(G)-nitro-L-arginine methyl ester blocked the anandamide effects on Q(O(2)). We conclude that anandamide inhibits TAL Na transport-related Q(O(2)) via activation of CB1 receptor and NOS.

8-iso-prostaglandin-F2α stimulates chloride transport in thick ascending limbs: role of cAMP and protein kinase A

Salt reabsorption by the loop of Henle controls NaCl handling and blood pressure regulation. Increased oxidative stress stimulates NaCl transport in one specific segment of the loop of Henle called the thick ascending limb (TAL). The isoprostane 8-iso-prostaglandin-F2α (8-iso-PGF2α) is one of the most abundant nonenzymatic lipid oxidation products and has been implicated in the development of hypertension. However, it is not known whether 8-iso-PGF2α regulates transport or the mechanisms involved. Because protein kinase A (PKA) stimulates NaCl transport in several nephron segments, we hypothesized that 8-iso-PGF2α increases NaCl transport in the cortical TAL (cTAL) via a PKA-dependent mechanism. We examined the effect of luminal 8-iso-PGF2α on NaCl transport by measuring chloride absorption (J(Cl)) in isolated microperfused cTALs. Adding 8-iso-PGF2α to the lumen increased J(Cl) by 54% (from 288.7 ± 30.6 to 446.5 ± 44.3 pmol·min(-1)·mm(-1); P < 0.01), while adding it to the bath enhanced J(Cl) by 35% (from 236.3 ± 35.3 to 319.2 ± 39.8 pmol·min(-1)·mm(-1); P < 0.05). This stimulation was blocked by Na-K-2Cl cotransporter inhibition. Next, we tested the role of cAMP. Basal cAMP in the cTAL was 18.6 ± 1.6 fmol·min(-1)·mm(-1), and 8-iso-PGF2α raised it to 35.1 ± 1.4 fmol·min(-1)·mm(-1), an increase of 94% (P < 0.01). Because cAMP stimulates PKA, we measured J(Cl) using the PKA-selective inhibitor H89. In the presence of H89 (10 μM), 8-iso-PGF2α failed to increase transport regardless of whether it was added to the lumen (216.1 ± 16.7 vs. 209.7 ± 23.8 pmol·min(-1)·mm(-1); NS) or the bath (150.4 ± 32.9 vs. 127.1 ± 28.6 pmol·min(-1)·mm(-1); NS). We concluded that 8-iso-PGF2α stimulates cAMP and increases Cl transport in cTALs via a PKA-dependent mechanism.

Renal tubular acidosis and vasculitis associated with IgE deposits in the kidney and small vessels

We report a woman with a history of allergies, polyuria, polydipsia, proteinuria, renal loss of electrolytes, renal tubular acidosis, nephrocalcinosis, and palpable purpura. A proximal defect was excluded by a normal bicarbonate reabsorption curve, and a distal tubular defect was shown because urine pH did not decrease to less than 6.4 despite ammonium chloride-induced systemic acidosis. Moreover, furosemide failed to improve urinary acidification. Urine-to-blood PCO(2) gradient was less than 14 mm Hg, although the urine bicarbonate level reached values as high as 89 mEq/L. Combining bicarbonate and neutral phosphate infusions increased the urine-to-blood PCO(2) gradient to only 20 mm Hg. These subnormal PCO(2) gradient values point to proton-pump dysfunction in the collecting tubule. Histological evidence of tubulointerstitial disease accompanied the tubular defects. The striking histological feature was the presence of immunoglobulin E (IgE) deposits in glomeruli, tubuli, and vessels. Concurrent with these findings, she had high serum IgE titers and CD23 levels. IgE antibodies from her serum were reactive against human renal tubuli, with binding to two regions that matched two different proteins present in cortex and medulla. One of these proteins corresponded to carbonic anhydrase II (31 kd); the second, to an unidentified protein that seems attached to cell membranes. We suggest that these IgE antibodies could have had a pathogenic role in this patients glomerular, tubular, and small-vessel disease.

Mineralocorticoid Receptor Antagonism in AKI: A New Hope?

AKI is a leading cause of morbidity and mortality in hospitalized patients, particularly among the critically ill, and its incidence is increasing.[1][1],[2][2] This has piqued the interest of renal researchers, leading to a massive surge in our knowledge of its pathogenesis, systemic effects, and

Abnormal renal vasodilation to an amino acid infusion in congestive heart failure: Normalization by enalapril

In congestive heart failure (CHF), the neurohormonal mechanisms that cause renal vasoconstriction, particularly those depending on the renin-angiotensin system, could interfere with renal vasodilating mechanisms. To elucidate this issue, we studied the kidney response to an amino acid infusion (known to cause renal vasodilation in healthy individuals) in eight patients with CHF. We found that the amino acid infusion (0.7 mL/kg/h of a 10% solution) elicited no renal hemodynamic response, in marked contrast to healthy subjects. We next hypothesized that the renin-angiotensin system (known to be activated in heart failure) has a role in the lack of response to the amino acid infusion. To test this hypothesis, we repeated the study after two 5-mg doses of enalapril, an inhibitor of the angiotensin-converting enzyme, administered 12 hours apart. After enalapril treatment, the amino acid infusion caused a 45% increase in mean renal blood flow (RBF) from 383 +/- 55 to 557 +/- 51 mL/min at the fifth hour (P < 0.05). This normalization of the renal response to the amino acid infusion occurred without changes in cardiac output or in systemic vascular resistance. Hence, the renal fraction of the cardiac output increased during the amino acid infusion. The recovery of the renal vascular response was not accompanied by an increase in glomerular filtration rate (GFR; filtration fraction decreased), suggesting a predominant efferent arteriole dilatation. Our study shows that, in heart failure, the kidney loses its ability to increase RBF in response to an amino acid load. This lack of renal vascular response can be restored by inhibiting the renin-angiotensin system and is unrelated to changes in systemic hemodynamics.

Cognitive Impairment/Dementia in Chronic Renal Disease

Chronic kidney disease (CKD) is a worldwide public health problem that is increasing in prevalence, especially in the elderly. CKD and/or end stage renal disease (ESRD) patients have numerous comorbidities that increase the risk of cognitive impairment and dementia (CI/D). In fact, almost every stage of CKD is associated with an increased risk of CI/D; the risk increases as the severity of CKD increases. The mechanisms responsible for this increased risk are largely due to the accelerated vascular disease of CKD/ESRD that leads to an increase in vascular dementia. However, other factors such as increased risk of thrombotic and hemorrhagic strokes, uremic toxins, and suboptimal aspects of dialytic therapies also contribute to the development and progression of CI/D. The importance of CI/D in CKD/ESRD patients is that it impairs quality of life, and carries with it a greater risk of hospitalization, disability, dialysis withdrawal, and mortality. Despite the magnitude of the problem, CI/D is largely under-recognized in the renal patient, and optimal management strategies are unknown. The aim of this chapter is to provide an overview of the epidemiology, pathogenesis/pathophysiology, diagnostic approaches, and therapeutic considerations for CI/D in patients with CKD/ESRD.

Angiotensin II and Anti Diuretic Hormone Exert Synergistic Effects on Thick Ascending Limb Transport in Spontaneously Hypertensive Rats

Background: Sodium reabsorption is increased in the thick ascending limb (TAL) of Henle in several hypertensive models. In this segment, while transport is increased by ADH via cAMP, sodium reabsorption results from Ang II-induced superoxide (O₂^-) production. Surprisingly, it is unknown whether these mechanisms overlap in hypertension. We hypothesized that Ang II and ADH have accumulative effects on TALs transport during hypertension. Methods: The effect of ADH/Ang II in TALs from spontaneously hypertensive rats (SHR) on oxygen consumption (QO₂), cAMP and O₂^- was measured. Results: Basal QO₂ was 113.3 ± 14.2 nmol O₂/min/mg protein. Addition of ADH (1 n<smlcap>M</smlcap>) increased QO₂ by 198%. In the presence of ADH, Ang II (1 n<smlcap>M</smlcap>) elicited a QO₂ transient response and then rose to 321.5 ± 28.3 (p = 0.003 vs. ADH). These accumulative effects could be due to nitric oxide synthase (NOS) uncoupling, lower Ang II ability to decrease cAMP or increased O₂^-. We first measured QO₂ using a NOS inhibitor. Pretreatment with <smlcap>L</smlcap>-NAME did not block the observed interaction (p = 0.001 Ang II vs. ADH). Also, Ang II blocked the ADH-stimulated cAMP accumulation in TAL of SHRs. In the presence of ADH, Ang II increased O₂^- production in TALs from SHR by 309% (p = 0.015 vs. basal). The O₂^- scavenger tempol blocked the Ang II effects on QO₂. In the presence of the NADPH oxidase inhibitor apocynin, the accumulative effects of ADH and Ang II were abolished. We conclude that (1) in SHR, Ang II has accumulative effects on ADH-stimulated transport; (2) this effect is mediated by AT1 receptors, and increased O₂^- production.