Different Patterns of Kidney Fibrosis Are Indicative of Injury to Distinct Renal Compartments

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.

Exploring the Effect of Dapagliflozin on Alcoholic Kidney Injury and Renal Interstitial Fibrosis in Rats Based on TIMP-1/MMP-24 Pathway

“…In the examination of the kidney tissue of rats in the alcohol group, we also found that the inflammation of the kidney tissue and the progress of renal fibrosis are high, which may be due to chronic alcohol consumption causing renal interstitial fibrosis to be affected by oxidative stress and inflammatory regulation [ 18 ]. More and more pieces of evidence show that the stress and inflammatory cytokines produced by the oxidation of reactive oxygen species are very important in renal tubular cell proliferation and renal fibrosis [ 19 – 21 ].…”

Effectiveness of thiazide and thiazide-like diuretics in advanced chronic kidney disease: a systematic review and meta-analysis

“…In people with advanced CKD, substances that have renal clearance by tubular secretion build up at a higher concentration than substances cleared by glomerular filtration [ 24 ]. Another important thing to note is that in some kidney diseases, the level of tubulointerstitial damage is not related to the level of glomerular damage, and as glomerular filtration goes down, tubular secretion goes up as an adaptive response [ 25 , 26 ]. Therefore, the exclusive use of the GFR calculation to assess the clearance of compounds with preferential elimination by tubular secretion can be quite imprecise.…”

Noninvasive evaluation of IgA nephropathy fibrosis using Doppler ultrasound

“…To the best of our knowledge, this is the first large sample-size study to use color ultrasound to predict IgAN TA/IF. Irreversible damage to the nephrons, due to chronic glomerular or tubular injury, lead to TA/IF around the damaged nephrons [ 7 ]. The degree of renal fibrosis correlates with the loss of renal function and renal damage progression.…”

“…The evaluation of TA/IF is currently based on renal biopsy which has the limitations of being invasive, possible sampling errors, and provides limited spatial information. These make it unsuitable for long-term monitoring of disease progression or treatment response [ 7 ].…”

“…Roberts used MEST criteria to predict the outcome of IgAN in 13 studies: endocapillary hypercellularity had independent prognostic value in four, segmental glomerulosclerosis in four, and tubular atrophy/interstitial fibrosis (T, referred to here as TA/IF) in 10 of the studies [ 6 ]. TA/IF is the result of chronic glomerular and tubular injury, and its degree is related to the development of ESRD [ 7 ]. It is considered a risk prediction tool in IgAN [ 8 ].…”