A multi-center randomized controlled trial to investigate potential effects of exercise therapy on renal function stratified by renal disorders and renal pathology: beneficial or harmful effect in immunoglobulin a nephropathy.

BACKGROUND: The effects of exercise therapy (ET) on renal function in chronic kidney disease (CKD) remain unclear. METHODS: In a randomized controlled trial (UMIN-CTR number: UMIN000038415), we investigated whether ET affects renal function in CKD; eligible patients had undergone renal biopsy in the past 3 months. We stratified patients by disease (immunoglobulin A [IgA] nephropathy, n = 16; diabetic nephropathy, n = 4; benign nephrosclerosis, n = 13; and other CKD types, n = 13) and randomized them to 12 weeks' observation and 24 weeks' ET comprising home-based aerobic exercise 3×/week and resistance training 2×/week (intervention group) or usual care (non-intervention group). Primary endpoint was creatinine-based estimated glomerular filtration rate (eGFR) or serum cystatin C-based eGFR (eGFRcys). Secondary endpoints included urinary protein and exercise tolerance. RESULTS: Seventy patients were enrolled, 50 fulfilled the inclusion criteria, but 4 discontinued before randomization. No items significantly differed between week 0 to 24 in either group (intervention group, n = 23; non-intervention group, n = 23) or between groups at week 24 (intention-to-treat population) in the total study population. The eGFRcys slope showed no significant intergroup difference in the observation period, but eGFRcys improved significantly in IgA nephropathy patients (n = 16) in the intervention group (stratified comparison; week 0, 48.3 ± 18.2; week 24, 51.6 ± 17.6; p = 0.043). In these patients, urinary protein was significantly worse at week 24 in the non-intervention group (p = 0.046) and worsened significantly less in the intervention group (p = 0.039). CONCLUSION: ET did not improve renal function overall in CKD patients but might help maintain renal function in patients with IgA nephropathy.

Is hyperuricemia an independent prognostic factor for IgA nephropathy: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Hyperuricemia has been reported to be correlated with IgA nephropathy (IgAN). However, whether hyperuricemia or elevated serum uric acid (SUA) is an independent prognostic factor of IgAN remains unknown. Therefore, this systematic review and meta-analysis evaluated the prognostic value of hyperuricemia and elevated SUA in IgAN. METHODS: Databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Open Gray were reviewed systematically. The kidney failure events of IgAN were defined as a doubling of serum creatinine, halving of eGFR, end-stage renal disease (ESRD), or death. The risk ratio (RR) between hyperuricemia and IgAN-caused kidney failure was evaluated before and after adjustment for relevant covariates. The RR between elevated SUA and IgAN-caused kidney failure was evaluated after adjustment for relevant covariates. RESULTS: A total of 11 548 patients from 14 studies were included in this meta-analysis. Hyperuricemia was found to be an independent prognostic factor of IgAN (unadjusted RR = 2.79, 95% CI = 1.93-4.03, p for heterogeneity <0.00001, I2 = 91%; adjusted RR = 2.12, 95% CI = 1.64-2.73, p for heterogeneity = 0.86, I2 = 0%). Subgroup and sensitivity analyses confirmed the stability of these results. Similarly, elevated SUA was positively correlated with kidney failure events of IgAN (adjusted RR = 1.25, 95% CI = 1.19-1.31, p for heterogeneity = 0.6, I2 = 0%). CONCLUSION: Our meta-analysis showed that hyperuricemia and elevated SUA were both independently associated with an increased incidence of kidney failure events in IgAN patients.

The efficacy and safety of hydroxychloroquine in pregnant patients with IgA nephropathy: A retrospective cohort study.

AIM: Hydroxychloroquine (HCQ) is used to control proteinuria in IgA Nephropathy (IgAN) However, its efficacy and safety in pregnant IgAN patients remains unknown. This study aimed to verify the safety of HCQ in pregnant IgAN patients and compare renal function and pregnancy outcomes with those of patients not treated with HCQ. METHODS: We retrospectively reviewed medical records of all pregnant IgAN patients and singleton gestations at Peking University First Hospital from 2003-2021. Patients who did and did not receive HCQ treatment during pregnancy were compared. RESULTS: We found no significant pre- or post-pregnancy differences in proteinuria or renal function between the two groups. However, the HCQ (+) group had higher proteinuria at the time of kidney biopsy (2.04 [1.26, 2.56] g/d vs. 0.80 [0.44, 1.11] g/d, P < .001); the proteinuria level at HCQ therapy initiation was also higher than that at the beginning of pregnancy (1.87 [1.30, 2.59] g/d vs. 1.08 [0.75, 1.50] g/d, P = .001). Despite no difference in preterm birth, birth weight, preeclampsia or postpartum haemorrhage, the proportion of patients with a previous history of spontaneous abortion was higher in the HCQ (+) group than in the HCQ (-) group (48.0% vs. 20.6%, P = .010). The eGFR (regression coefficient, 0.981; 95%CI 0.964-0.998) was a predictive factor for obstetrical complications. CONCLUSION: HCQ is safe for IgAN treatment during pregnancy with effective reduction of proteinuria. HCQ might also be helpful in patients with a history of spontaneous abortion.

NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies.

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene (NR3C1) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs-rs6198, rs41423247 and rs17209237-in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN (p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs (p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy (p = 0.013) and IgAN (p = 0.021); and in the same groups treated with steroids (p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings (p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN.

The prognostic role of heart rate recovery after exercise and metabolic syndrome in IgA nephropathy.

BACKGROUND: Cardiovascular (CV) morbidity and mortality are higher in chronic kidney disease (CKD) than in the general population. Reduced heart rate recovery (HRR) is an independent risk factor for CV disease. The aim of the study was to determine the prognostic role of HRR in a homogenous group of CKD patients. METHODS: One hundred and twenty-five IgA nephropathy patients (82 male, 43 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for average 70 months. We performed a graded exercise treadmill stress test. HRR was derived from the difference of the peak heart rate and the heart rate at 1 min after exercise. Patients were divided into two groups by the mean HRR value (22.9 beats/min). The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularisation (CV) and end-stage renal disease, renal replacement therapy (renal). RESULTS: Patients with reduced HRR (< 23 bpm) had significantly more end point events (22/62 patients vs. 9/53 patients, p = 0.013) compared to the higher HRR (≥23 bpm). Of the secondary the endpoints (CV or renal separately) rate of the renal endpoint was significantly higher in the lower HRR group (p = 0.029), while there was no significant difference in the CV endpoint between the two HRR groups (p = 0.285). Independent predictors of survival were eGFR and diabetes mellitus by using Cox regression analysis. Kaplan-Meier curves showed significant differences in metabolic syndrome and non-metabolic syndrome when examined at the combined endpoints (cardiovascular and renal) or at each endpoint separately. The primary endpoint rate was increased significantly with the increased number of metabolic syndrome component (Met.sy. comp. 0 vs. Met. sy. comp. 2+, primary endpoints, p = 0.012). CONCLUSION: Our results showed that reduced HRR measured by treadmill exercise test has a predictive value for the prognosis of IgA nephropathy. The presence of metabolic syndrome may worsen the prognosis of IgA nephropathy.

Poly-IgA Complexes and Disease Severity in IgA Nephropathy.

BACKGROUND AND OBJECTIVES: Poly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serologic detection of poly-IgA levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A novel ELISA method using recombinant CD89 as a "capturing" probe was established for detecting poly-IgA immune complex in plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital who had IgA nephropathy or other kidney disease types, as compared with healthy controls. The longitudinal trend of the poly-IgA index and the association with pathologic parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry. RESULTS: Recombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7 [interquartile range (IQR) 17.1-42.6] U/ml) in IgA nephropathy were significantly higher than those in healthy controls (15.5 [IQR 10.7-20.0] U/ml; P<0.001) or in controls with non-IgA nephropathy disease (14.8 [IQR 10.5-21.9] U/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (area under the curve [AUC], 0.78; 95% confidence interval [95% CI], 0.72 to 0.83; P<0.001), significantly outperforming galactose-deficient IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. After a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular composition of IgA immune complex in patients with IgA nephropathy. CONCLUSIONS: Higher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease and with treatment response to steroids and immunosuppressants.

Normotensive and hypertensive Immunoglobulin a nephropathy with ischemic renal injury: clinicopathological characteristics and prognosis.

OBJECTIVES: This study aimed to investigate the clinicopathological characteristics and prognosis of normotensive and hypertensive IgAN patients with ischemic renal injury. METHODS: A total of 344 cases of IgAN with ischemic renal injury were included in the study, including 99 normotensive IgAN patients (28.8%) and 245 hypertensive IgAN patients (71.2%). In addition, 467 IgAN patients without ischemic renal injury were included as controls, including 205 normotensive patients and 262 hypertensive patients. Clinicopathological and prognostic data were collected and analyzed. RESULTS: Compared with patients without ischemic renal injury, IgAN patients with ischemic renal injury displayed a higher proportion of hypertention, a higher proportion of ischemic glomerulosclerosis, tubular atrophy/interstitial fibrosis and vascular lesions (all p < .05). There was no significant difference in cumulative survival between the normotensive IgAN patients groups (Log-rank χ2 = 0.479; p = .489). Furthermore, ischemic renal injury was not a risk factor for end-point events in normotensive IgAN patients (HR = 1.103; 95% CI: 0.279-4.365; p = .889). There was lower cumulative survival in hypertensive IgAN patients with ischemic renal injury (Log-rank χ2 = 11.352, p = .001). Moreover, ischemic renal injury was a risk factor for end-point events in hypertensive IgAN patients (HR = 1.889; 95% CI: 1.124-3.178; p = .016). CONCLUSIONS: Ischemic renal injury can occur in normotensive IgAN patients. Although the pathological changes may not affect the long-term prognosis of normotensive IgAN patients, the prognosis for hypertensive IgAN patients remains poor. Therefore, increased attention should be paid to the clinical management of ischemic lesions in hypertensive IgAN patients.

Huangqi Guizhi Wuwu Decoction attenuates Podocyte cytoskeletal protein damage in IgA nephropathy rats by regulating AT1R/Nephrin/c-Abl pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu Decoction(HQGZWWD) is a Traditional Chinese Medicine formula from Synopsis of Golden Chamber used to treat blood arthralgia. According to the principle that the same treatment can be used for different diseases, HQGZWWD has proven effective for IgA nephropathy (IgAN) associated with spleen and kidney yang deficiency. AIM OF THE STUDY: In this study, we investigated the mechanism by which HQGZWWD alleviates proteinuria and protects renal function in rats with IgAN by regulating the AT1R/Nephrin/c-Abl pathway. METHODS: Rats were randomly divided into six groups: control, IgAN model, IgAN model treated with low-dose HQGZWWD, IgAN model treated with medium-dose HQGZWWD, IgAN model treated with high-dose HQGZWWD, and IgAN model treated with valsartan. IgAN was induced using bovine γ-globulin. We evaluated the mediating effects of HQGZWWD on podocyte cytoskeletal proteins, the AT1R/Nephrin/c-Abl pathway, upstream tumor necrosis factor-α (TNF-α), and TNF-α receptor-1 (TNFR1). RESULTS: The IgAN rats displayed proteinuria, IgA deposition in the mesangial region, and podocyte cytoskeletal protein damage. The expression of TNF-α, TNFR1, AT1R, and c-Abl was increased in the IgAN rat kidney, whereas the expression of nephrin, podocin, ACTN4, and phosphorylated nephrin (p-nephrin) was reduced. HQGZWWD treatment significantly alleviated podocyte cytoskeletal protein damage in the IgAN rats, upregulated the expression of nephrin, podocin, and ACTN4, and the colocalized expression of F-actin and nephrin. This study demonstrates that HQGZWWD attenuates podocyte cytoskeletal protein damage by regulating the AT1R-nephrin- c-Abl pathway, upregulating the expression of p-nephrin, and downregulating the expression of AT1R and c-Abl. CONCLUSIONS: These results indicate that HQGZWWD attenuates podocyte cytoskeletal protein damage in IgAN rats by regulating the AT1R/Nephrin/c-Abl pathway, providing a potential therapeutic approach for IgAN.

Co-occurrence of IgA nephropathy and IgG4-Tubulointersitial nephritis effectively treated with tacrolimus: a case report.

BACKGROUND: Cases of concurrent immunoglobulin A nephropathy (IgAN) and IgG4-related tubulointerstitial nephritis (IgG4-TIN) are rare and previous case reports have lacked important data. KDIGO suggests a treatment with systemic glucocorticoids in IgAN patients. Glucocorticoids are recommended as the first-line therapy for IgG4-TIN. The use of tacrolimus as a long-term maintenance treatment has not been described. We report the case of a man who developed IgAN and IgG4-TIN without abnormalities in extra-renal tissue, without renal function abnormalities or impairment as well, and was treated by tacrolimus as a long-term maintenance during 45 months follow-up. CASE PRESENTATION: A 56-year-old Chinese man first presented to our hospital with the chief complaint of foamy urine for 1 year and hematuria for 3 months, with a medical history of hypertension. Testing revealed a notable increase in serum IgG4 level without abnormalities in renal function or imaging, or in dysfunction other organs. Renal biopsy showed mesangial extracellular matrix proliferation, increased mesangial cell numbers and infiltration of plasma cells. Immunofluorescence showed mesangial positivity for IgA and C3. Immunohistochemistry staining showed widespread IgG4 and increased CD38 and CD138 expression. Electron microscopy showed immune complexes located on the tubular basement membrane. He was diagnosed with IgAN and IgG4-TIN. He received glucocorticoids, leflunomide and tacrolimus to induce remission. He was given tacrolimus as long-term maintenance treatment. When tacrolimus was temporarily withdrawn, proteinuria recurred. After resuming tacrolimus therapy, he again entered complete remission. After 45 months of therapy, he remains in complete remission and the serum IgG4 level is normal. CONCLUSIONS: The finding of concurrent IgAN and IgG4-TIN without abnormalities in renal function, imaging or extra-renal tissue is rare and their coexistence may be coincidental. Long-term treatment with tacrolimus proved effective and he has remained in remission during 45 months follow-up.

Severity of arterial and/or arteriolar sclerosis in IgA nephropathy and the effects of renin-angiotensin system inhibitors on its prognosis.

IgA nephropathy (IgAN) patients often suffer from arterial and/or arteriolar sclerosis (AAS); however, it is unclear whether these features are associated with a poor prognosis. This retrospective cohort study aimed to analyse the prognosis of IgAN patients with AAS and assess whether treatment with renin-angiotensin system inhibitors (RASI) improved their survival. The study included 678 IgAN patients, who were grouped into AAS0 (n = 340; AAS absent) and AAS1 (n = 338; AAS present) groups. Each patient's clinical, laboratory, and histological backgrounds and 20-year renal prognosis were analysed. In the AAS1 group, the impact of RASI initiated during the follow-up period on the renal prognosis was also evaluated after adjustments for background characteristics. IgAN patients with AAS had significantly higher age, blood pressure, body mass index, total cholesterol, uric acid levels, and proteinuria than patients without AAS; they also had more severe histological findings, decreased renal function, and lower survival rates than those without AAS (64.0 versus 84.7%, p < 0.001). Multivariate Cox regression analysis incorporating clinical and histological findings and treatments revealed AAS as an independent factor for disease progression (hazard ratio: 2.23, p = 0.010). Participants in the AAS1 group treated with RASI during follow-up had a significantly higher renal survival rate than those who were not (75.5 versus 44.3%, p = 0.013). In conclusion, AAS was found to be associated with serious clinical, laboratory, and histological findings and poor prognosis. RASI initiated during the follow-up period was found to improve renal prognosis.

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN. METHODS: A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years). RESULTS: Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10-4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period. CONCLUSIONS: Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

Cigarette smoking may accelerate the progression of IgA nephropathy.

BACKGROUND: Whether cigarette smoking is associated with the progression of immunoglobulin A nephropathy (IgAN) remains uncertain; therefore, we aimed to evaluate the effect of cigarette smoking on the prognosis of IgAN. METHODS: We divided 1239 IgAN patients from West China Hospital of Sichuan University who met the inclusion criteria into smoker (current or former) and non-smoker groups. The endpoint was end-stage renal disease (ESRD: eGFR < 15 mL/min/1.73 m2 or undergoing renal replacement treatment) and/or eGFR decreased by > 50%. Kaplan-Meier, correlation, logistic regression and Cox proportional hazards analyses were performed. The association between cigarette smoking and IgAN was further verified by propensity-score-matched cohort analysis. RESULTS: During the mean follow-up period of 61 months, 19% (40/209) of the smoker group and 11% (110/1030) of the non-smoker group reached the study endpoint (p < 0.001). Multivariate Cox regression analysis revealed that cigarette smoking (hazard ratio (HR) = 1.58; p = 0.043) was an independent risk factor predicting poor renal progression in IgAN, and that IgAN patients with chronic kidney disease (CKD) stage 3-4 were more susceptible to cigarette smoking (p < 0.001). After propensity score matching (PSM), a significant correlation between cigarette smoking and renal outcomes in IgAN patients was seen. Furthermore, Spearman's correlation test revealed that smoking dose was negatively correlated with eGFR (r = 0.141; p < 0.001) and positively related with proteinuria (r = 0.096; p = 0.001). CONCLUSIONS: Cigarette smoking is an independent risk factor for IgAN progression, especially for advanced patients.

O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. METHODS: To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. RESULTS: Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. CONCLUSIONS: Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

Volume of Crescents Affects Prognosis of IgA Nephropathy in Patients without Obvious Chronic Renal Pathology.

INTRODUCTION: A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in the kidney tissue predicted a worse renal outcome. However, the effect of C1 lesion (crescents in <1/4th of all glomeruli) and their volume on the prognosis of IgAN is still unclear. We explored the association of C1 lesion with the renal prognosis in IgAN patients without obvious chronic renal lesions (glomerulosclerosis <25%, T score <2). METHODS: We investigated 305 biopsy-proven IgAN patients without obvious chronic renal lesions. Clinicopathologic features and treatment modalities were recorded. The patients were divided into several groups according to the presence or absence of a global crescent: no crescent (NC) group, only segmental crescent (SC) group, and global crescent (GC) group. The outcome was the survival from a combined event defined by a ≥15% decline in the estimated glomerular filtration rate (eGFR) after 1 year or ≥30% decline in the eGFR after 2 years. RESULTS: Among all patients, 75.7% were in the NC group, 14.8% were in the SC group, and 9.5% were in the GC group. Compared with the NC group, patients in the SC group and the GC group had more urine protein, lower eGFR, and presented with more severe pathological change. During a median follow-up of 34.8 (26.16-57.95) months, the combined event occurred in 34 individuals (11.1%). In a multivariate model, the GC group (HR = 2.756, 95% CI = 1.068-7.109) was associated with an increased risk of the combined event. CONCLUSIONS: In IgAN patients without obvious chronic renal lesions, the GC group had more severe clinical and pathological manifestations than in the NC group. GC is an independent risk factor for the progression of IgAN renal function.

Evaluation of appropriate treatment for IgA nephropathy with mild proteinuria and normal renal function.

BACKGROUND: Tonsillectomy and steroid pulse therapy (TSP) for immunoglobulin A nephropathy (IgAN) is frequently employed in many Japanese institutions; however, performing this invasive treatment in patients with mild IgAN is controversial. This study aimed to evaluate the appropriate treatment for IgAN patients with mild proteinuria. METHODS: In this retrospective cohort analysis, 122 IgAN patients with mild proteinuria (0.5-1.0 g/day) and estimated glomerular filtration rate of ≥ 60 mL/min/1.73 m2 were classified into three groups as follows: patients treated with TSP (n = 32), oral prednisolone (oPSL, n = 33), and conservative therapy (CONS, n = 47). The clinical and histological backgrounds, 5-year remission rates of urinary findings, and 10-year renal survival rates were analyzed. RESULTS: The backgrounds were similar among the three groups. The remission rates of hematuria, proteinuria, and both were significantly higher for TSP and oPSL than for CONS; however, they were similar for TSP and oPSL. In the multivariate Cox regression analysis, TSP and oPSL were independent factors for the remission of urinary findings compared with CONS; however, the relapse rates of urinary abnormalities were similar among the three groups. No patient progressed to end-stage renal disease (ESRD) within 10 years. Adverse effects of corticosteroid therapy were significantly more frequent in oPSL than in TSP. CONCLUSION: In IgAN patients with mild proteinuria and stable renal function, similar to oPSL, TSP showed higher remission rates of hematuria and/or proteinuria than CONS, and no case progressed to ESRD regardless of the treatment methods. Therefore, appropriate treatments should be carefully considered for each patient.

Relationship between blood neutrophil-lymphocyte ratio and renal tubular atrophy/interstitial fibrosis in IgA nephropathy patients.

BACKGROUND: The study aimed to explore the relationship between neutrophil-lymphocyte ratio(NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: A Total of 263 IgAN patients were included. The participants were categorized into four groups based on quartile of NLR. The clinical data, pathological features, and 2-year renal survival rates were compared among the four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. RESULTS: The percentage of renal tubular atrophy/interstitial fibrosis increased with the increase of NLR level (p=0.003). The tubular atrophy/interstitial fibrosis score T1 and T2 in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%, p=0.033) and Group Q3 (22.39%, p=0.029). NLR [ß=1.230, 95%CI (0.081, 2.379), p=0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN. The area under curve predicted by NLR was 0.596 (95%CI 0.534~0.656, p=0.007) with the specificity 88.24% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years, and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%, p=0.029). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be a significant factor for predicting the prognosis in the IgAN. BACKGROUND: IgA nephropathy (IgAN) is an important cause of the end stage renal disease (ESRD). The study aimed to explore the relationship between neutrophil-lymphocyte ratio (NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: Total 263 IgAN patients confirmed by renal biopsy pathology were included from January 2013 to May 2018 in Ningbo Hwamei Hospital, University of Chinese Academy of Sciences. The peripheral blood samples were taken from these participants and the NLR was analyzed. The participants were categorized into four groups based on the median and upper and lower quartile of NLR, which were Group Q1 (NLR<1.64), Group Q2 (1.64≤NLR<2.19), Group Q3 (2.19≤NLR<3.00), and Group Q4 (NLR≥3.00), respectively. The clinical data and pathological features were compared among four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. The diagnostic ability of NLR for renal tubular atrophy/interstitial fibrosis was evaluated by the area under receiver operating characteristic curve (AUC). The 2-year renal survival rates were compared among the four groups. RESULTS: The levels of white blood cell count, neutrophil count, highly sensitive C-reactive protein, and the percentage of renal tubular atrophy/interstitial fibrosis were increased while lymphocyte count and estimated glomerular filtration rate were decreased with the increase of NLR level (P < 0.05). The percentage of tubular atrophy/interstitial fibrosis 26%-50% (T1) and >50% (T2) in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%) and Group Q3 (22.39%), with significant difference (P < 0.05). NLR [ß = 1.230, 95%CI (0.081, 2.379), P = 0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN according to multivariate linear regression analysis results. The AUC predicted by NLR was 0.596 (95%CI 0.534~0.656, P = 0.007) with the specificity 88.24%, the sensitivity 30.00% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years; and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%), with significant difference (P < 0.05). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be an significant factor for predicting the prognosis in IgAN.

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12.

AIMS: Nephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM. METHODS: A cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline. RESULTS: Average follow-up was 12.4 years. The eGFR change was -0.80 ±â€¯2.23 ml/min/1.73 m2 per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m2 per year), moderate decliners (-2.9/-1 ml/min/1.73 m2 per year) and slow/no decliners (>-1.0 ml/min/1.73 m2 per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline. CONCLUSIONS: A rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy.

Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy.

BACKGROUND: Complement activation plays an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate the relationship between mesangial C3 deposition and histologic lesions and to investigate the role of mesangial C3 deposition and serum C3 reduction in predicting renal outcome in IgAN children. METHODS: We performed a retrospective cohort study in children with biopsy-proven IgAN. Mesangial C3 deposition (< 2+ vs. ≥ 2+) was detected by the immunofluorescence. Histopathologic kidney grades were determined by the Oxford classification. A decreased serum C3 concentration (hypoC3) was defined when C3 < 90 mg/dl. The endpoint was composite kidney outcome with either a 30% decline in glomerular filtration rates from baseline or kidney failure during the follow-up period. RESULTS: A total of 98 children were analyzed. Mesangial hypercellularity (M) was an independent factor associated with mesangial C3 deposition (HR 3.267; 95% CI 1.028-10.389; P = 0.045). After a median follow-up period of 25 months (interquartile range 18-36 months), 6 (6.1%) children reached the endpoint. Compared with other children, a significantly higher proportion of children with composite kidney outcomes had mesangial C3 deposition ≥ 2+ and hypoC3 (3.4% versus 27.3%, P = 0.002). After adjustment for clinicopathologic risk factors, mesangial C3 deposition ≥ 2+ and hypoC3 were associated with renal outcome (HR 9.772; 95% CI 1.264-75.518; P = 0.029). CONCLUSION: Mesangial C3 deposition was associated with M in IgAN. Mesangial C3 deposition and hypoC3 were risk factors for renal outcome in children with IgAN.