Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

COVID vaccine-induced lupus nephritis: Case report and review of the literature.

Vaccines offer an effective strategy to prevent infectious diseases with minimal adverse effects. On rare occasions, vaccination can disrupt the immune response leading to induction of autoimmune diseases. We describe a case of new-onset lupus nephritis following COVID-19 vaccination with the first dose of the Pfizer vaccine. Her symptoms and lab values improved with steroids, hydroxychloroquine, and mycophenolate mofetil.

Living kidney donors with HIV: experience and outcomes from a case series by the HOPE in Action Consortium.

Background: Living kidney donation is possible for people living with HIV (PLWH) in the United States within research studies under the HIV Organ Policy Equity (HOPE) Act. There are concerns that donor nephrectomy may have an increased risk of end-stage renal disease (ESRD) in PLWH due to HIV-associated kidney disease and antiretroviral therapy (ART) nephrotoxicity. Here we report the first 3 cases of living kidney donors with HIV under the HOPE Act in the United States. Methods: Within the HOPE in Action Multicenter Consortium, we conducted a prospective study of living kidney donors with HIV. Pre-donation, we estimated the 9-year cumulative incidence of ESRD, performed genetic testing of apolipoprotein L1 (APOL1), excluding individuals with high-risk variants, and performed pre-donation kidney biopsies (HOPE Act requirement). The primary endpoint was ≥grade 3 nephrectomy-related adverse events (AEs) in year one. Post-donation, we monitored glomerular filtration rate (measured by iohexol/Tc-99m DTPA [mGFR] or estimated with serum creatinine [eGFR]), HIV RNA, CD4 count, and ART. Findings: There were three donors with two-four years of follow-up: a 35 year-old female, a 52 year-old male, and a 47 year-old male. Pre-donation 9-year estimated cumulative incidence of ESRD was 3.01, 8.01, and 7.76 per 10,000 persons, respectively. In two donors with APOL1 testing, no high-risk variants were detected. Biopsies from all three donors showed no kidney disease. Post-donation, two donors developed nephrectomy-related ≥grade 3 AEs: a medically-managed ileus and a laparoscopically-repaired incisional hernia. GFR declined from 103 to 84 mL/min/1.73 m2 at four years (mGFR) in donor 1, from 77 to 52 mL/min/1.73 m2 at three years (eGFR) in donor 2, and from 65 to 39 mL/min/1.73 m2 at two years (eGFR) in donor 3. HIV RNA remained <20 copies/mL and CD4 count remained stable in all donors. Interpretation: The first three living kidney donors with HIV under the HOPE Act in the United States have had promising outcomes at two-four years, providing proof-of-concept to support living donation from PLWH to recipients with HIV. Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria.

BACKGROUND: Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD. METHODS: Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria. RESULTS: Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m2 was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose. CONCLUSIONS: Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m2, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.

Adalimumab-Induced Lupus Nephritis: Case Report and Review of the Literature.

Tumor necrosis factor-alpha inhibitors are known causative agents of systemic lupus erythemato- sus but have rarely been implicated in lupus nephritis. A patient with Crohn's disease on long-term adalimumab treatment presented with new-onset Raynaud's phenomenon and was found to have hematuria and proteinuria. Elevated antinuclear, anti-dsDNA, and MPO antibodies were found. A renal biopsy confirmed the diagnosis of lupus nephritis. Adalimumab was discontinued ensuing improvement in urine studies and resolution of dsDNA and MPO antibodies. Adalimumab can induce systemic lupus erythematosus and lupus nephritis.

Association Between Left Ventricular Relative Wall Thickness and Acute Kidney Injury After Noncardiac Surgery.

BACKGROUND: Acute kidney injury (AKI) after major noncardiac surgery is commonly attributed to cardiovascular dysfunction. Identifying novel associations between preoperative cardiovascular markers and kidney injury may guide risk stratification and perioperative intervention. Increased left ventricular relative wall thickness (RWT), routinely measured on echocardiography, is associated with myocardial dysfunction and long-term risk of heart failure in patients with preserved left ventricular ejection fraction (LVEF); however, its relationship to postoperative complications has not been studied. We evaluated the association between preoperative RWT and AKI in high-risk noncardiac surgical patients with preserved LVEF. METHODS: Patients ≥18 years of age having major noncardiac surgery (high-risk elective intra-abdominal or noncardiac intrathoracic surgery) between July 1, 2016, and June 30, 2018, who had transthoracic echocardiography in the previous 12 months were eligible. Patients with preoperative creatinine ≥2 mg/dL or reduced LVEF (<50%) were excluded. The association between RWT and AKI, defined as an increase in serum creatinine by 0.3 mg/dL from baseline within 48 hours or by 50% within 7 days after surgery, was assessed using multivariable logistic regression adjusted for preoperative covariates. An additional model adjusted for intraoperative covariates, which are strongly associated with AKI, especially hypotension. RWT was modeled continuously, associating the change in odds of AKI for each 0.1 increase in RWT. RESULTS: The study included 1041 patients (mean ± standard deviation [SD] age 62 ± 15 years; 59% female). A total of 145 subjects (13.9%) developed AKI within 7 days. For RWT quartiles 1 through 4, respectively, 20 of 262 (7.6%), 40 of 259 (15.4%), 39 of 263 (14.8%), and 46 of 257 (17.9%) developed AKI. Log-odds and proportion with AKI increased across the observed RWT values. After adjusting for confounders (demographics, American Society of Anesthesiologists [ASA] physical status, comorbidities, baseline creatinine, antihypertensive medications, and left ventricular mass index), each RWT increase of 0.1 was associated with an estimated 26% increased odds of developing AKI (odds ratio [OR]; 95% confidence interval [CI]) of 1.26 (1.09-1.46; P = .002). After adjusting for intraoperative covariates (length of surgery, presence of an arterial line, intraoperative hypotension, crystalloid administration, transfusion, and urine output), RWT remained independently associated with the odds of AKI (OR; 95% CI) of 1.28 (1.13-1.47; P = .001). Increased RWT was also independently associated with hospital length of stay and adjusted hazard ratio (HR [95% CI]) of 0.94 (0.89-0.99; P = .018). CONCLUSIONS: Left ventricular RWT is a novel cardiovascular factor associated with AKI within 7 days after high-risk noncardiac surgery among patients with preserved LVEF. Application of this commonly available measurement of risk stratification or perioperative intervention warrants further investigation.

New-onset lupus nephritis associated with COVID-19 infection.

A dysregulated immune response plays a critical role in systemic lupus erythematosus (SLE) pathogenesis. Environmental factors such as viruses, including coronavirus 2 (COVID-19), have been described to play a role in SLE presentation and exacerbation. These viruses trigger a host's humoral and cellular immunities typically essential in elimination of the viral infection. We present a case of a Hispanic male who developed new-onset lupus nephritis class II after a COVID-19 infection.

High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the Accelerating Medicines Partnership.

OBJECTIVE: Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. METHODS: A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. RESULTS: At biopsy, 54 patients had UPCR <1 and 221 had UPCR ≥1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at 1 year. CONCLUSION: In this prospective study, three-quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.

The Effect of Mycophenolate Mofetil as First-Line Therapy on the Timing of Urine Protein-to-Creatinine Ratio Reduction in Immunosuppressant-Naive Patients With Lupus Nephritis at a Single Center.

BACKGROUND/OBJECTIVES: Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis (LN). The purpose of this study was to assess the effect of mycophenolate mofetil (MMF) on the timing of urine protein-to-creatinine ratio reaching 200 mg or less after starting MMF as initial therapy for class III, IV, or V in immunosuppressant-naive patients with LN. METHODS: Patients who had a diagnosis of biopsy-proven LN were included in this cohort study. The initial dose of MMF was 1000 mg twice daily. If no improvement, it was increased to 1500 mg twice daily after 1 month. For statistical analysis, exact binomial distribution 95% confidence intervals were calculated. RESULTS: Nine patients were identified. There were 3 patients with class III, 3 with class IV, 1 with class III to V, 1 with class II to V, and 1 with class V lupus nephritis. The majority were African Americans (70%). At baseline, proteinuria ranged between 0.41 and 4 g, and 88% had normal estimated glomerular filtration rate. Forty-four percent of patients reached 0.28 g of proteinuria within 8 weeks of starting MMF (95% confidence interval, 14%-79%), all of which maintained the same level of response and normal estimated glomerular filtration rate at 12 months. Thirty-three percent of patients achieved the American College of Rheumatology complete response at 8 weeks. CONCLUSIONS: This study demonstrates that only a minority of immunosuppressant-naive LN patients achieved the American College of Rheumatology complete response at 8 weeks after initiation of MMF. A rapid decline in the proteinuria to 0.28 g within the first 8 weeks of the treatment correlated strongly with achieving the same level of response at 12 months.

History of proliferative glomerulonephritis predicts end stage kidney disease in pure membranous lupus nephritis.

OBJECTIVES: Pure membranous (class V) LN is considered a less aggressive phenotype, but tissue fibrosis and chronic kidney disease may still develop. This study aimed to elucidate the prognostic value of a history of class switch in pure membranous LN. METHODS: We included LN patients with at least two clinically indicated kidney biopsies. New onset of end stage kidney disease (ESKD) was defined as estimated glomerular filtration rate <15 ml/min/1.73 m2, initiation of dialysis or kidney transplantation. RESULTS: Among 220 patients (542 biopsies), 199 (90%) were female, and 118 (54%) were African American, 59 (27%) Caucasian, with median age of 28 years at the first kidney biopsy. Patients with pure class V in a first biopsy converted to proliferative LN in 41% of cases. Pure class V in a repeat biopsy was preceded by proliferative LN in 52%. Trajectory analysis of up to four repeat biopsies revealed that ISN class switch may happen at any time, even after multiple biopsies with the same class. New onset ESKD was observed within 2 years in 5/56 (9%) patients with pure class V in a repeat biopsy. All five patients had proliferative LN in the first biopsy (log rank P = 0.024). CONCLUSIONS: The conversion from proliferative to membranous (and vice-versa) is frequent in SLE. It can occur at any time in the course of disease, limiting the prognostic value of the first biopsy. Evidence of prior proliferative LN is key as it is associated with higher risk of ESKD in non-proliferative LN.

Urine Proteomics and Renal Single-Cell Transcriptomics Implicate Interleukin-16 in Lupus Nephritis.

OBJECTIVE: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment. METHODS: We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients. RESULTS: Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor ß mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury. CONCLUSION: Urine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker.

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network.

OBJECTIVES: In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis. METHODS: 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines. RESULTS: 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved. CONCLUSIONS: Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus.

BACKGROUND: Kidney involvement is common in patients with systemic lupus erythematosus (SLE). This study investigates the clinical and prognostic characteristics of thrombotic microangiopathy (TMA) compared to class IV lupus nephritis in SLE patients. METHODS: A retrospective review of patients who underwent kidney biopsy, with a primary diagnosis of SLE and TMA between June 2006 and September 2018 was conducted. Those patients were subsequently compared to patients with class IV lupus nephritis between January 2018 and December 2018. Demographics, laboratory, and serological data at the time of biopsy were abstracted. RESULTS: Among 214 SLE patients records screened, 27 were included in the final analysis. Eight patients had lupus-related TMA without evidence of active lupus nephritis, while 19 patients had class IV lupus nephritis without evidence of TMA. TMA patients had significantly higher lactate dehydrogenase levels (718 ± 499 vs. 264 ± 107.7 U/L, p = 0.009), serum C3 (100.6 ± 39.3 vs. 65.8 ± 27 mg/dL, p = 0.049), white blood cell count (14743.8 ± 7933.3 vs. 5807.9 ± 2053.2 × 10E3/uL, p < 0.001), and total bilirubin (0.8 ± 0.5 vs. 0.3 ± 0.1 mg/dL, p = 0.007) in addition to significantly lower platelet counts (158.4 ± 88.6 vs. 240.3 ± 100.3 × 10E3/uL, p = 0.03), and haptoglobin (68.8 ± 116.1 vs. 166.8 ± 95.4 mg/dL, p = 0.03). After a median follow-up time of 53 weeks, 3 patients with TMA were dialysis-dependent (37.5%), compared with none in class IV lupus nephritis patients (p = 0.002). CONCLUSIONS: TMA-associated SLE has worse prognosis compared to class IV lupus nephritis. An array of laboratory and pathological findings may be of value in discriminating between those two entities.

Use of Intravenous Gadolinium-Based Contrast Media in Patients With Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation.

Inaugural consensus statements were developed and endorsed by the American College of Radiology (ACR) and National Kidney Foundation to improve and standardize the care of patients with kidney disease who have indication(s) to receive ACR-designated group II or group III intravenous gadolinium-based contrast media (GBCM). The risk of nephrogenic systemic fibrosis (NSF) from group II GBCM in patients with advanced kidney disease is thought to be very low (zero events following 4931 administrations to patients with estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2; upper bounds of the 95% confidence intervals: 0.07% overall, 0.2% for stage 5D chronic kidney disease [CKD], 0.5% for stage 5 CKD and no dialysis). No unconfounded cases of NSF have been reported for the only available group III GBCM (gadoxetate disodium). Depending on the clinical indication, the potential harms of delaying or withholding group II or group III GBCM for an MRI in a patient with acute kidney injury or eGFR less than 30 mL/min per 1.73 m2 should be balanced against and may outweigh the risk of NSF. Dialysis initiation or alteration is likely unnecessary based on group II or group III GBCM administration.

Protocol for Local On-Site Dialysate Production for Continuous Renal Replacement Therapy during the COVID-19 Pandemic.

AKI frequently occurs in patients with COVID-19, and kidney injury severe enough to require RRT is a common complication among patients who are critically ill. During the surge of the pandemic, there was a high demand for dialysate for continuous RRT, and this increase in demand, coupled with vulnerabilities in the supply chain, necessitated alternative approaches, including internal production of dialysate. Using a standard hemodialysis machine and off-the-shelf supplies, as per Food and Drug Administration guidelines, we developed a method for on-site dialysate production that is adaptable and can be used to fill multiple bags at once. The use of a central reverse osmosis unit, dedicated hemodialysis machine, sterile bags with separate ports for fill and use, and frequent testing will ensure stability, sterility, and-therefore-safety of the produced dialysate. The dialysate made in house was tested and it showed both stability and sterility for at least 30 hours. This detailed description of our process for generating dialysate can serve as a guide for other programs experiencing similar vulnerabilities in the demand versus supply of dialysate.