Low-Grade Proteinuria Does Not Exclude Significant Kidney Injury in Lupus Nephritis.
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ABSTRACT:
SUBMITTER: De Rosa M
PROVIDER: S-EPMC7335958 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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Low-Grade Proteinuria Does Not Exclude Significant Kidney Injury in Lupus Nephritis.
De Rosa Marcelo M Rocha Angela Sánchez AS De Rosa Graciela G Dubinsky Diana D Almaani Salem J SJ Rovin Brad H BH
Kidney international reports 20200413 7
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Project description:Background and objectivesLupus nephritis remains a common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current guidelines recommend performing a kidney biopsy at a urine protein-creatinine ratio of ≥0.5 g/g. However, cross-sectional studies reported a high prevalence of active histologic lupus nephritis lesions, and even chronic irreversible scarring, in patients with low-grade proteinuria. This study was initiated to assess disease progression in patients with SLE and low-grade proteinuria to identify risk factors for progression to overt proteinuria suggestive of clinical lupus nephritis.Design, setting, participants, & measurementsPatients with SLE who had an incident urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g without known lupus nephritis were identified from the Einstein Rheumatic Disease Registry. Patients who developed a random urinary protein-creatinine ratio of ≥0.5 g/g with or without biopsy during the follow-up period were defined as "progressors." Patients who progressed to a urinary protein-creatinine ratio of ≥0.5 g/g within 2 years of developing a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g were defined as "fast progressors," a subgroup expected to benefit most from early biopsies and therapeutic interventions.ResultsAmong 151 eligible patients with SLE and low-grade proteinuria at study entry, 76 (50%) progressed to a urinary protein-creatinine ratio of ≥0.5 g/g, of which 44 underwent a clinically indicated biopsy. The median (interquartile range) time from a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g to progression was 1.2 (0.3-3.0) years. Of the 20 biopsies performed in the first 2 years, 16 specimens showed active, treatable lupus nephritis. Low complement and shorter SLE duration at low-grade proteinuria onset were associated with progression to overt proteinuria across different analyses. Other associated factors included hypertension, diabetes mellitus, younger age, and the presence of hematuria.ConclusionsIn this longitudinal cohort of patients with SLE and low-grade proteinuria at study entry, over half progressed to a urinary protein-creatinine ratio of ≥0.5 g/g in a short time period.
| S-EPMC9435982 | biostudies-literature
Project description:The kidney is a frequent target of autoimmune injury, including in systemic lupus erythematosus; however, how immune cells adapt to kidney's unique environment and contribute to tissue damage is unknown. We found that renal tissue, which normally has low oxygen tension, becomes more hypoxic in lupus nephritis. In the injured mouse tissue, renal-infiltrating CD4+ and CD8+ T cells express hypoxia-inducible factor-1 (HIF-1), which alters their cellular metabolism and prevents their apoptosis in hypoxia. HIF-1-dependent gene-regulated pathways were also up-regulated in renal-infiltrating T cells in human lupus nephritis. Perturbation of these environmental adaptations by selective HIF-1 blockade inhibited infiltrating T cells and reversed tissue hypoxia and injury in murine models of lupus. The results suggest that targeting HIF-1 might be effective for treating renal injury in autoimmune diseases.
| S-EPMC8055156 | biostudies-literature
Project description:Fewer biomarkers can be used to predict systemic lupus erythematosus (SLE) related kidney injury. This paper presents an apriori algorithm of association rules to mine the predictive biomarkers for SLE-related kidney injury of negative proteinuria. An apriori algorithm of association rules was employed to identify biomarkers, and logistic regression analysis and spearman correlation analysis were used to evaluate the correlation between triglycerides and SLE-related kidney injury of negative proteinuria. Triglycerides were mined out by the apriori algorithm of association rules. The level of triglycerides was significantly higher, and it was an independent risk factor for SLE-related kidney injury. In the high-triglycerides group, the number of patients with SLE-related kidney injury, SLEDAI-2K, urine P-CAST, the level of blood urea nitrogen, serum creatinine, and proteinuria were increased. Triglycerides level was positively correlated with proteinuria and P-CAST and negatively correlated with albumin and IgG. The area under the ROC curve of triglycerides and triglycerides combined proteinuria was 0.72 and 0.82, respectively. Significantly, 50% of SLE-related kidney injuries of negative proteinuria could be identified by high triglycerides levels. High triglycerides level was found at the time of onset of kidney injury, and it was opposite to glomerular filtration rate. Triglycerides may be a potential marker for predicting SLE-related kidney injury, especially in SLE-related kidney injury of negative proteinuria. Triglycerides combined proteinuria could predict SLE-related kidney injury effectively.
| S-EPMC9312825 | biostudies-literature
Project description:Prediction of prognosis in patients who have lupus nephritis is inadequate, limiting individualization of potentially toxic therapy. Advances in tissue molecular techniques offer new approaches to study mechanisms underlying kidney injury, and add to prognostic information gleaned from biopsy specimens. Analysis of mRNA expression in formalin-fixed, paraffin-embedded renal biopsy specimens is limited by both quantity and quality of RNA, requiring RNA pre-amplification, which can introduce bias. Accordingly, we developed a new technique for RNA extraction from human kidney formalin fixed paraffin embedded biopsy specimens, and used Taqman low-density arrays Applied Biosystems, Carlsbad, CA to simultaneously measure 48 mRNAs in duplicate, in a single biopsy. We extracted mRNA from more than 150 blocks to determine the quantity and vintage of biopsy tissue suitable for analysis using this protocol. We then used Taqman low-density arrays to identify suitable housekeeping genes in lupus nephritis. Finally, we measured expression of 48 mRNA transcripts in archived lupus biopsy specimens (n = 54). We identified that the mRNA levels of three transcripts (MMP7, EGF, COL1A1) relate to pathological indices of kidney injury and kidney function at the time of biopsy; these were associated with parallel changes in expression of these proteins. This new method for measurement of kidney biopsy mRNA expression has enabled us to identify tissue biomarkers of kidney damage and function, and potentially can increase the information yielded from diagnostic kidney biopsy specimens to improve tailoring of therapy.
| S-EPMC3128621 | biostudies-literature
Project description:BackgroundIn a phase 3 study of adults with active lupus nephritis, addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids led to significant improvements in the proportion of participants achieving complete and partial renal response as well as sustained reduction in proteinuria. This analysis examined the efficacy and safety of voclosporin in a subgroup of the phase 3 study with proliferative lupus nephritis and high levels of proteinuria.MethodsParticipants were randomized to oral voclosporin (23.7 mg twice daily) or placebo for 12 months; all participants received MMF and low-dose glucocorticoids. This analysis includes participants with class III or IV (±class V) lupus nephritis and baseline urine protein-creatinine ratio (UPCR) ≥3 g/g. Efficacy end points included complete renal response (UPCR ≤0.5 g/g with stable eGFR, low-dose glucocorticoids, and no rescue medication), partial renal response (≥50% reduction from baseline UPCR), and UPCR over time. Safety outcomes were also assessed.ResultsA total of 148 participants were in the voclosporin ( n =76) and control ( n =72) arms. At 12 months, 34% and 11% of participants in the voclosporin and control arms, respectively, achieved a complete renal response (odds ratio, 4.43; 95% confidence interval [CI], 1.78 to >9.99; P = 0.001). A partial renal response was achieved by 65% of the voclosporin arm and 51% of the control arm at 12 months (odds ratio, 1.60; 95% CI, 0.8 to 3.20; P = 0.18). More voclosporin- than control-treated participants achieved UPCR ≤0.5 g/g (51% versus 26%), and voclosporin-treated participants met this end point significantly earlier (hazard ratio, 2.07; 95% CI, 1.19 to 3.60; P = 0.01). The incidence of adverse events was similar between the arms; mean eGFR values remained stable and within normal range in both arms.ConclusionsAddition of voclosporin to MMF and low-dose glucocorticoids resulted in a significantly higher proportion of participants with proliferative lupus nephritis achieving complete and partial renal responses as well as earlier reductions in proteinuria, with no evidence of worsening kidney function.
| S-EPMC10937024 | biostudies-literature
Project description:IntroductionIn patients with systemic lupus erythematosus (SLE) without concurrent active urinary sediment or unexplained acute kidney injury (AKI), current guidelines recommend performing a kidney biopsy in those with at least 500 mg/24-hour (European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA]) or 1000 mg/24-hour (American College of Rheumatology [ACR]) proteinuria. To evaluate the relevance of these indications, we studied histopathologic findings in patients with SLE with proteinuria below these cutoffs.MethodsWe retrospectively reviewed the clinical, laboratory and histological characteristics of patients with SLE with <1000 mg/24-hour proteinuria (or mg/g urinary protein-to-creatinine ratio [UPCR]) who underwent their first kidney biopsy between 2003 and 2018.ResultsWe identified 87 patients with SLE with proteinuria less than 1000 mg/24-hour (or mg/g UPCR); 52 of 87 (60%) with isolated proteinuria, that is, without AKI or active urinary sediment (hematuria). Histologic evidence of lupus nephritis (LN) was present in 40 of 52 (76%). Of the 40 patients with LN, 12 had class I or II, 14 had class III or IV, 8 had class V, 6 had a combined proliferative and membranous LN. Non-lupus diagnoses included focal segmental glomerulosclerosis, acute interstitial nephritis, and others. Patient's age, low C3, low C4, and positivity for anti-double-stranded DNA (anti-dsDNA) antibodies predicted the histological diagnosis of LN on univariate logistic regression; however, a multivariate model including these parameters as independent covariates failed to predict LN.ConclusionsPatients with SLE with low-level proteinuria may have significant lupus- or non-lupus-related kidney disease with management implications. There was a significant burden of severe forms of LN. The presence of LN was not predicted by laboratory abnormalities. Based on our findings, we suggest current guidelines be revised to expand kidney biopsy indications to include isolated proteinuria of any grade.
| S-EPMC7710831 | biostudies-literature
Project description:Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy is <50% and renal impairment still occurs in 40% of affected patients. An appreciation of the factors that lead to the development of chronic kidney disease following acute or subacute renal injury in patients with systemic lupus erythematosus is beginning to emerge. Processes that contribute to end-stage renal injury include continuing inflammation, activation of intrinsic renal cells, cell stress and hypoxia, metabolic abnormalities, aberrant tissue repair and tissue fibrosis. A deeper understanding of these processes is leading to the development of novel or adjunctive therapies that could protect the kidney from the secondary non-immune consequences of acute injury. Approaches based on a molecular-proteomic-lipidomic classification of disease should yield new information about the functional basis of disease heterogeneity so that the most effective and least toxic treatment regimens can be formulated for individual patients.
| S-EPMC4820834 | biostudies-other
Project description:Ferroptosis is a druggable, iron-dependent form of cell death that is characterized by lipid peroxidation but has received little attention in lupus nephritis. Kidneys of lupus nephritis patients and mice showed increased lipid peroxidation mainly in the tubular segments and an increase in Acyl-CoA synthetase long-chain family member 4, a pro-ferroptosis enzyme. Nephritic mice had an attenuated expression of SLC7A11, a cystine importer, an impaired glutathione synthesis pathway, and low expression of glutathione peroxidase 4, a ferroptosis inhibitor. Lipidomics of nephritic kidneys confirmed ferroptosis. Using nephrotoxic serum, we induced immune complex glomerulonephritis in congenic mice and demonstrate that impaired iron sequestration within the proximal tubules exacerbates ferroptosis. Lupus nephritis patient serum rendered human proximal tubular cells susceptibility to ferroptosis which was inhibited by Liproxstatin-2, a novel ferroptosis inhibitor. Collectively, our findings identify intra-renal ferroptosis as a pathological feature and contributor to tubular injury in human and murine lupus nephritis.
| S-EPMC10810556 | biostudies-literature
Project description:IntroductionThere are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis.ObjectiveThe aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN).MethodsIn a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN.ResultsWe found higher adiponectin levels in the LN group compared with the no LN group (20.4 ± 10.3 vs 15.6 ± 7.8 μg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 ± 31.4 vs 22.5 ± 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti-dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01-1.12; p = 0.02). Instead, leptin was not associated with LN.ConclusionThese findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse.
| S-EPMC5595281 | biostudies-literature
Project description:Diabetic kidney disease (DKD) is heterogeneous in terms of proteinuria. Patients with DKD who present with low-grade proteinuria are more likely to have nephrosclerosis rather than traditional diabetic nephropathy. The amount of proteinuria might reflect the underlying pathology of renal failure and influence the prognosis after dialysis initiation. Clinical implications of proteinuria at the start of dialysis have not been confirmed, while greater proteinuria is associated with higher risk of cardiovascular disease (CVD) in the predialysis stages of chronic kidney disease. We performed a retrospective multicenter cohort study enrolling incident hemodialysis patients with diabetes. Patients were stratified using proteinuria quartiles. We examined the association of proteinuria quartiles with types of subsequent CVD. Among the enrolled 361 patients, the estimated mean glomerular filtration rate and proteinuria was 5.4 mL/min/1.73 m2 and 6.3 g/gCr, respectively. Lower quartile of proteinuria (cut-offs: 3.0, 5.4, and 8.8 g/gCr) was significantly associated with male, older age, and history of atherosclerotic CVD including coronary artery disease, peripheral arterial disease, and cerebral infarction (Ptrend<0.05). Kidney size was smaller in patients with lower levels of proteinuria. Patients with higher levels of proteinuria were more likely to have proliferative diabetic retinopathy (Ptrend<0.05). Multivariate competing risk analysis revealed that the first quartile of proteinuria was associated with a greater risk of atherosclerotic CVD than the third quartile (subhazard ratio [95% confidence interval]: 2.04 [1.00-4.14]). This association was attenuated after additional adjustments for history of atherosclerotic CVD. Furthermore, patients with lower quartiles of proteinuria were more likely to die of atherosclerotic CVD than those with non-atherosclerotic CVD (Ptrend = 0.01). Diabetic patients with lower proteinuria at dialysis initiation were characterized by severer macroangiopathy, as shown by a more atrophic kidney and higher prevalence of past atherosclerotic CVD. Hence, they are at a high risk of developing atherosclerotic CVD.
| S-EPMC8880428 | biostudies-literature