Regression Lines in Chronic Kidney Disease

Abstract

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 20 th 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).

Cellular and Molecular Pathways that Lead to Progression and Regression of Renal Fibrogenesis

“…Angiotensin II stimulates ECM protein synthesis directly v i a both hemodynamic and nonhemodynamic mechanisms and induces fibrogenic molecules such as TGF-β 1 and MCP-1, while inhibiting matrix degradation by directly inducing PAI-1 and TIMP-1 [127,128]. Growing evidence suggests significant fibrogenic actions of aldosterone [129].…”

Electroacupuncture and Moxibustion Attenuate the Progression of Renal Disease in 5/6 Nephrectomized Rats

“…Blocking these common mechanisms and modulation of fibrotic agents may inhibit the progression of CKD, independent of the underlying primary disease. Synergistic therapies could halt the progression of fibrosis and may potentially cause regression of any existing renal scarring [3,8,9] .…”

Compelling drug indications in diabetic and nondiabetic nephropathy

“…A study in type 1 diabetic patients with nephropathy showed that after isolated pancreas transplantation, partial reversal of glomerular pathology had occured after 10 years [84], implying the possibility of glomerular self repair. Partial reversal of glomerulosclerosis has also been observed in nondiabetic models of renal damage after administration of high doses of ACEIs or angiotensin receptor blockers [3,4,85]. Whether in the future this will be a realistic therapeutic goal in humans as well is currently under investigation.…”