Effect of Rituximab on 24-Hour Urine Protein and Albumin or Renal Function in Patients with Glomerulonephritis.

This study aimed to investigate the correlation between the urine protein/creatinine ratio (PCR) and 24 h urine total protein quantity (24hUTP) in morning and random urine and its prediction equation. Rituximab (RTX), a monoclonal antibody that acts on the B cell epitope CD20, has been used in the renal field since 2005 and has become a hot topic in the clinical treatment of many glomerulonephritis diseases. Apart from focusing on the safety and efficacy of RTX in clinical treatment, some scholars are still working on the mechanism of its action in the treatment of renal diseases, trying to find its specific targets in renal tissues. Results. There was no significant difference between morning urine PCR, random urine PCR, and 24hUTP (P=0.81); there was a significant positive correlation between morning urine PCR and 24hUTP (r = 0.90, P < 0.01) and between random urine PCR and 24hUTP (r = 0.95, P < 0.01), and the correlation between random urine PCR and 24hUTP was higher than that between morning urine PCR and 24hUTP. The results of the ROC curve analysis showed that the correlation between morning urine PCR, random urine PCR, and 24hUTP was higher than that between morning urine PCR and 24hUTP in different groups. The optimal threshold values for random urine PCR to predict 2.4hUTP were 0.56 g/g (sensitivity 93.5%; specificity 75.4%), 1.11 g/g (sensitivity 98.3%; specificity 92.4%), and 3.43 g/g (sensitivity 87.9%; specificity 89.9%), respectively. The equations for predicting 24hUTP by morning urine PCR and random urine PCR were as follows: (1) 24hUTP(g) = 0.793 + 0.793 × morning urine PCR + 0.124 × total cholesterol - 0.177 × Alb (coefficient of determination R 2 = 0.87); (2) 24hUTP(g) = 0.369 + 0.856 × random urine PCR + 0.132 × total cholesterol - 0.092 × Alb (coefficient of determination R 2 = 0.92); the prediction equation of random urine was more accurate than that of morning urine. The correlation was not affected by gender, age, 24 h urine volume, etiology, eGFR, Alb, or total cholesterol level, and the correlation between random urine PCR and 24hUTP was higher than that of morning urine PCR. CR prediction equation was used instead of the 24hUTP test.

C3 Glomerulonephritis Associated with Monoclonal Gammopathy of Renal Significance.

INTRODUCTION: Monoclonal gammopathy of renal significance (MGRS) is described as a hematologic condition characterized by nephrotoxicmonoclonal proteins produced by a non-malignant B-cell or plasma cell clone. Nevertheless, MGRS can cause serious renal lesions, leading to high morbidity. In C3 glomerulonephritis, a monoclonal protein can cause renal damage indirectly. Acting as an autoantibody, the protein cannot be detected in the kidney biopsy, promoting the dysregulation of the alternative pathway of the complement system. MATERIAL AND METHODS: This non-systematic review was based on a comprehensive search in databases and scientific journals, such as PubMed, Nature Reviews Nephrology and Kidney International, including the terms 'C3 Glomerulonephritis' and 'Monoclonal gammopathy of renal significance'. We review the pathophysiology, presentation, diagnosis, differential diagnosis and treatment of C3 glomerulonephritis associated with MGRS. DISCUSSION: With the increasing understanding of the complex interaction between monoclonal gammopathy and renal damage, such as C3 glomerulonephritis, it becomes clear that an early recognition is crucial, as Ig-directed therapy might improve outcomes. In this context, and in order to maximize the chance of a correct diagnosis, renal biopsy is mandatory to determine the exact nature of the lesion, and the severity of renal disease. Conclusion: It is important to make an early diagnosis of MGRS-associated C3 glomerulonephritis in order to prevent not only the progression to a hematological malignancy, but also end-stage renal disease.

Introdução: A gamopatia monoclonal de significado renal (MGRS) é descrita como uma doença hematológica caracterizada pela existência de proteínas monoclonais nefrotóxicas produzidas por um clone não maligno de células B ou plasmócitos. A MGRS pode causar lesões renais graves, levando a elevada morbilidade. Na glomerulonefrite C3, a proteína monoclonal pode causar indiretamente lesão renal. A proteína atua como auto-anticorpo, não sendo detetada na biópsia renal, promovendo a desregulação da via alternativa do complemento. Material e Métodos: Esta revisão não sistemática foi baseada numa pesquisa abrangente com recurso a base de dados e revistascientíficas, como a PubMed, Nature Reviews Nephrology e Kidney International, utilizando os termos 'Glomerulonefrite C3' e 'Gamopatia monoclonal de significado renal'. Apresentamos uma revisão da fisiopatologia, apresentação clínica, diagnóstico, diagnóstico diferencial e tratamento de glomerulonefrite C3 associado a MGRS Discussão: Com a crescente compreensão da complexa interação entre a gamopatia monoclonal e a lesão renal, como é exemplo a glomerulonefrite C3, torna-se claro que um reconhecimento precoce é crucial, dado que a terapia dirigida à Ig pode melhorar o resultado. Neste contexto, para maximizar a probabilidade de um diagnóstico correto, uma biópsia renal é necessária para determinar a natureza exata da lesão e a severidade da doença renal. Conclusão: É importante realizar um diagnóstico precoce de glomerulonefrite G3 associada a MGRS de modo a prevenir não apenas a progressão para uma neoplasia hematológica, mas também para doença renal terminal.

Chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for glomerulonephritis in chronic kidney disease.

Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. In addition, decreased levels of urinary KIM-1, ß2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients.

Urinary Soluble CD163 and Disease Activity in Biopsy-Proven ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: ANCA-associated GN is a common cause of rapidly progressive GN, with high relapse rates. The early recognition of an ANCA-associated GN relapse is of importance to prevent loss of kidney function. Urinary soluble CD163 has been identified as a promising marker of active ANCA-associated GN. Previous studies, however, are limited by the lack of histologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed urinary soluble CD163 in 95 patients with ANCA-associated vasculitis who underwent a kidney biopsy. In total, 125 kidney tissue sections (first kidney biopsy, n=67; repeated biopsy, n=58) with concurrent 24-hour urine samples were studied. Correlation analyses comparing urinary soluble CD163 levels and morphologic features of ANCA-associated GN were performed using Spearman rank correlation analysis. The diagnostic performance of biomarkers to detect relapsing ANCA-associated GN was evaluated using receiver operating characteristics curve analysis. RESULTS: High levels of urinary soluble CD163 were found in 96 (87%) of 110 biopsies with active ANCA-associated GN compared with one (7%) of 15 biopsies without active ANCA-associated GN and one (6%) of 17 healthy controls. Urinary soluble CD163 correlated with fibrinoid necrosis (Rho=0.48, P<0.001) and cellular crescents (Rho=0.70, P<0.001) on kidney biopsy. In repeated biopsies, urinary soluble CD163's sensitivity of 0.94 and specificity of 0.91 for the recognition of relapsing ANCA-associated GN appeared better than routine clinical measures. The presence of CD163+ cells in affected glomeruli confirmed urinary soluble CD163's origin. CONCLUSIONS: Urinary soluble CD163 is associated with active ANCA-associated GN and correlates with histologic features as seen in ANCA-associated GN. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_17_CJN07210520_final.mp3.

Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model.

Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.

Evaluation of podocin in urine in horses using qualitative and quantitative methods.

No sensitive method for diagnosing early kidney dysfunction in horses has been identified so far. Many studies carried out in humans and small animals show that podocin can be useful to diagnose various kidney diseases, mainly affecting the glomeruli. The aim of this study was to perform a qualitative and quantitative analysis of podocin in urine samples obtained from healthy horses, horses with clinical kidney dysfunction and horses at risk of acute kidney injury. The study objectives aimed to assess: (1) whether the selected podocin tryptic peptide for LC-MS-MRM allows for podocin detection in horse; and (2) whether the species-specific ELISA test makes this detection possible as well;, (3) whether the chosen methods are sensitive enough to detect kidney dysfunction and glomerular injury, (4) whether the results of the tests applying both methods correspond with one another, (5) whether the results correlate with the hematological and biochemical data. The signals that may indicate the presence of trypsin fragments of podocin were found in three healthy horses, all the horses diagnosed with kidney dysfunction and half of the animals at risk for acute kidney injury. The concentration of podocin, diagnosed with the ELISA test was as follows: from 0.19 to 1.2 ng/ml in healthy animals, from 0.19 to 20.0 ng/ml in AKI horses, from 0.29 to 5.71 ng/ml in horses at risk for acute kidney injury. The results of both methods corresponded significantly. Podocin may be a potential biomarker of clinical kidney disease in horses and may be used in the detection of glomerular injury. However, its use is limited by the possibility of physiological podocyturia. LC-MS-MRM seems to be a more sensitive method to evaluate the presence of podocin than the ELISA test, whilst selected tryptic peptides of podocin appear to apply to horses. The ELISA test showed greater effectiveness in excluding the disease than in confirming it.

Detection of Podocin in Human Urine Sediment Samples by Charge Derivatization and LC-MS-MRM Method.

Detection of podocytes in urine might serve as a useful diagnostic tool in both primary and secondary glomerular diseases. The utility of podocyturia has been confirmed for both pre-eclampsia and glomerulonephritis. Here, we present a new and sensitive method for qualitative LC-MS-multiple-reaction-monitoring (MRM) analysis of podocin, serving as a podocyturia biomarker in urine sediments. The following podocin tryptic peptides with the 169LQTLEIPFHEIVTK182, 213AVQFLVQTTMK223, 240SIAQDAK246, and 292MIAAEAEK299 sequences were applied as a model. The selective chemical derivatization of the ε amino group of C-terminal lysine residue in tryptic peptides, by 2,4,6-triphenylpyrylium salt (TPP) as a fixed charge tag, was employed to increase the ionization efficiency, in routine ESI-MS analysis. Additionally, the generation of a reporter ion, in the form of a protonated 2,4,6-triphenylpyridinium cation, makes the derivatized peptide analysis in the MRM mode unambiguous. Identification of derivatized and non-derivatized peptides were performed, and the obtained results suggest that the peptide with the 292MIAAEAEK299 sequence may serve as a marker of podocyturia.

Heat shock protein 90 and NFkB levels in serum and urine in patients with chronic glomerulonephritis.

Heat shock proteins play an important role in immune inflammation and the formation and restoration of proteins. In recent years, the importance of heat shock protein 90 (Hsp90) in the activation of immune inflammation through nuclear factor kB (NFkB) has been discussed. To assess the activation of the Hsp90-NFkB system by measuring serum and urinary levels in patients with chronic glomerulonephritis (CGN). This study included 32 patients with active forms of CGN and 14 patients with Fabry nephropathy. The control group included 10 healthy individuals. Twenty-one out of 32 CGN patients had nephrotic syndrome (NS). Eleven out of 32 CGN patients had proteinuria levels from 1 to 3 g/day without nephrotic syndrome. A total of 17 patients had renal dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73m2). Fourteen patients with Fabry nephropathy had proteinuria without nephrotic syndrome. Serum and urine HSP-90 and NFkB p65 levels were determined using an enzyme-linked immunosorbent assay. The levels of HSP-90 and NFkB in the serum of patients with CGN were significantly higher than in healthy individuals and patients with Fabry nephropathy. In patients with Fabry nephropathy, the HSP-90 and NFkB levels in the urine and serum did not significantly differ from those in the control subjects. Serum Hsp90 levels were significantly higher in the CGN patients with NS than in patients without NS, as well as in patients with normal renal function compared with patients with an eGFR < 60 ml/min/1.73 m2 and patients with tubulo-interstitial fibrosis. Higher levels of HSP-90 and NFkB in serum were observed in patients with nephrotic forms of CGN, including focal segmental glomerulosclerosis, minimal change disease and membranous nephropathy. There were no correlations between the clinical signs of CGN and urinary HSP90/NFkB levels. Activation of the HSP-90-NFkB system, which is directly involved in the development of immune inflammation in CGN, was found in patients with an active course of CGN, especially in those with nephrotic syndrome.

Weight-gain induced changes in renal perfusion assessed by contrast-enhanced ultrasound precede increases in urinary protein excretion suggestive of glomerular and tubular injury and normalize after weight-loss in dogs.

Early detection of obesity-related glomerulopathy in humans is challenging as it might not be detected by routine biomarkers of kidney function. This study's aim was to use novel kidney biomarkers and contrast-enhanced ultrasound (CEUS) to evaluate the effect of obesity development and weight-loss on kidney function, perfusion, and injury in dogs. Sixteen healthy lean adult beagles were assigned randomly but age-matched to a control group (CG) (n = 8) fed to maintain a lean body weight (BW) for 83 weeks; or to a weight-change group (WCG) (n = 8) fed the same diet to induce obesity (week 0-47), to maintain stable obese weight (week 47-56) and to lose BW (week 56-83). At 8 time points, values of systolic blood pressure (sBP); serum creatinine (sCr); blood urea nitrogen (BUN); serum cystatin C (sCysC); urine protein-to-creatinine ratio (UPC); and urinary biomarkers of glomerular and tubular injury were measured. Glomerular filtration rate (GFR) and renal perfusion using CEUS were assayed (except for week 68). For CEUS, intensity- and time-related parameters representing blood volume and velocity were derived from imaging data, respectively. At 12-22% weight-gain, cortical time-to-peak, representing blood velocity, was shorter in the WCG vs. the CG. After 37% weight-gain, sCysC, UPC, glomerular and tubular biomarkers of injury, urinary immunoglobulin G and urinary neutrophil gelatinase-associated lipocalin, respectively, were higher in the WCG. sBP, sCr, BUN and GFR were not significantly different. After 23% weight-loss, all alterations were attenuated. Early weight-gain in dogs induced renal perfusion changes measured with CEUS, without hyperfiltration, preceding increased urinary protein excretion with potential glomerular and tubular injury. The combined use of routine biomarkers of kidney function, CEUS and site-specific urinary biomarkers might be valuable in assessing kidney health of individuals at risk for obesity-related glomerulopathy in a non-invasive manner.

Uptake of further investigations following universal urinary screening among elementary and junior high school students in Shiga Prefecture, Japan: A retrospective cohort study.

AIM: This study aimed to investigate the current progression status from screening phase to further investigation phase in the Japanese school urine mass screening (SUS) project. METHODS: This retrospective cohort study on the SUS project across the Shiga Prefecture during 2012 to 2017 analysed data from school life instruction sheets, which are principal documents in the SUS project, regarding urinalysis, attendance at follow-up and diagnoses. RESULTS: Between the years 2012 to 2017, a median of 107 out of 83 749 elementary school students (aged 6-11 years) and 215 out of 42 870 junior high students (aged 12-14 years) had urine abnormalities identified for the first time in the SUS project. Among those with urine abnormalities, a mean of 4.2% of elementary school and 1.8% of junior high school students, respectively, were diagnosed with suspected glomerulonephritis for the first time. Overall, 5.9% (95% confidence interval [CI] 4.1, 7.7) and 23.6% (95% CI 21.3, 25.9) of proteinuria-positive elementary and junior high school students, respectively, did not undergo further investigations. The probability of a student undergoing further investigations was not affected by the local availability of medical care benefits. CONCLUSION: In the current SUS project, screening frequently does not lead to further investigation, especially among junior high school students. To maintain the integrity of the SUS project and to prevent the progression of renal disease in young students, efforts including elucidation of barriers to further investigations should be made to reduce the proportions of students not undergoing further investigations for abnormal urinalysis findings.

Urinary ERdj3 and mesencephalic astrocyte-derived neutrophic factor identify endoplasmic reticulum stress in glomerular disease.

Podocyte injury and endoplasmic reticulum (ER) stress have been implicated in the pathogenesis of various glomerular diseases. ERdj3 (DNAJB11) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are ER chaperones lacking the KDEL motif, and may be secreted extracellularly. Since podocytes reside in the urinary space, we examined if podocyte injury is associated with secretion of KDEL-free ER chaperones from these cells into the urine, and if chaperones in the urine reflect ER stress in glomerulonephritis. In cultured podocytes, ER stress increased ERdj3 and MANF intracellularly and in culture medium, whereas GRP94 (KDEL chaperone) increased only intracellularly. ERdj3 and MANF secretion was blocked by the secretory trafficking inhibitor, brefeldin A. Urinary ERdj3 and MANF increased in rats injected with tunicamycin (in the absence of proteinuria). After induction of passive Heymann nephritis (PHN) and puromycin aminonucleoside nephrosis (PAN), there was an increase in glomerular ER stress, and appearance of ERdj3 and MANF in the urine, coinciding with the onset of proteinuria. Rats with PHN were treated with the chemical chaperone, 4-phenyl butyrate (PBA), starting at the time of disease induction, or after disease was established. In both protocols, 4-PBA reduced proteinuria and urinary ER chaperone secretion, compared with PHN rats treated with saline (control). In conclusion, urinary ERdj3 and MANF reflect glomerular ER stress. 4-PBA protected against complement-mediated podocyte injury and the therapeutic response could be monitored by urinary ERdj3 and MANF.

Urinary podocyte mRNA is a potent biomarker of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) is a critical kidney disease that sometimes results in an unfavorable renal outcome. Cellular crescent formation is a hallmark of ANCA-GN and is associated with renal prognosis, response to treatment, and it was reportedly associated with podocyte detachment. Because there is a need to explore non-invasive biomarkers for the evaluation of ANCA-GN activity, we tested whether urinary podocyte mRNA might be a potent non-invasive biomarker. METHODS: We measured two different types of urinary podocyte mRNA, including podocin mRNA in relation to urine creatinine concentration (U-PodCR) and urinary podocin mRNA in relation to nephrin mRNA (U-PNR), which were reportedly associated with the activity of various glomerular diseases. RESULTS: In ANCA-GN patients (n = 19), we discovered that U-PodCR was positively correlated with the percent of crescent formation until 50% crescent was reached because of podocyte depletion; U-PNR was correlated with the percent of crescent formation in all patients. Furthermore, patients with high levels of urinary podocyte mRNA exhibited a favorable renal outcome compared with the outcomes of patients with low levels of urinary podocyte mRNA. The levels of urinary podocyte mRNA were correlated with the rate of improvement in estimated glomerular filtration rate. CONCLUSIONS: U-PodCR, U-PNR or a combination of these parameters might serve as a non-invasive potential biomarker in patients with ANCA-GN to predict the percent of crescent formation and renal prognosis.

Acute and chronic glomerular damage is associated with reduced CD133 expression in urinary extracellular vesicles.

Extracellular vesicles released into urine (uEVs) can represent interesting biomarkers of renal cell damage. CD133, a stem/progenitor cell marker expressed by renal progenitor cells, is highly expressed in uEVs of healthy individuals. In the present study, we evaluated the level of CD133 in the uEVs of patients with acute and chronic glomerular damage by cytofluorimetric analysis. The level of CD133+ uEVs was significantly decreased in pediatric patients with acute glomerulonephritis during the acute phase of renal damage, while it was restored after the subsequent recovery. A similar decrease was also observed in patients with chronic glomerulonephritis. Moreover, CD133+ uEVs significantly declined in patients with type 2 diabetes, used as validation group, with the lowest levels in patients with albuminuria with diabetic nephropathy. Indeed, receiver-operating characteristic curve analysis indicates the ability of CD133+ uEV values to discriminate the health condition from that of glomerular disease. In parallel, a significant decrease of CD133 in renal progenitor cells and in their derived EVs was observed in vitro after cell treatment with a combination of glucose and albumin overload, mimicking the diabetic condition. These data indicate that the level of CD133+ uEVs may represent an easily accessible marker of renal normal physiology and could provide information on the "reservoir" of regenerating cells within tubules.

Serum uromodulin is associated with the severity of clinicopathological findings in ANCA-associated glomerulonephritis.

BACKGROUND: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG). MATERIALS AND METHODS: Sixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated. RESULTS: AAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves. CONCLUSION: Low sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG.

Clinicopathological analysis of ANCA-associated glomerulonephritis focusing on plasma cell infiltrate.

BACKGROUND: When we encounter glomerulonephritis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides demonstrating many plasma cell infiltrations, histological overlapping of immunoglobulin G4-related disease (IgG4-RD) often comes into the differential diagnosis. No previous study has focused on the degree of plasma cells in the kidney infiltrate in ANCA-associated glomerulonephritis (ANCA-GN), and the significance of massive plasma cell infiltrate has not been investigated. METHODS: To clarify the plasma cell ratio in renal biopsy specimens of ANCA-GN and the histological characteristic of "plasma cell-rich" ANCA-GN, 20 cases of ANCA-GN were reviewed and clinicopathologically analyzed. RESULTS: Plasma cell ratio was widely distributed between 1.4 and 81%, and the median ratio was 10%. Three patients were categorized in "plasma cell-rich" ANCA-GN, defined as over 45% plasma cell ratio. They tended to include many active glomerular lesions compared to chronic lesions and to display severe tubulointerstitial inflammation. It is suggested that plasma cell-rich ANCA-GN may be acute onset of the disease, and the target of early inflammation may also be in the tubulointerstitial region. Two of the three plasma cell-rich ANCA-GN cases demonstrated numerous IgG4+ cells, but no bird's-eye pattern fibrosis or obliterative phlebitis. CONCLUSIONS: Plasma cell-rich ANCA-GN is not rare and demonstrates distinct clinicopathological characteristics. This study also reminds us that the presence of the significant number of plasma cells in ANCA-GN, as such, is not a histological diagnostic basis for overlap ANCA-GN and IgG4-related disease.

[Determining of cytokine levels in the urine in clinical practice.]

The paper presents data on the study of the content of cytokines (IL-1ß, RAIL-1ß, IL-2, IL-4, IL-10, IL-17A, TNF-, IFN-γ) in the morning urine using enzyme immunoassay in healthy individuals (n = 20) and in patients with acute glomerulonephritis (n = 93). The determination of cytokine levels in patients was carried out in the debut of the disease and 12 months after the onset of the disease. The obtained indicators of cytokine content in the urine are presented as absolute values in pg/ml and creatinine-normalized values calculated by the formula: cytokine level (pg/ml) / urine creatinine (µmol/ml). The study was made of changes in the content of cytokines in the urine of patients with glomerulonephritis with respect to a group of healthy individuals, as well as the dynamics of the content of cytokines in the urine during the 12-month observation period. The results of the study showed that the absolute values of cytokines in urine can distort the true picture of the cytokine profile of urine in renal pathology. Normalized values of the predominant number of pro- and anti-inflammatory cytokines (IL-1ß, IL-2, IL-8, IL-10, IL-17A and TNF-α) in patients with glomerulonephritis were significantly higher than the corresponding indicators of healthy individuals. The normalized values of cytokines were shown to be as more sensitive indicators than absolute values in the course of analyzing differences in the cytokine profile in patients with glomerulonephritis, depending on chronic and acute course of the disease. These indicators influenced the outcome of glomerulonephritis, assessed, as a rule, 12 months after the onset of the disease. Thus, the low levels of IL-1ß, IL-8 and IL-17А detected in the debut of the disease in combination with the high level of RAIL-1ß determined the chronization of glomerulonephritis. So, the creatinine-normalized cytokine levels in the urine expand the possibilities of using the evaluation of the cytokine profile of urine to establish changes in the cytokine content in the urine in renal pathology and predict the chronization of glomerulonephritis.

Mercury-associated glomerulonephritis: a retrospective study of 35 cases in a single Chinese center.

BACKGROUND: Long-term exposure of mercury may induce glomerulonephritis. Clinical and pathological features of mercury-associated glomerulonephritis are not fully clear. This study retrospectively analyzed 35 cases of mercury-associated glomerulonephritis in a single Chinese center. METHODS: Thirty-five patients of mercury-associated glomerulonephritis were enrolled. Clinical data on diagnosis and during follow-up were collected. Plasma anti-phospholipase A2 receptor (PLA2R) antibody, glomerular PLA2R and glomerular IgG subclasses deposition were detected in the cases with membranous nephropathy (MN). RESULTS: Mercury exposure was caused by skin lighting cream (20 patients), mercury-containing pills (9 patients), hair-dyeing agents (4 patients), and unidentified reasons (2 patients). All patients presented with proteinuria and normal renal function. The median of urinary protein was 4.6 (range 1.6~19.7) g/24 h. Twenty-two patients (62.9%) had nephrotic syndrome. Renal histopathology showed minimal change disease (MCD) in 21 patients (60.0%), MN in 13 (37.1%) and focal segmental glomerular sclerosis (FSGS) in 1 patient (2.9%). The proportion of MCD increased along with urinary mercury concentration (P = 0.024). In 13 cases of MN, all patients were negative for plasma anti-PLA2R antibody and glomerular PLA2R antigen. IgG1 (61.5%) and IgG4 (46.2%) deposits were noted along the glomerular capillary loops. Among the 16 patients received mercury detoxification monotherapy, 14 patients received 4.5 ± 2.8 (range 1~12) rounds of regimen and achieved complete remission in 4.5 (range 0.3~23.0) months, 2 patients stayed no remission. CONCLUSIONS: MCD was the most common pathological type of mercury-associated glomerulonephritis, followed by MN. The proportion of MCD increased along with the increase of urinary mercury concentration. Most patients could achieve complete remission after mercury detoxification.

Urine macrophages reflect kidney macrophage content during acute tubular interstitial and glomerular injury.

Macrophage polarization is a major contributing factor in acute kidney injury (AKI). We aim to determine its biomarker value in differentiating etiologic causes of various intrinsic renal AKI. A total of 205 patients with renal intrinsic AKI were enrolled. Urinary sCD163 was quantified and macrophage subtypes in urine and in renal biopsy were determined. Compared to healthy controls and AKI due to interstitial or tubular injuries (0 pg/µmol), urinary sCD163 was markedly higher in glomerulopathy, especially in diffuse proliferative glomerulonephritis (275.5 pg/µmol) and significantly correlated with cellular crescent formation. Urine sediment analysis of M1/M2 ratio could differentiate acute tubulointerstitial nephritis (M1/M2 > 2.35) from crescentic glomerulonephritis (M1/M2 < 0.27). Urinary sCD163 levels and M2 subtype positively correlated with infiltrated M2 in the glomeruli, whereas urine M1 positively correlated with infiltrated M1 in the interstitium. Of note, urinary sCD163 showed better diagnositic performance in differentiating disease etiologies compared to tradiational urinary biomarkers of AKI (NGAL and KIM-1) and markers of myeloid cells (CD11b) and pan macrophages (CD68). Thus markers of macrophage polarization could be viewed as the noninvasive "liquid biopsy" in the presence of various intrinsic kidney diseases.