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)-ß1 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-ß1. 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.

The efficiency of potassium removal during bicarbonate hemodialysis.

Patients on chronic hemodialysis often portray high serum [K+]. Although dietary excesses are evident in many cases, in others, the cause of hyperkalemia cannot be identified. In such cases, hyperkalemia could result from decreased potassium removal during dialysis. This situation could occur if alkalinization of body fluids during dialysis would drive potassium into the cell, thus decreasing the potassium gradient across the dialysis membrane. In 35 chronic hemodialysis patients, we compared two dialysis sessions performed 7 days apart. Bicarbonate or acetate as dialysate buffers were randomly assigned for the first dialysis. The buffer was switched for the second dialysis. Serum [K+], [HCO3-], and pH were measured in samples drawn before dialysis; 60, 120, 180, and 240 min into dialysis; and 60 and 90 min after dialysis. The potassium removed was measured in the dialysate. During the first 2 hr, serum [K+] decreased equally with both types of dialysates but declined more during the last 2 hr with bicarbonate dialysis. After dialysis, the serum [K+] rebounded higher with bicarbonate bringing the serum [K+] up to par with acetate. The lower serum [K+] through the second half of bicarbonate dialysis did not impair potassium removal (295.9 +/- 9.6 mmol with bicarbonate and 299.0 +/- 14.4 mmol with acetate). The measured serum K+ concentrations correlated with serum [HCO3-] and blood pH during bicarbonate dialysis but not during acetate dialysis. Alkalinization induced by bicarbonate administration may cause redistribution of K during bicarbonate dialysis but this does not impair its removal. The more marked lowering of potassium during bicarbonate dialysis occurs late in dialysis, when exchange is negligible because of a low gradient.

Hyperkalemia, renal failure, and converting-enzyme inhibition: an overrated connection.

Hyperkalemia is widely viewed as a common complication of ACE inhibition in azotemic patients. These renal failure patients are the patients who benefit most from ACE inhibition. Because we could not confirm this notion after a retrospective evaluation of 236 azotemic patients, we studied 2 models of renal mass reduction. In the first, we did a 5/6 nephrectomy (Nx) on rats and studied them 2 weeks after surgery (before chronic renal changes had developed). A second group was studied 16 weeks after Nx, once chronic renal failure was established. Rats in both models were treated with quinapril in drinking water. After baseline evaluation, we challenged them either by a high-K(+) diet or by blocking aldosterone receptors. We found that although quinapril blocked the K(+)-induced increase in aldosterone, serum K(+) levels and K(+) balance were maintained before and during high K(+) intake or during simultaneous spironolactone administration. We conclude that in hemodynamically stable rats with reduced renal mass and renal dysfunction, the administration of an ACE inhibitor does not cause severe hyperkalemia.

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 patient's glomerular, tubular, and small-vessel disease.

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.

Abnormal endothelium-dependent responses in early radiation nephropathy.

While arterial hypertension and renal dysfunction are well recognized complications of renal irradiation, the mechanisms that trigger the development of these complications are unknown. Recently, it was reported that the endothelium is a major target in radiation injury. Because dysfunction of the endothelial cells may lead or contribute to the development of hypertension and renal dysfunction in radiation nephropathy, we tested the hypothesis that endothelium-dependent vasodilation is impaired in radiated kidneys prior to the onset of hypertension. To test this hypothesis, we used Long-Evans rats that had undergone left nephrectomy (3 weeks earlier) and irradiation (3000 r's) to the right kidney 8 days earlier (mean blood pressures in the irradiated rats were not different than in the controls). We then measured the changes in renal blood flow (RBF) induced by endothelium-dependent (acetylcholine and bradykinin) and -independent (nitroprusside, norepinephrine, and angiotensin II) vasoactive agents. We found that the increases in RBF induced by the endothelium-dependent but not independent vasodilators were markedly impaired in the irradiated kidneys. Blocking nitric oxide synthesis with nitro L-arginine methyl ester in sham rats mimicked the blunted responsiveness of the irradiated rats, whereas indomethacin (an inhibitor of prostaglandin synthesis) had no effect on either sham or irradiated rats. Finally, the RBF responses to the endothelium-independent vasoconstrictors, norepinephrine and angiotensin II, were not altered in the irradiated kidneys. These results suggest that renal irradiation causes endothelial dysfunction (prior to the onset of hypertension) but spares the vascular smooth muscle cells.

Right-sided bacterial endocarditis due to Flavobacterium odoratum in a patient on chronic hemodialysis.

Bacterial endocarditis, particularly involving the left side, has been shown to occur in patients in regular hemodialysis. We report a case of right-sided endocarditis characterized by a very torpid evolution. Although the diagnosis was suspected early in the course, confirmation was obtained 2 months after the onset. Flavobacterium odoratum was identified in the fourth month of evolution and only after multiple blood cultures had been obtained. We believe the very low infectivity of F. odoratum and its very slow growth in culture media prevented an early diagnosis.

Renal response to amino acid infusion in essential hypertension.

In the present study, we evaluated the renal response to a 4-hour infusion of amino acids in essential hypertensive patients, as well as the effects that dietary sodium restriction and enalapril (a converting enzyme inhibitor) had on this renal response. During normal sodium intake, amino acid infusion significantly increased renal plasma flow from 383 +/- 58 to 478 +/- 51 mL/min and glomerular filtration rate from 82 +/- 8 to 100 +/- 13 mL/min. All these effects were abolished when the patients received a low sodium diet (40 mmol/d) for 3 days before the amino acid infusion. The administration of enalapril to the patients during sodium restriction restored the amino acid-induced increment in renal plasma flow (from 388 +/- 35 to 573 +/- 48 mL/min) and glomerular filtration rate (from 88 +/- 9 to 103 +/- 10 mL/min). Mean arterial pressure remained unaltered under all experimental conditions. The results show that in patients with essential hypertension dietary sodium restriction prevents amino acid-induced increments in glomerular filtration rate and renal plasma flow and that this effect is restored during the simultaneous administration of enalapril.

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.

The effect of upright tilt on nifedipine-induced natriuresis.

Calcium channel blockers are antihypertensive agents with diuretic actions. Yet edema occurs in some patients receiving long-term treatment with these drugs. As with other vasodilators, stimulation for fluid retention could result from systemic vasodilation. We speculated that the upright posture could enhance sodium retention. To test this hypothesis, we studied the effect of upright tilt in 10 patients before and after the oral administration of 20 mg nifedipine. Before nifedipine upright tilt caused a 41% drop in the sodium excretion rate, from 0.27 +/- 0.04 to 0.16 +/- 0.03 meq/min (p less than 0.05). Fractional sodium excretion decreased by 46%, from 2.4 +/- 0.5 to 1.3 +/- 0.3% (p less than 0.01). Urinary volume and renal plasma flow also decreased (p less than 0.05). Plasma renin activity (PRA) rose by 46% (p less than 0.005). With the patients in the supine posture nifedipine increased the sodium excretion rate to 0.49 +/- 0.09 meq/min (p less than 0.05). Fractional sodium excretion was 3.1 +/- 0.6 meq/min (p = 0.2). The natriuresis took place despite a fall in mean blood pressure and a significant rise in PRA (up 115% from prenifedipine supine values, p less than 0.005). Renal plasma flow also increased (p less than 0.01). The upright tilt caused a reversal of the nifedipine-induced natriuresis. The sodium excretion rate dropped to 0.23 +/- 0.05 meq/min and fractional sodium excretion to 1.3 +/- 0.2% (both not different from control). This drop in natriuresis occurred while mean blood pressure was at its lowest and PRA was 254% above the initial levels (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of hypertension in renal radiation.

This study was undertaken to investigate the role played by renal functional and structural changes in the development of radiation-induced hypertension. Four groups of rats were studied: 1) left kidney radiated, 2) sham procedure, 3) uninephrectomy followed 3 weeks later by radiation of the contralateral kidney, and 4) uninephrectomy followed by sham procedure 3 weeks later. All radiated rats became hypertensive at 12 weeks (p less than 0.05) and had higher protein excretion (p less than 0.05). In the presence of an intact contralateral kidney, radiation causes mild-to-moderate histological abnormalities, and therefore, creatinine clearance and water and sodium handling do not change. Plasma renin activity increased in this group (p less than 0.05). Radiated uninephrectomized rats showed decreased creatinine clearance (p less than 0.05), but renin activity remained unchanged. These rats developed severe histological abnormalities in glomeruli, interstitia, tubuli, and vessels resulting in increased sodium and water output. The average of individual tubular and interstitial scores correlated significantly with both water intake and output but not with sodium excretion. These studies suggest that in the presence of an intact kidney, renin is an important determinant in the development or maintenance of radiation hypertension, whereas in the absence of the contralateral kidney, severe histological changes and renal failure are prominent despite increased water intake and output. The more severe glomerular sclerosis and proteinuria in the latter model could be related to diminished renal mass.

Patient compliance and angiotensin converting enzyme inhibitors in hypertension.

Patient compliance is crucial to successful medical treatment. Many factors contribute to compliance, including age, sex, other sociodemographic factors, finances, intelligence, complexity of therapeutic regimen, and patient-physician rapport. Compliance is especially critical in medical conditions requiring prolonged therapy, such as hypertension. Historically, compliance among hypertensive patients has been alarmingly poor, with a 50% drop-off after 1 year and fewer than 20% still in therapy after 5 years. The use of enalapril, the long-acting angiotensin converting enzyme (ACE) inhibitor that allows for a once-daily regimen, has improved treatment success and compliance. This probably is due to the efficacy of the drug, coupled with a low incidence of side effects.

Blood pressure and renal prostaglandin E2-like content in unilateral kidney radiation

Se estudiaron los efectos de la irradiación renal con rayos X sobre la concentración de prostaglandina medular y la tensión arterial en la rata. A tales fines, 26 ratas fueron divididas en los siguientes grupos: 6 controles (operados pero no irradiadas) fueron sacrificadas a las 12 semanas; a 20 se les irradió un riñón expuesto a través de una incisión en el flanco recibiendo una dosis de 3000r. Estas ratas fueron sacrificadas en grupos de cinco a 1, 4, 8 y 12 semanas después de la irradiación. Se determinó tensión arterial sistólica, concentración de sustancia tipo PGE2 y tamaño renal. La tensión arterial promedio aumentó progresiva y significativamente (p<0,005). El riñon irradiado disminuyó en tamaño y la diferencia con el riñon opuesto fue estadísticamente significativa a 8 y 12 semanas post-irradiación (p<0,05). Al mismo tiempo el contenido de PGE2 tanto en el riñon irradiado como en el opuesto disminuyó significativamente (p<0,005 y 0,001, respectivamente). Hubo una correlación negativa estadísticamente significativa entre la tensión arterial y el contenido de sustancia tipo PGE2 en ambos riñones (r=-0,50), así como también entre los valores tensionales y el promedio y la suma del contenido de PGE2 de ambos riñones (r=0,53). Los resultados sugieren un rol de las prostaglandinas renales en el desarrollo de la hipertensión en este modelo experimental

Unilateral renal radiation blood pressure and PGE2-Like renal substance: a one-kidney model

La nefritis por irradiación puede producir hipertensión arterial. Se estudiaron los efectos que la irradiación, producía sobre un modelo uninefrectomizado en la rata. Se evaluó tensión arterial sistólica, tamaño renal y concentración en médula renal de sustancia tipo PGE2. A cuarenta y una ratas se les practicó nefrectomía de un riñon. Tres semanas después a cinco ratas se les aplicaron las técnicas quirúrgicas previamente descriptas pero sin irradiarlas. Estas ratas fueron sacrificadas doce semanas después y sirvieron de control. A 20 ratas se les irradió el riñon remanente con una dosis de 3000r y luego fueron sacrificadas en grupos de cinco a 1, 4, 8 y 12 semanas después de la irradiación. A 16 ratas se les aplicó una dosis de 1000r sobre el riñon y se las sacrificó en grupos de cuatro en iguales períodos. Hubo un aumento significativo aunque desigual de la tensión arterial sistólica en los dos grupos (p<0,05 para la dosis de 1000r y p<0,0005 para las ratas que recibieran 3000r). En ambos grupos hubo una disminución progresiva y significativa del contenido de sustancia tipo PGE2 (p<0,001 para ambos). El tamaño renal no cambió. El grupo que recibiera 3000r sufrió hipertensiones sistólicas más severas y presentó concentraciones medulares de PGE2 más bajas. Ambas grupos demostraron valores tensionales más altos que aquellos observados previamente en el modelo de dos riñones. Los resultados sugieren que en este modelo experimental la hipertensión puede estar relacionada a la disminución de la concentración renal de prostaglandinas

Blood pressure and renal prostaglandin E2-like content in unilateral kidney radiation

Se estudiaron los efectos de la irradiación renal con rayos X sobre la concentración de prostaglandina medular y la tensión arterial en la rata. A tales fines, 26 ratas fueron divididas en los siguientes grupos: 6 controles (operados pero no irradiadas) fueron sacrificadas a las 12 semanas; a 20 se les irradió un riñón expuesto a través de una incisión en el flanco recibiendo una dosis de 3000r. Estas ratas fueron sacrificadas en grupos de cinco a 1, 4, 8 y 12 semanas después de la irradiación. Se determinó tensión arterial sistólica, concentración de sustancia tipo PGE2 y tamaño renal. La tensión arterial promedio aumentó progresiva y significativamente (p<0,005). El riñon irradiado disminuyó en tamaño y la diferencia con el riñon opuesto fue estadísticamente significativa a 8 y 12 semanas post-irradiación (p<0,05). Al mismo tiempo el contenido de PGE2 tanto en el riñon irradiado como en el opuesto disminuyó significativamente (p<0,005 y 0,001, respectivamente). Hubo una correlación negativa estadísticamente significativa entre la tensión arterial y el contenido de sustancia tipo PGE2 en ambos riñones (r=-0,50), así como también entre los valores tensionales y el promedio y la suma del contenido de PGE2 de ambos riñones (r=0,53). Los resultados sugieren un rol de las prostaglandinas renales en el desarrollo de la hipertensión en este modelo experimental (AU)