Direct-acting antiviral therapy slows kidney function decline in patients with Hepatitis C virus infection and chronic kidney disease.
Kidney international
Hepatitis C virus (HCV) infection is common and can accelerate chronic kidney disease (CKD) progression. Direct-acting antiviral (DAA) therapies against hepatitis C have consistently shown rates of sustained viral remission. However, the effect on kidney function is unknown. In a retrospective observational cohort study of HCV-infected patients receiving DAA therapies from 2013 to 2017, the slopes of estimated glomerular filtration rate (eGFR) decline were compared in the three years before DAA therapy to the slope after therapy. Pre- and post-treatment albuminuria values were also compared. In all, 1,178 patients were included; mean age of 56, 64% male, 71% white, 21% were diabetic, and 42% with cirrhosis. In patients with eGFR less than 60ml/min per 1.73m, the annual decline in eGFR in the three years prior to treatment was -5.98 ml/min per year (95% confidence interval -7.30 to -4.67) and improved to -1.32 ml/min per year (95% confidence interval -4.50 to 1.88) after DAA therapy. In patients with eGFR greater than 60ml/min per 1.73m the annual decline in eGFR in the three years prior to treatment was -1.43 ml/min per year (95% confidence interval -1.78 to -1.08) and after DAA therapy was -2.32 ml/min per year (95% confidence interval -3.36 to -1.03). Albuminuria improved significantly in patients without diabetes, but not in those with diabetes. Predictors of eGFR improvement included having CKD at baseline and being non-diabetic. Events of acute kidney injury were rare, occurring in 29 patients, and unrelated to antiviral therapy in 76% of cases. Thus, DAA therapy for HCVs infection may slow CKD progression.
10.1016/j.kint.2019.04.030
Prognostic Value of Serum Biomarkers of Autoimmunity for Recurrence of IgA Nephropathy after Kidney Transplantation.
Berthoux Francois,Suzuki Hitoshi,Mohey Hesham,Maillard Nicolas,Mariat Christophe,Novak Jan,Julian Bruce A
Journal of the American Society of Nephrology : JASN
A prognostic biomarker for IgA nephropathy (IgAN) recurrence after renal transplant is lacking. We followed 96 consecutive first renal transplant recipients with native kidney IgAN (79 men; 92 deceased donors; mean age =48.1 years) on calcineurin inhibitor-based immunosuppression over 10 years for death, allograft failure, and clinicopathologic recurrence (CPR; clinically evident and biopsy-proven). Using time-dependent Cox regression analysis and receiver operating characteristic curves, we assessed prognostic significance of levels of galactose-deficient IgA1 (Gd-IgA1; autoantigen) and Gd-IgA1-specific IgG and IgA autoantibodies in serum obtained at time of transplant or native-kidney IgAN diagnosis (30 patients only). Overall, 13 patients died, 34 kidneys failed (17 due to CPR), and 34 patients developed CPR after a mean interval of 5.8 years. Compared with healthy controls (=30), patients had significantly elevated serum Gd-IgA1 levels at diagnosis and transplant, but levels did not associate with any outcome. Patients also had significantly elevated levels of normalized (but not total) serum Gd-IgA1-specific IgG autoantibodies at diagnosis and transplant, and the level at transplant associated with higher risk of CPR (relative risk, 2.68; 95% confidence interval, 1.26 to 5.71; =0.01; area under the receiver operating characteristic curve, 0.62; 95% confidence interval, 0.51 to 0.74; =0.05). Normalized Gd-IgA1-specific IgG autoantibody level remained an independent risk factor for CPR in multivariate analysis. Serum Gd-IgA1-specific IgA autoantibody level did not change between diagnosis and transplant or predict outcome. This study emphasizes post-transplant prognostic value of normalized serum IgG antiglycan autoantibody level in patients with IgAN.
10.1681/ASN.2016060670
Effects of Tripterygium wilfordii Induction Therapy to IgA Nephropathy Patients with Heavy Proteinuria.
Wang Zhen,Yu Chao,Zhou Li-Na,Chen Xin
Biological & pharmaceutical bulletin
Although some new drugs have been developed, Tripterygium wilfordii HOOK F. (TWHF) has the merits of relatively lower price and fewer side effects. Unfortunately, the efficacy and safety of the TWHF (especially dosage 120 mg/d) in the immunoglobulin A (IgA) nephropathy (IgAN) are still lacking. A cohort study including 49 IgAN patients with heavy proteinuria who received induction therapy was undertaken. Patients were divided into three groups: Prednisone (PRE), conventional-dose TWHF (CTW) and double-dose TWHF (DTW). The clinical features, laboratory data, histological manifestations and outcomes of the groups were compared. We found that urinary protein excretion and rates of elevated n-acetyl-β-D-glucosaminidase (NAG) and retinol binding protein (RBP) were prominent in all groups. Neither histopathological changes nor the rates of renal insufficiency were significantly different among groups. Patients in the PRE (69.2%) and DTW groups (87.5%) achieved complete remission; none of the CTW group did. Furthermore, the total remission rate of the DTW group was substantially higher than that of the CTW group. The degree of hypoproteinemia, improved considerably in the PRE and DTW groups. Treatment was well tolerated in all patients, and no serious adverse events were observed. Our findings suggested that induction therapy with double dose TWHF significantly improved response rates in IgAN patients with heavy proteinuria, and did not considerably increase side effects.
10.1248/bpb.b17-00134
Comparison of long-term follow-up outcomes between multiple-drugs combination therapy and tonsillectomy pulse therapy for pediatric IgA nephropathy.
Kawasaki Yukihiko,Maeda Ryo,Kanno Syuto,Suzuki Yuichi,Ohara Shinichiro,Suyama Kazuhide,Hosoya Mitsuaki
Clinical and experimental nephrology
BACKGROUND:To clarify the long-term efficacy of multiple-drugs combination therapy (PWDM) and tonsillectomy pulse therapy (TPT) for pediatric IgA nephropathy (IgAN), we retrospectively evaluated the clinical and laboratory findings as well as the prognosis for IgAN patients treated with each treatment at long-term follow-up. METHODS:We collected data on 61 children who had been diagnosed with severe IgAN. The children were retrospectively divided into two groups. Group 1 consisted of 44 severe IgAN children treated with PWDM, and Group 2 consisted of 17 severe IgAN children treated with TPT. The clinical features, pathological findings, and prognosis were analyzed for both groups. RESULTS:The mean urinary protein excretion, serum creatinine, IgA levels, MESTCG scores, and percentage of glomeruli showing crescents in both groups at the second renal biopsy were lower than those at the first renal biopsy. At the time of the second biopsy, the IgA level in Group 2 was lower than that in Group 1; however, there were no significant differences in the mean urinary protein excretion, frequency of hematuria, serum albumin, creatinine, or e-GFR between the two groups. At the most recent follow-up, there were no significant differences in prognosis between the groups. CONCLUSIONS:Our study suggested that PWDM and TPT are effective in ameliorating urinary abnormalities and improving the long-term outcome of pediatric IgAN.
10.1007/s10157-017-1515-5
The clinical course of IgA nephropathy after kidney transplantation and its management.
Lionaki Sophia,Panagiotellis Konstantinos,Melexopoulou Christine,Boletis John N
Transplantation reviews (Orlando, Fla.)
Immunoglobulin (Ig) A nephropathy is one of the most common primary glomerulonephritides worldwide causing end stage renal disease in up to 20-40% of affected patients, nearly two decades post diagnosis. Kidney transplantation is the treatment of choice for patients with renal failure, secondary to glomerular diseases. However, IgA nephropathy has a strong tendency to recur in the graft, and although initially thought to be a benign condition, several reports of graft loss, due to recurrent IgA nephropathy, there have been over the last three decades. Overall graft survival has been significantly improved in kidney transplantation, as a result of reduced incidence of acute rejection, as more potent and more specific immunosuppressive agents are now available in clinical practice. Thus, the rates of IgA nephropathy and other glomerulonephritides recurrence are expected to increase, since graft survival has been improved. However, the reported incidence of IgA nephropathy recurrence in the graft varies substantially across centers, as a consequence of different levels of interest, diverse biopsy policies and differing durations of follow up, of the published studies. Notably, recurrence rates of patients receiving graft biopsies by clinical indication only, ranges from 13% to 50% with graft loss being between 1.3% and 16%. The aim of this review is to underline important pathogenetic insights of IgA nephropathy, describe the clinical course of the disease after kidney transplantation, with emphasis on the incidence of recurrence and the associated risk factors, and finally provide all available options for its management in transplant recipients.
10.1016/j.trre.2017.01.005
Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial.
Lv Jicheng,Zhang Hong,Wong Muh Geot,Jardine Meg J,Hladunewich Michelle,Jha Vivek,Monaghan Helen,Zhao Minghui,Barbour Sean,Reich Heather,Cattran Daniel,Glassock Richard,Levin Adeera,Wheeler David,Woodward Mark,Billot Laurent,Chan Tak Mao,Liu Zhi-Hong,Johnson David W,Cass Alan,Feehally John,Floege Jürgen,Remuzzi Giuseppe,Wu Yangfeng,Agarwal Rajiv,Wang Hai-Yan,Perkovic Vlado,
JAMA
Importance:Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective:To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants:The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions:Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures:The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results:After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). Conclusions and Relevance:Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration:clinicaltrials.gov Identifier: NCT01560052.
10.1001/jama.2017.9362
Comparison of oral steroids with tonsillectomy plus steroid pulse therapy in patients with IgA nephropathy.
Hoshino Yoshie,Moriyama Takahito,Uchida Keiko,Tsuchiya Ken,Nitta Kosaku
Clinical and experimental nephrology
BACKGROUND:Treatment of IgA nephropathy (IgAN) in Japan has recently changed, from oral prednisolone (oPSL) to tonsillectomy plus steroid pulse (TSP) therapy. However, a few studies have compared their efficacy and safety. METHODS:IgAN patients diagnosed in our institution between 1991 and 2013, treated with TSP or oPSL, aged ≥16 years, with ≥1 g/day proteinuria, and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m, and no other renal disease were selected. Baseline clinical and histological findings, clinical outcomes, and adverse events were compared. Clinical remission (CR) was defined as <0.3 g/day proteinuria and <5 urinary red blood cells per high-powered field. RESULTS:Sixty-six patients were identified; after propensity score adjustment, 26 patients were selected in each group. CR rates were significantly higher at 12 (30.8 % vs. 3.9 %), 36 (47.3 % vs. 7.9 %), and 72 (57.8 % vs. 20.1 %) months (p < 0.01), and the renal survival rate, defined as the development of a 25 % reduction from baseline eGFR, was significantly higher at 12 (96.2 % vs. 69.2 %), 36 (96.2 % vs. 61.5 %), and 72 (96.2 % vs. 41.0 %) months in the TSP than the oPSL group (p < 0.001). Multivariate analysis showed that TSP was the only independent factor associated with CR (hazard ratio, 3.58; 95 % confidence interval, 1.32-10.91, p = 0.01). The number of patients with adverse events was significant lower in TSP group than in oPSL group (11.5 % vs. 34.6 %, p = 0.04). CONCLUSIONS:CR rates are higher; protection of renal function and prevention from adverse events were superior with TSP than with oPSL in patients with IgAN and moderate-to-severe proteinuria.
10.1007/s10157-016-1324-2
Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial.
Liu Li-Jun,Yang Ya-Zi,Shi Su-Fang,Bao Yun-Fei,Yang Chao,Zhu Sai-Nan,Sui Gui-Li,Chen Yu-Qing,Lv Ji-Cheng,Zhang Hong
American journal of kidney diseases : the official journal of the National Kidney Foundation
RATIONALE & OBJECTIVE:Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN. STUDY DESIGN:Double-blind, randomized, placebo-controlled, phase 2 clinical trial. SETTING & PARTICIPANTS:Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m) and were receiving optimized RAAS inhibitor therapy. INTERVENTIONS:Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months. OUTCOMES:The primary outcome was percentage change in proteinuria between baseline and 6 months. RESULTS:60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (-48.4% [IQR, -64.2%, -30.5%] vs 10.0% [IQR, -38.7%, 30.6%]; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 [IQR, 0.6, 1.0] g/d vs 1.9 [IQR, 0.9, 2.6] g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group. LIMITATIONS:The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety. CONCLUSIONS:HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials. FUNDING:This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund. TRIAL REGISTRATION:Registered at ClinicalTrials.gov with study number NCT02942381.
10.1053/j.ajkd.2019.01.026
Efficacy and safety of immunosuppressive treatment in IgA nephropathy: a meta-analysis of randomized controlled trials.
Zhang Zheng,Yang Yue,Jiang Shi-Min,Li Wen-Ge
BMC nephrology
BACKGROUND:Immunosuppressive agents have been widely used in the treatment of IgA nephropathy (IgAN), but the efficacy and safety remain controversial. The recent STOP-IgAN and TESTING studies have again focused attention on the application of immunosuppressive agents in IgAN. This study investigated the benefits and risks of immunosuppressive agents in IgAN. METHODS:MEDLINE, EMBASE, the Cochrane Library, and article reference lists were searched for randomized controlled trials (RCTs) comparing immunosuppressive agents with any other non-immunosuppressive agents for treating IgAN. A meta-analysis was performed on the outcomes of proteinuria, creatinine (Cr), estimated glomerular filtration rate (eGFR), and adverse events in patients with IgAN, and trial sequential analyses were also performed for outcomes. RESULTS:Twenty-nine RCTs (1957 patients) that met our inclusion criteria were identified. Steroids (weighted mean difference [WMD] -0.70, 95% confidence interval [CI] -1.2 to - 0.20), non-steroidal immunosuppressive agents (NSI) (WMD -0. 43, 95% CI - 0.55 to - 0.31), and combined steroidal and non-steroidal immunosuppressive agents (S&NSI) (WMD -1.46, 95% CI - 2.13 to - 0.79) therapy significantly reduced proteinuria levels compared with the the control group. Steroid treatment significantly reduced the risk of end-stage renal disease (ESRD) (relative risk [RR] 0.39, CI 0.19 to 0.79) compared with the control group. The immunosuppressive therapy group showed significant increases in gastrointestinal, hematological, dermatological, and genitourinary side effects, as well as impaired glucose tolerance or diabetes. Hyperkalemia was more common in the control group. CONCLUSION:Immunosuppressive therapy can significantly reduce proteinuria and ESRD risk in patients with IgAN, but with a concomitant increase in adverse reactions. Therefore, care is required in the application of immunosuppressive agents in IgAN.
10.1186/s12882-019-1519-3
IgA Nephropathy.
Clinical journal of the American Society of Nephrology : CJASN
IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.
10.2215/CJN.07420716
Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.
Fellström Bengt C,Barratt Jonathan,Cook Heather,Coppo Rosanna,Feehally John,de Fijter Johan W,Floege Jürgen,Hetzel Gerd,Jardine Alan G,Locatelli Francesco,Maes Bart D,Mercer Alex,Ortiz Fernanda,Praga Manuel,Sørensen Søren S,Tesar Vladimir,Del Vecchio Lucia,
Lancet (London, England)
BACKGROUND:IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. METHODS:We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. FINDINGS:Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). INTERPRETATION:TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. FUNDING:Pharmalink AB.
10.1016/S0140-6736(17)30550-0
Recurrence of crescentic IgA nephropathy after renal transplantation.
Zagkotsis Georgios,Vourlakou Christina,Paraskevopoulos Aristeidis,Apostolou Theofanis
CEN case reports
IgA nephropathy (IgAN) is one of the most common recurrent glomerulonephritis after renal transplantation. Rarely, it is accompanied with the presence of crescents that leads to rapid deterioration of renal function and graft loss. We present a 54-year-old patient with IgAN that received a cadaveric kidney allograft, but developed biopsy proven recurrent IgAN 7 months after renal transplantation. He was treated with intravenous steroids and angiotensin-converting enzyme inhibitor and remission was achieved. 4 years later, he presented again with heavy proteinuria, hematuria and deterioration of renal function. Allograft biopsy revealed recurrent IgAN with crescents, which was successfully treated with pulse intravenous steroids and six monthly doses of intravenous cyclophosphamide. This regime resulted in long-term sustained remission with a stable functioning graft 3 years later. Although it is not an established treatment as in native kidneys, intravenous cyclophosphamide should probably be considered in kidney transplants with potentially reversible recurrent crescentic IgAN.
10.1007/s13730-018-0341-2
The gut-kidney axis in IgA nephropathy: role of microbiota and diet on genetic predisposition.
Coppo Rosanna
Pediatric nephrology (Berlin, Germany)
Recent data suggest that gut-associated lymphoid tissue (GALT) plays a major role in the development of immunoglobulin A (IgA) nephropathy (IgAN). A genome-wide association study showed that most loci associated with the risk of IgAN are also associated with immune-mediated inflammatory bowel diseases, maintenance of the intestinal barrier and regulation of response to gut pathogens. Studies involving experimental models have demonstrated a pivotal role of intestinal microbiota in the development of IgAN in mice producing high levels of IgA and in transgenic mice overexpressing BAFF, a B-cell factor crucial for IgA synthesis, indicating the role of genetic background, B-cell activity, GALT intestinal immunity and diet. The effect of diet was suggested by pilot studies carried out 30 years ago which showed that a gluten-rich diet induced IgAN in mice and that some patients benefited from a gluten-free diet. A recent experimental model in mice expressing human IgA1 and Fc alpha receptor CD89 reported clinical and histological improvement after a gluten-free diet. Clinical observations have elicited new interest in GALT hyper-reactivity in IgAN patients. In a pilot study, a reduction in proteinuria was attained using an enteric controlled-release formulation of the corticosteroid budesonide targeted to the Peyer's patches at the ileocecal junction. This formulation was tested in the placebo-controlled NEFIGAN phase 2b trial, with a reduction in proteinuria after 9 months of treatment together with stabilization of renal function in patients with persistent proteinuria. In conclusion, the gut-kidney axis modulated by microbiota and diet is a promising target for focused treatment of IgAN in genetically predisposed patients at risk of progression.
10.1007/s00467-017-3652-1
Recent advances in risk prediction, therapeutics and pathogenesis of IgA nephropathy.
Moran Sarah M,Cattran Daniel C
Minerva medica
Immunoglobulin A nephropathy (IgAN) is the world's commonest primary glomerular disease with variable clinical presentation and progression rates that are dependent on clinical-pathologic phenotype and duration of follow-up. Overall 4-40% of patients progress to end-stage kidney disease (ESKD) by 10 years. Treatment decisions remain a challenge due to these variations. The ultimate goal of management is to prevent progression to ESKD and of vital importance is the potential reversible early detection of active glomerular inflammation prior to scarring. IgAN is globally, is the most common biopsy proven glomerulonephritis and a leading cause of ESKD. The Oxford pathological classification was devised by a collaborative pathology and nephrology network to provide an evidence-based scoring system with reproducible independent pathology features of predictive value. Clinical variables that alter prognosis include male sex, increasing age, increased body weight, smoking, Pacific Asian ethnicity, hypertension, proteinuria, and complement deficiency. Excellent conservative therapy is the cornerstone of therapy with tight blood control, renin-angiotensin system inhibition, and statin therapy. The role of immunosuppressive therapy including corticosteroids in IgAN remains open with ongoing clinical trials of low dose oral corticosteroids and enteric coated budesonide. Complement activation contributes to the pathogenic process of IgAN with evidence from genetic, serological, histological and in-vitro studies. This knowledge has translated to clinical trials of investigational agents directly targeting the alternative pathway.
10.23736/S0026-4806.19.06165-2
A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy.
Myette James R,Kano Toshiki,Suzuki Hitoshi,Sloan Susan E,Szretter Kristy J,Ramakrishnan Boopathy,Adari Hedy,Deotale Ketan D,Engler Frank,Shriver Zachary,Wollacott Andrew M,Suzuki Yusuke,Pereira Brian J G
Kidney international
IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA, IgM, and IgG B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.
10.1016/j.kint.2019.01.031
The Gut-Renal Connection in IgA Nephropathy.
Coppo Rosanna
Seminars in nephrology
The connection between a dysregulated gut-associated lymphoid tissue and IgA nephropathy (IgAN) was supposed decades ago after the observation of increased association of IgAN with celiac disease. Pivotal studies have shown a role for alimentary antigens, particularly gliadin in developing IgAN in BALB/c mice, and a reduction in IgA antigliadin antibodies and proteinuria was reported after gluten free-diet in patients with IgAN. Recently a genome-wide association study showed that most loci associated with IgAN also are associated with immune-mediated inflammatory bowel diseases, maintenance of the intestinal barrier, and response to gut pathogens. Transgenic mice that overexpress the B-cell activating factor develop hyper-IgA with IgAN modulated by alimentary components and intestinal microbiota. Mice expressing human IgA1 and a soluble form of the IgA receptor (sCD89) develop IgAN, which is regulated by dietary gluten. Recent observations have confirmed gut-associated lymphoid tissue hyper-reactivity in IgAN patients with IgA against alimentary components. Interesting results were provided by the NEFIGAN randomized controlled trial, which adopted an enteric controlled-release formulation of the corticosteroid budesonide targeted to Peyer's patches. After 9 months of treatment, a reduction in proteinuria was observed with stabilized renal function and limited adverse events. The gut-renal connection is an area of promising new treatment approaches for patients with IgAN.
10.1016/j.semnephrol.2018.05.020
Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.
Clinical journal of the American Society of Nephrology : CJASN
IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.
10.2215/CJN.08600718
Pregnancy-induced complications in IgA nephropathy: A case report.
Chen Hui,Li Xuelan,Wu Yue,Fan Lihong,Tian Gang
Medicine
RATIONALE:IgA nephropathy is one of the most common causes of renal hypertension. The clinical management of IgA renal patients during pregnancy is challenging, as complex pathophysiological changes may occur that affect both the patient's prognosis and the outcome of the pregnancy. PATIENT CONCERNS:A 36-year-old woman with a family history of hypertension and at least one year of untreated mild high blood pressure was admitted to our hospital in the 28th week of pregnancy. She suffered from hypertensive disorder complicating pregnancy (HDCP) with renal insufficiency and stillbirth. Treatment with duplex antihypertensive drugs did not improve her blood pressure and she presented with abnormal renal function. DIAGNOSES:A renal biopsy led to the diagnosis of a grade IV IgA nephropathy (Lee's grading system) with renal hypertension. INTERVENTIONS:The prescribed treatment regimen consisted of low dose cyclophosphamide 0.2 g per day for two days, followed by daily oral administration of 30 mg prednisone, 30 mg Nifedipine extended-release tablets and 80 mg Telmisartan to regulate the blood pressure. OUTCOMES:The medication with a combination of antihypertensive and immunosuppressive drugs led to a clinical improvement with a nearly normal renal function and a stable blood pressure during the one-year follow-up. LESSONS:This case underlines that 1) the pregnancy outcomes of patients with IgA nephropathy are variable and depend on the renal function, blood pressure, status of urine proteins and the renal histological grade, and 2) especially female patients of childbearing age with hypertension need to be carefully examined to determine the cause of hypertension to avoid damage to target organs and complications during pregnancy.
10.1097/MD.0000000000010470
New strategies and perspectives on managing IgA nephropathy.
Selvaskandan Haresh,Cheung Chee Kay,Muto Masahiro,Barratt Jonathan
Clinical and experimental nephrology
IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge. Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease. Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future. In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy.
10.1007/s10157-019-01700-1
A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction.
Lafayette Richard A,Canetta Pietro A,Rovin Brad H,Appel Gerald B,Novak Jan,Nath Karl A,Sethi Sanjeev,Tumlin James A,Mehta Kshama,Hogan Marie,Erickson Stephen,Julian Bruce A,Leung Nelson,Enders Felicity T,Brown Rhubell,Knoppova Barbora,Hall Stacy,Fervenza Fernando C
Journal of the American Society of Nephrology : JASN
IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m, to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.
10.1681/ASN.2016060640
Comparison of the effects of valsartan plus activated vitamin D versus valsartan alone in IgA nephropathy with moderate proteinuria.
International urology and nephrology
BACKGROUND/AIMS:To compare the effects of valsartan plus activated vitamin D with valsartan alone on urinary protein excretion and eGFR in IgA nephropathy with moderate proteinuria. METHODS:A prospective, single-center, randomized, controlled study was performed between Jan, 2008 and Jan, 2018 on patients with IgA nephropathy who had moderate proteinuria with urinary protein excretion 1.0-3.0 g/24 h. These IgAN patients were randomly assigned to receive either valsartan 160 mg/day treatment or valsartan 160 mg/day plus activated vitamin D (calcitriol) 0.5 μg/day treatments. The changes of the clinical, biochemical data, and the adverse events during the observation period were all analyzed in the two groups. The primary endpoint was defined as changes in urinary protein excretion at week 24 compared with the baseline and the secondary endpoint was to observe the changes in estimated glomerular filtration rate (eGFR) between baseline and the end of the study. RESULTS:Baseline characteristics between the two groups were comparable. At the end of the treatment period, urinary protein excretion in both two groups decreased significantly (P < 0.05). However, there was a more significant decrease in proteinuria in IgAN patients who received valsartan plus activated vitamin D treatment (from 2.39 ± 0.77 to 1.43 ± 0.57 g/24 h, P < 0.01) compared to valsartan treatment alone (from 2.46 ± 0.81 to 1.78 ± 0.60 g/24 h, P < 0.05). The percentage change in urine protein excretion at week 24 was - 40.2% in valsartan plus activated vitamin D treatment group (P < 0.01) and - 27.6% in valsartan treatment group (P < 0.05). No significant change in blood pressure, estimated glomerular filtration rate, serum calcium, and serum potassium was observed. The incidence of adverse events was similar between the two groups, respectively (P > 0.05). CONCLUSION:Combination therapy with valsartan plus activated vitamin D is more effective than valsartan alone in reduction of moderate proteinuria in IgA nephropathy and without more adverse events.
10.1007/s11255-019-02329-5
Clinical and histological features and therapeutic strategies for IgA nephropathy.
Moriyama Takahito
Clinical and experimental nephrology
Chronic glomerulonephritis is the second most common reason, after diabetic nephropathy, for initiation of dialysis in Japan and IgA nephropathy (IgAN) is the most prevalent form of chronic glomerulonephritis. In the half century since IgAN was initially reported, our understanding of the long-term prognosis, clinical and histological features, pathogenesis of onset and progression, risk factors for progression, and appropriate treatment under different clinical and histological conditions, has steadily increased. Strong experimental and clinical evidence, the Clinical Practice Guidelines for IgA Nephropathy in Japan, the Oxford Classification, and the Kidney Disease Improving Global Outcomes guidelines have all contributed to the appropriate treatment of IgAN. Several intensive therapies, such as tonsillectomy, steroid therapy, and their combinations, can result in clinical remission, and prevent the progression to end stage renal disease (ESRD). However, some IgAN patients still progress to ESRD even when treated with intensive therapies. In this review, we discuss the clinical and histological features of IgAN, focusing primarily on our previous reports, and our opinions on therapeutic strategies for IgAN.
10.1007/s10157-019-01735-4
Clinical and pathological factors of renal anaemia in patients with IgA nephropathy in Chinese adults: a cross-sectional study.
Wang Yang,Wei Ri-Bao,Su Ting-Yu,Huang Meng-Jie,Li Ping,Chen Xiang-Mei
BMJ open
OBJECTIVE:Few studies with large sample populations concerning renal anaemia and IgA nephropathy have been reported worldwide. The purpose of this cross-sectional study was to examine the clinical and pathological characteristics and influencing factors associated with renal anaemia in patients with IgA nephropathy, which is the most common aetiology of chronic kidney disease. METHODS:A total of 462 hospitalised patients with IgA nephropathy confirmed by renal biopsy who met the inclusion criteria were consecutively recruited from January 2014 to January 2016. Their general information, routine blood test results, blood chemistries, estimated glomerular filtration rates (eGFRs) and renal pathologies were collected. The Oxford classification was used to characterise the renal pathologies. Univariable and multivariate logistic regression models were used to analyse the influencing factors of anaemia associated with IgA nephropathy. RESULTS:The incidence of renal anaemia was 28.5% (132/462 patients) in our study (21.3% in males and 38.9% in females). The anaemia type was primarily normocytic and normochromic. The rate of anaemia in patients with eGFR values of 30-59 mL/min/1.73 m was higher than that in patients with an eGFR >60 mL/min/1.73 m (42.9% vs 17.8%, p<0.001). Notably, in the group with eGFR values <15 mL/min/1.73 m, the anaemia rate was 100%. Logistic regression analysis showed that factors affecting anaemia in patients with IgA nephropathy included being female (OR 3.02, 95% CI 1.76 to 5.17), low albumin levels (OR 0.87, 95% CI 0.82 to 0.93), reduced eGFR values (OR 0.98, 95% CI 0.97 to 0.99) and renal tubulointerstitial lesions >50% (OR 2.57, 95% CI 1.22 to 5.40). CONCLUSIONS:The female sex, hypoalbuminaemia, reduced eGFR levels and severe renal tubulointerstitial lesions were correlated with renal anaemia in patients with IgA nephropathy. These results provide new insight into our understanding of anaemia in IgA nephropathy and may improve the management and treatment of clinical renal anaemia.
10.1136/bmjopen-2018-023479
Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.
10.1038/s41379-019-0259-z
Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy.
Rauen Thomas,Fitzner Christina,Eitner Frank,Sommerer Claudia,Zeier Martin,Otte Britta,Panzer Ulf,Peters Harm,Benck Urs,Mertens Peter R,Kuhlmann Uwe,Witzke Oliver,Gross Oliver,Vielhauer Volker,Mann Johannes F E,Hilgers Ralf-Dieter,Floege Jürgen
Journal of the American Society of Nephrology : JASN
The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m: 6-month corticosteroid monotherapy; GFR=30-59 ml/min per 1.73 m: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; =0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; =0.30). The end point of GFR loss ≥15 ml/min per 1.73 m did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.
10.1681/ASN.2017060713
Long-term outcomes of tonsillectomy for IgA nephropathy patients: A retrospective cohort study, two-centre analysis with the inverse probability therapy weighting method.
Matsumoto Keiichiro,Ikeda Yuki,Yamaguchi Sae,Sanematsu Mai,Fukuda Makoto,Takashima Tsuyoshi,Kishi Tomoya,Miyazono Motoaki,Uchiumi Saori,Yoshizaki Mai,Nonaka Yasunori,Matsumoto Ryoko,Kanaya Akiko,Fukunari Kenichi,Ikeda Yuji
Nephrology (Carlton, Vic.)
AIM:The effect of tonsillectomy on IgA nephropathy remains controversial. The aim of this study was to compare the effect of tonsillectomy on the outcome, end stage kidney disease (ESKD) and all-cause death in IgA nephropathy patients who did and did not undergo tonsillectomy. METHODS:All basic data were retrospectively gathered from patients who had undergone renal biopsies at two Japanese clinical centres. Two hundred and twenty-seven patients were eligible for the study, with a median age of 34 (Interquartile range (IQR): 25-43) years and median follow-up of 92 (IQR: 40-178) months. The primary endpoint was the composite outcome of the onset of ESKD and all-cause death before ESKD. We performed a Cox proportional hazard regression analysis after adjusting for patient characteristics using the inverse probability therapy weighting (IPTW) method and a Cox analysis using the Matching method. Similarly, we analyzed these outcomes in a mild cohort. RESULTS:We were unable to find any significant advantages of tonsillectomy in either analysis (IPTW and matching, HR: 0.40 (0.12-1.36) P = 0.072 and 0.78 (0.13-4.64) P = 0.786). However, in the mild cohort analysis, our data showed that the Tonsillectomy group tended to be less likely to reach the composite outcomes than the Not Tonsillectomy group with statistical significance (hazard ratio (HR), <0.001 [CI <0.001 to <0.001, P = 0.039]). CONCLUSION:In this study, our findings led us to conclude that performing tonsillectomy in an early and timely manner may have predisposition of less poor prognosis.
10.1111/nep.13108
Steroid therapy in children with IgA nephropathy.
Cambier Alexandra,Boyer Olivia,Deschenes Georges,Gleeson James,Couderc Anne,Hogan Julien,Robert Thomas
Pediatric nephrology (Berlin, Germany)
IgA nephropathy (IgAN) is one the most common primary glomerulonephritis in children and adolescents worldwide, with 20% of children developing end-stage kidney disease (ESKD) within 20 years of diagnosis. There is a need for treatment guidelines, especially for steroids in children with primary IgAN, since the STOP-IgA trial casts doubts on the use of steroids in adults with intermediate risk. Pediatricians are prone to prescribe steroids in addition to renin-angiotensin system blockade (RASB) when proteinuria is > 0.5 g/l, eGFR deteriorates < 70 ml/min/1.73 m, or when a biopsy sample shows glomerular inflammation. Lack of randomized controlled trials (RCTs) in children with IgAN has led to an absence of consensus on the use of immunosuppressive agents in the treatment of progressive IgAN. This literature review evaluates the available evidence on steroid treatment in children with IgAN.
10.1007/s00467-018-4189-7
Neutrophil-to-lymphocyte ratio: An effective predictor of corticosteroid response in IgA nephropathy.
Yang Hu,Zhang Weiwei,Li Ying,Li Rong
International immunopharmacology
BACKGROUND:The neutrophil-to-lymphocyte ratio (NLR) has been shown to have a strong predictive ability for the prognosis of various diseases. However, the role of the NLR in IgA nephropathy is currently unknown. In this study, we attempted to evaluate how useful the NLR is for predicting corticosteroid response in IgA nephropathy. METHODS:For retrospective cohort with IgA nephropathy, the patients who received corticosteroid therapy were recruited. To identify independent factors for corticosteroid response, the NLR and other parameters were analyzed using the multivariate regression model. The predictive usefulness was determined by the area under the receiver operating characteristics curve (AUROC). Survival analysis was conducted to compare the corticosteroid response between different groups according to the cut-off of NLR. RESULTS:Multivariate analyses showed that NLR, serum creatinine, uric acid, and estimated glomerular filtration rate (eGFR) were independent factors for corticosteroid response. The AUROC of NLR (0.748) was higher than those of other factors. Patients with NLRs <2.43 had a higher remission rate than those with NLR ≥2.43 (P < 0.001). CONCLUSION:NLR is an effective predictor of corticosteroid response in IgA nephropathy.
10.1016/j.intimp.2019.105678
Mesangial C4d Deposits in Early IgA Nephropathy.
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:The prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:This retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR≥80 ml/min per 1.73 m at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available. RESULTS:In total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; =0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; =0.04), had a higher protein-to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; <0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; <0.01), and showed a larger reduction in eGFR (-1.6 versus -0.8 ml/min per 1.73 m per year; =0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival. CONCLUSIONS:C4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment.
10.2215/CJN.02530317
IgA Nephropathy in Elderly Patients.
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. RESULTS:We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 ( value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. CONCLUSIONS:The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.
10.2215/CJN.13251118
The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy.
Rizk Dana V,Maillard Nicolas,Julian Bruce A,Knoppova Barbora,Green Todd J,Novak Jan,Wyatt Robert J
Frontiers in immunology
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20-40% of patients within 20 years of diagnosis. There is accumulating clinical, genetic, and biochemical evidence that complement plays an important role in the pathogenesis of IgA nephropathy. The presence of C3 differentiates the diagnosis of IgA nephropathy from the subclinical deposition of glomerular IgA. Markers for the activation of the alternative and mannan-binding lectin (MBL) pathways in renal-biopsy specimens are associated with disease activity and portend a worse renal outcome. Complement proteins in the circulation have also been evaluated in IgA nephropathy and found to be of prognostic value. Recently, genetic studies have identified IgA nephropathy-associated loci. Within these loci are genes encoding products involved in complement regulation and interaction with immune complexes. Put together, these data identify the complement cascade as a rational treatment target for this chronic kidney disease. Recent case reports on the successful use of humanized anti-C5 monoclonal antibody eculizumab are consistent with this hypothesis, but a better understanding of the role of complement in IgA nephropathy is needed to guide future therapeutic interventions.
10.3389/fimmu.2019.00504
Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: An unusual association.
Annamalai Ishwarya,Chandramohan G,Srinivasa Prasad N D,Fernando Edwin,Sujith S
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia
Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating IgG antibodies (rarely IgA and IgM) to the carboxyterminal, noncollagenous 1 (NC1) domain of type IV collagen of GBM also known as Goodpasture antigen. Patients typically present with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage in the presence of which it is referred to as Goodpasture's disease. Anti-GBM disease has been reported to coexist with pauci-immune antineutrophil cytoplasmic autoantibody-positive glomerulonephritis and membranous glomerulopathy. The sequential or concurrent presentation of anti-GBM disease with IgA nephropathy has been rarely described. We herein report a case of a 22-year-old female who presented with RPGN, and renal biopsy revealed crescentic glomerulonephritis with strong linear IgG (+2) staining of GBM and extensive mesangial IgA (+3) deposits. The patient was treated with three pulses of IV methylprednisolone followed by oral steroids. Plasmapheresis and cytotoxic agents were not included in the therapeutic armamentarium as the patient had no pulmonary hemorrhage and biopsy revealed established chronic changes. The association of anti-GBM disease with IgA nephropathy could open up new vistas on the implication of these IgA mesangial deposits in the pathogenesis and prognosis of anti-GBM disease.
10.4103/1319-2442.220866
Lisinopril versus lisinopril and losartan for mild childhood IgA nephropathy: a randomized controlled trial (JSKDC01 study).
Shima Yuko,Nakanishi Koichi,Sako Mayumi,Saito-Oba Mari,Hamasaki Yuko,Hataya Hiroshi,Honda Masataka,Kamei Koichi,Ishikura Kenji,Ito Shuichi,Kaito Hiroshi,Tanaka Ryojiro,Nozu Kandai,Nakamura Hidefumi,Ohashi Yasuo,Iijima Kazumoto,Yoshikawa Norishige,
Pediatric nephrology (Berlin, Germany)
BACKGROUND:Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children. METHODS:This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy. RESULTS:There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups. CONCLUSIONS:We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy. CLINICAL TRIAL REGISTRATION:Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .
10.1007/s00467-018-4099-8
Combination therapy with or without warfarin and dipyridamole for severe childhood IgA nephropathy: an RCT.
Shima Yuko,Nakanishi Koichi,Kaku Yoshitsugu,Ishikura Kenji,Hataya Hiroshi,Matsuyama Takeshi,Honda Masataka,Sako Mayumi,Nozu Kandai,Tanaka Ryojiro,Iijima Kazumoto,Yoshikawa Norishige,
Pediatric nephrology (Berlin, Germany)
BACKGROUND:Two previous randomized controlled trials showed that treatment of severe childhood immunoglobulin A (IgA) nephropathy using prednisolone with azathioprine, heparin-warfarin, or dipyridamole prevented the increase of sclerosed glomeruli. Prednisolone alone, however, did not prevent further increase. These studies indicated the importance of immunosuppressants in the treatment. An additional pilot study using mizoribine instead of azathioprine enabled us to complete 2 years of combined regimen. It showed non-numerical inferior effectiveness compared with the azathioprine regimen. Further examination of the additional efficacy of warfarin and dipyridamole was required. METHODS:A randomized control trial of prednisolone and mizoribine with (group 1) or without (group 2) warfarin and dipyridamole was administered for treatment of 71 children with severe IgA nephropathy to evaluate the efficacy of additional warfarin and dipyridamole. RESULTS:Thirty of 34 patients (88.2%) in group 1, and 27 of 36 patients (75.0%) showed the disappearance of proteinuria as defined by early morning urinary protein to creatinine ratio of < 0.2 during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan-Meier method showed that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 (log-rank P = 0.04). There was no significant difference in pathological findings, but there was a tendency of increase of global sclerosis in group1 which might be related to warfarin. Most of the adverse effects were related to prednisolone, but fortunately transient. CONCLUSIONS:The balance between minimal benefits of warfarin/dipyridamole and potential adverse effects may be in favor of avoiding them in children with IgA nephropathy.
10.1007/s00467-018-4011-6
High serum IgA/C3 ratio better predicts a diagnosis of IgA nephropathy among primary glomerular nephropathy patients with proteinuria ≤ 1 g/d: an observational cross-sectional study.
Gong Wen-Yu,Liu Man,Luo Dan,Liu Fan-Na,Yin Liang-Hong,Li Yuan-Qing,Zhang Jun,Peng Hui
BMC nephrology
BACKGROUND:The serum immunoglobulin A (IgA)/C3 ratio is considered to be an effective predictor of IgA nephropathy (IgAN). This study sought to explore the diagnostic value of the IgA/C3 ratio in IgAN among primary glomerular nephropathy patients in China. METHODS:We recruited 1095 biopsy-diagnosed primary glomerular nephropathy patients, including 757 IgAN patients and 338 non-IgAN patients. Patient demographics, serum immunological indices, and other clinical examinations were measured. IgAN cases were propensity score matched (PSM) to non-IgAN cases on the logit of the propensity score using nearest neighbor matching in a 1:1 fashion, with a caliper of 0.02 with no replacements, according to age, gender, BMI, proteinuria level, and estimated glomerular filtration rate (eGFR). RESULTS:We found that in both the full cohort and PSM cohort, the IgA/C3 ratio in the IgAN group was significantly higher than that of the non-IgAN group. The same results were also obtained with stratification by different levels of proteinuria and renal function. In the PSM cohort, there was no difference in IgA/C3 ratio in patients with IgAN between different proteinuria groups and different chronic kidney disease (CKD) groups. The area under the ROC curve (AUROC) of the IgA/C3 ratio in distinguishing IgAN among primary glomerular disease was 0.767 in the full cohort, and 0.734 in the PSM cohort. The highest AUROC of the IgA/C3 ratio was in the ≤1 g/d proteinuria group (0.801 in the full cohort, and 0.803 in the PSM cohort); however, there was no difference between all CKD groups. Meanwhile, the diagnostic accordance rate for the diagnosis of IgAN among all patients with an IgA/C3 ratio > 3.5304 was as high as 92.02% in the full cohort. IgAN was independently correlated with IgA/C3 ratio in the full cohort by multivariate logistic regression analysis. CONCLUSIONS:The present study provides clear evidence that the IgA/C3 ratio is an effective predictor of IgA diagnosis, especially in patients with proteinuria ≤1 g/d. In order to study the effectiveness of this biomarker, and to determine a standardized cut-off value, additional multicenter large-scale studies are needed.
10.1186/s12882-019-1331-0
Update on treatment of immunoglobulin A nephropathy.
Zhang Yue-Miao,Zhang Hong
Nephrology (Carlton, Vic.)
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the most common cause of end-stage renal disease in young adults. However, there are still no specific therapies capable of targeting key pathways involved in disease pathogenesis. Recently, many large randomized controlled trials have been reported, such as Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy, Targeted-release Budesonide Versus Placebo in Patients with IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global, which are considered to update the 2012 Kidney Disease: Improving Global Outcomes Guideline. More importantly, with a deeper understanding of the roles of mucosal immunity, B-cell activation and complement activation in IgAN, the studies of targeting pathogenic pathways are ongoing. In this review, by systemically searching the clinical trials in IgAN on ClinicalTrials.gov (https://clinicaltrials.gov/), we update the evidence for corticosteroids/immunosuppressive therapy in IgAN and explore the promising targeting pathogenic pathway therapeutic options. With better understanding of pathogenesis of IgAN, emerging therapies will soon become a reality in future.
10.1111/nep.13453
The Role of IgA in the Pathogenesis of IgA Nephropathy.
Perše Martina,Večerić-Haler Željka
International journal of molecular sciences
Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy.
10.3390/ijms20246199
Genetic study of immunoglobulin A nephropathy: From research to clinical application.
Li Ming,Yu Xueqing
Nephrology (Carlton, Vic.)
Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritis throughout the world and a major cause of end-stage renal disease among East Asian population. It is widely considered that genetic factors play an important role in the pathogenesis of IgAN. The genetic studies of IgAN, is from the association studies of candidate genes and family-based designs, to the genome-wide association studies. Altogether there are five large genome-wide association studies performed, which have identified multiple susceptibility loci for IgAN, including several novel loci found in Chinese population. The discovery of these susceptibility loci has provided important insight into the potential biological mechanisms and pathways that influence genetic risk to IgAN. In addition, genetic interaction and structural variation (such as copy number variation) studies were also conducted to identify more variants associated with IgAN and disease progression. The genetic studies of IgAN have made great achievements in recent years. Most of susceptibility loci discovered up to date contain genes involved in the response to mucosal pathogens, suggesting that intestinal immune network for IgA production may be involved in the pathogenesis of IgAN. While the genetic studies of the complex diseases remain to be challenging, new genetic and analytical techniques and methods, especially next-generation sequencing-based studies, need to be applied to advance the genetic studies of IgAN. More importantly, we need to identify the genetic factors which influence the clinical phenotypes and renal progression to end-stage renal disease. This will require the integration of genomic data with other omics profiles (e.g. transcriptomics, metabolomics and immunomics) in patients with long-term clinical follow-up data to better understand the factors underlying inter-individual variability, not only in disease susceptibility, but also in the long-term prognosis and healthcare requirements.
10.1111/nep.13470
Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort.
Berthelot Laureline,Jamin Agnès,Viglietti Denis,Chemouny Jonathan M,Ayari Hamza,Pierre Melissa,Housset Pierre,Sauvaget Virginia,Hurtado-Nedelec Margarita,Vrtovsnik François,Daugas Eric, ,Monteiro Renato C,Pillebout Evangeline,
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Background:Henoch-Schönlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods:This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results:We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions:Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome.
10.1093/ndt/gfx300
Successful treatment with steroid and cyclosporine A in a patient with immunoglobulin A-proliferative glomerulonephritis with monoclonal immunoglobulin deposits.
Sato Keisuke,Makabe Shiho,Iwabuchi Yuko,Kojima Kaori,Sato Masayo,Kataoka Hiroshi,Moriyama Takahito,Taneda Sekiko,Tsuchiya Ken,Nitta Kosaku,Mochizuki Toshio
Nephrology (Carlton, Vic.)
We report a case of glomerulonephritis with monoclonal immunoglobulin (Ig) A deposits as a form of monoclonal gammopathy of renal significance (MGRS) caused by monoclonal immunoglobulins without blood disorders in a 41-year-old woman. She developed lower leg oedema and was hospitalized because of nephrotic syndrome. Serum and urine were negative for M protein, and the free light chain κ/λ ratio was within the normal range. Renal histopathological findings included mesangial proliferation, endocapillary cell proliferation, and a double-contour appearance of the capillary walls. Immunofluorescent staining indicated IgA and C3 deposits on the mesangium and capillary walls. Only λ chain and IgA1 deposits were noted. Fine granular sub-endothelial deposits with no specific structure were observed under electron microscopy. The patient was diagnosed with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits (IgA-PGNMID). The patient had decreased urine protein and sediment erythrocytes after she underwent two rounds of steroid pulse therapy and oral steroid therapy, but proteinuria and haematuria still remained. Four months later, the patient was administered 50 mg/day cyclosporine (CsA), and proteinuria and haematuria dramatically decreased. Only a few case reports have been published on IgA-PGNMID. This case is rare in that the patient achieved successful treatment using a combination of steroids and CsA.
10.1111/nep.13261
Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF.
He Liyu,Peng Xiaofei,Chen Yinyin,Liu Guoyong,Liu Zhiwen,Zhu Jiefu,Liu Yexin,Liu Hong,Liang Yumei,Liu Fuyou,Sun Lin,Peng Youming
American journal of nephrology
BACKGROUND:Immunoglobulin (Ig) A nephropathy (IgAN) is the xFB01;nding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the 'mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. METHODS:The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. RESULTS:Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 μg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. CONCLUSION:These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.
10.1159/000445697
Interleukin-6 is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice.
Rops Angelique L W M M,Jansen Erik,van der Schaaf Alie,Pieterse Elmar,Rother Nils,Hofstra Julia,Dijkman Henry B P M,van de Logt Anne-Els,Wetzels Jack,van der Vlag Johan,van Spriel Annemiek B
Kidney international
Immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is characterized by IgA depositions in the kidney. Deficiency of CD37, a leukocyte-specific tetraspanin, leads to spontaneous development of renal pathology resembling IgAN. However, the underlying molecular mechanism has not been resolved. Here we found that CD37 expression on B cells of patients with IgAN was significantly decreased compared to B cells of healthy donors. Circulating interleukin (IL)-6 levels, but not tumor necrosis factor-α or IL-10, were elevated in Cd37 mice compared to wild-type mice after lipopolysaccharide treatment. Cd37 mice displayed increased glomerular neutrophil influx, immune complex deposition, and worse renal function. To evaluate the role of IL-6 in the pathogenesis of accelerated renal pathology in Cd37mice, we generated Cd37xIl6 double-knockout mice. These double-knockout and Il6 mice displayed no glomerular IgA deposition and were protected from exacerbated renal failure following lipopolysaccharide treatment. Moreover, kidneys of Cd37 mice showed more mesangial proliferation, endothelial cell activation, podocyte activation, and segmental podocyte foot process effacement compared to the double-knockout mice, emphasizing that IL-6 mediates renal pathology in Cd37 mice. Thus, our study indicates that CD37 may protect against IgA nephropathy by inhibition of the IL-6 pathway.
10.1016/j.kint.2018.01.005
Decreased Serum C3 Levels in Immunoglobulin A (IgA) Nephropathy with Chronic Kidney Disease: A Propensity Score Matching Study.
Yang Xi,Wei Ri-Bao,Wang Yang,Su Ting-Yu,Li Qing-Ping,Yang Ting,Huang Meng-Jie,Li Kun-Ying,Chen Xiang-Mei
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND The effects of low serum C3 levels and the activation of the complement system on the development and the prognosis of IgAN are unclear. The present study aimed to determine whether decreased levels of complement C3 influence the prognosis of IgAN patients with chronic kidney disease. MATERIAL AND METHODS We enrolled a total of 1564 patients with primary IgAN diagnosed by renal biopsy at the Chinese PLA General Hospital from January 2011 to March 2015. The endpoint was end-stage renal disease (ESRD) or a doubling of the baseline serum creatinine (D-SCr) level. All patients were using 1: 1 propensity score matching (PSM), and the baseline values were not significantly different between these 2 groups (P>0.05). RESULTS During a follow-up period, 14 patients in the group with decreased C3 levels reached the endpoint, with 12 patients with normal C3 levels. There was no significant difference between the 2 groups in achieving D-SCr or ESRD (P=0.676). In multivariate Cox analysis, adjusted for demographic and laboratory examination, the risk of reaching the endpoint was comparable in the 2 groups (HR, 0.70; 95% CI, 0.27-1.78; P=0.449;). Furthermore, the risk of reaching ESRD (HR, 0.83; 95% CI, 0.25-2.75; P=0.757) and D-SCr (HR, 1.45; 95% CI, 0.20-10.60; P=0.718) did not differ between the 2 groups. CONCLUSIONS Decreased serum C3 levels in IgA nephropathy with chronic kidney disease did not play a decisive role in renal progression.
10.12659/msm.903102