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Biomedical subjects

B M Brenner

Publications and source records attributed to B M Brenner.

At least 55 records · Page 3Linked to original sources
PubMed1997

Candesartan cilexetil reduces chronic renal allograft injury in Fisher-->Lewis rats.

OBJECTIVES: To determine the effects of the angiotensin II receptor antagonist, candesartan cilexetil, on glomerular and systemic blood pressures and the development of renal injury in Lewis rat recipients of a single Fisher kidney (F334--> LEW transplantation), an established rat model of chronic renal allograft failure. DESIGN: Recent studies have shown that chronic injury of renal allografts in F334-->LEW rats may be virtually abrogated by supplying the Lewis recipients with two Fisher kidneys or, alternatively, by retaining a native kidney. These findings imply a major contribution from processes associated with nephron loss to the pathogenesis of chronic renal allograft failure, a notion supported by the observation that transplanting two kidneys also normalizes glomerular capillary pressure (PGC) in F344-->LEW rats. Thus, a pharmacological reduction in PGC, by blocking the effects of angiotensin II, should also lessen renal injury in F344-->LEW rats. MATERIALS AND METHODS: Bilaterally nephrectomized F344--> LEW rats were treated with the angiotensin II receptor blocker candesartan cilexetil (TCV-116) at 40 mg/l or with vehicle, administered in drinking water. Proteinuria and systolic blood pressure were assessed monthly, and histological studies were carried out after 24 weeks. The glomerular filtration rate and glomerular pressures were determined after 10 weeks in additional rats by clearance and micropuncture studies. RESULTS: Treatment with candesartan cilexetil lowered systemic blood pressure, normalized PGC at 10 weeks and greatly reduced proteinuria and allograft glomerulosclerosis at 24 weeks. CONCLUSIONS: These data indicate that the development of renal injury in F344-->LEW renal allografts can be prevented by the pharmacological blockade of angiotensin II receptors using candesartan cilexetil. This suggests that angiotensin-dependent processes contribute significantly to chronic injury in this model of late renal allograft failure.

Angiotensin Receptor Antagonists↗
PubMed1997

Implications of the linear pressure-natriuresis relationship and importance of sodium sensitivity in hypertension.

Although the concept of the pressure-natriuresis curve is very clear, considerable confusion concerning its importance and utility in understanding the pathophysiology of hypertension persists. We recently showed that the pressure-natriuresis curve could be considered linear. In this brief review, we would like to stress the advantages of treating it as a line. Its linear approximation simplifies understanding of the sodium sensitivity of the blood pressure and mechanisms of hypertension. The blood pressure can be expressed as the sum of two components: the non-sodium-sensitive component determined by the x intercept of the pressure-natriuresis curve and the sodium sensitive one determined by the product of the reciprocal of the slope and the amount of sodium intake. Theoretically, it can be affected in two different ways to cause hypertension; either a parallel shift along the blood pressure axis toward a higher blood pressure level due to the increase in the x intercept or a decrease in the slope. The parallel shift induces non-sodium-sensitive hypertension, whereas the decrease in slope induces sodium-sensitive hypertension. Thus, the linear approximation makes the definition of the sodium sensitivity of the blood pressure very clear and, furthermore, suggests that mechanisms of hypertension can be clarified if the determinants of the x intercept and the slope of the pressure-natriuresis curve are known. A clear definition of sodium sensitivity allows us to study its importance as a marker of a greater risk of renal and cardiovascular complications.

Animals↗
PubMed1997

Indirect assessment of glomerular capillary pressure from pressure-natriuresis relationship: comparison with direct measurements reported in rats.

It is examined whether glomerular hemodynamics can be indirectly estimated from the pressure-natriuresis relationship. There are only two animal studies reported, one in normal and the other in 5/6 nephrectomized Munick-Wistar rats, which permits plotting the pressure-natriuresis relationship and comparison of indirect estimations with directly measured glomerular hemodynamic data. Normal and extensive renal ablation rats were placed on relatively high and low sodium diets. Plotting mean arterial pressure (MAP) on the x-axis and 24 h urinary sodium excretion rate on the y-axis, the pressure-natriuresis relationship was drawn. As the difference between MAP (121 +/- 1 and 169 +/- 12 mmHg) on relatively high sodium diet and the extrapolated x-intercept (122 and 138 mmHg) of the pressure-natriuresis relationship, based on previous proposal, the effective filtration pressure across the glomerular capillary walls was estimated to be-1 and 31 mmHg for normal and 5/6 nephrectomized rats. Then, the glomerular capillary hydraulic pressure (PGC) was calculated to be 33 and 64 mmHg. Micropuncture studies showed that directly measured PGC of 47 +/- 1 and 65 +/- 2 mmHg was close agreement with those estimated indirectly. Therefore, an approach from the pressure-natriuresis relationship provides a noninvasive means to predict an approximation of PGC. This approach to estimating glomerular hemodynamics may have invaluable implications for clinical practice; in the early detection of loss of filtration capacity and in the assessment of an important risk factor for the development of chronic renal failure.

Animals↗
PubMed1997

Antigen-independent determinants of graft survival in living-related kidney transplantation.

We used the United Network of Organ Sharing database to define the antigen independent risk factors which contributed to the survival of 8,582 kidney transplants performed in the U.S. between October 1987 and December 1991, using multivariable regression techniques. In this analysis, death with a functioning graft was censored. The risk ratio for graft loss was high when recipients were African-American or had high body surface area, or when donors were older or female. The analysis shows that antigen independent factors that are associated with lower donor kidney mass or increased recipient size play a significant role in living donor kidney transplant loss, as they do in cadaver kidney transplantation.

Adolescent↗
PubMed1997

Nephron mass as a risk factor for progression of renal disease.

Partial ablation of renal mass initiates a cycle of progressive glomerular injury in the remnant. This process is associated with glomerular hypertrophy, hyperfiltration and systemic hypertension. Congenital deficits in nephron number are also associated with adverse effects on the kidney. Since intrauterine growth retardation is associated with formation of fewer nephrons, the recent observation that low birth weight is associated with increased risk of hypertension in later life raises the possibility that even modest reductions in nephron complement may also predispose to renal injury. Likewise, the numbers of viable nephrons supplied to renal, allograft recipients may be critical determinants of late allograft success or failure, since subsequent acute ischemia and rejection combine to lower the nephron complement to levels akin to the more extensive reductions in renal mass seen in patients with surgical reduction of a solitary kidney, in whom predisposition to hypertension and glomerulosclerosis is evident. This article summarizes recent findings suggesting that congenital nephron endowment is a significant factor in the pathogenesis of chronic renal disease and hypertension.

Disease Progression↗
PubMed1997

Angiotensin receptor antagonists in experimental models of chronic renal failure.

The efficacy of angiotensin converting enzyme inhibitors (ACEI) in slowing the advancement of chronic renal disease attests to the importance of angiotensin II (Ang II) in the pathophysiological mechanisms underlying disease progression. It is apparent from studies of the effects of orally-active AT1 receptor antagonists (AT1RA) in experimental models of chronic progressive renal disease, that AT1RA have broadly similar effects to those of ACEI, implying that the favorable effects of ACEI on systemic and renal hemodynamics and indices of glomerular injury are mediated, in large part, by reducing the action of Ang II at AT1 receptors. The possibility remains, however, that differences in the modes of action of ACEI and AT1RA are significant in terms of renal protection and that the two classes of drugs are not therapeutically equivalent. Thus far, however, virtually all experimental studies comparing the renal protective effects of ACEI versus AT1RA have failed to show any convincing differences between the two classes of drug that cannot be attributed to discrepancies in the levels of blood pressure control achieved. As many rodent studies have adopted protocols originally designed to distinguish between the effects of treatment versus no treatment, however, it may be premature to conclude that ACEI and AT1RA are, essentially, therapeutically equivalent. Since both classes of drug have such potent renoprotective effects, the extent of injury that develops in treated rats may be so slight as to compromise the sensitivity of the experimental comparison. Fresh experimental approaches may be required to overcome this issue and resolve any outstanding questions concerning the therapeutic equivalence of AT1RA and ACEI in slowing the progression of renal disease.

Angiotensin II↗
PubMed1996

[Low birth weight--increased risk of diabetic nephropathies?].

It has been demonstrated that intrauterine growth retardation gives rise to a reduction in nephron number. Oligonephropathy has been suggested to enhance the risk for expression of renal disease following exposure to potentially injurious renal stimuli. In a case-control study we investigated if low birth weight is a risk factor for development of diabetic nephropathy in 184 IDDM patients with diabetic nephropathy (persistent albuminuria > 300 mg/24 hours) and 182 normoalbuminuric (< 30 mg/24 hours) patients. In women with birthweight < 10 th centile (< or = 2,700 g, n = 16) 75% had nephropathy compared to only 35% among patients > 90 th centile (> or = 4,000 g, n = 17) (p = 0.05). In men with birth-weight < 10th centile (< or = 2,910 g, n = 22) the prevalence of nephropathy: 50%, was similar to the prevalence among patients > 90th centile (> or = 4,200 g, n = 24) 54%. Mean weight at birth were similar in patients with and without diabetic nephropathy. Men with diabetic nephropathy were significantly shorter than men with normoalbuminuria (176.9 (7.1) vs 179.4 (6.5), p < 0.01). In conclusion, our study supports the hypothesis that genetic predisposition or factors operating in utero or early childhood, or both, contribute to the development of diabetic nephropathy.

Adult↗
PubMed1996

Antigen-independent determinants of cadaveric kidney transplant failure.

OBJECTIVE: To determine the association of various antigen-independent factors with long-term cadaveric kidney transplant failure. DESIGN: Cohort analytic study. SETTING: Kidney transplant centers (N=131) in the United States. PATIENTS: A total of 31 515 patients who received cadaveric kidney transplants between October 1987 and December 1991. Patients with unknown or uninterpretable vital status or graft survival time (n=264 [0.8%]) were excluded. MAIN OUTCOME MEASURE: Graft failure, estimated at 2 extremes, depending on whether the death of a patient with a functioning graft was censored ("censored graft failure") or not ("uncensored graft failure"). RESULTS: During the 62-month study period, 5883 patients required the reinstitution of dialysis because of graft failure, 2404 patients died with graft failure, and 2041 patients died with a functioning graft. The relative risks of censored and uncensored graft failure were significantly associated with donor age, sex, and race and recipient body surface area, after adjusting for recipient age, sex, race, diabetes, cold ischemia time, panel cross-reactivity, pretransplant blood transfusions, previous renal transplantation, functional status, and HLA antigen mismatch. CONCLUSIONS: In cadaveric kidney transplantation, selected demographic and anthropometric factors are significantly related to long-term graft outcomes, even after adjusting for well-known antigen-dependent risk factors. These results support the hypothesis that the supply of viable donor nephrons and the physiologic demands of the transplant recipient are important determinants of long-term graft failure. Antigen-independent factors such as donor age should be incorporated into organ allocation algorithms to optimize equity and efficiency.

Adolescent↗
PubMed1996

Osmotic stress protein 94 (Osp94). A new member of the Hsp110/SSE gene subfamily.

Preservation of cell viability and function in the hyperosmolar environment of the renal medulla is a complex process that requires selective gene expression. We have identified a new member of the heat shock protein (hsp) 70 superfamily that is up-regulated in renal inner medullary collecting duct cells (mIMCD3 cells) during exposure to hyperosmotic NaCl stress. Known as osmotic stress protein 94, or Osp94, this 2935-base pair cDNA encodes an 838-amino acid protein that shows greatest homology to the recently discovered hsp110/SSE gene subfamily. Like the hsps, Osp94 has a putative amino-terminal ATP-binding domain and a putative carboxyl-terminal peptide-binding domain. The in vitro translated Osp94 product migrated as a 105-110-kDa protein on SDS-polyacrylamide gel electrophoresis. In mIMCD3 cells, Osp94 mRNA expression was greatly up-regulated by hyperosmotic NaCl or heat stress. In mouse kidney, Osp94 mRNA expression paralleled the known corticomedullary osmolality gradient showing highest expression in the inner medulla. Moreover, inner medullary Osp94 expression was increased during water restriction when osmolality is known to increase. Thus, Osp94 is a new member of the hsp110/SSE stress protein subfamily and likely acts as a molecular chaperone.

Amino Acid Sequence↗
PubMed1996

An observational study of cardiovascular characteristics of long-term end-stage renal disease survivors.

Long-term survival with end-stage renal disease (ESRD) on dialysis is uncommon, mainly because of the high mortality associated with cardiovascular disease. To define the clinical characteristics of long-term ESRD survivors, especially their cardiovascular risk profile, patients were identified with > or = 15 years of ESRD having at least 10 years on dialysis. Seventeen patients were identified with a duration of ESRD of 21.0 +/- 4.3 years (mean +/- SD). The age of the patients at the initiation of dialysis was 38.4 +/- 14.5 years. Eighty-eight percent of the survivors were white, and 12% were African-American. The primary causes of ESRD were glomerulonephritis, 65%; polycystic kidney disease, 18%; tubulointerstitial/obstructive disorders, 12%; and hypertension, 6%. At the initiation of dialysis, these long-term survivors presented with a low prevalence of cardiovascular risk factors (hypertension, 53%; diabetes mellitus, 0%; active smoking, 11.8%; family history, 25%) and cardiovascular disease (coronary heart disease, 5.9%; congestive heart failure, 5.9%; arrhythmias, 0%; peripheral vascular disease, 0%; and cerebrovascular disease, 5.9%). In addition, only 6.6% of the long-term ESRD survivors presented with systolic blood pressures < 110 mm Hg, a level suggestive of systolic dysfunction. After > or = 15 years of dialysis, these long-term survivors remained with a low prevalence of cardiovascular risk factors and cardiovascular disease. These results suggest that the low cardiovascular risk profile and morbidity experienced by these patients may contribute to their prolonged survival on dialysis.

Adult↗
PubMed1996

Transcriptional responses to tubule challenges.

Adaptation to physiological stimuli often involves changes in gene transcription. Studies of hyperosmolar stress in renal epithelial cells have provided an ideal paradigm for understanding regulation of gene expression. Renal epithelial cells respond very differently to hyperosmolar NaCl and urea and several strategies including cloning based on known biological function, candidate gene analysis, and differential display analysis have successfully identified many genes induced by these hyperosmolar challenges. Hyperosmolar NaCl produces adverse effects on cellular biosynthetic processes and compensatory increases are observed in transcription of transporters, stress proteins, and metabolic enzymes. In contrast, hyperosmolar urea fails to inhibit biosynthetic processes but, nonetheless, initiates a very specific program of gene expression in renal epithelial cells. This program appears to involve a urea sensor/receptor system which activates transcription and translation of the zinc-finger transcription factor Egr-1. This work highlights the concept that rapid analysis of differential gene expression will enable one to define cellular programs of gene expression involving up- and down-regulation of functionally-related gene families.

Animals↗
PubMed1996

The hyperfiltration theory: a paradigm shift in nephrology.

Experimental studies incriminate glomerular hypertension in mediating progressive renal damage after any of a variety of initiating injuries. Prevention of glomerular hypertension by dietary protein restriction or antihypertensive therapy lessens progressive glomerular damage in several experimental models of chronic renal disease. Glomerular hypertension and hyperfiltration also occur in humans with diabetes mellitus, solitary or remnant kidneys, and various forms of acquired renal disease. Clinical studies indicate that dietary protein restriction and antihypertensive therapy also slow progression in many of these disorders. Large multicenter trials confirm the beneficial effects of these therapeutic maneuvers on the rate of progression of chronic renal disease.

Humans↗
PubMed1996

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Animals↗
PubMed1996

Congenital oligonephropathy: The fetal flaw in essential hypertension?

In 1988, Brenner, Garcia and Anderson advanced the hypothesis that the nephron endowment at birth is inversely related to the risk of developing essential hypertension in later life. This novel perspective on the origins of essential hypertension was taken from the viewpoint that the development and maintenance of hypertension must involve a renal factor favoring sodium retention, thereby preventing pressure-induced natriuresis from restoring blood pressure toward normal levels. Since nephron numbers in the normal population range from 300,000 to 1,100,000 or more, it was reasoned that a congenital shortfall in nephron endowment itself could be the renal risk factor for hypertension: demographic groups in whom hypertension is unusually prevalent tend to have smaller kidneys, implying fewer nephrons, and some inbred hypertensive rat strains have, on average, fewer nephrons than their respective normotensive counterparts. Recent independent observations in humans, relating low birth weight to both increased risk of hypertension in later life and the formation of fewer nephrons at birth, lend support to this nephron number hypothesis. Moreover, independent experimental studies in rodents suggest that maternal protein intake during gestation is directly related to the numbers of nephrons formed, and when protein intake is restricted, the offspring develop hypertension in maturity. The concept that nephron numbers may be programmed during gestation, as these observations imply, is discussed in relation to the potential advantages and disadvantages of such a mechanism for the next generation. Parallels are drawn with the relationship of low birth weight to pancreatic beta cell development and maturity-onset diabetes. We suggest that the programming of fewer nephrons at birth may provide a fitting and overlooked explanation for the eventual development of hypertension in those of low birth weight.

Animals↗
PubMed1996

The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

Angiotensin Receptor Antagonists↗