Management review of scleroderma renal crisis: An update with practical pointers.

Scleroderma renal crisis (SRC) represents severe, fatal internal organ involvement brought on by systemic sclerosis. A high rate of renal replacement therapy and mortality persists despite various treatments. Depending on the stage of SRC, a vasodilator called angiotensin-converting enzyme inhibitor is the treatment of choice. The efficacy of various other vasodilators (i.e. endothelin-1 receptor antagonist) and complement cascade blocker for SRC have been investigated; however, no randomized control trial has been conducted. A new approach has been proposed for the management of SRC, categorized by specific clinical features of narrowly defined SRC and systemic sclerosis-thrombotic microangiopathy. SRC prophylaxis using angiotensin-converting enzyme inhibitor might be harmful, leading to a poor renal outcome, so the pathogenesis of SRC needs to be clarified in order to identify other possible preventions or therapies.

Association between Opisthorchis viverrini Infection and Glomerular Disease in Thailand.

INTRODUCTION: Opisthorchis viverrini (OV) is a major cause of infection in Southeast Asia. Previous studies in mouse models have shown that OV infection can contribute to immune-complex glomerulonephritis (GN). However, OV infection in human kidney tissue has never been demonstrated. Herein, we evaluated the association of OV infection with biopsy-proven glomerular disease. METHODS: This study was performed in adult patients who underwent kidney biopsy between July 2016 and February 2017. All kidney tissue samples were processed using the standard techniques for renal pathological diagnoses and immunohistochemistry techniques to detect OV antigen. Pre-implanted donor kidney tissue samples were used as controls. The participants were also assessed for OV infection by serum OV immunoglobulin G antibody (Ab) levels and/or presence of OV eggs in stool. RESULTS: Forty-three renal tissue samples from glomerular disease patients and 50 from transplant donors were included in the study. Mean age in the GN group was 41.7 ± 15.9 years, estimated glomerular filtration rate (eGFR) was 70.65 ± 36.61 mL/min/1.73 m2, and median proteinuria was 3.17 (1.70-4.95) g/day. Lupus nephritis (LN) was the most common diagnosis (32.6%), followed by IgA nephropathy (23.3%), IgM nephropathy (18.6%), and primary membranous nephropathy (MN; 7%). The OV antigen was observed in kidney tissue from patients with IgA nephropathy, LN, primary MN, focal segmental glomerulosclerosis, and IgM nephropathy. By contrast, no OV antigen was detected in tissue samples from the control group. The presence of OV antigens was observed in glomerular endothelial cells, mesangial cells, tubular cells, and peritubular capillaries. The odds ratio of positive serum OV Ab to predict the presence of OV antigen in kidney tissues was 4.47 (p = 0.057), and there was a negative correlation between levels of serum OV Ab and eGFR (r = -0.31, p = 0.04). DISCUSSION/CONCLUSION: This is the first study to demonstrate the presence of OV antigen in human kidney tissue, which indicates that OV infection may be associated with biopsy-proven glomerular diseases.

Knockout of the neonatal Fc receptor in cultured podocytes alters IL-6 signaling and the actin cytoskeleton.

The neonatal Fc receptor (FcRn) has been shown to be required for antigen presentation in dendritic cells, and global knockout of FcRn attenuates immune-mediated kidney disease. Podocytes express interleukin-6 (IL-6) receptor and produce IL-6 under proinflammatory conditions. Here we examined the role of FcRn in the IL-6-mediated inflammatory response in podocytes. We examined IL-6 production by ELISA and expression by qPCR in wild type (WT) and FcRn knockout (KO) podocytes after treatment with proinflammatory stimuli as well as IL-6-mediated signaling via the JAK/STAT pathway. We also examined podocyte motility in cultured WT and KO podocytes after a proinflammatory challenge. We found that FcRn KO podocytes produced minimal amount of IL-6 after treatment with albumin, IgG, or immune complexes whereas WT podocytes had a robust response. FcRn KO podocytes also had minimal expression of IL-6 compared with WT. By Western blotting, there was significantly less phosphorylated STAT3 in KO podocytes after treatment with IFNγ or immune complexes. In a scratch assay, FcRn KO podocytes showed increased motility comparted KO, suggesting a defect in actin dynamics. Cultured FcRn KO podocytes also demonstrated abnormal stress fibers compared with WT and the defect could be rescued by IL-6 treatment. This study shows that in podocytes, FcRn modulates the IL-6 mediated response to proinflammatory stimuli and regulates podocytes actin structure, motility and synaptopodin expression.

Clinical features and risk factors of renal dysfunctions in thalassemic patients.

INTRODUCTION: Chronic anemia, iron overload, and iron chelation therapy are the main contributing factors for renal complications in thalassemia, e.g., nephrolithiasis, glomerular disease, and renal tubular dysfunction. The prevalence and associated factors for developing renal dysfunctions in Thai patients with thalassemia, however, remained limited. This study aimed to determine the prevalence and risk factors of renal dysfunctions in patients with thalassemia. METHODS: A cross-sectional study was conducted on adult patients with thalassemia disease at Srinagarind Hospital, Khon Kaen University, Thailand. All patients were evaluated for complete blood count, blood chemistry, urinalysis, and urine biochemistry. Renal tubular dysfunction was defined as existing in at least one of the following parameters including; proteinuria, hypercalciuria, hypouricemia with uricosuria, or hypophosphatemia with phosphaturia. Logistic regression analysis was used to identify associated factors for renal dysfunctions. RESULTS: Of 105 patients, renal tubular dysfunction was found in 60 patients (57.1%). In multivariate analysis of the clinical risk factors for renal tubular dysfunction in thalassemia patients, age per 10 year increase (adjusted odds ratio [AOR] = 1.4, 95% CI: 1.0-2.0, p value 0.01) and Hb E/beta-thalassemia (AOR = 3.6, 95% CI: 1.3-10.3, p value 0.01) were statistically proven to be associated with renal tubular dysfunction. Hyperuricosuria was a significantly associated factor for microhematuria. (AOR = 2.9, 95% CI: 1.1-8.0, p value 0.03). CONCLUSIONS: Renal dysfunctions are prevalent in thalassemia patients, with older age and Hb E/beta-thalassemia genotype as significant risk factors for renal tubular dysfunction. Hyperuricosuria is a risk factor for microhematuria. Renal dysfunctions should be recognized and monitored in aging patients with Hb E/beta-thalassemia.

Cefazolin Plus Ceftazidime versus Cefazolin Monotherapy in the Treatment of Culture-Negative Peritonitis: A Retrospective Cohort Study.

BACKGROUND: Based on current ISPD guidelines, it is unclear as to whether ceftazidime should be discontinued in subsequent management of culture-negative peritonitis if it is used as empirical gram-negative coverage. Herein, we aim to compare the clinical outcomes of cefazolin plus ceftazidime versus cefazolin alone. METHODS: This was a retrospective cohort study. Adult peritoneal dialysis (PD) patients who were diagnosed with culture-negative peritonitis between 2014 and 2020 were included. Patients were categorized into two groups according to treatment regimen. Primary response rate, peritonitis relapse rate, and time to primary response were compared. Factors that predicted primary response were determined using Cox regression analysis. RESULTS: A total of 58 patients were included in the study. Of these, 42 received cefazolin plus ceftazidime and 16 received cefazolin monotherapy. Overall, the mean age was 65.7±10.4 years. Most of the patients (81.3%) were prescribed continuous ambulatory peritoneal dialysis. Initial effluent WBC was 4211±10357 in the combination group and 3833±6931 cell/mm3 in the monotherapy group (p=0.89). There was no significant difference in primary response at day 5 between the two groups (95.2% in the combination group vs93.7% in the monotherapy group, p=0.82). However, cumulative probability of primary response by the Kaplan-Meier analysis in the combination group was higher than in the monotherapy group (p=0.02). Adjusted HR of serum potassium level to predict a primary response was 1.83 according to multivariate analysis (p=0.03). There was no difference between the two groups in terms of peritonitis relapse or catheter removal. CONCLUSION: This is the first study to compare clinical outcomes between cefazolin plus ceftazidime versus cefazolin monotherapy in culture-negative peritonitis. Our results suggest that if peritonitis is resolving at day 3, discontinuation of ceftazidime could yield favorable treatment outcomes and might be appropriate for subsequent management. However, the risk of not having gram-negative coverage should be considered.

Risk factors and clinical outcomes of multidrug-resistant Acinetobacter baumannii bacteremia at a university hospital in Thailand.

Multidrug-resistant (MDR) Acinetobacter baumannii has become a major cause of hospital-acquired infection worldwide. There are few papers regarding this particular subject. Our aim was to assess the incidence of bacteremia due to MDR Acinetobacter baumannii, factors associated with the infection, and clinical outcomes. We studied 49 cases of A. baumannii bacteremia in adult patients admitted to a university hospital in Northeast Thailand between 2005 and 2007. The incidence of MDR A. baumannii bacteremia was 3.6 episodes per 10,000 hospital admissions. Significantly independent factors associated with MDR A. baumannii bacteremia were previous: 1) ICU admission [odds ratio (OR) 10.01; 95% confidence interval (CI) 1.39-72.20]; 2) use of beta-lactam/beta-lactamase inhibitor antibiotics (OR 8.06; 95%CI 1.39-46.64); and 3) use of a carbapenem antibiotics (OR 11.40; 95%CI 1.44-89.98). The overall mortality rate was significantly higher in the MDR group than in the susceptible group (91.7% vs 48%, respectively) (p=0.001). The significantly independent factors related to mortality were: 1) APACHE II score (OR 1.25; 95%CI 1.03-1.52) and 2) secondary bacteremia (OR 14.86; 95%CI 1.37-161.90). This study revealed the significantly independent factors associated with MDR A. baumannii bacteremia were prior ICU admission and prior use of broad spectrum antibiotics. This infection has a high mortality rate. Emphasis needs to be on prevention, strict application of infection control and appropriate use of antibiotics.

Clinical comparisons between previously diagnosed SLE and newly diagnosed SLE by kidney biopsy.

BACKGROUND: Lupus nephritis is a type of major organ involvement in systemic lupus erythematosus (SLE) patients that leads to higher rates of morbidity and mortality and may present initially in 28% of SLE patients. However, there are limited data available on clinical differences or predictors for biopsy-proven lupus nephritis in established versus newly diagnosed SLE cases. METHODS: Adult patients undergoing kidney biopsy for the first time with a diagnosis of lupus nephritis were eligible for inclusion. Patients were categorized into two groups: those with previously diagnosed SLE and those with newly diagnosed SLE by kidney biopsy. Factors associated with newly diagnosed SLE were determined using logistic regression analysis. RESULTS: There were 68 patients diagnosed with lupus nephritis by kidney biopsy. Of those, 31 cases (45.58%) were newly diagnosed. The newly diagnosed SLE group was significantly older (36.87 vs 30.95 years) and had a lower proportion of females (74.19% vs 91.89%) than the previously diagnosed group. A new-onset hypertension was the only factor independently associated with newly diagnosed SLE by kidney biopsy. The adjusted odds ratio (95% CI) was 5.152 (1.046, 25.363). CONCLUSIONS: Nearly half of the biopsy-proven lupus nephritis cases in this study were patients with newly diagnosed SLE. Patients with previously diagnosed SLE and newly diagnosed SLE by kidney biopsy had clinical differences.

Podocyte-specific knockout of the neonatal Fc receptor (FcRn) results in differential protection depending on the model of glomerulonephritis.

Podocytes have been proposed to be antigen presenting cells (APCs). In traditional APCs, the neonatal Fc receptor (FcRn) is required for antigen presentation and global knockout of FcRn protects against glomerulonephritis. Since podocytes express FcRn, we sought to determine whether the absence of podocyte FcRn ameliorates immune-mediated disease. We examined MHCII and costimulatory markers expression in cultured wild type (WT) and FcRn knockout (KO) podocytes. Interferon gamma (IFNγ) induced MHCII expression in both WT and KO podocytes but did not change CD80 expression. Neither WT nor KO expressed CD86 or inducible costimulatory ligand (ICOSL) at baseline or with IFNγ. Using an antigen presentation assay, WT podocytes but not KO treated with immune complexes induced a modest increase in IL-2. Induction of the anti-glomerular basement membrane (anti-GBM) model resulted in a significant decrease in glomerular crescents in podocyte-specific FcRn knockout mouse (podFcRn KO) versus controls but the overall percentage of crescents was low. To examine the effects of the podocyte-specific FcRn knockout in a model with a longer autologous phase, we used the nephrotoxic serum nephritis (NTS) model. We found that the podFcRn KO mice had significantly reduced crescent formation and glomerulosclerosis compared to control mice. This study demonstrates that lack of podocyte FcRn is protective in immune mediated kidney disease that is dependent on an autologous phase. This study also highlights the difference between the anti-GBM model and NTS model of disease.

Renal pathology and clinical associations in systemic sclerosis: a historical cohort study.

BACKGROUND: The information guiding the treatment decision(s) for renal diseases in systemic sclerosis (SSc) is the renal pathological finding. This study aimed to evaluate the renal pathological diagnosis and its clinical feature among SSc. METHOD: A historical cohort study was performed on adult Thai SSc patients who underwent renal biopsy during January 2005-December 2016. The renal pathologic findings and patient clinical characteristics were reviewed. Chi-square or Fisher's exact test was applied to analyze the association between clinical manifestation and renal pathology. RESULTS: Of the 26 SSc patients identified (77% female), 46% had the diffuse cutaneous SSc subtype. The mean age at the time of biopsy was 53.2±14.4 years and median duration of disease was 2.4 years (IQR 0.5-7.0). Rapidly progressive glomerulonephritis (RPGN) was the most common renal manifestation (53.9%) followed by nephrotic syndrome (19.2%) and nephritis (11.5%). The pathological diagnosis included lupus nephritis (LN) class IV (26.9%), LN class V (19.2%), scleroderma renal crisis (SRC; 19.3%), progressive renal disease in scleroderma (7.7%), and IgA nephropathy (7.7%). The nephrotic syndrome was the most common renal feature among LN class V patients, whereas RPGN was the commonest renal presentation among LN class IV and SRC patients (p=0.001). Dialysis treatment at the time of kidney biopsy was significantly higher in SRC patients than in the other groups (p<0.001). The SRC tended to have more frequent cardiac involvement, pulmonary fibrosis, and shorter disease duration than the other groups. CONCLUSION: This is the first report of renal pathologic findings in Thai SSc patients. RPGN is the commonest renal manifestation among SSc who underwent kidney biopsy; for whom LN was the most common pathological finding. Nephrotic syndrome is a clinical feature of glomerular diseases other than renal involvement in SSc.

Differential trafficking of albumin and IgG facilitated by the neonatal Fc receptor in podocytes in vitro and in vivo.

Proteinuria is strongly associated with kidney disease progression but the mechanisms underlying podocyte handling of serum proteins such as albumin and IgG remain to be elucidated. We have previously shown that albumin and IgG are transcytosed by podocytes in vitro. In other epithelial cells, the neonatal Fc receptor (FcRn) is required to salvage albumin and IgG from the degradative pathway thereby allowing these proteins to be transcytosed or recycled. Here we directly examine the role of FcRn in albumin and IgG trafficking in podocytes by studying handling of these proteins in FcRn knockout (KO) podocytes in vitro and in a podocyte-specific FcRn knockout mice in vivo. In vitro, we find that knockout of FcRn leads to IgG accumulation in podocytes but does not alter albumin trafficking. Similarly, in vivo, podocyte-specific knockout of FcRn does not result in albumin accumulation in podocytes in vivo as measured by mean albumin fluorescence intensity whereas these mice demonstrate significant intraglomerular accumulation of IgG over time. In addition we find that podocyte-specific FcRn KO mice demonstrate mesangial expansion as they age and activation of mesangial cells as demonstrated by increased expression of α-smooth muscle actin. Taken together, these results suggest that trafficking pathways for albumin and IgG differ in podocytes and that sustained disruption of trafficking of plasma proteins alters glomerular structure.