Abstract
Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting a wound healing response as a consequence of infarction. In the kidney, chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and finally interstitial fibrosis/tubular atrophy (IF/TA). Compared to this glomerulus-induced focal replacement scar, diffuse fibrosis independent of tubular atrophy appears to be a different pathogenic process. Kidney fibrosis appears to develop in a compartment-specific manner, but whether focal and diffuse fibrosis has distinct characteristics associated with other glomerular or tubulointerstitial lesions remains elusive. In the present study, we aimed to analyze renal fibrotic patterns related to renal lesions, which directly contribute to renal fibrogenesis, to unravel fibrotic patterns and manifestations upon damage to distinct renal compartments. Patterns of kidney fibrosis were analyzed in experimental models of CKD and various renal pathologies in correlation with histopathological and ultrastructural findings. After the induction of isolated crescentic glomerulonephritis (GN) in nephrotoxic serum-nephritis (NTN), chronic glomerular damage resulted in predominantly focal fibrosis adjacent to atrophic tubules. By contrast, using unilateral ureteral obstruction (UUO) as a model of primary injury to the tubulointerstitial compartment revealed diffuse fibrosis as the predominant pattern of chronic lesions. Finally, folic acid-induced nephropathy (FAN) as a model of primary tubular injury with consecutive tubular atrophy independent of chronic glomerular damage equally induced predominant focal IF/TA. By analyzing several renal pathologies, our data also suggest that focal and diffuse fibrosis appear to contribute as chronic lesions in the majority of human renal disease, mainly being present in antineutrophil cytoplasmic antibody (ANCA)-associated GN, lupus nephritis, and IgA nephropathy (IgAN). Focal IF/TA correlated with glomerular damage and irreversible injury to nephrons, whereas diffuse fibrosis in ANCA GN was associated explicitly with interstitial inflammation independent of glomerular damage and nephron loss. Ultrastructural analysis of focal IF/TA versus diffuse fibrosis revealed distinct matrix compositions, further supported by different collagen signatures in transcriptome datasets. With regard to long-term renal outcome, only the extent of focal IF/TA correlated with the development of end-stage kidney disease (ESKD) in ANCA GN. In contrast, diffuse kidney fibrosis did not associate with the long-term renal outcome. In conclusion, we here provide evidence that a focal pattern of kidney fibrosis seems to be associated with nephron loss and replacement scarring. In contrast, a diffuse pattern of kidney fibrosis appears to result from primary interstitial inflammation and injury.
Highlights
Kidney fibrosis is a common manifestation and the hallmark of a wide variety of chronic kidney diseases (CKD) leading to end-stage kidney disease (ESKD), regardless of the underlying etiology [1]
Diffuse fibrosis as a result of glomerular or tubular injury, we first challenged mice with experimental models of primary glomerular injury leading to glomerular sclerosis induced by nephrotoxic serum-nephritis (NTN), diffuse tubulointerstitial injury due to postrenal failure with renal hemodynamic and metabolic changes caused by unilateral ureteral obstruction (UUO), and a specific model of tubular injury leading to tubular atrophy by folic acid-induced nephropathy (FAN, Figure 1A) [26,27,28]
Diffuse fibrosis was predominantly present in cases of antineutrophil cytoplasmic antibody (ANCA) GN, lupus nephritis, and IgA nephropathy (IgAN) as kidney diseases with glomerular and interstitial injury (Figure 2C). These findings suggest that distinct patterns of kidney fibrosis are present in various renal pathologies, including antibody-associated glomerulonephritis (ANCA GN), and that
Summary
Kidney fibrosis is a common manifestation and the hallmark of a wide variety of chronic kidney diseases (CKD) leading to end-stage kidney disease (ESKD), regardless of the underlying etiology [1]. Kidney fibrosis can appear in different morphological patterns, suggesting other pathogenic causes [2]. Chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and interstitial fibrosis/tubular atrophy (IF/TA) [4,5]. Compared to this glomerulus-induced focal replacement scar, fibrosis independent of tubular atrophy (in the following, referred to as diffuse fibrosis) appears to be a different pathogenic process [6,7]. Tubular atrophy is defined as a loss of specialized transport and metabolic capacity and is typically characterized by small tubules, epithelial cells with pale cytoplasm, or dilated very thin tubules
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