Physiological principles underlying the kidney targeting of renal nanomedicines.

Kidney disease affects more than 10% of the global population and is associated with considerable morbidity and mortality, highlighting a need for new therapeutic options. Engineered nanoparticles for the treatment of kidney diseases (renal nanomedicines) represent one such option, enabling the delivery of targeted therapeutics to specific regions of the kidney. Although they are underdeveloped compared with nanomedicines for diseases such as cancer, findings from preclinical studies suggest that renal nanomedicines may hold promise. However, the physiological principles that govern the in vivo transport and interactions of renal nanomedicines differ from those of cancer nanomedicines, and thus a comprehensive understanding of these principles is needed to design nanomedicines that effectively and specifically target the kidney while ensuring biosafety in their future clinical translation. Herein, we summarize the current understanding of factors that influence the glomerular filtration, tubular uptake, tubular secretion and extrusion of nanoparticles, including size and charge dependency, and the role of specific transporters and processes such as endocytosis. We also describe how the transport and uptake of nanoparticles is altered by kidney disease and discuss strategic approaches by which nanoparticles may be harnessed for the detection and treatment of a variety of kidney diseases.

Late onset granulomatous interstitial nephritis after booster dose of COVID-19 vaccination: Case report and review of literature.

Billions of doses of COVID-19 vaccine have been administered to combat the coronavirus pandemic. Though the vaccine is generally well tolerated, several cases of new onset or relapsing glomerulonephritis have been reported. In comparison, post-vaccination tubulointerstitial nephritis (TIN) has rarely been reported, mostly after the first or the second dose of the vaccine. Acute interstitial nephritis after booster dose of COVID-19 vaccination has not yet been reported. We report a case of acute granulomatous TIN shortly after the booster dose of Moderna vaccine. Our patient had no clinical evidence of renal injury after the first two doses of vaccine. Renal dysfunction was incidentally observed ~ 1 month after the booster dose of vaccine. The patient responded to steroids with rapid improvement in kidney function. While it is difficult to ascertain the causal relationship between the vaccination and development of TIN, it is important to be vigilant about such delayed side effects of the vaccine.

Discovery of Novel Circulating Immune Complexes in Lupus Nephritis Using Immunoproteomics.

Objective: The goal is to discover novel circulating immune complexes (ICx) in the serum of lupus nephritis (LN) as potential biomarkers. Methods: Protein A/G magnetic beads or C1q-coated plates were used to capture ICx in the serum of LN, followed by the identification of immunoglobulin-binding proteins using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Bioinformatic approaches and single-cell RNA sequencing (scRNA Seq) databases were used to select potential candidate ICx markers in LN. The selected ICx markers were further validated using ELISA. Results: A total of 300 immunoglobulin-binding proteins were discovered in the screening, among which 77 proteins were detectable only in LN samples. Bioinformatics-assisted selection allowed us to further identify 10 potential immunoglobulin-binding proteins, which form ICx as potential biomarkers in LN. In a validation cohort of 62 LN patients and 21 healthy controls (HC), we found that prolyl 3-hydroxylase 1 (P3H1), phosphatase and actin regulator 4 (PHACTR4), and regulator of G-protein signaling 12 (RGS12) ICx exhibited discriminative capability in distinguishing LN from HC, with an area under the curve (AUC) values of 0.82, 0.99, and 0.90, respectively. Furthermore, a biomarker panel comprising CD14, CD34, cystatin A, myocyte enhancer factor 2C (MEF2C), RGS12, and ubiquitin C (UBC) ICx could distinguish active LN from inactive LN with an AUC value of 0.85, which is comparable to or better than pathological parameters such as renal activity index (AI) and renal chronicity index (CI). Conclusion: Immunoproteomics-based discovery studies have enabled us to identify circulating immune complexes as potential biomarkers of LN.

De novo or recurrent glomerulonephritis and acute tubulointerstitial nephritis after COVID-19 vaccination: A report of six cases from a single center.

Billions of COVID-19 vaccine doses have been administered to combat the ongoing global pandemic caused by severe acute respiratory syndrome coronavirus-2. While these vaccines are considered safe, with most adverse events being mild to moderate and transient, uncommon systemic side effects of the vaccines, including de novo or re-activation of various glomerular diseases have recently been observed. We report 6 patients who developed glomerular or acute tubulointerstitial disease shortly after receiving COVID-19 vaccinations. Five of these patients received mRNA vaccines (3 Moderna, 2 Pfizer-BioNTech) and 1 received adenovirus-26 vector vaccine (Johnson and Johnson/Janssen). Four of our patients developed de novo glomerulonephritis or acute tubulointerstitial nephritis (ATIN), while the other 2 had re-activation of prior glomerulonephritis. Two patients presented with acute kidney injury (AKI) characterized by severe ATIN. While both of them also had evidence of immune complex glomerular disease, ATIN was the dominant feature on the biopsies. Two other patients presented with high-grade proteinuria and AKI. Like the aforementioned patients, these patients had evidence of immune complex glomerular disease, but acute onset nephrotic syndrome was the leading clinical feature. Another patient presented with de novo myeloperoxidase-anti-neutrophil-cytoplasmic-antibody-associated pauci-immune crescentic glomerulonephritis. Yet another patient had re-activation of immunoglobulin-A glomerulonephritis that had been quiescent for several years prior to the vaccination. It is difficult to ascertain any causal relationship between COVID-19 vaccination and onset/recurrence of kidney diseases. However, vigilance about occurrence of such complications is imperative. Importantly, all our cases responded well to the immunosuppressive treatment.

Upregulation of Proinflammatory Bradykinin Peptides in Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Our recent study has implicated bradykinin (BK) signaling as being of pathogenic importance in lupus. This study aims to investigate the biomarker potential of BK peptides, BK and BK-des-arg-9, in lupus and other rheumatic autoimmune diseases. Sera from systemic lupus erythematosus (SLE) patients and healthy subjects were screened for BK and BK-des-arg-9 by liquid chromatography-mass spectrometry metabolomics. Serum from 6-mo-old C57BL/6 mice and three murine lupus strains were also screened for the two peptides by metabolomics. Given the promising initial screening results, validation of these two peptides was next conducted using multiple reaction monitoring in larger patient cohorts. In initial metabolomics screening, BK-des-arg-9 was 22-fold higher in SLE serum and 106-fold higher in mouse lupus serum compared with healthy controls. In validation assays using multiple reaction monitoring and quadrupole time-of-flight mass spectrometry, BK and BK-des-arg-9 showed significant elevations in SLE serum compared with controls (p < 0.0001; area under the curve = 0.79-0.88), with a similar but less pronounced increase being noted in rheumatoid arthritis serum. Interestingly, increased renal SLE disease activity index in lupus patients was associated with reduced circulating BK-des-arg-9, and the reasons for this remain to be explored. To sum, increased conversion of BK to the proinflammatory metabolite BK-des-arg-9 appears to be a common theme in systemic rheumatic diseases. Besides serving as an early marker for systemic autoimmunity, independent studies also show that this metabolic axis may also be a pathogenic driver and therapeutic target in lupus.

Association of Urine sCD163 With Proliferative Lupus Nephritis, Fibrinoid Necrosis, Cellular Crescents and Intrarenal M2 Macrophages.

CD163 is a marker for alternatively activated macrophages, which have been implicated in the pathogenesis of lupus nephritis (LN). In our preliminary screening of urine proteins in LN, urine soluble CD163 (sCD163) was significantly elevated in patients with active LN. To evaluate the potential of sCD163 as a biomarker in LN, urine sCD163 was assayed in patients with active LN, active non-renal lupus patients (ANR), inactive SLE and healthy controls (HC), using ELISA and normalized to urine creatinine. The correlation of urine sCD163 with clinical parameters and renal pathological attributes was further investigated in LN patients with concurrent renal biopsies. A total of 228 SLE patients and 56 HC were included from three cohorts. Results demonstrated that urine sCD163 was significantly elevated in active LN when compared with HC, inactive SLE, or ANR in African-American, Caucasian and Asian subjects (all P < 0.001). In LN patients with concurrent renal biopsies, urine sCD163 was significantly increased in patients with proliferative LN when compared with non-proliferative LN (P < 0.001). Urine sCD163 strongly correlated with SLEDAI, rSLEDAI, activity index (AI) of renal pathology, fibrinoid necrosis, cellular crescents, and interstitial inflammation on biopsies (all P < 0.01). Macrophages, particularly M2 macrophages, the predominant cells expressing CD163 within LN kidneys, represented a potential source of elevated urine sCD163, based on single-cell RNA sequencing analysis. To conclude, urine sCD163 discriminated patients with active LN from other SLE patients and was significantly elevated in proliferative LN. It strongly correlated with concurrent AI and several specific pathological attributes, demonstrating its potential in predicting renal pathology.

Chemokine releasing particle implants for trapping circulating prostate cancer cells.

Prostate cancer (PCa) is the most prevalent cancer in U.S. men and many other countries. Although primary PCa can be controlled with surgery or radiation, treatment options of preventing metastatic PCa are still limited. To develop a new treatment of eradicating metastatic PCa, we have created an injectable cancer trap that can actively recruit cancer cells in bloodstream. The cancer trap is composed of hyaluronic acid microparticles that have good cell and tissue compatibility and can extend the release of chemokines to 4 days in vitro. We find that erythropoietin (EPO) and stromal derived factor-1α can attract PCa in vitro. Animal results show that EPO-releasing cancer trap attracted large number of circulating PCa and significantly reduced cancer spreading to other organs compared with controls. These results support that cancer trap may serve as a unique device to sequester circulating PCa cells and subsequently reduce distant metastasis.

Lupus nephritis.

Lupus nephritis (LN) is a form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE). Most patients with SLE who develop LN do so within 5 years of an SLE diagnosis and, in many cases, LN is the presenting manifestation resulting in the diagnosis of SLE. Understanding of the genetic and pathogenetic basis of LN has improved substantially over the past few decades. Treatment of LN usually involves immunosuppressive therapy, typically with mycophenolate mofetil or cyclophosphamide and with glucocorticoids, although these treatments are not uniformly effective. Despite increased knowledge of disease pathogenesis and improved treatment options, LN remains a substantial cause of morbidity and death among patients with SLE. Within 10 years of an initial SLE diagnosis, 5-20% of patients with LN develop end-stage kidney disease, and the multiple comorbidities associated with immunosuppressive treatment, including infections, osteoporosis and cardiovascular and reproductive effects, remain a concern. Clearly, early and accurate diagnosis of LN and prompt initiation of therapy are of vital importance to improve outcomes in patients with SLE.

Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis.

OBJECTIVE: This study evaluates the utility of urinary pro-thrombotic molecules such as tissue factor (TF), anti-thrombotic molecules such as tissue factor pathway inhibitor (TFPI), and fibrinolytic molecules such as plasmin and d-dimer as biomarkers of lupus nephritis (LN). METHODS: Urine samples from 113 biopsy-proven LN patients (89 active LN and 24 inactive LN), 45 chronic kidney disease patients, and 41 healthy controls were examined for d-dimer, plasmin, TF, and TFPI levels by ELISA. The area under the receiver operating characteristic curve (AUC) analysis, multivariate regression analysis, and Bayesian network analysis were performed to assess the diagnostic value of the assayed molecules in LN. RESULTS: Although urinary d-dimer, plasmin, TF, and TFPI were all elevated in active LN compared to all control groups, and correlated with rSLEDAI and SLICC RAS disease activity indices, urine plasmin emerged as the strongest independent predictor of eGFR and renal disease status, by multivariate regression analysis and Bayesian network analysis. Whereas urine plasmin discriminated active LN from inactive disease with an AUC of 0.84, the combination of urine plasmin and TFPI discriminated ALN from ILN with an AUC of 0.86, with both surpassing the specificity and positive predictive value of traditional markers such as anti-dsDNA and complement C3. CONCLUSION: Both thrombogenic and thrombolytic cascades appear to be upregulated in lupus nephritis, with proteins from both cascades appearing in the urine. Of the coagulation cascade proteins surveyed, urine plasmin emerges as the strongest predictor of eGFR and clinical renal disease in patients with LN.

Urine angiostatin and VCAM-1 surpass conventional metrics in predicting elevated renal pathology activity indices in lupus nephritis.

AIM: The goal of this study is to investigate how urinary angiostatin, vascular cell adhesion molecule 1 (VCAM-1) and established measures of renal function relate to specific histologic findings in paired kidney biopsy samples from patients with lupus nephritis (LN). METHOD: Urine samples were collected from 54 LN patients together with paired kidney biopsy samples and examined for urinary angiostatin and VCAM-1 protein levels. Nonparametric tests were used to examine the association of both urinary biomarkers and established traditional laboratory markers of renal function with nine specific renal histologic features seen in LN, including glomerular leukocyte infiltration, endocapillary proliferation, cellular crescents, fibrinoid necrosis, wire loops, interstitial inflammation, glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. RESULTS: Compared to traditional renal disease metrics, both urinary angiostatin and VCAM-1 exhibited outstanding potential (area under the curve 0.97, 0.98, respectively) to predict renal biopsy activity index score ≥ 7, which is associated with poor long-term prognosis. Whereas urine VCAM-1 was most significantly associated with fibrous crescents, urine angiostatin was most significantly associated with endocapillary proliferation, cellular crescents, fibrinoid necrosis and fibrous crescents in concurrent renal biopsies. CONCLUSION: Urinary angiostatin and VCAM-1 are predictive of specific histological changes in concurrent LN renal biopsies. Both urinary biomarkers are good candidates for use as noninvasive measures of renal pathology activity changes in LN.

Prognostic significance of repeat biopsy in lupus nephritis: Histopathologic worsening and a short time between biopsies is associated with significantly increased risk for end stage renal disease and death.

BACKGROUND/PURPOSE: Approximately half of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), a major cause of morbidity and early mortality in that disease. Prolonged renal inflammation is associated with irreversible kidney damage which confers a 30% risk of end stage renal disease (ESRD), making early, aggressive treatment mandatory. Failure to achieve therapeutic response or recurrence of renal flare often prompts repeat biopsy. However, the role of repeat biopsy in determining long-term renal prognosis remains controversial. For this reason repeat biopsies are usually not utilized unless clinical evidence of refractory or recurrent disease is already present, despite known mismatches between clinical and biopsy findings. The current study quantifies the degree to which histopathologic worsening between first and second biopsies and duration between them predicts ESRD and death. METHODS: Medical records of 141 LN patients with more than one biopsy were obtained from a single large urban medical center. Cases were attained using billing codes for diagnosis and procedures from 1/1999-1/2015. Biopsy worsening was defined as unfavorable histopathologic classification transitions and/or increased chronicity; if neither were present, the patient was defined as non-worsening. We used Cox proportional hazard models to study the relationship between ESRD and survival adjusting for covariates which included age at first biopsy, gender, race, initial biopsy class, and initial induction therapy. RESULTS: Of 630 patients screened, 141 had more than one biopsy. Advancing chronicity was detected in 48 (34.0%) and a renal class switch to worse grade of pathology was found in 54 (38.3%). At least one of these adverse second biopsy features was reported in 79 (56.0%) patients. Five years following initial biopsy, 28 (35.4%) of those with worsening histopathology on second biopsy developed ESRD, compared to 6 (9.7%) of non-worsening patients and 10 (12.7%) of patients with worsening histopathology had died compared to 2 (3.2%) of non-worsening patients. Biopsy worsening was associated with a significantly greater 15-year risk of ESRD (Hazard Ratio 4.2, p=0.0001) and death (Hazard Ratio 4.3, p=0.022), adjusting for age, gender, race, biopsy class, and treatment. Time between first and second biopsies was <1year in 32 patients, 1-5years in 81, and >5years in 28. Over a 15-year period, those with <1year between first and second biopsies (presumably enriched for patients with early clinical signs of progression) had a significantly greater risk of ESRD (Hazard Ratio 13.7, p<0.0001) and death (Hazard Ratio 16.9, p=0.0022) after adjusting for age, gender, race, biopsy class, and treatment. CONCLUSION: A repeat renal biopsy demonstrating worsening pathology increases the risk of ESRD and death more than four-fold compared to non-worsening patients. Given known potential mismatch between biopsy and clinical data, repeat biopsies may add important information and justify changes in treatment not considered on clinical grounds. Earlier detection of poor prognostic signs in those without early clinical deterioration might improve outcomes in enough patients to reconsider cost effectiveness of routine repeat biopsy.

Antibody-Array-Based Proteomic Screening of Serum Markers in Systemic Lupus Erythematosus: A Discovery Study.

A discovery study was carried out where serum samples from 22 systemic lupus erythematosus (SLE) patients and matched healthy controls were hybridized to antibody-coated glass slide arrays that interrogated the level of 274 human proteins. On the basis of these screens, 48 proteins were selected for ELISA-based validation in an independent cohort of 28 SLE patients. Whereas AXL, ferritin, and sTNFRII were significantly elevated in patients with active lupus nephritis (LN) relative to SLE patients who were quiescent, other molecules such as OPN, sTNFRI, sTNFRII, IGFBP2, SIGLEC5, FAS, and MMP10 exhibited the capacity to distinguish SLE from healthy controls with ROC AUC exceeding 90%, all with p < 0.001 significance. These serum markers were next tested in a cohort of 45 LN patients, where serum was obtained at the time of renal biopsy. In these patients, sTNFRII exhibited the strongest correlation with eGFR (r = -0.50, p = 0.0014) and serum creatinine (r = 0.57, p = 0.0001), although AXL, FAS, and IGFBP2 also correlated with these clinical measures of renal function. When concurrent renal biopsies from these patients were examined, serum FAS, IGFBP2, and TNFRII showed significant positive correlations with renal pathology activity index, while sTNFRII displayed the highest correlation with concurrently scored renal pathology chronicity index (r = 0.57, p = 0.001). Finally, in a longitudinal cohort of seven SLE patients examined at ∼3 month intervals, AXL, ICAM-1, IGFBP2, SIGLEC5, sTNFRII, and VCAM-1 demonstrated the ability to track with concurrent disease flare, with significant subject to subject variation. In summary, serum proteins have the capacity to identify patients with active nephritis, flares, and renal pathology activity or chronicity changes, although larger longitudinal cohort studies are warranted.

Insulin-Like Growth Factor Binding Protein-4 as a Marker of Chronic Lupus Nephritis.

Kidney biopsy remains the mainstay of Lupus Nephritis (LN) diagnosis and prognostication. The objective of this study is to identify non-invasive biomarkers that closely parallel renal pathology in LN. Previous reports have demonstrated that serum Insulin-like growth factor binding protein 4 (IGFBP-4) was increased in diabetic nephropathy in both animal models and patients. We proceeded to assess if IGFBP4 could be associated with LN. We performed ELISA using the serum of 86 patients with LN. Normal healthy adults (N = 23) and patients with other glomerular diseases (N = 20) served as controls. Compared to the healthy controls or other glomerular disease controls, serum IGFBP-4 levels were significantly higher in the patients with LN. Serum IGFBP-4 did not correlate well with systemic lupus erythematosus disease activity index (SLEDAI), renal SLEDAI or proteinuria, but it did correlate with estimated glomerular filtration rate (R = 0.609, P < 0.0001). Interestingly, in 18 patients with proliferative LN whose blood samples were obtained at the time of renal biopsy, serum IGFBP-4 levels correlated strongly with the chronicity index of renal pathology (R = 0.713, P < 0.001). IGFBP-4 emerges a potential marker of lupus nephritis, reflective of renal pathology chronicity changes.

Novel source of human hematopoietic stem cells from peritoneal dialysis effluents.

Hematopoietic stem cells (HSCs) hold great promise for the treatment of various diseases and blood disorders. However, limited availability of these cells has hampered their applications in clinical and biological research. Here we have identified a new source of autologous human HSCs in peritoneal dialysis (PD) effluents from patients with end stage renal diseases (ESRDs). Cells isolated from PD effluents contain a Lin-/CD34+/CD38-/CD90+ sub-population and can repopulate NOD/SCID/gamma-/- mice in serial transplantation. Differing from cord blood HSCs, PD-derived HSCs have high tendencies to repopulate peritoneal cavity and spleen with myeloid cells and B lymphocytes. Repopulating HSCs also reside in peritoneal cavities in mice. The isolation of HSCs from peritoneal cavities provides a novel and promising source of autologous and functional HSCs for stem cell research and possible clinical use.

A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin.

Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.

Peritoneal dialysis access: open versus laparoscopic surgical techniques.

AIM: To outline pros and cons with the open and laparoscopic techniques when placing peritoneal dialysis (PD) catheters. BACKGROUND: Controversy exists regarding which technique, the open and laparoscopic, if any, is superior to the other. In addition, there is the question of which approach is best in rescuing malfunctioning PD catheters. RESULTS: Rather than promoting one doctrine fits all, philosophically, doing the right thing for the patient by specific criteria is ethically the better model. These specific selection criteria include patient characteristics, the team's skills and knowledge and institutional resources and commitment. Also, the sophistication of a PD unit for training and monitoring of patients is crucial for successful outcomes. Open paramedian and two laparoscopic approaches are described in detail, outlining advantages and disadvantages of each, with suggestions when one method is preferred. CONCLUSIONS: In general, the laparoscopic technique is associated with longer operative times, higher costs and the need to utilize general anesthesia. It is, however, the preferred method when rescuing malfunctioning catheters and may increase the PD patient population in patients with previous abdominal surgeries. The dialysis access surgeon should be familiar with both open and laparoscopic techniques and appropriately choose the ideal method based upon the individual patient and institutional resources.

The effect of erythropoietin on autologous stem cell-mediated bone regeneration.

Mesenchymal stem cells (MSCs) although used for bone tissue engineering are limited by the requirement of isolation and culture prior to transplantation. Our recent studies have shown that biomaterial implants can be engineered to facilitate the recruitment of MSCs. In this study, we explore the ability of these implants to direct the recruitment and the differentiation of MSCs in the setting of a bone defect. We initially determined that both stromal derived factor-1alpha (SDF-1α) and erythropoietin (Epo) prompted different degrees of MSC recruitment. Additionally, we found that Epo and bone morphogenetic protein-2 (BMP-2), but not SDF-1α, triggered the osteogenic differentiation of MSCs in vitro. We then investigated the possibility of directing autologous MSC-mediated bone regeneration using a murine calvaria model. Consistent with our in vitro observations, Epo-releasing scaffolds were found to be more potent in bridging the defect than BMP-2 loaded scaffolds, as determined by computed tomography (CT) scanning, fluorescent imaging and histological analyses. These results demonstrate the tremendous potential, directing the recruitment and differentiation of autologous MSCs has in the field of tissue regeneration.

Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis.

INTRODUCTION: Although renal pathology is highly predictive of the disease course in lupus nephritis, it cannot be performed serially because of its invasive nature and associated morbidity. The goal of this study is to investigate whether urinary levels of CXC ligand 16 (CXCL16), monocyte chemotactic protein-1 (MCP-1) or vascular cell adhesion molecule-1 (VCAM-1) in patients with lupus nephritis are predictive of particular features of renal pathology in renal biopsies obtained on the day of urine procurement. METHODS: CXCL16, MCP-1, and VCAM-1 levels were measured in urine samples from 74 lupus nephritis patients and 13 healthy volunteers. Of the patients enrolled, 24 patients had a concomitant kidney biopsy performed at the time of urine collection. In addition, patients with other renal diatheses were also included as controls. RESULTS: All three molecules were elevated in the urine of systemic lupus erythematosus patients, although VCAM-1 (area under curve = 0.92) and MCP-1 (area under curve = 0.87) were best at distinguishing the systemic lupus erythematosus samples from the healthy controls, and were also most strongly associated with clinical disease severity and active renal disease. For patients in whom concurrent renal biopsies had also been performed, urine VCAM-1 exhibited the strongest association with the renal pathology activity index and glomerulonephritis class IV, although it correlated negatively with the chronicity index. Interestingly, urinary VCAM-1 was also elevated in anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis, focal segmental glomerulosclerosis and membranous nephropathy but not in minimal-change disease. CONCLUSION: Urinary VCAM-1 emerges as a reliable indicator of the activity:chronicity ratios that mark the underlying renal pathology in lupus nephritis. Since VCAM-1 is involved in the acute phase of inflammation when leukocytic infiltration is ongoing, longitudinal studies are warranted to establish whether tracking urine VCAM-1 levels may help monitor clinical and pathological disease activity over time.

Metabolic disturbances associated with systemic lupus erythematosus.

The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid ß oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.

Peritoneal catheter implantation elicits IL-10-producing immune-suppressor macrophages through a MyD88-dependent pathway.

Catheters are implanted into the peritoneal cavity during the process of peritoneal dialysis. Though these catheters may be effective and beneficial, the impact of catheters on the immune system is poorly understood. Catheters and other devices implanted in the peritoneal cavity elicit a foreign body reaction. However, the immunological consequences of this remain uncharacterized. To model this, catheters were implanted into the peritoneal cavity of healthy mice. Catheter implantation induced rapid cellular changes within the peritoneal cavity. Whereas B-cells and T-cells were reduced, catheter implantation was associated with the rapid expansion of F4/80-low-positive, CD11b-positive macrophages that elaborated IL-10, and suppressed T-cell division and Th1 skewing in co-culture assays. Peritoneal catheter elicited macrophages had increased Jmjd3 but reduced NF-κB activation, and their emergence was MyD88-dependent. Collectively, these studies indicate that foreign body implantation into the peritoneal cavity is associated with the expansion of suppressor macrophages. Whether peritoneal cavity catheter implantation may have systemic immunoregulatory roles remains to be explored.