Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus

Brunner, Hermine I.; Gulati, Gaurav; Klein‐Gitelman, Marisa S.; Rouster‐Stevens, Kelly; Tucker, Lori B.; Ardoin, Stacey P.; Onel, Karen; Mainville, Rylie; Turnier, Jessica L; Avar-Aydın, Pınar Özge; Witte, David P.; Huang, Bin; Bennett, Michael; Devarajan, Prasad

doi:10.1007/s00467-018-4049-5

Cited by 35 publications

(33 citation statements)

References 52 publications

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“…Many of these proteins have already been reported as potential biomarkers for renal dysfunction, mostly in native kidney diseases. α 1 -B glycoprotein, 14 afamin 15 , apolipoprotein A1 and A4, 16 , 17 , 18 , 19 , 20 leucine-rich α 2 -glycoprotein 1, 21 , 22 , 23 α 1 -antitrypsin, 24 , 25 antithrombin, 26 , 27 transferrin, 28 , 29 and Ig heavy chain α 1 and γ 4 are not specific for disease processes or histologic lesions and have been associated with a wide range of kidney diseases or kidney dysfunction. It could be that some of the proteins in the panel might represent general injury or injury mechanisms, rather than being specific for antibody-mediated injury.…”

Section: Discussionmentioning

confidence: 99%

Urinary Protein Biomarker Panel for the Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Recipients

Mertens

Willems

Loon

et al. 2020

Kidney International Reports

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Introduction: Antibody-mediated rejection (ABMR) impacts kidney allograft outcome. The diagnosis is made based on findings from invasive kidney transplant biopsy specimens. The aim of this study was to identify a noninvasive urinary protein biomarker for ABMR after kidney transplantation. Methods: We performed a multicenter case-control study to identify a urinary biomarker for ABMR (training cohort, n ¼ 249) and an independent, prospective multicenter cohort study for validation (n ¼ 391). We used concomitant biopsies to classify the samples according to the Banff classification. After untargeted protein identification and quantification, we used a support vector machine to train the model in the training cohort. The primary endpoint was the diagnostic accuracy of the urinary biomarker for ABMR in the validation cohort. Results: We identified a set of 10 urinary proteins that accurately discriminated patients with (n ¼ 60) and without (n ¼ 189) ABMR in the training cohort with an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.96-1.00). The diagnostic accuracy was maintained in the validation cohort (AUC, 0.88; 95% CI, 0.8-0.93) for discriminating the presence (n ¼ 43) from the absence (n ¼ 348) of ABMR. The negative predictive value of the 10-protein marker set for exclusion of ABMR was 0.99, and the positive predictive value was 0.33. The diagnostic accuracy was independent of the reason for performing the biopsy, time after transplantation, and better than the accuracy of gross proteinuria (AUC, 0.76). Conclusions: We identified and validated a urinary protein biomarker set that can be used to exclude ABMR.

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Section: Discussionmentioning

confidence: 99%

Urinary Protein Biomarker Panel for the Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Recipients

Mertens

Willems

Loon

et al. 2020

Kidney International Reports

View full text Add to dashboard Cite

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“…The development of a non-invasive method to detect and monitor kidney injury would be a major advance over the current need for a kidney biopsy. Numerous studies have attempted to study urine to understand renal pathology in lupus, generally with a focus on urine proteins, and have identified factors associated with lupus nephritis, including TWEAK and MCP1 [105][106][107][108][109] . Immune cells accumulate in urine of patients with lupus nephritis 51,[110][111][112] , raising the possibility that these cells reflect renal pathology.…”

Section: Competing Interestsmentioning

confidence: 99%

Design and application of single-cell RNA sequencing to study kidney immune cells in lupus nephritis

et al. 2019

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The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of affected kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts by high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to noninvasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.

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“…Whether changes in urinary transferrin filtration and excretion represent an epiphenomenon or an accomplice to renal injury in lupus nephritis remains a tantalizing question. A prospective study reported continued high urinary transferrin levels in pediatric SLE patients who displayed renal function decline within 12 months of biopsy (33). The same group reported that marked reduction of urinary transferrin during treatment is predictive of achieving remission (34).…”

Section: Discussionmentioning

confidence: 98%

Evidence of Renal Iron Accumulation in a Male Mouse Model of Lupus

et al. 2020

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Lupus nephritis represents a common and serious complication of the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical studies suggest that several proteins related to iron metabolism, including transferrin, serve as urinary biomarkers of lupus nephritis. We previously reported that in female NZBWF1 mice, a commonly used mouse model of SLE with a female sex bias, increased urinary transferrin excretion and renal iron accumulation occur around the onset of albuminuria. The current study investigated whether similar findings occur in male mice of a different mouse model of SLE, the MRL/lpr mouse. Two different cohorts were studied: MRL/lpr mice at an early, pre-albuminuric age (8 weeks), and after developing albuminuria (>100 mg/dL, confirmed by ELISA); age-matched MRL/MpJ control strain mice served for comparison. Urinary transferrin excretion was dramatically increased in the older, albuminuric MRL/lpr mice compared to the age-matched MRL/MpJ (P < 0.05), but there was no significant difference between strains at 8 weeks of age. Similarly, there were no significant differences between strains in renal cortical or outer medullary non-heme iron concentrations at 8 weeks. In the older, albuminuric MRL/lpr mice, renal cortical and outer medullary non-heme iron concentrations were significantly increased compared with age-matched MRL/MpJ mice, as was the expression of the iron storage protein ferritin (P < 0.01). Together, these data show that increased urinary transferrin excretion and renal tissue iron accumulation also occurs in albuminuric male MRL/lpr mice, suggesting that renal iron accumulation may be a feature of multiple mouse models of SLE.

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Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus

Cited by 35 publications

References 52 publications

Urinary Protein Biomarker Panel for the Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Recipients

Urinary Protein Biomarker Panel for the Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Recipients

Design and application of single-cell RNA sequencing to study kidney immune cells in lupus nephritis

Evidence of Renal Iron Accumulation in a Male Mouse Model of Lupus

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