Development of a clinical prediction model of chronic kidney disease in primary Focal Segmental Glomerulosclerosis

Abstract Background: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the risk factors of progression of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors. Methods: 201 patients with primary FSGS (59% male, mean age: 38±15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated. Results: During 55±27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR:1.39, 95%CI: 1.15-1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR: 1.03, 95% CI: 1.02-1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR: 1.03, 95% CI: 1.01-1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95%CI: 0.77-0.90) for prediction of CKD/ESKD . Median renal survival was 3.1 years (95% CI: 2.2-4.1 years) in patients with highest risks score (baseline eGFR<25 ml/min/1.73 m 2 + IF/TA/SGS> 50%), and 8.1 years (95% CI: 7.7-8.6 years).in those with lowest score (baseline eGFR>75 ml/min/1.73 m 2 + IF/TA/SGS <5%). Conclusion: In primary FSGS, higher baseline SCr, increased SGS and IF/TA were the predictors for CKD/ESKD. Baseline proteinuria did not predict the risk of CKD/ESKD. Collapsing variant did not increase the risk of CKD/ESKD after adjustment for IF/TA score. These findings indicated the importance of baseline GFR and the degree of chronicity at biopsy as predictors of kidney outcome .

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Kidney Outcome in Primary Focal Segmental Glomerulosclerosis (FSGS) by Using a Predictive Model

10.21203/rs.2.11407/v3 ◽

2020 ◽

Author(s):

Shahrzad Ossareh ◽

Mansoureh Yahyaei ◽

Mojgan Asgari ◽

Hanri Afghahi

Keyword(s):

Kidney Disease ◽

Predictive Model ◽

Focal Segmental Glomerulosclerosis ◽

Interstitial Fibrosis ◽

Cox Model ◽

Tubular Atrophy ◽

Model Interaction ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Adjusted Model

Abstract Background: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the risk factors of progression of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors.Methods: 201 patients with primary FSGS (59% male, mean age: 38±15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated.Results: During 55±27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR:1.39, 95%CI: 1.15-1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR: 1.03, 95% CI: 1.02-1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR: 1.03, 95% CI: 1.01-1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95%CI: 0.77-0.90). Median renal survival was 3.1 years (95% CI: 2.2-4.1 years) in patients with highest risks score (baseline eGFR<25 ml/min/1.73 m2+ IF/TA/SGS> 50%), and 8.1 years (95% CI: 7.7-8.6 years).in those with lowest score (baseline eGFR>75 ml/min/1.73 m2+ IF/TA/SGS <5%).Conclusion: In primary FSGS, higher baseline SCr, increased SGS and IF/TA, but not baseline proteinuria and collapsing pathology, were the predictors for CKD/ESKD. These findings indicated the importance of timely detection and referral in prognosis of primary FSGS.

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Kidney Outcome in Primary Focal Segmental Glomerulosclerosis (FSGS) by Using a Predictive Model

10.21203/rs.2.11407/v1 ◽

2019 ◽

Author(s):

Shahrzad Ossareh ◽

Mansoureh Yahyaei ◽

Mojgan Asgari ◽

Hanri Afghahi

Keyword(s):

Kidney Disease ◽

Predictive Model ◽

Focal Segmental Glomerulosclerosis ◽

Interstitial Fibrosis ◽

Cox Model ◽

End Stage Kidney Disease ◽

Model Interaction ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Adjusted Model

Abstract Background: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the risk factors of progression of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors. Methods: 201 patients with primary FSGS (59% male, mean age: 38±15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated. Results: During 55±27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR:1.39, 95%CI: 1.15-1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR: 1.03, 95% CI: 1.02-1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR: 1.03, 95% CI: 1.01-1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95%CI: 0.77-0.90). Median renal survival was 3.1 years (95% CI: 2.2-4.1 years) in patients with highest risks score (baseline eGFR<25 ml/min/1.73 m2+ IF/TA/SGS> 50%), and 8.1 years (95% CI: 7.7-8.6 years).in those with lowest score (baseline eGFR>75 ml/min/1.73 m2+ IF/TA/SGS <5%). Conclusion: In primary FSGS, higher baseline SCr, increased SGS and IF/TA, but not baseline proteinuria and collapsing pathology, were the predictors for CKD/ESKD. These findings indicated the importance of timely detection and referral in prognosis of primary FSGS. Keywords: Focal segmental glomerulosclerosis, End stage kidney disease, Pathology

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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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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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Chronic kidney disease: a review of proteomic and metabolomic approaches to membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy biomarkers

Proteome Science ◽

10.1186/s12953-019-0155-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 4

Author(s):

Amir Taherkhani ◽

Reyhaneh Farrokhi Yekta ◽

Maede Mohseni ◽

Massoud Saidijam ◽

Afsaneh Arefi Oskouie

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Iga Nephropathy ◽

Focal Segmental Glomerulosclerosis ◽

Membranous Glomerulonephritis ◽

Renal Diseases ◽

Segmental Glomerulosclerosis ◽

Therapeutic Procedures ◽

Definition Of ◽

End Stage

AbstractChronic Kidney Disease (CKD) is a global health problem annually affecting millions of people around the world. It is a comprehensive syndrome, and various factors may contribute to its occurrence. In this study, it was attempted to provide an accurate definition of chronic kidney disease; followed by focusing and discussing on molecular pathogenesis, novel diagnosis approaches based on biomarkers, recent effective antigens and new therapeutic procedures related to high-risk chronic kidney disease such as membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy, which may lead to end-stage renal diseases. Additionally, a considerable number of metabolites and proteins that have previously been discovered and recommended as potential biomarkers of various CKDs using ‘-omics-’ technologies, proteomics, and metabolomics were reviewed.

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Lithium Nephrotoxicity

Journal of the American Society of Nephrology ◽

10.1681/asn.v1181439 ◽

2000 ◽

Vol 11 (8) ◽

pp. 1439-1448 ◽

Cited By ~ 6

Author(s):

GLEN S. MARKOWITZ ◽

JAI RADHAKRISHNAN ◽

NEERAJA KAMBHAM ◽

ANTHONY M. VALERI ◽

WILLIAM H. HINES ◽

...

Keyword(s):

Serum Creatinine ◽

Focal Segmental Glomerulosclerosis ◽

Interstitial Fibrosis ◽

Renal Cysts ◽

Significant Degree ◽

Fisher Exact Test ◽

Tubular Atrophy ◽

Segmental Glomerulosclerosis ◽

Tubulointerstitial Nephropathy ◽

Collecting Tubules

Abstract. This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P= 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P= 0.008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.

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Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied With Gut Microbiota Change in Chronic Kidney Disease Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.780924 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunlan Ji ◽

Yin Li ◽

Yenan Mo ◽

Zhaoyu Lu ◽

Fuhua Lu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Intestinal Microbiota ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Underlying Mechanism ◽

Uremic Toxins ◽

16S Rrna Sequence ◽

Tubular Atrophy ◽

The Impact

Objectives: Trimethylamine N-oxide (TMAO), a metabolic product of gut flora, is increased in chronic kidney disease (CKD) subjects and is recognized as one type of uremic toxins which is associated with poor cardiovascular outcomes and kidney function loss. Previous studies have suggested that rhubarb enema could reduce circulating uremic toxins such as urea, creatinine, and indoxyl sulfate and also regulate the intestinal microbiota. However, whether rhubarb enema retards kidney dysfunction by reducing circulating TMAO and its underlying mechanism, are still unclear. The present study aims to investigate the impact of rhubarb enema on TMAO and its precursors, as well as on the intestinal microbiota in 5/6 nephrectomized (5/6Nx) CKD rats.Design: Rats in the treatment groups were given rhubarb enema after modeling. At the end of the study, blood, feces, and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses.Results: Rhubarb enema reduced serum TMAO and trimethylamine (TMA) levels, inhibited the expression of inflammatory markers (interleukin-6, tumor necrosis factor α and Interferon-γ) and alleviated tubular atrophy, monocyte infiltration and interstitial fibrosis in 5/6Nx CKD rats. Moreover, rhubarb enema significantly increased the abundance of some symbiotic bacteria and probiotics, while reduced the abundance of some potential pathogens at the genus level. In addition, Spearman’s correlation analysis revealed that lachnospiraceae and romboutsia were positively correlated with TMAO.Conclusion: Rhubarb enema decreases circulating TMAO level and improves renal fibrosis in 5/6Nx CKD rats, which may be related to the regulation of intestinal microbial community.

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The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease

Kidney & Blood Pressure Research ◽

10.1159/000515528 ◽

2021 ◽

pp. 1-8

Author(s):

Ryo Zamami ◽

Kentaro Kohagura ◽

Kojiro Kinjyo ◽

Takuto Nakamura ◽

Takanori Kinjo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Biopsy ◽

Focal Segmental Glomerulosclerosis ◽

Characteristic Curve ◽

Area Under The Curve ◽

Glomerular Hypertrophy ◽

Glomerular Lesion ◽

Segmental Glomerulosclerosis ◽

Glomerular Size

Introduction: When nephron loss occurs, the glomerular filtration rate (GFR) is suggested to be maintained by glomerular hypertrophy, but excessive hypertrophy can rather lead to the formation of focal segmental glomerulosclerosis (FSGS), thereby causing progressive kidney damage. However, it is not clear how much glomerular hypertrophy leads to the formation of FSGS. We examined the association between glomerular diameter and FSGS lesions in chronic kidney disease (CKD) patients. Methods: We recruited 77 patients who underwent renal biopsy during 2016–2017; however, those identified with primary FSGS and glomerulonephritis with active glomerular lesion were excluded. We evaluated the maximal glomerular diameter (Max GD), an indicator of glomerular size, in each renal biopsy specimen and examined its association with FSGS lesion. Results: The median age, blood pressure, and estimated GFR of the patients were 53 years, 122/70 mm Hg, and 65 mL/min/1.73 m2, respectively. The optimal cutoff threshold of Max GD for predicting the presence of FSGS lesions, assessed by receiver operating characteristic curve analysis, was determined to be at 224 μm (area under the curve, 0.81; sensitivity, 81%; specificity, 72%). Multivariate logistic regression analyses demonstrated that Max GD ≥224 μm was significantly associated with the presence of FSGS lesions, independent of other confounding factors (odds ratio, 11.70; 95% confidence interval, 1.93–70.84). Discussion/Conclusion: Glomerular hypertrophy (Max GD ≥224 μm) has been associated with FSGS lesions in CKD patients and may reflect the limits of the compensatory process.

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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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Jian-Pi-Yi-Shen Formula Alleviates Chronic Kidney Disease in Two Rat Models by Modulating QPRT/NAD+/SIRT3/Mitochondrial Dynamics Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6625345 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Xinhui Liu ◽

Siqi Liu ◽

Bing Zhang ◽

Denggui Luo ◽

Shiying Huang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Interstitial Fibrosis ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Periodic Acid ◽

Enzyme Linked Immunosorbent Assay ◽

Tubular Atrophy ◽

Rat Models ◽

Matrix Deposition

Objective. Jian-Pi-Yi-Shen formula (JPYSF) is a traditional Chinese herbal decoction and has been used for treating chronic kidney disease (CKD) in clinics for decades. However, the potential mechanisms have not been fully elucidated. This study was designed to test the efficacy of JPYSF in treating CKD and explore the underlying mechanism. Methods. Two CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. The intervention dose of JPYSF was 10.89 g/kg/d by gastric irrigation. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Periodic acid-Schiff (PAS) and Masson’s trichrome staining were used to evaluate renal histopathological changes. The levels of nicotinamide adenine dinucleotide (NAD+) were measured by using the enzyme-linked immunosorbent assay kit. The proteins expressions of renal fibrosis, quinolinate phosphoribosyltransferase (QPRT), sirtuin 3 (SIRT3), and mitochondrial dynamics were determined and quantified by Western blot analysis. Results. The results show that administration of JPYSF significantly lowered Scr and BUN levels, improved renal tubular atrophy and interstitial fibrosis, and decreased renal extracellular matrix deposition in two CKD rat models. In addition, CKD rats exhibited suppressed QPRT/NAD+/SIRT3 signal, increased mitochondrial fission, and decreased mitochondrial fusion. JPYSF treatment promoted QPRT/NAD+/SIRT3 signal and restored mitochondrial fission/fusion balance. Conclusion. In conclusion, administration of JPYSF effectively alleviated CKD progression in two rat models, which may be related with regulation of the QPRT/NAD+/SIRT3/mitochondrial dynamics pathway.

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