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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2002  |  Volume : 13  |  Issue : 3  |  Page : 250-256
Mechanisms of Progression of Chronic Renal Disease

1 Mario Negri Institute for Pharmacological Research and Division of Nephrology and Dialysis, Aldo e Cele Daccò, Villa Camozzi-Ranica, Italy
2 Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi-Ranica, Italy

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Many patients with proteinuric chronic nephropathies progress relentlessly to end-stage renal failure (ESRF). Research in animal and human models has helped to identify the mechanisms involved in this progression and to indicate effective intervention. We review the main factors associated with the progression of chronic renal diseases including systemic and intra-glomerular hypertension, glomerular hypertrophy, proteinuria, hyperlipidemia, and intrarenal precipitation of calcium phosphate. We also describe a therapeutic strategy aimed at achieving maximal reno-protection.

Keywords: Chronic renal disease, Progression, End-stage renal failure, Hypertension, Proteinuria.

How to cite this article:
Pisoni R, Aros C, Ruggenenti P, Remuzzi G. Mechanisms of Progression of Chronic Renal Disease. Saudi J Kidney Dis Transpl 2002;13:250-6

How to cite this URL:
Pisoni R, Aros C, Ruggenenti P, Remuzzi G. Mechanisms of Progression of Chronic Renal Disease. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2022 Nov 29];13:250-6. Available from: https://www.sjkdt.org/text.asp?2002/13/3/250/33113
The course of most proteinuric chronic renal diseases (CRD) is characterized by an inexorable progression to ESRF that is usually associated with the histologic findings of glomerulosclerosis and interstitial fibrosis. [1],[2] Many studies in animals and humans suggest that this progression may be due to factors that are unrelated to the activity of the initial disease. Such as systemic and intraglomerular hypertension, glomerular hypertrophy, hyperlipidemia, and intrarenal precipitation of calcium phospate [Table - 1].

Therapeutic strategies aimed at treating these factors should be successful in preventing or minimizing further renal damage. We will review the data about the role of these factors in the progression of CRD, with special emphasis on the role of excessive protein filtration through the glomerular barrier, and we will formulate a comprehensive intervention strategy in order to achieve maximal Reno protection.

   Intra-glomerular Hypertension and Glomerular Hypertrophy Top

Intra-glomerular hypertension has been demonstrated in many animal models of progressive renal disease and, indirectly, in humans as well. [1] It may be the consequence of glomerular hyperperfusion such as in diabetes mellitus or a compensatory response to nephron loss in order to maintain the total glomerular filtration rate (GFR). [2] In rats, when renal mass is reduced, the remaining nephrons undergo sudden hyper­trophy, reduced arteriolar resistance, and increased glomerular blood flow. [3],[4]

Since afferent arteriolar tone decreases more than the efferent one, intra-glomerular pressure and the amount of filtrate formed by single nephron, rise. [5] However, these adaptive hemodynamic changes may be deleterious in the long-term, [2] and therapies that limit these changes reduce histologic damage and slow the GFR decline over time. [2] The mechanisms by which intra­glomerular hypertension and glomerular hypertrophy induce renal injury are incom­pletely understood and many hypotheses have been proposed. Intra-glomerular hypertension may alter the size-selectivity of the glomerular barrier by enlarging the radius of the glomerular pores. [6] This mechanism, that has been deeply inves­tigated in our laboratories in the last decades, is in part mediated by angiotensin II [7],[8] and leads to abnormal protein filtration through the diseased glomeruli. The filtered proteins are then reabsorbed by proximal tubular cells, where they accumulate and contribute to interstitial lesions and renal scarring. The proposed mechanisms by which abnormal protein filtration through the glomerular barrier contribute to renal injury include: activation of tubular intra­cellular events that cause up-regulation of vasoactive and inflammatory genes; [2],[9] direct tubular injury with subsequent extravasation of cellular contents into the interstitium;10' 10,11 mesangial toxicity; and toxicity from specific proteins such as transferrin and iron. Both in vitro and in vivo, protein overload causes increased production of inflammatory mediators such as endothelin-1, monocyte chemo-attractant protein-1 (MCP-1), regulated upon activation normal T-cell expressed and secreted (RANTES), which is a chemo­tactic cytokine for monocytes and memory T cells, and osteopontin. [2] Their accumu­lation in the interstitium may induce fibroblast proliferation, increased synthesis of matrix, and inflammation that ultimately lead to renal scarring. [2] Components of the complement system, also filtered across the glomerular barrier, may contribute to interstitial injury. [2],[12] Also the release of free iron in the tubular lumen, subsequent to the abnormal filtration of the iron-transferrin complex, may induce tubular damage through the formation of hydroxyl radicals. [13] The importance of the altered size-selective function of the glomerular barrier in the progression of chronic renal diseases is also suggested by data, both in animals and humans, showing that drugs that limit protein filtration through the glomerular membrane, limit or halt renal injury. [2] Besides their effect on the size-permeability of the glomerular barrier, increased glomerular capillary pressure and glomerular hyper­trophy might be directly toxic to the endo­thelium by increasing the wall stress. [14] This causes accumulation of large circulating macromolecules (immunoglobulins, com­plement, and fibrinogen) in the sub­endothelial space, where they may narrow the capillary lumen, leading to reduced glomerular perfusion and filtration. [1],[15]

Increased wall stress also stimulates mesangial cells to produce inflammatory cytokines and matrix, [16],[17],[18] thereby reducing capillary filtration area.

   Excess angiotensin II Top

Excess angiotensin II has an important role in the process leading to renal scarring. Besides inducing preferential vasocons­triction of the efferent arteriole and subsequent glomerular hypertension, and having a direct role in altering glomerular permeability to proteins, angiotensin II has also various non-hemodynamic effects that may be important in CRD progression such as induction of cytokine release, macrophage activation, increased phagocytosis, mesangial cell proliferation, and mesangial matrix formation. [2],[19]

   Hyperlipidemia Top

Abnormalities of serum lipids are common in patients with chronic nephropathies, especially in those with the nephrotic syndrome. Hyperlipidemia not only accele­rates the onset of atherosclerosis but might also contribute to the progression of chronic nephropathies. [20] Experimental data show that cholesterol loading induces glomerular injury 21 and drugs which reduce serum lipid levels slow the rate of the progression of the disease. [19],[22],[23] The mechanisms by which this occurs are not completely understood and include increased intra-glomerular pressure and mesangial lipid deposition that stimulate mesangial cells to proliferate and produce inflammatory cytokines. [20],[22] In humans, the benefits of lipid lowering on the progression of CRD are unproven and the few published data are conflicting. [24],[25]

The results of a recent meta-analysis showing a lower reduction of GFR and a decrease in proteinuria associated with lipid reduction, need to be confirmed in large randomized prospective trials. [26]

   Intrarenal precipitation of calcium phosphate Top

The tendency to retain phosphate, that occurs as soon as renal function starts to decline, might also contribute to the prog­ression of CRD. The intrarenal precipitation of calcium phosphate salts may in fact cause tubulointerstitial inflammation. [27] However, the efficacy of isolated low phosphate diet is unproven in humans. [27]

   Metabolic acidosis Top

With advancing renal failure, hydrogen ion excretion by the kidney is not sufficient to balance endogenous acid production or exogenous acid loads, thus resulting in metabolic acidosis. Studies in animals show that interstitial accumulation of ammonium activates the complement system and induces tubulointerstitial injury that is limited by alkali therapy. [28] However, the efficacy of correction of acidosis on the progression of CRD is unproven in humans.

   Other factors Top

Other factors, such as the retention of ultra-filterable toxins and reduced levels of nitric oxide, might contribute to further renal injury. This is suggested by studies in non-uremic animals showing that dialysis limits their rate of GFR loss over time [29] and that, in the rat remnant kidney model, the administration of the precursor of nitric oxide, arginine, ameliorates renal function. 30 However, the supplementation of L-arginine failed to detect benefits in patients with [3] CRD. [1]

   The role of tubulointerstitial disease Top

Tubulointerstitial injury is fundamental in the process leading CRD to ESRF since most chronic nephropathies, even glomerulo­pathies, are associated with marked tubulo­interstitial damage. In fact, the severity of the latter predicts better the rate of GFR loss over time and the risk of ESRF, than the severity of glomerular involvement. [2] Tubulointerstitial injury may represent the final pathway of the action of most of the above mentioned factors. As previously described, the excessive tubular protein overload has an important role in the development of immunologically mediated tubulointerstitial injury. In addition, calcium phosphate deposition, [27] metabolic acidosis, [28] and chronic hypoxia [32] (that may be derived from the compromise of post-glomerular capillary circulation) might also contribute.

   Predictors of accelerated progression Top

As expected, the clinical predictors of accelerated CRD progression are strictly linked to the factors which contribute to CRD progression. Urinary protein excretion rate, which reflects an alteration in glomerular barrier integrity, was tightly correlated with the rate of GFR decline both in diabetic and non-diabetic chronic nephropathy. [23] Inde­pendent from the nature of the underlying renal disease, proteinuria was the strongest independent predictor of renal outcome in multivariate analysis both of the Modi­fication of Diet in Renal Disease (MDRD) study [33] and of the Ramipril Efficacy In Nephropathy (REIN) study. [34] Not only baseline proteinuria, but also its short-term changes in response to therapy correlated with long-term renal outcome. [23] Higher blood pressure, lower serum HDL cholesterol and transferrin, and smoking also reached significance in predicting a faster GFR decline. [23],[33]

   The current practice Top

Strict blood pressure control, reduction of proteinuria, and inhibition of the renin-angiotensin system (RAS) are potent tools in order to improve the renal outcome in patients with CRD. Lowering systemic hypertension is invariably associated with improved long-term renal outcome both in diabetic and non-diabetic chronic nephro­pathy. [23],[35],[36] The MDRD study showed that the protection of renal failure, achieved by reducing blood pressure, was dependent on the extent of initial proteinuria. [33] Thus, independent of the type of the antihyper­tensive medications used, the authors recommended the achievement and main­tenance of a blood pressure of less than 125/75 mm Hg in patients with CRD and proteinuria more than 1 g/d and less than 130/80 mm Hg in those with proteinuria of between 0.25 to 1 g/day. However, since several studies showed the presence of a point at which further blood pressure lowering may increase the risk of cardiovascular and/or renal events (J-curve effect), [37] we recommend that one be very cautious in reducing the blood pressure below values of 100/70 mm Hg, especially in patients at risk. Which anti-hypertensive should be used first? Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists, which inhibit the renin angiotensin system (RAS) have been clearly demonstrated to be Reno protective in both diabetic and non-diabetic chronic nephro­pathy. [23] This may be due to their better anti­proteinuric effect than other antihypertensive agents at comparable levels of blood pressure control. The addition of a low sodium diet and/or a diuretic improves the anti-proteinuric action of the RAS inhibitors, by maximally activating the RAS. [23] Since not all the patients in the MDRD study received an ACE inhibitor, the optimal level of blood pressure control in patients with CRD and on ACE inhibitor therapy is unknown. We are now evaluating this in a large-scale randomized trial. Besides their effects on the kidney, the cardioprotective action of the RAS inhibitors provides a further rationale for their use in patients with CRD. [38] Since these drugs may slow CRD progression by a maximum of 50%, [19] other therapeutic options targeted to the factors involved in CRD progression are required [Table - 2]. Clinical trials are ongoing evaluating the systemic and renal effects of the combination of ACE inhibitor and AII receptor antagonist. Despite the beneficial effects of dietary protein restriction on glomerular hemodynamics and renal long-term outcome in most animal models, clinical studies have failed to clearly support its use in humans. A meta-analysis of 13 randomized and 11 non-randomized trials found only a small benefit in the randomized trials. [39]

Although further study is needed, it seems reasonable to advise a dietary protein intake of 0.8 g/kg/d to patients with CRD. Although the role of lipid-lowering agents is not clearly defined in patients with CRD, their use, together with a low cholesterol diet, is advised in order to reduce the already high cardiovascular risk associated with renal insufficiency. Smoking cessation, glycemic and acidosis control are also recommended. Recently, we showed that such an approach has been successful, further improving the renal outcome, in non active immune diseases in which proteinuria was secondary to renal adaptive hemodynamic changes. [23]

Future clinical studies should evaluate the optimal level of intervention for these risk factors and explore the effects of newer factors involved in the progression of CRD, such as endothelin-1 and natriuretic peptides.

   References Top

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Correspondence Address:
Roberto Pisoni
Clinical Research Center for Rare Diseases, Aldo e Cele Daccò -Villa Camozzi, 'Mario Negri' Institute for Pharmacological Research via Gavazzeni, 24125 Bergamo
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Source of Support: None, Conflict of Interest: None

PMID: 18209421

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