Kidney international. Supplement最新文献

Mechanism of transforming growth factor-beta1 signaling: Role of the mitogen-activated protein kinase. Transforming growth factor-beta1 (TGF-beta1) regulates diverse biologic activities including cell growth, cell death or apoptosis, cell differentiation, and extracellular matrix (ECM) synthesis. TGF-beta1 is believed to be a key mediator of tissue fibrosis as a consequence of ECM accumulation in pathologic states such as progressive renal diseases including diabetic nephropathy. TGF-beta1 actions are mediated by the heteromeric interactions of types I and II serine/threonine kinase receptors. Initiation of signaling requires binding of TGF-beta1 to TGF-beta type II receptor (TbetaR-II), a constitutively active serine/threonine kinase, which subsequently transphosphorylates TGF-beta type I receptor (TbetaR-I). However, the signaling pathway following the initial receptor interaction with ligand remains poorly understood. Much of current investigation, including in our laboratory, is now focused on the elucidation of the intracellular signaling components that mediate TGF-beta1 signals downstream of the cell-surface receptors. An emerging body of evidence implicates the mitogen-activated protein kinase (MAPK) as an important TGF-beta1 signaling pathway.

The most serious side effects induced by hemodialysis therapy are caused by changes in sodium concentration and subsequent water shift between the intracellular and extracellular fluid compartment. Because of inadequate precision of proportioning, a certain sodium concentration and considerable error in the measurement of sodium concentration in dialysis fluid and plasma water, an error of up to 10 g in the diffusive exchange of sodium chloride remains in most dialysis sessions. Common side effects occur within this sodium balance error. Sodium modeling is a simplified mathematical method to describe quantitatively the fluid exchange in the body caused by changes in extracellular sodium concentration. It is based on fundamental physiologic properties of sodium and its permeability through the corresponding membranes. It also explains the different working mechanisms of sodium- and urea-related changes in osmolarity. Sodium modeling is a helpful tool for the illustration of the effects of changes in sodium concentration and ultrafiltration rate on sodium balance during one dialysis session. Sodium profiling is a method employed to avoid unwanted side effects of hemodialysis therapy by deliberately changing the sodium concentration in dialysis fluid during the course of a dialysis session. Clinical reports on practicing sodium profiling are unsatisfactory, involving only short trial periods in most cases. Most of the studies reported positive sodium balance with temporary decreases in intradialytic hypotension and less blood volume reduction, but with increases in thirst and body weight. To date, no validated studies with suitable control of sodium balance have been published that clearly demonstrate the long-term benefits of this mode of therapy compared with the use of constant dialysate sodium concentrations.

Hypertension in chronic renal failure (CRF) is very common and contributes to morbidity and mortality and to the progression of renal disease. The pathogenesis of hypertension in CRF has been attributed mostly to sodium retention and to activation of the renin-angiotensin-aldosterone system. More recently an abundance of evidence has accumulated to support a role for increased sympathetic nervous system (SNS) activity in the genesis of hypertension associated with CRF. Evidence from our laboratory has also demonstrated that the rise in central SNS activity is mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NO) production, and that the upregulation of NO production in the brain is mediated by IL-1beta.

A number of kidney diseases, and their progression to end-stage renal disease, are driven, in part, by the effects of angiotensin II. Increasing levels of angiotensin II may in turn up-regulate the expression of growth factors and cytokines, such as transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), osteopontin, vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-kappaB (NF-kappaB), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor. Most of these compounds promote cell growth and fibrosis. Angiotensin II also stimulates oxidative stress. This stress in turn may potentiate the vasoconstrictor effect of the peptide due, in part, to increased catabolism of nitric oxide (NO). Oxidative stress, fueled in part by angiotensin II, up-regulates the expression of adhesion molecules, chemoattractant compounds and cytokines. The angiotensinogen gene, which provides the precursor for angiotensin production, is stimulated by NF-kappaB activation. NF-kappaB is activated by angiotensin in the liver and in the kidney. This provides an autocrine reinforcing loop that up-regulates angiotensin production. Angiotensin II activates NF-kappaB through both AT1 and AT2 receptors. In addition, angiotensin-converting enzyme (ACE) inhibition markedly decreases NF-kappaB activation in the setting of renal disease.

Background: A role for hypertension in the progression of renal disease has been convincingly shown in experimental animals only. In human studies, the relation between hypertension and progression is difficult to demonstrate due to several confounding factors: age, gender, race; the difficult choice of blood pressure (BP) parameters that correlate with progression; the abnormal circadian BP pattern; and the many non-hemodynamic factors of progression. An important role for hypertension in progressive nondiabetic renal disease has been suggested by observational studies and clinical trials originally intended to evaluate the effect of dietary protein restriction on progression. In addition, several studies, summarized by a recent meta-analysis, have shown that pharmacological agents which lower both BP and proteinuria, mainly the angiotensin-converting enzyme inhibitors (ACEI), significantly slow the rate of progression in these diseases.

Methods: In this article we review the effect of lowering BP on the progression of nondiabetic chronic renal disease, the patient characteristics that are associated with a greater or lesser benefit of blood pressure reduction, and the choice of antihypertensive regimens associated with better outcomes in patients with renal disease.

Results: Lower levels of achieved BP are associated with a slower decline in renal function, both in patients with and without proteinuria. ACEI are effective BP lowering agents and are associated with better preservation of renal function as opposed to antihypertensive regimens without ACEI. This protective effect of ACEI is in addition to their BP and urine protein lowering effects. The protective effect of ACEI on renal function is more pronounced in patients with proteinuria.

Conclusion: In patients with nondiabetic renal disease and proteinuria, the risk of progression can be minimized by lowering both BP and proteinuria. ACEI have an additional beneficial effect.

Background: Disease-specific pathogenic mechanisms may be major determinants of the spontaneous rate of progression of chronic renal failure (CRF). To clarify the role of different underlying renal diseases, we examined the rate of CRF progression in 886 patients with chronic nephropathies.

Methods: Secondary analysis of two multicenter, prospective randomized trials: the Northern Italian Cooperative study (NIC) and the AIPRI study (ACE-Inhibition in Progressive Renal Insufficiency). Univariate and multivariate analyses of variance were used to select the covariates possibly related to CRF progression (estimated by means of the slope of the reciprocal of SCr against time), focusing on the contributory role of primary renal diseases.

Results: The overall rate of CRF progression was relatively low but there was a considerable difference in the slopes relating to the underlying nephropathy (particularly evident in the patients with chronic glomerulonephritis (CGN)). The median rate of CRF progression in both studies was more rapid in patients with polycystic kidney disease (PKD) and CGN than in those with other nephropathies. Multivariate analysis showed PKD as an independent predictor of the CRF progression rate only in the NIC Study (P < 0.0015); the selected variables in both studies predicted a variation of only 15-18% in the CRF progression rate.

Conclusion: The underlying renal disease certainly plays a role in the natural history of CRF, but the variability of the CRF progression rates related to different renal diseases and between individuals with the same diagnosis underlines the need for caution in evaluating risk factors and predicting single patient outcomes.

Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic (r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients (r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic (r = 0.73, P < 0.001) as well as nondiabetic patients (r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin (r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs.

The development and progression of sclerosis is determined by complex interactions of many mechanisms, including direct hemodynamic actions, modulation of glomerular cell injury, and growth factor actions. The interplay of these factors determines the balance of cell growth and proliferation versus cell death by necrosis or apoptosis, and the balance of matrix accumulation versus degradation. Sclerosis may even be reversed when therapies inhibit these mechanisms and augment matrix degradation processes, both by directly increasing proteolytic activity and by down-regulating inhibitors of matrix degradation. We will focus in this review on the roles of glomerular hemodynamics and growth in the progression of renal diseases.

The question of why chronic renal diseases progress is a topic only recently investigated. Putative causes such as proteinuria do not account for all aspects of progressive renal disease. An alternative mechanism, chronic hypoxia, is proposed that might better explain certain elements of progressive renal disease, but elements of the hypothesis remain subject to further study.