Regression Lines in Chronic Kidney Disease
Authors: Agnes B. Fogo
Journal: Journal of the American Society of Nephrology (2003)

Chronic kidney disease (CKD) has been recognized for millennia. The great physicians Rhazes (865–925 AD) and Abu Sina (aka Avicenna, 980–1037 AD) in ancient Persia described kidney diseases in detail. In medieval times, the pisse prophets predicted outcomes for patients on the basis of uroscopy analyses. Categorization of CKD developed in the 20th century from the nonspecific “Bright’s disease” with the advent of renal biopsy analysis. Patients could now survive with CKD with dialysis, made possible by the inventions of Kolf, Scribner, and others, or transplant. The rate of progression in individual patients could be determined by analyzing the linear regression plots of the inverse of serum creatinine versus time (1). Progress was made in slowing this relentless course of CKD by recognizing the key role of systemic BP control. The importance of intraglomerular BP control was recognized by the key studies of Brenner and colleagues (2). Currently, we aim beyond slowing the rate of progression. Is it possible to achieve regression of existing renal scarring? Are there treatments beyond BP control that could affect such goals? The interesting studies by Adamczak et al. (3) confirm in an experimental model that it is possible to remodel existing CKD. The authors extend previous observations and show that remodeling of vascular sclerosis, tubulointerstitial fibrosis, and even existing glomerulosclerosis is feasible (4,5). This was achieved by treatment with angiotensin-converting enzyme inhibitor (ACEI) at doses far beyond BP control. What could be possible mechanisms involved in this regression? Clearly, both systemic and local glomerular pressures are key in perpetuating a vicious cycle of progressive damage. Numerous additional factors have also been implicated in progressive renal scarring, including for instance reactive oxygen species, growth factors, chemokines, cytokines, proteinuria, and cell-specific injury. This plethora of pro-fibrotic mechanisms indicates that it is unlikely that any single intervention could have optimal effect on amelioration, let alone regression of progressive kidney diseases. Although new glomeruli cannot be grown after birth, glomeruli can regenerate new segments after injury, both by capillary lengthening and branching (6). Mesangial cells and glomerular endothelial cells readily proliferate after injury. In contrast, the podocyte exhibits high expression of cyclin-dependent kinase inhibitors, and normally has minimal capacity to proliferate (7). Of note, although regression was achieved by high-dose angiotensin inhibition by Adamczak et al., podocytes did not show any detectable change in number or size, perhaps reflecting this limited growth responsiveness. On the basis of our mathematical analysis, glomeruli with greater than 50% of their tuft sclerosed are not capable of regeneration of the remaining tuft (5). Strategies to overcome this growth inhibition in the podocyte, without promoting deleterious dedifferentiation and proliferation as seen in collapsing glomerulopathy and HIV-associated nephropathy will indeed be a major challenge. Whether manipulation of bone marrow-derived cells can augment glomerular cell regeneration, perhaps even of the podocyte, remains to be seen. Low birth weight at term is linked to decreased nephron number, and is a risk factor for development of CKD and hypertension (8,9). Both environmental and genetic influences likely contribute to decreased nephron number, which is far more frequent in African Americans than in Caucasians. These fewer nephrons are postulated to undergo greater hemodynamic stress. Gene polymorphisms that govern intrauterine renal development and nephron glomerular number may also modulate responses to injuries in adulthood. Future genetic and molecular studies will perhaps allow more precise identification of individuals at high risk for progressive kidney disease. Kretzler et al. (10) have elegantly demonstrated the feasibility of specific quantitative molecular analysis from small human biopsy samples in carefully controlled RT-PCR analyses. New strategies aimed at determining pharmacologic response profiles based on genetic polymorphism and mutation analysis, so-called pharmacogenomics, may allow better-targeted and earlier interventions. Tubulointerstitial fibrosis is currently the morphologic predictor most tightly linked to progressive injury. Interstitial fibrosis is not merely a consequence of glomerulosclerosis. Proteinuria may contributed to it (11). The possibility of dedifferentiation of tubular cells, allowing their migration into the interstitium as pro-fibrotic myofibroblasts, so-called epithelial-mesenchymal transition, has been proven in principle by Neilson et al. (12). Tubulointerstitial infiltration by monocytes and macrophages also stimulates pro-fibrotic mechanisms. Bone marrow-derived cells may, however, also have beneficial effects on injury. The macrophage angiotensin type 1 (AT1) receptor has an early beneficial effect on interstitial injury healing (13). In contrast, at later stages, macrophages are linked to increased fibrosis. Inhibition of interstitial fibrosis may be targeted directly decreasing migration of profibrotic macrophages (14). Bone marrow–derived stem cells may also repopulate injured tubules and glomeruli, thus enhancing recovery and regeneration of functional tissue after injury (15). New strategies may be developed to further enhance this stem cell–based healing mechanism. To achieve regression of sclerosis, matrix degradation must exceed matrix synthesis. Key factors that promote collagen synthesis include pressure, angiotensin II, transforming growth factor–β (TGF-β), platelet-derived growth factor-B, and numerous other growth factors. Tissue inhibitor of metalloproteinase–1 (TIMP-1) and plasminogen activator inhibitor–1 (PAI-1) are key inhibitors of proteolysis. Importantly, angiotensin stimulates matrix synthesis directly both by hemodynamic and nonhemodynamic mechanisms and induces other profibrotic molecules (e.g. TGF-β). Angiotensin also inhibits matrix degradation by directly inducing TIMP-1 and PAI-1 primarily via the AT1 receptor (16). Inhibitors of the renin angiotensin system can thus be viewed as antifibrotic as well as antihypertensive drugs. The studies by Adamczak et al. confirm previous studies that high0dose angiotensin inhibition (by either ACEI or AT1 receptor antagonist, AT1RA) can induce regression of sclerosis. Previous studies with similar high doses of ACEI or AT1RA resulted in regression in approximately 50% of the animals, associated with significant decreases in PAI-1 and TIMP-1 mRNA expressions (4,17). To maximize the potential for regression, a multi-pronged attack will probably be necessary. The efficacy of combining AT1RA with ACEI has been explored in several studies. Remuzzi et al. (18) showed that ACEI and AT1RA, with or without added statins, led to further regression than monotherapy in experimental CKD. However, the AT2 receptor promotes apoptosis, and its absence has resulted in inadequate apoptosis and greater fibrosis (19). Thus, maintaining local AT2 receptor activation could potentially promote regression, while increased bradykinin caused by ACEI decreases renal fibrosis (20). In summary, the current study confirms that regression of CKD certainly can be achieved in rats. Are these results applicable to humans? The potential for achieving regression of progressive human renal disease has already been demonstrated in a small study of diabetic patients who received pancreas transplants (21). The severity of the diabetic nephropathy was unchanged at 5 yr; however, at 10 yr, both glomerulosclerosis and tubulointerstitial lesions had regressed. These exciting results point to an untapped potential for regression of existing renal disease. Combination strategies will probably be necessary to optimize regression, and ideally should be directed at stage-specific mechanisms. The exciting potential of stem cell–derived regeneration of renal parenchyma may be realized. Genetically determined profibrotic risks may also dictate therapeutic approaches. Although major obstacles remain, specifically the challenges of optimally modulating the podocyte to effect regeneration, there is ample reason for optimism. Perhaps in the future we will plot true lines of regression of CKD for our patients.