Association Between Urinary Epidermal Growth Factor and Renal Prognosis in Lupus Nephritis.

OBJECTIVE: To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN). METHODS: A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long-term follow-up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected. RESULTS: Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8-12.3 in patients with active LN versus median 48.0, IQR 45.3-64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme-linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P < 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman's r = -0.67, P < 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end-stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of <5.3 ng/mg. CONCLUSION: Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long-term kidney outcomes.

Urinary Soluble CD163: a Novel Noninvasive Biomarker of Activity for Lupus Nephritis.

BACKGROUND: Clinical distinction between patients with lupus nephritis who have active inflammation or chronic kidney damage is challenging. Studies have shown soluble CD163, which derives from cleavage of the CD163 M2c macrophage receptor and can be quantified in urine, correlates with active lupus nephritis. METHODS: We measured urine CD163 at lupus nephritis flares in patients from a Mexican cohort and cross-sectional and longitudinal United States cohorts. We also performed serial urine CD163 measurements during the treatment of flares in a subset of patients from the Mexican and longitudinal United States cohorts, and assessed response to therapy at 12 months. In addition, we evaluated urinary CD163 agreement with histologic activity in 19 patients from the Mexican cohort who had repeated kidney biopsies on follow-up. RESULTS: Urinary CD163 levels were significantly higher in patients with active lupus nephritis than in patients with active extrarenal SLE, inactive SLE, and other glomerular diseases, and correlated with disease clinical severity, histologic class, and the histologic activity index. Urinary CD163 increased from 6 months preflare to flare, diminishing progressively in complete and partial responders, whereas it remained elevated in nonresponders. Urinary CD163 <370 ng/mmol at 6 months predicted complete renal response at 12 months with >87% sensitivity and >87% specificity. Urinary CD163 <370 ng/mmol or >370 ng/mmol perfectly agreed (κ=1.0) with a histologic activity index ≤1 or >1 in repeated biopsies, respectively. Evaluation of urinary CD163 in patients with persistent proteinuria at 6 months improved the prediction of who would achieve complete renal response at 12 months. CONCLUSIONS: Urinary CD163 reflects histologic inflammation in lupus nephritis and is a promising activity biomarker that varies over time with lupus nephritis activity and treatment.

Correction to: Validation of a renal risk score in a cohort of ANCA-associated vasculitis patients with severe kidney damage.

The footnote of Figure 2 in the published original version of the above article went missing and the correct figure is presented in this article.

Validation of a renal risk score in a cohort of ANCA-associated vasculitis patients with severe kidney damage.

OBJECTIVE: To validate the renal risk score in a cohort of patients with advanced kidney damage. METHODS: A total of 72 patients with biopsy-proven ANCA glomerulonephritis with >12 months of follow-up were studied. The renal risk score was calculated and evaluated by survival analysis for time of renal survival. Cohort-specific clinical, histopathologic, and post-treatment factors associated with renal survival were determined by Cox regression analysis. RESULTS: Kidney biopsies were classified as focal, crescentic, mixed, and sclerotic classes in 6 (8%), 4 (6%), 25 (35%), and 37 (51%) patients, respectively. The 1-, 3-, and 5-year renal survival rates were 79%, 73%, and 68%, respectively. Patients were segregated by the risk score in low- (18%), medium- (47%), and high-risk (35%) groups. Patients in the low-risk group had 36-, 60-, and 84-month renal survival of 100%; those in the medium risk 85% (95% CI 72-92), 81% (95% CI 66-95), and 76% (95% CI 60-92), respectively; and those in the high risk 37% (95% CI 17-57), 26% (95% CI 7-45), and 18% (95% CI 1-36), respectively. Six (43%) of the 14 patients in the high-risk group recovered renal function after the initial episode, and 2 (14%) remained dialysis-free. Other parameters associated with renal survival included age, proteinuria, general symptoms, cellular crescents, glomerulosclerosis, tubulointerstitial lesions, best post-treatment eGFR, and renal relapses. CONCLUSIONS: We validated the renal risk score as a prognostic tool in a cohort with predominantly mixed and sclerotic histologic categories. Since patients in the high-risk group still benefited from immunosuppressive therapy, this score should be used in conjunction with other predictive parameters to aid therapeutic decisions.Key Points• The ANCA renal risk score is validated in a cohort with advanced kidney damage.• Patients in the high-risk group still benefited from immunosuppressive therapy.• Parameters not included in the risk score are associated with renal survival and may be useful.

High frequency of nocturnal hypertension in lupus nephritis: should ABPM be implemented in usual practice?

INTRODUCTION/OBJECTIVES: Hypertension management in lupus nephritis (LN) is guided by in-office blood pressure (BP); however, recent studies demonstrate that lupus patients frequently have nocturnal hypertension and reduced BP dipping. The aim of the study was to evaluate 24-h blood pressure in patients with active LN and after response to treatment. METHODS: Seventy active LN patients were evaluated during a LN flare by ambulatory blood pressure monitoring (ABPM). Later, 10 patients with complete response were re-evaluated after 12 months along with 20 matched controls. Overall, daytime and nightime BP, day-to-night dipping, BP load and variability, and the incidence of abnormal BP patterns were assessed. Blood pressure levels were correlated with clinical and histologic parameters and independent associations evaluated by linear regression. RESULTS: Overall systolic hypertension occurred in 25 (36%) patients and diastolic hypertension in 28 (40%). Nighttime systolic and diastolic hypertension occurred in 35 (50%) and 44 (63%) of patients, respectively. Nocturnal systolic day-to-night BP decrease was abnormal in 59 (84%) patients. Only 18 (26%) were diagnosed with HT by in-office evaluation while 29 (41%) had masked hypertension (MH)/masked uncontrolled hypertension (MUCH), and 3 (4%) had white coat hypertension. Patients with MH had lower eGFR, complement C3, hemoglobin, and higher systolic variability compared with patients with normal BP. Systolic and diastolic BP levels were associated with the years under corticosteroid treatment, activity biomarkers (proteinuria, complement C3), and the degree of interstitial inflammation in the kidney biopsy. A re-evaluation at 12 months showed that although 9 out of 10 patients had normal in-office BP and BP loads improved, still 5 patients remained with MH due to nocturnal hypertension, and 7 remained with abnormal day-to-night dipping. These numbers were higher than those of matched controls. CONCLUSIONS: Due to the high frequency of nocturnal hypertension and abnormal day-to-night dipping, office BP measurements alone may not be sufficient to guide hypertension management in patients with LN.Key Points• Nocturnal hypertension and abnormal BP patterns are frequent and not detectable by the standard in-office BP evaluation in LN patients.• BP abnormalities may not be fully corrected after a complete clinical response to treatment in lupus nephritis and are only detectable by ABPM.• The degree of interstitial inflammation in the kidney biopsy in LN patients is associated to BP levels. This supports the hypotheses underlining the role of interstitial inflammation in salt sensitivity and hypertension.