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

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.

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Clinicopathological Patterns and Predictors of the Functional Restoration of Immunoglobulin G4-Related Kidney Disease: A Chinese Single-Center Cohort Study

Frontiers in Medicine ◽

10.3389/fmed.2021.736098 ◽

2021 ◽

Vol 8 ◽

Author(s):

Tao Su ◽

Hui Wang ◽

Suxia Wang ◽

Li Yang

Keyword(s):

Regression Analysis ◽

Kidney Disease ◽

Immunosuppressive Therapy ◽

Kidney Biopsy ◽

Renal Outcome ◽

Clinicopathological Parameters ◽

Disease Relapse ◽

Immunoglobulin G4 ◽

Interstitial Inflammation

Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunoreactivity-based fibro-inflammatory disease. Immunoglobulin G4-related kidney disease (IgG4-RKD) is a frequently overlooked diagnosis. This study aimed to describe IgG4-RKD and examine the factors relevant to the renal outcomes of IgG4-RD.Methods: We studied a prospective IgG4-RKD cohort between January 2012 and December 2020 with close follow-up. Clinicopathologic data at kidney biopsy were collected and analyzed. We aimed to explore independent risk factors for long-term renal outcome and disease relapse. Patients with an eGFR<45 ml/min per 1.73m2 at 12 months were defined as having poor outcomes.Results: The included 42 patients with IgG4-RKD had a mean age of 58.5 ± 8.7 years (male-to-female ratio = 5:1). The IgG4-RD responder index (RI) was 12.2 ± 3.3. A total of 66.7% of the patients presented with acute on kidney disease or acute on chronic kidney disease. Eight patients (19.0%) showed nephrotic-range proteinuria, and nine (21.4%) had high-titer IgG4-autoantibodies, including antineutrophil cytoplasmic antibody and anti-phospholipase A2 receptor. A kidney biopsy was conducted in 40 patients. Thirty-seven (90.0%) patients were diagnosed with IgG4-related tubulointerstitial nephritis, and 19 (47.5%) of them had concurrent glomerular diseases (membranous nephropathy [MN], n = 3; crescentic glomerulonephritis [CrGN], n = 11; diabetic kidney disease, n = 3; and both MN and CrGN, n = 2). IgG4-RD RI had a close relationship with serum C3 (R = −0.509, P = 0.001), C4 (R = −0.314, P = 0.049) levels, and peripheral blood eosinophil count (PBEC; R = 0.377, P = 0.024), factors that were not included in RI scores. Correlation analysis disclosed that IgG4-RD RI (R = 0.422, P = 0.007), organs involved (R = 0.452, P = 0.003), and C3 (R = −0.487, R = 0.002) were correlated with the percentage decrease of serum creatinine at 1 month. However, multivariate regression analysis failed to identify any clinicopathological parameters that could predict short-term renal restoration and IgG4-RKD relapse. Ten out of 29 variables, of most importance, were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis. By multivariate logistic regression a higher serum IgG4 (OR = 0.671, P = 0.010), IgG1 (OR = 1.396, P = 0.049), IgG3 (OR = 19.154, P = 0.039), and erythrocyte sedimentation rate (ESR; OR = 1.042, P = 0.032) were found to be independent factors for poor long-term outcome. Conventional immunosuppressive medications and/or rituximab were prescribed, and in 83.3% of the patients, the kidney function improved. Repeat kidney biopsies confirmed the remission of interstitial inflammation in two patients under immunosuppressive therapy. However, the disease relapse rate was as high as 31.0%.Conclusions: We strongly recommend a kidney biopsy in active IgG4-RD, especially when there is proteinuria and renal dysfunction, because concurrent glomerular involvement and active interstitial inflammation should be assessed. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however, elevated IgG4 predicted a good renal prognosis, and appropriate and timely immunosuppressive therapy can help achieve a better prognosis.

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Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

AJP Cell Physiology ◽

10.1152/ajpcell.00414.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. C591-C603 ◽

Cited By ~ 105

Author(s):

Gabriela Campanholle ◽

Giovanni Ligresti ◽

Sina A. Gharib ◽

Jeremy S. Duffield

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Innate Immune ◽

Cellular Mechanisms ◽

Tubular Atrophy ◽

Kidney Fibrosis ◽

Capillary Rarefaction ◽

Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

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Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz168 ◽

2019 ◽

Cited By ~ 4

Author(s):

Yu Ho Lee ◽

Ki Pyo Kim ◽

Sun-Hwa Park ◽

Dong-Jin Kim ◽

Yang-Gyun Kim ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Interstitial Fibrosis ◽

Renal Outcome ◽

Enzyme Linked Immunosorbent Assay ◽

Glomerular Injury ◽

Tubular Atrophy ◽

Diabetic Kidney ◽

Cytokines And Chemokines ◽

Pathologic Features

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

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P0514USP30 INHIBITOR ATTENUATES PROGRESSIVE FIBROSIS IN ISCHEMIA INDUCED CHRONIC KIDNEY DISEASE (CKD), EVEN AFTER DELAYED TREATMENT INITIATION AFTER INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa143.p0514 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

David Bedford ◽

Jamie Wright ◽

Song Rong ◽

Paul Thompson ◽

Nelli Shushakova ◽

...

Keyword(s):

Kidney Disease ◽

Small Molecule ◽

Renal Injury ◽

Small Molecule Inhibitor ◽

Macrophage Infiltration ◽

Metabolic Adaptation ◽

Tubular Atrophy ◽

Large Pedigree ◽

Kidney Fibrosis ◽

Molecule Inhibitor

Abstract Background and Aims Much literature evidence points towards an essential role of mitochondrial quality control mechanisms in acute kidney injury progression. Renal ischemic-reperfusion injury (IRI) results in metabolic adaptation of proximal tubule epithelial cells, a site of high mitochondrial turnover (1). Moreover, exacerbation of renal injury has been demonstrated following IRI in both PTEN-induced kinase 1 (PINK1) knockout and Parkin knockout mice (2). The identification of a single point mutation (m.547A>T) within the mitochondrial genome of a large pedigree of patients with maternally-inherited tubulointerstitial kidney disease, highlights the importance of mitochondrial integrity in human renal pathophysiology (3). USP30 is a mitochondrial associated deubiquitylating enzyme that acts on the mitochondrial import receptor subunit TOM20 to repress PINK1/Parkin-mediated mitophagy and modulate mitochondrial protein transport (4,5). Within kidney, USP30 expression is predominantly tubular and accordingly, USP30 inhibition may provide a mechanism to protect against IRI. MTX008 is a selective small molecule inhibitor of USP30. Prophylactic administration of MTX008 15 mg/kg (p.o.) BID has shown robust and reproducible efficacy in a mouse model of IRI-induced kidney fibrosis (6). Here we present data showing that dosing MTX008 15 mg/kg (p.o.) BID in a therapeutic paradigm, also results in efficacy in the same IRI-induced kidney fibrosis model. Method On Day 0 (zero) C57BL/6 mice were anaesthetized, and their left renal pedicle was clamped transiently for 45 min, causing circulatory arrest in the kidney with consecutive IRI. Mice were then administered either vehicle or MTX008 15 mg/kg (p.o.) BID for 21 days, with first treatment starting five hours following IRI surgery (i.e. therapeutics dosing). Mice were monitored and kidneys harvested at Day +21. Kidney sections were quantitatively assessed for relative cellular morphology, fibrosis and macrophage infiltration using blinded histological scoring methods. Results Body weight was similar between groups and remained constant throughout the observation periods. Masson trichrome staining revealed significantly less tubular atrophy in MTX008 treated animals on Day +21. Similarly, fibronectin expression and macrophage infiltration in the cortex was also significantly reduced in MTX008 treated mice on Day +21. Conclusion MTX008, a novel selective small molecule inhibitor of USP30 has shown efficacy in a model of IR-induced CKD when dosed therapeutically. Initiating treatment after the establishment of IRI has shown significant benefits towards reduced progression to CKD with less tubular atrophy and renal fibrosis. Mission Therapeutics is investigating MTX008 in a variety of preclinical renal injury models with a view to developing this novel molecule towards the clinic. Therapeutic dosing opens a new and attractive opportunity for the treatment of AKI and sets our UPS30 inhibitor apart from other molecules currently in development.

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Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

PLoS ONE ◽

10.1371/journal.pone.0252758 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252758

Author(s):

Nicholas A. Maksimowski ◽

James W. Scholey ◽

Vanessa R. Williams ◽

Keyword(s):

Kidney Disease ◽

Focal Segmental Glomerulosclerosis ◽

Current Knowledge ◽

Interstitial Fibrosis ◽

Linear Regression Analysis ◽

Renin Angiotensin System ◽

Multiple Linear Regression Analysis ◽

Tubular Atrophy ◽

Kidney Fibrosis ◽

Segmental Glomerulosclerosis

Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

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Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.737708 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samy Hakroush ◽

Désirée Tampe ◽

Philipp Ströbel ◽

Peter Korsten ◽

Björn Tampe

Keyword(s):

Mononuclear Cell ◽

Plasma Cells ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Tubular Atrophy ◽

Interstitial Inflammation ◽

Tubulointerstitial Lesions ◽

Mononuclear Cell Infiltrates ◽

Immune Cell Infiltrates

BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

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MP352PREDICTORS OF LONG TERM RENAL OUTCOME IN PREGNANT WOMEN WITH CHRONIC KIDNEY DISEASE ATTENDING A COMBINED REGIONAL RENAL OBSTETRIC SERVICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfx169.mp352 ◽

2017 ◽

Vol 32 (suppl_3) ◽

pp. iii556-iii556

Author(s):

Monisha Chakravorty ◽

Nadia Sarween ◽

Jemma Proudfoot-Jones ◽

Rachel Clements ◽

Ellen Knox ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Pregnant Women ◽

Renal Outcome

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Lithium-Associated Kidney Microcysts

The Scientific World JOURNAL ◽

10.1100/tsw.2008.112 ◽

2008 ◽

Vol 8 ◽

pp. 828-829 ◽

Cited By ~ 7

Author(s):

Jennifer Tuazon ◽

David Casalino ◽

Ehteshamuddin Syed ◽

Daniel Batlle

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Mr Imaging ◽

Interstitial Fibrosis ◽

Renal Cysts ◽

Lithium Therapy ◽

Tubular Atrophy ◽

Advanced Chronic Kidney Disease ◽

Tubulointerstitial Nephropathy

Long-term lithium therapy is associated with impairment in concentrating ability and, occasionally, progression to advanced chronic kidney disease from tubulointerstitial nephropathy. Biopsy findings in patients with lithium-induced chronic tubulointerstitial nephropathy include tubular atrophy and interstitial fibrosis interspersed with tubular cysts and dilatations. Recent studies have shown that cysts are seen in 33–62.5% of the patients undergoing lithium therapy. MR imaging is highly capable of defining renal morphological features and has been demonstrated to be superior to US and CT scan for the visualization of small renal cysts. The microcysts are found in both cortex and medulla, particularly in the regions with extensive atrophy and fibrosis, and can be multiple and bilateral. They tend to be sparse and do not normally exceed 12 mm in diameter. The renal microcysts in the image here reported are subtle, but consistent with lithium-induced chronic nephropathy. An MRI of the kidneys provides noninvasive evidence that strengthens the diagnosis of lithium-induced nephropathy.

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Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy

BMC Nephrology ◽

10.1186/s12882-021-02510-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Miho Shimizu ◽

Kengo Furuichi ◽

Shinji Kitajima ◽

Tadashi Toyama ◽

Megumi Oshima ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Interstitial Fibrosis ◽

Long Term Outcomes ◽

Renal Interstitial Fibrosis ◽

Tubular Atrophy ◽

Tubulointerstitial Lesions ◽

The Impact

Abstract Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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ANCA-associated vasculitis with dominant renal involvement: clinical and morphological presentation and outcomes

Nephrology (Saint-Petersburg) ◽

10.36485/1561-6274-2019-236-29-44 ◽

2019 ◽

Vol 23 (6) ◽

pp. 29-44

Author(s):

V. A. Dobronravov ◽

A. V. Karunnaya ◽

A. V. Kazimirchik ◽

A. V. Smirnov

Keyword(s):

Kidney Disease ◽

Serum Creatinine ◽

Clinical Remission ◽

Kidney Biopsy ◽

Morphological Parameters ◽

Baseline Serum ◽

Interstitial Inflammation ◽

Baseline Serum Creatinine

THE AIM: The analysis of clinical and morphological presentations and outcomes of primary systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA-V) with dominant kidney involvement; the determination of clinical and morphological parameters associated with prognosis.PATIENTS AND METHODS. Eighty nine patients with morphologically confirmed ANCA-associated kidney vasculitis on standard immunosuppressive therapy (IST) were included in this retrospective study. Clinical, immunological, and histological indices were analyzed at the time of the kidney biopsy, and early in the short-term (3-6 months) and in the long-term follow-up. The following outcomes were evaluated: the achievement of clinical and immunological remission of the disease; eGFR at the end of follow-up, the progression of renal disease (by the composite point: initiation of renal replacement therapy (RRT) or the estimated glomerular filtration rate (eGFR) <15 ml/min/1.73m2 or decrease in eGFR >50 %); all-cause mortality. The prognostic significance of clinical and morphological parameters was evaluated in multivariable regression models.RESULTS. Most of cases (78 %) were represented by rapidly progressive or acute nephritic syndrome. Mean eGFR was 23 ml/min/1.73 m2. Fifteen percent of patients required acute dialysis. Dominant morphological phenotypes of glomerular lesions were sclerotic (34 %) and mixed (36 %) according to the International Pathology Classification (IPC). Median follow-up was 24 (8; 55) months. Cumulative 5-year and 10-year patient’s survivals and were 92 % and 86 %, respectively. Cumulative 5-year and 10-year renal survivals were 86 % and 68 %, respectively. The cumulative 5-year and 10-year proportions of cases without progression of kidney disease were 80 % and 55 %, respectively. Within 3-6 months of the induction IST 81 % of patients achieved clinical remission (complete (59 %) or partial (22 %)) (CR3-6), while 84 % of patients had immunological remission. Serum creatinine (Pcr) at the time of kidney biopsy was only the factor associated with the risk of renal progression (Expβ=1.73 (95 %CI 1.40-2.14) per 0.1 mmol/l increase). IPC classes and ANCA Renal Risk Score (ARRS) groups as well as other morphological indices of kidney injury had no independent associations with the renal outcomes in Cox models adjusted for Pcr. The independent factors associated with eGFR at the end of follow-up were: CR3-6 (β=0.36±0.08, p<0.001); age (β=-0.34±0.09, p<0.001), Pcr (β=-0.35±0.09, p<0.001) and the global glomerulosclerosis (β=0.28±0.08, p<0.001). CR3-6 (β=0.57±0.10, p<0.001), and the proportion of cellular crescents (β=0.26±0.12, p=0.023) and interstitial inflammation (β=0.27±0.11, p=0.026) were also independently associated with the change of eGFR by the end of follow-up.CONCLUSION. An unfavorable renal prognosis for ANCA-V determined by severe renal dysfunction due to inflammatory and fibrotic alterations of the organ can be significantly improved by adequate therapy with the achievement of higher patient’s and kidney’s survival. The baseline serum creatinine is only the factor associated with the long-term risks of dialysis and kidney disease progression. In addition to baseline serum creatinine and the development of early clinical remission, the separate assessment of global glomerular sclerosis, cellular crescents, and interstitial inflammation may be more useful for the individual prediction of long-term eGFR changes than IPC classes or ARRS.

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