The Tubulointerstitial Pathophysiology of Progressive Kidney Disease

Abstract

Accumulating evidence suggests that the central locus for the progression of CKD is the renal proximal tubule. As injured tubular epithelial cells dedifferentiate in attempted repair, they stimulate inflammation and recruit myofibroblasts. At the same time, tissue loss stimulates remnant nephron hypertrophy. Increased tubular transport workload eventually exceeds the energy-generating capacity of the hypertrophied nephrons, leading to anerobic metabolism, acidosis, hypoxia, endoplasmic reticulum stress, and the induction of additional inflammatory and fibrogenic responses. The result is a vicious cycle of injury, misdirected repair, maladaptive responses, and more nephron loss. Therapy that might be advantageous at one phase of this progression pathway could be deleterious during other phases. Thus, interrupting this downward spiral requires narrowly targeted approaches that promote healing and adequate function without generating further entry into the progression cycle.

Keywords: CKD; Fibrosis; Proximal tubule; Remnant nephron.

FIGURE 1

Multiple biological processes contribute to repair of the injured kidney.

FIGURE 2

Possible outcomes of repair after injury. If repair is appropriately applied and adequate, normal function is re-established. But if repair is insufficient, nephron mass is decreased; if it is excessive or misapplied, dysfunctional tissue results. In either of these latter cases, the remnant kidney must adapt. Successful adaptation also re-establishes homeostasis, but maladaptation leads to further cycles of injury and repair and chronic, progressive disease.

FIGURE 3

Biological process involved in progression are parallel to those involved in repair. Compare this figure with Figure 1. Although activated cells show increased metabolic activity, for progression the metabolic response is placed before activation to emphasize the role of altered metabolism after the compensatory hypertrophic response of the nephron.

FIGURE 4

Both glomerular and tubular injury lead to tubulointerstitial responses and renal tubular cell activation, potentially initiating progressive CKD. Reprinted with permission from.

FIGURE 5

Remnant nephron hypertrophy may create a vicious cycle in which processes that preserve functional homeostasis drive further nephron loss. Adapted with permission from.