Can We Really Lessen Kidney Damage to the Point that the Loss of Renal Function of Progressive Nephropathy May Revert?

The results of experimental studies and clinical trials have identified blockade of the renin angiotensin system (RAS) as a cardinal way of arresting the progression of renal disease to end-stage failure (1). Slowing the rate of progression has been the key goal until recently; however, current approaches have already taken additional steps forward by looking at ways to halt progression and even promote increases of GFR over baseline values and improvement of associated structural injury, that is to achieve regression of renal disease. The rationale for such approaches rests on two basic considerations. First, many forms of chronic nephropathy evolve to end-stage through a series of events that are relatively independent of the initial insults that cause parenchymal damage when the injury affects a critical number of nephrons. Blocking the common pathway(s) of injury by angiotensin blockade could then spare renal structures from damage via angiotensin II, maladaptive mechanisms, and protein trafficking. Still more open was the possibility that drug therapies may eradicate certain structural components of injury that are usually believed to be inevitably irreversible, thus fully protecting renal function and minimizing the risks of evolutive disease. Experimental lines of evidence have suggested that such possibility is credible and worth investigating further. The background again can be derived from seminal studies using low-protein diet or angiotensin I–converting enzyme inhibitors (ACE-I), the first ones to show that the glomeruli can be protected against the development of sclerosis in rats with progressive nephropathy due to extensive reduction of renal mass or streptozotocin diabetes (2). Compared with a non–ACE-I regimen that achieved equivalent systemic BP control, ACE-I better reduced renal injury partially via amelioration of glomerular hypertension. Recent years have yielded convincing demonstration that both glomerulosclerosis and chronic tubulointerstitial injury, once developed, can be stabilized and even revert. In Munich Wistar Frömter (MWF) rats with spontaneous disease, ACE-I given late during the animal’s life, when animals were already heavily proteinuric, decreased proteinuria and stopped the disease from progressing, as documented by a lower incidence of glomeruli affected by sclerotic lesions and less interstitial injury than in untreated controls (3). In few studies of other models, the disease was usually not severe enough (4–7), as judged by baseline proteinuria, nor was the dose of ACE-I high enough (8,9) to draw definitive conclusions on the degree of regression of renal functional and structural changes. However, the overall data substantiated the results of previous morphologic studies showing that ACE-I, at doses exceeding the antihypertensive doses, imparted an additional benefit to glomerular structure, reverting the early glomerular lesion but not the advanced lesions (9). Sclerosis was also remodeled in aging rats by inhibiting the RAS with an AIIRA given at high doses for 6 mo (10). The effect was attributed to the modulation of cortical cell turnover and inhibition of plasminogen activator-1 (PAI-1) expression. Combination therapies have most recently offered a powerful tool to address the extent to which drug treatments effectively induce regression of renal disease at functional and structural levels. In a recently published study, treatment with ACE-I and AIIRA given to MWF rats during the interval between 25 and 40 wk of age had remarkable effects (11). Combined therapy completely reversed protein excretion and ameliorated renal plasma flow and the glomerular ultrafiltration coefficient. The reduction of the extent of existing structural damage was a key finding. Specifically the percentage of glomeruli with sclerotic lesions affecting less than 25% of the tuft decreased in respect to baseline in the absence of increases in the percentage of glomeruli with more severe lesions. The degree of tubulointerstitial injury, including protein cast formation, macrophage infiltration, and type III collagen accumulation was also reduced by treatment. In this model, the glomerular permselective dysfunction attributable to large, nonselective pores of the membrane precedes and may play a role in structural injury independently of increased glomerular capillary hydraulic pressure. Given the ability of angiotensin II to disrupt the permselective function of the glomerular filtering barrier, the primary functional barrier amelioration action of drug therapy, presumably at the podocyte level, could contribute to prevention of detrimental effects of sustained proteinuria and chemokine stimulation. From the clinical standpoint, preliminary data in the same model suggest that the stabilization of disease can be achieved, even when treatment is started at an advanced stage, if the study is designed to achieve significant regression of glomerulosclerosis. The simultaneous inhibition of RAS and other pathways of injury provided superior benefit and partial regression of tubulointerstitial injury in another progressive model, passive Heymann nephritis in uninephrectomized rats (12). Combining ACE-I, AIIRA, and statin was therapeutic when given between 2 and 10 mo. Triple drug therapy, despite similar BP control compared with less effective treatments, led to reduction of urinary protein to normal values and full prevention of renal failure. Reduction of intrarenal leukocyte accumulation and expression of TGF-β may concur to mediate the beneficial effects (12). The article by Boffa et al. (13) in this issue of JASN adds new data in support of the regression of renal microvascular and interstitial damage by drug therapy. Using the hypertensive model of nitric oxide deficiency in rats, they found that renal function normalized after treatment with AIIRA and renal lesions were significantly reduced compared with untreated animals. The number of glomeruli falling in the high score for glomerulosclerosis here was remarkably lower in treated rats at the end of the observation period in respect to untreated rats at baseline. One possible limitation of this study is that the course of renal disease in this model is rather stable, as reflected by stable high levels of serum creatinine in the surviving rats between the two main time points (4 and 8 wk) in the untreated group. Also, the predominant component lesion in glomeruli appeared to be an increase in the mesangial matrix associated with ischemic changes ensuing as a predictable consequence of vascular lesions. Nevertheless, the results are convincingly in line with the studies we mentioned above and converge to indicate that the regression of glomerulosclerosis is feasible and may have functional impact. The article also provides hints to potential mechanisms of regression. The beneficial effects of AIIRA were independent of BP control, as hydralazine failed to improve renal function despite a similar degree of systolic BP decrease. Collagen gene expression was markedly inhibited (collagen IV) or even normalized (collagen I), whereas the activities of collagen-degrading enzyme metalloproteinases remained high as in untreated controls or comparable to normal. Although important issues were not yet explored, particularly whether changes in major regulatory proteins such as tissue inhibitors of metalloproteinases could be affected and the precise significance of MMP2 and MMP9 in this model, the data may further suggest that the modulation of the normal proteolytic network plays a significant role in the therapeutic action of AIIRA. Among the downstream mediators of prosclerosing and fibrogenic actions of the activated RAS, TGF-β has been increasingly recognized to play a major role both by stimulating the synthesis and by inhibiting the degradation of extracellular matrix components. Studies on regression of renal injury, including the study by Boffa et al. (13) showing decreases in TGF-β gene and protein expression by AIIRA treatment, also suggest that the inhibition of TGF-β is an important mechanism underlying the ability of drug therapy to ameliorate established lesions (13,14). In this respect, a considerable component of the protective action of RAS blockade is exerted in the tubulointerstitial compartment. Importantly, agents to block the action of TGF-β, such as neutralizing antibodies, are available, and the results of preliminary studies indicate that they may prove to be very efficacious. Like TGF-β, other chemokines and growth factors of tubular and/or inflammatory cell origin, such as interleukin-1 and tissue plasminogen activator (tPA), contribute to the production and regulation of glomerular and interstitial extracellular matrix. Some of these factors might demonstrate interrelated actions that are potentially relevant to regression of lesions. This appears to be the case, for instance, in mice lacking tPA that were protected against tPA-induced MMP9 gene expression and renal fibrosis (15). To achieve regression in advanced stages of disease, one may predict that combination therapies will be the strategy of choice in future experimental studies and hopefully in patients. Besides RAS-blocking agents and TGF-β inhibitors, they may include vasopeptidase inhibitors (16), statins (17), and agents to block immune and inflammatory reactions, such as mycophenolate mofetil (18), complement inhibitory molecules (19), and anti-TNF antibodies that have been shown to induce regression of interstitial inflammation (20). Evidence that regression of renal progressive disease and of the underlying lesion is achievable in humans can only be indirect, but it is fairly consistent and encouraging. Clinical findings of reduction of proteinuria to < 0.3 g/24 h and increasing GFR indicate regression of proteinuric chronic nephropathy, possibly reflecting improvement of renal structural changes (1). In patients with nondiabetic chronic nephropathy and heavy proteinuria at least equal to 3 g/24 h, 5-yr ramipril therapy progressively reduced the rate of GFR decline to < 0.1 ml/min per month (21,22), an achievable target also in diabetic nephropathy, as shown by the pivotal study by Parving’s group in nine type 1 diabetic patients over 9-yr antihypertensive therapy (23). More surprisingly, GFR slopes in sixteen nondiabetic patients (24) progressively stabilized or were worsening so slowly that end-stage renal disease (ESRD) would be delayed beyond the patients’ expected lifetime. Ten patients showed an improvement of GFR to the point that they might never reach ESRD (24). On the same line, Wilmer et al. (25) described seven type 1 diabetic patients who had remission of proteinuria and stabilization of their serum creatinine over 7-yr continued captopril therapy. Breyer Lewis et al. (26) achieved full remission (proteinuria < 0.5 g/24 h) in 57% of 126 type 1 diabetic patients given high-dose (10 mg/d) ramipril. Even more encouraging results can be achieved by multidrug treatment titrated to urinary proteins rather than to BP. Combined therapy with ACE-I, AIIRA, diuretics, and statins blunted proteinuria and stabilized GFR for almost 10 yr in a young girl with nephrotic-range proteinuria who might otherwise have required dialysis within months (27). In a series of ours, more than twenty-six patients whose proteinuria had been at least 3 g for more than 6 mo despite ACE-I therapy have been put on a standardized multidrug treatment. Nineteen of these patients achieved full remission of proteinuria, and their renal function stabilized over 24 mo. Whether renal damage can also be reduced in parallel with clinical remission is still matter of investigation. In support is the evidence by repeated biopsy of a trend regressing renal damage, leading to less mesangial expansion, more open capillaries, and less interstitial fibrosis (28). At least 10 yr were needed to revert the lesions, which is entirely consistent with the concept that the timing of institution of therapy, besides the drug doses and combinations, is critical in the human setting exactly like in the experimental animal. In summary, regression of lesions may have a significant effect on progressive renal disease and its sequelae. One might wonder why we should pursue the goal of improving renal structure and function if we can already successfully stabilize the disease perhaps for a lifetime. First and most obviously, improving renal function may have a major effect in reducing the number of patients with chronic renal disease that progresses to ESRD. Any improvement of renal structure and function should also translate into less risk of ESRD for those who have less compromised renal function. This would apply both to young patients and to the elderly, who may incur more critical renal and cardiovascular risks. The economic impact of even a partial improvement would be enormous, as documented by findings that a 30% reduction in the rate of GFR decline would translate into a saving of more than 60 billion dollars for providing renal replacement therapy to patients progressing to ESRD in the US by the year 2010 (29). Finally, in certain settings, such as membranous nephropathy, focal and segmental sclerotic lesions predict worse prognosis. What would happen if we could revert them? Understanding the mechanisms by which a given lesion may regress and its relationship to function will be crucial to understanding the relevant renal cell biology and therapeutic targets. Once again, investigation in experimental models will prove indispensable to the new task and will clarify whether renal damage can be reverted to such a point that renal function may be fully prevented from worsening and may even possibly improve. We are indebted to Dr. Piero Ruggenenti for suggestions and criticism.