Hemodynamics of hyperuricemia.

Prolonged hyperuricemia is associated with the development of hypertension, renal arteriolosclerosis, glomerulosclerosis, and tubulointerstitial injury. It confers a greater risk than proteinuria for developing chronic renal disease and is associated with the development of hypertension. Mild chronic hyperuricemia without intrarenal crystal deposition was induced in rats by inhibiting uricase with oxonic acid. Hyperuricemic rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis. Additionally, hyperuricemia accelerated renal damage and vascular disease in rats undergoing renal ablation. To better understand the role of hyperuricemia in the kidney, micropuncture studies were performed. Hyperuricemia resulted in renal cortical vasoconstriction (single nephron glomerular filtration rate (SNGFR) 35%, P < .05) and glomerular hypertension (P < .05). The possibility that hyperuricemia could modify renal hemodynamic disturbances during progression of renal disease was tested in rats with 5/6 nephrectomy. Hyperuricemia accentuated the renal vascular damage and caused cortical vasoconstriction (SNGFR 40%, P < .05) and persistent glomerular hypertension. In conclusion, hyperuricemia impairs the autoregulatory response of preglomerular vessels, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening results in severe vasoconstriction. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis as well as arterial hypertension.

A unifying pathway for essential hypertension.

We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process.

Tubulointerstitial damage and progression of renal failure.

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

Prevalance of proteinuria in Mexico: a conjunctive consolidation approach with other cardiovascular risk factors: the Mexican Health Survey 2000.

BACKGROUND: A number of cross-sectional or serial studies have demonstrated the clinical impact of microproteinuria and macroproteinuria by identifying individuals at risk of both end-stage renal disease and major cardiovascular events. This study focused on the prevalence of proteinuria in Mexico and its relationship with other cardiovascular risk factors such as hypertension, type 2 diabetes mellitus, body mass index, smoking, age, and gender. METHODS: The prevalence of proteinuria in Mexico was obtained from the probabilistic cross-sectional national health survey performed in the year 2000. The proportion of urine dipstick samples that tested positive for protein (defined as > or =1+) in adults from 20 to 69 years of age was determined. The analysis was performed using both algebraic and multicategorical models. Potential interactions between proteinuria and other major cardiovascular risk factors were investigated. RESULTS: A total of 46,523 adult survey participants were included in the analysis. In the general population, 9.2% had proteinuria. By univariate, multivariate, and multicategorical analysis, hypertension, diabetes, obesity, and age were strongly associated with the prevalence of proteinuria (P < 0.001). However, in Mexico, the specific distribution of age groups demonstrated that the absolute number of patients without hypertension that had proteinuria is not irrelevant. To identify 1 case of proteinuria, one would need to screen 3 persons with diabetes mellitus, 5 patients with hypertension without diabetes, or 6 persons over the age of 55 years. When proteinuria is present, the probability of having a noncommunicable chronic disease or other major cardiovascular risk factor is more than 85%. CONCLUSION: Proteinuria is prevalent. When considered together, dipstick-positive proteinuria, blood pressure level, body mass index > or =30 m(2)/kg, and abnormal fasting blood glucose measured on a single occasion identifies different segments of the population. Studies such as this may be a suitable initial clinical approach to general population screening for renal and cardiovascular risk stratification.

[National Re-survey of Arterial Hypertension (RENAHTA). Mexican consolidation of the cardiovascular risk factors. national follow-up cohort]. / Re-encuesta Nacional de Hipertensión Arterial (RENAHTA): consolidación Mexicana de los factores de riesgo cardiovascular. Cohorte nacional de seguimiento.

OBJECTIVE: Based on a National Re-survey on Hypertension (HTA) and other cardiovascular risk factors performed in Mexico during 2003 and 2004 in the adult population with HTA, as identified in the 2000 National Survey of Health, this study was planed to determine: 1) morbidity and mortality rates; 2) the incidence and interrelation with other risk factors, such as overweight, obesity, dyslipidemia, nephropathy and diabetes; 3) the main risk factors associated to HTA involved in its complications, need for hospitalization and number of days; and, 4) the degree of therapeutical adhesion and the type of antihypertensive drugs used. METHODS: The survey was of type III using the step by step method described by WHO. Sampling was weighed a priori taking into account a national prevalence average of HTA of 30.05% and its corresponding rate for each federal state. Permissible maximum error in the estimation = 0.28. Effect of design = 4.5; and, Rate of awaited answer (0.70). RESULTS: From the initial 14,567 interviewed patients, 1,165 (8%) subjects were considered non-hypertensive or false positives at the 2000 survey. From the 13,402 remaining patients, 335 died during the first 2 years of pursuit, which implies an annual mortality of approximately 1.15% in the hypertensive population. Thus, 13,067 survivors were subjected to the final analysis. The mean age at the re-survey was 45.6 +/- 12.6; 40.5% were men (n = 5,295). There was a statistically significant difference in height, but not in weight between both genders. The control HTA was raised 14.6% in the year 2000 and 19.2% in 2004. The prevalence of diabetes was duplicated from 16% to 30% (< .001). Fifty four percent of the whole population required hospitalization at least once during the period of study. The rates of overweight, obesity, and dyslipidemia rose significantly (p < 0.05) independently from age, federal state, and gender. CONCLUSION: RENAHTA shows the impact of hypertension on the morbidity and mortality during the 3.1 +/- 1.5 years of follow-up in Mexico. It alerts us on the need to reinforce the strategies of attention and prevention of this crucial risk factor and of screening the dynamic nonlinear interaction between the main cardiovascular risk factors in Mexico. New hypotheses are proposed for the metabolic syndrome.

Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation.

Glomerular hemodynamic adaptations to loss of renal mass are thought to be the initiating factor of progression to renal failure; however, tubulointerstitial (TI) injury correlates better with progression than with glomerular damage. Thus, it is conceivable that tubulointerstitial alterations participate in the pathophysiology of renal disease progression by modifying the adaptive responses of glomerular hemodynamics. In experimental models of progressive renal disease, suppressing tubulointerstitial inflammatory cell infiltration with anti-inflammatory drugs reduces renal damage despite persistence of systemic hypertension. In recent studies in rats with subtotal renal ablation, we found that treatment with polysulphate pentosan (PPS) and with mycophenolate mofetil (MMF) prevented proteinuria, glomerular hypertension, and hyperfiltration, despite persisting arterial hypertension due to higher afferent resistance. In addition, arteriolopathy was significantly attenuated by MMF, suggesting preservation of vascular structure and function. Association of vascular injury of afferent arterioles, glomerular hemodynamic changes, and renal lesions has been described in other conditions such as hyperuricemia, protein overload, fawn-hooded rats, and aging spontaneously hypertensive rats (SHR). Arteriolopathy results in a maladaptive function that permits the transmission of systemic hypertension to glomerular capillaries. Glomerular hypertension results in mechanical damage to the capillary wall and increased filtration of proteins to tubular lumen. Enhanced tubular reabsorption induces synthesis of proinflammatory and profibrotic factors, resulting in tubulointerstitial inflammation and fibrosis. In conditions in which there is overactivity of the renin-angiotensin system (RAS), such as mild hyperuricemia and protein overload, arteriolopathy is associated with increased glomerular pressure and reduced glomerular plasma flow that results in post-glomerular ischemia and tubulointerstitial injury.

Apoptosis and NFkappaB activation are simultaneously induced in renal tubulointerstitium in experimental hypertension.

BACKGROUND: Oxidative stress is known to induce apoptosis and activation of pro-inflammatory transcription factor nuclear factor kappa B (NFkappaB), which are biologic effects that may play a role in the renal damage associated with arterial hypertension. We investigated if increased apoptosis and NFkappaB activation were present in experimental models of hypertension. METHODS: Sprague-Dawley rats fed with regular rodent chow and free access to water were studied. The Ang II group (N = 6) received 435 ng/kg/min of angiotensin II during 2 weeks by subcutaneous minipumps. The l-NAME group (N = 5) received Nomega-nitro-l-arginine-methyl-ester (l-NAME) in the drinking water (70 mg/100 mL) for 3 weeks. The control group consisted of 6 rats. Systolic blood pressure (tail cuff plethysmography), serum creatinine, and proteinuria were determined weekly. Kidneys were examined for superoxide-positive cells (histochemistry) and for apoptosis [terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling (TUNEL)-positive cells], proliferation [proliferating cell nuclear antigen (PCNA)-positive cells), and activation of NFkappaB (p65 subunit) with the appropriate antibodies. RESULTS: As expected, hypertension developed in experimental groups. Tubulointerstitial superoxide-positive cells were increased 7 times (P < 0.001), TUNEL-positive cells were increased 3 to 4 times (P < 0.001), PCNA-positive cells were increased 20 to 30 times (P < 0.001), and NFkappaB activation was increased 4 to 5 times (P < 0.001) in the experimental groups. NFkappaB expression correlated with the number of interstitial lymphocytes (r = 0.667, P < 0.01) and macrophages (r = 0.835, P < 0.001). CONCLUSION: Angiotensin II infusion and l-NAME administration induce oxidative stress and increased apoptosis and activation of the transcription factor NFkappaB. These effects may participate in the development of progressive renal injury resulting from uncontrolled hypertension

Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition.

BACKGROUND: Angiotensin II (Ang II) infusion and nitric oxide synthesis (NOS) inhibition with Nomega-nitro-l-arginine-methyl-ester (l-NAME) are experimental models of hypertension associated with renal inflammation and oxidative stress. To gain insight into the nature of the tubulointerstitial injury induced in these models, we studied lectin-binding specificities, vimentin expression, and heat shock protein (HSP) 60 and 70 in these experimental models. METHODS: Sprague-Dawley rats received Ang II infusion (435 ng/kg/min) for 2 weeks by subcutaneous minipumps (Ang II group, N = 5) or l-NAME in the drinking water (70 mg/100 mL) for 3 weeks (l-NAME group N = 7). The control group consisted of 10 rats. Systolic blood pressure (tail-cuff plethysmography), serum creatinine, and proteinuria were determined weekly. At the end of the treatment period, rats were sacrificed and kidneys studied. Binding specificities of fluorescein-labeled lectins were examined in frozen sections, and cellular infiltrates were identified by immunohistology and expression of vimentin and HSP 60 and 70 with immunohistochemistry and computer image analysis. RESULTS: Tubulointerstitial accumulation of macrophages, lymphocytes, and Ang II-positive cells were present in the Ang II group and l-NAME group. Vimentin, HSP 60, and HSP 70 were increased 8 to 20 times in the cortex of the rats of the Ang II group and the l-NAME groups. Neoexpression of vimentin and HSPs was found primarily in proximal tubular cells. CONCLUSION: Ang II infusion and NOS inhibition induce tubular injury with epithelial cell transdifferentiation and expression of stress proteins. The role of these changes in the accumulation and activation of the interstitial inflammatory infiltrate merits further investigation.

[Arterial hypertension and diabetic nephropathy. Evidence based therapy]. / Hipertensión arterial y nefropatía diabética. La terapéutica basada en evidencia.

Diabetic nephropathy (DN) is the most common cause of chronic renal failure (CRF), in Mexico prevalence of diabetes is higher than other countries. Genetic susceptibility, arterial hypertension, proteinuria and initial hyperfiltration are risk factors for CRF. Renal injury is mediated by protein glycation, proteinuria and hemodynamics alterations induced by arterial hypertension and impaired renal autoregulation. Angiotensin II is directly involved in renal injury through its hemodynamic effects, oxidative stress, induction of proinflammatory and profibrotic factors and cellular proliferative effect. Prospective, well controlled clinical trials in patients with type 1 and type 2 DM have shown that interrupting the renin angiotensin system with CEI or ARA effectively prevent progression of DN. Combination of both drugs may provide further nephroprotection. Antihypertensive therapy in patients with DN must include CEI or ARA and to reduce BP below 130/85 mmHg and if proteinuria is present, under 120/75.

Hypertension: a microvascular and tubulointerstitial disease.

The vast majority of patients with essential hypertension have structural changes in their kidneys consisting of preglomerular vascular disease ('arteriolosclerosis') and tubulointerstitial injury. Most authorities have assumed that these structural changes occur secondary to hypertensive renal injury. However, Goldblatt proposed that primary renal microvascular disease might be the cause of some forms of hypertension. In this paper we present recent studies from our group that support a role for both preglomerular vascular disease as well as the tubulointerstitial inflammatory response in mediating salt-sensitivity. We propose that subtle acquired renal injury may underlie the etiology of some forms of salt-sensitive hypertension.

The role of immune cells infiltrating the kidney in the pathogenesis of salt-sensitive hypertension.

This work summarizes recent evidence that suggests that renal infiltration with immune cells plays a role in the pathogenesis of salt-sensitive hypertension. The presence of immunocompetent cells is a conspicuous finding in conditions associated with hypertension induced or maintained by a high salt intake. Studies in models of salt-sensitive hypertension following angiotensin II infusion and nitric oxide synthesis inhibition indicate that a reduction in the tubulointerstitial infiltration of lymphocytes and macrophages during the induction period results in protection from the subsequent development of salt-sensitive hypertension. Reduction of the renal immune infiltrate in spontaneously hypertensive rats results in near normalization of the blood pressure. The reduction in the immune infiltrate is associated with a reduction in the number of cells expressing angiotensin II (some of which are immune cells) and a reduction in renal oxidative stress. Since increased intrarenal angiotensin activity tends to reduce filtered sodium and increase sodium reabsorption, and the tubulointerstitial damage resulting from oxidative stress can induce a shift to the right in the pressure-natriuresis relationship, these findings suggest potential mechanisms by which the immune infiltrate could induce or worsen salt-driven hypertension.

Restoration of glomerular haemodynamics and renal injury independent of arterial hypertension in rats with subtotal renal ablation.

To study whether prevention of renal injury using the anti-inflammatory drugs pentosan polysulphate (PPS) and mycophenolate mofetil (MMF) is associated with improvement of glomerular haemodynamics, PPS and MMF were compared with losartan. The awake systolic blood pressure (SBP), proteinuria (Uprot) and micropuncture studies were performed 30 days after five-sixths nephrectomy in untreated rats and in rats treated with PPS (100 mg/kg per day), MMF (30 mg/kg per day) or losartan (30 mg/kg per day). In the rats receiving no treatment, there was a rise in SBP (to 180-200 mmHg) and in Uprot, which were prevented by losartan. In the PPS and MMF groups, the SBP was elevated but the Uprot did not increase. In the untreated rats the total glomerular filtration rate (GFR) decreased (-80%) and the single-nephron GFR (37-42%), plasma flow (67-127%) and glomerular pressure (10-15 mmHg) increased. These changes were prevented by PPS and MMF to the same extent as by losartan: the rise in single-nephron GFR and plasma flow were reduced by 50% and the glomerular pressure was normal. In rats receiving losartan, this was due to the fall in arterial pressure, whereas in PPS- and MMF-treated rats it was due to a rise in afferent resistance, indicating autoregulatory capacity. Total GFR was similar, despite the lower single-nephron GFR in treated groups, suggesting a larger proportion of functioning nephrons. Losartan, PPS and MMF significantly reduced glomerular sclerosis and tubular dilation and atrophy in association with a reduction in the lymphocyte and macrophage infiltrate. These results suggest an interaction between the haemodynamic and inflammatory changes that perpetuate each other during progression of renal injury. Renal protection provided by anti-inflammatory drugs is partially mediated by the prevention of glomerular haemodynamic alterations.

Effects of acute and chronic L-arginine treatment in experimental hyperuricemia.

Experimental hyperuricemia (HU) results in preglomerular arteriolopathy, cortical vasoconstriction, and glomerular hypertension. Recently, uric acid has been shown to induce endothelial dysfunction. We therefore studied the effect of acute and chronic administration of l-arginine (a substrate for endothelial nitric oxide synthase) on the renal hemodynamic and vascular structural alterations induced by HU. To induce HU, oxonic acid (OA; 750 mg.kg(-1).day(-1)) was administered in male Sprague-Dawley rats. To study the acute effect of arginine, nine rats received l-arginine (l-Arg; 15 mg.kg(-1).min(-1)) during micropuncture. To elucidate the chronic effect of l-Arg, OA + 1% l-Arg (n = 8) and OA + 2.5% l-Arg (n = 6; drinking water) were evaluated throughout the 5-wk period. Eight normal control (N), and eight OA, rats were also studied. Kidneys were fixed by perfusion and afferent arteriole morphology was evaluated. HU rats developed the renal functional and structural alterations described and had suppressed urinary excretion of NO(2)(-)/NO(3)(-). Acute stimulation of nitric oxide (NO) synthesis markedly increased urinary NO(2)(-)/NO(3)(-), lowered systemic blood pressure, and relieved cortical vasoconstriction despite a significant increment of glomerular hypertension and afferent arteriole damage. Increasing doses of chronic l-Arg were associated with increasing excretion of urinary NO(2)(-)/NO(3)(-), reduction of systemic hypertension, and prevention of cortical vasoconstriction (2.5% l-Arg). In addition, both doses prevented glomerular hypertension and preglomerular arteriolopathy. Thus an acute relief of renal vasoconstriction in the setting of afferent arteriole damage cannot reverse glomerular hypertension, likely due to impairment in preglomerular autoregulation. On the other hand, chronic l-Arg preserved arteriolar structures probably mediated by the antiproliferative effect of NO on vascular smooth muscle cells.

Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats.

Fructose intake has been recently linked to the epidemic of metabolic syndrome and, in turn, the metabolic syndrome has been epidemiologically linked with renal progression. The renal hemodynamic effects of fructose intake are unknown, as well as the effects of different routes of administration. Metabolic syndrome was induced in rats over 8 wk by either a high-fructose diet (60%, F60, n = 7) or by adding fructose to drinking water (10%, F10, n = 7). Body weight and food and fluid intake of each rat were measured weekly during the follow-up. At baseline and at the end of wk 8, systolic blood pressure, plasma uric acid, and triglycerides were measured. At the end of week 8 glomerular hemodynamics was evaluated by micropuncture techniques. Wall thickening in outer cortical and juxtamedullary afferent arterioles was assessed by immunohistochemistry and computer image analysis. Fructose administration either in diet or drinking water induced hypertension, hyperuricemia, and hypertriglyceridemia; however, there was a progressive increment in these parameters with higher fructose intake (C

Uric acid--a uremic toxin?

Uric acid might often be regarded as a simple marker of renal disease. Although it is well known that hyperuricemia causes gout which is associated with renal insufficiency and cardiovascular disease, one might think that it could attribute to the intrarenal urate crystal, but not to uric acid per se. In order to clarify the role of uric acid in the kidney, we hypothesized that uric acid causes renal disease. To generate mild hyperuricemia without intrarenal crystal in rats, we used low doses of an uricase inhibitor (2% oxonic acid). Hyperuricemia induced systemic hypertension, glomerular hypertrophy/hypertension, afferent arteriolar sclerosis, and macrophage infiltration in normal rat kidney. In progressive renal disease, such as cyclosporine nephropathy and remnant kidney in rat, uric acid accelerated the progression of renal disease. Thus, we concluded that uric acid is not a simple marker, but a cause of renal disease.