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IgA nephropathy with acute kidney disease: Characteristics, prognosis, and causes

      Abstract

      Background

      The clinical manifestations and prognosis of IgA nephropathy (IgAN) are diverse. Some patients may present with kidney dysfunction lasting shorter than 3 months and meet the acute kidney disease (AKD) criteria. This study aimed to investigate the clinicopathological features, causes and prognosis of newly diagnosed cases of IgAN with AKD.

      Methods

      1320 IgAN patients diagnosed via kidney biopsy between January 2012 and June 2018 were included in this retrospective study, with a median follow-up period of 35 months. We analyzed the clinicopathological, etiological variables, as well as short-term and long-term prognosis. The main outcome was a composite event of 40% decline in eGFR, kidney failure or death.

      Results

      Incidence of AKD was 8.8% in the newly diagnosed IgAN patients, and was found to be an independent risk factor affecting the short-term (HR, 7.1; 95% CI, 2.3–22.2; P = 0.001) and long-term (HR, 1.8; 95% CI, 1.2–2.6; P = 0.006) prognosis, respectively. The most common cause of AKD was malignant hypertension-related AKD (MHT-AKD; 24.1%), followed by hematuria-related AKD (H-AKD; 12.9%), nephrotoxic–drug–exposure-related AKD (NTDE-AKD; 12.1%) and crescents-related AKD (C-AKD; 11.2%). The patients in AKD group had more severe clinicopathological characteristics and poor short-term and long-term prognosis than non-AKD group. In subgroup analysis, the MHT-AKD had the worst 5 years survival rate, followed by NTDE-AKD and C-AKD, whereas H-AKD had the best survival rate.

      Conclusions

      AKD is not rare among IgAN patients, and is an independent risk factor for short-term and long-term prognosis. IgAN patients with AKD resulting from different causes have different prognosis.

      Keywords

      1. Introduction

      IgA nephropathy (IgAN) has been recognized as the most common primary glomerular disease worldwide and a major cause of end-stage renal disease (ESRD). Recent epidemiological studies have reported that IgAN accounts for 40% of all primary glomerular disease diagnosed by kidney biopsy in Asia, and this rate is approximately 45% in China [
      • Li L.S.
      • Liu Z.H.
      Epidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies.
      ,
      • Magistroni R.
      • D'Agati V.D.
      • Appel G.B.
      • Kiryluk K
      New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
      ,
      • O’Shaughnessy M.M.
      • Hogan S.L.
      • Thompson B.D.
      • Coppo R.
      • Fogo A.B.
      • Jennette J.C.
      Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey.
      ]. IgAN can occur at different ages, with various clinical manifestations, such as asymptomatic microscopic hematuria, persistent proteinuria, and kidney function decline [
      • Floege J.
      • Moura I.C.
      • Daha M.R.
      New insights into the pathogenesis of IgA nephropathy.
      ]. The prognosis varies widely, and 30–40% of IgAN patients will develop kidney failure within 20 years [
      • Magistroni R.
      • D'Agati V.D.
      • Appel G.B.
      • Kiryluk K
      New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
      ].
      In clinical practice, we found that some IgAN patients can present with abnormal kidney function, such as decrease in eGFR or increase in serum creatine (Scr), and the duration less than 3 months. This condition meets the AKD diagnostic criterion proposed by KDIGO [
      Section 2: AKI Definition.
      ,
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      ,
      • Lameire N.H.
      • Levin A.
      • Kellum J.A.
      • et al.
      Harmonizing acute and chronic kidney disease definition and classification: report of a Kidney Disease: improving Global Outcomes (KDIGO) consensus conference.
      ].
      The clinicopathological features and short-term and long-term prognosis of IgAN patients with AKD versus those without AKD are currently unclear. Additionally, the causes that can lead to IgAN patients with AKD, and the differences in disease characteristics and prognosis among cases with different causes are unclear. Thus, this study aimed to identify IgAN patients with AKD and to provide new ideas for the diagnosis, treatment and management of IgAN patients by addressing the above-mentioned problems.

      2. Methods

      2.1 Patients

      This retrospective cohort study involved 1320 participants from The First Affiliated Hospital of Zhengzhou University and covered the period of January 2012 to June 2018. The patient records were collected from the Hospital Information System (Fig. 1). We included patients who had biopsy-proven primary IgAN and had follow-up data for > 6 months, or had kidney failure or a permanent reduction in eGFR of > 40% or death within 6 months [
      • Levey A.S.
      • Inker L.A.
      • Matsushita K.
      • et al.
      GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.
      ]. Patients were excluded who were younger than 18 years old, had kidney failure at the time of kidney biopsy, had no available MEST-C scores, had < 8 glomeruli in the biopsy, had > 50% missing information, or had missing baseline eGFR or proteinuria.
      According to the KDIGO criteria, AKD was defined as eGFR < 60 ml/min/1.73 m2, decrease in eGFR ≥ 35% or increase in Scr ≥ 50%, but the duration of abnormal kidney function < 3 months  [
      Section 2: AKI Definition.
      ,
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      ,
      • Lameire N.H.
      • Levin A.
      • Kellum J.A.
      • et al.
      Harmonizing acute and chronic kidney disease definition and classification: report of a Kidney Disease: improving Global Outcomes (KDIGO) consensus conference.
      ]. We assessed whether IgAN patients met the diagnostic criteria based on the SCr and eGFR levels [
      • James M.T.
      • Levey A.S.
      • Tonelli M.
      • et al.
      Incidence and prognosis of acute kidney diseases and disorders using an integrated approach to laboratory measurements in a universal health care system.
      ]. Baseline kidney function was defined as the minimum Scr or maximum eGFR value within 3 months before admission, if not available, the lowest Scr or highest eGFR value during hospitalization was taken. A total of 116 IgAN patients with AKD and 1204 without AKD (that is, NAKD) were finally included in this study.
      This study was approved by the medical ethics committee of The First Affiliated Hospital of Zhengzhou University.

      2.2 Data collection

      All of the predictors were defined and collected using identical methods. From the medical records, we obtained the following data collected at admission: age, gender, symptoms, history of drug usage, systolic and diastolic blood pressure, eGFR (according to the Chronic Kidney Disease Epidemiology Collaboration equation [
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ]), and hemoglobin, blood urea nitrogen, Scr, uric acid (UA), serum albumin (ALB), total cholesterol, triglyceride (TG), proteinuria and urine red blood cell (RBC). When 24-h urinary protein excretion data were missing, spot urine protein-creatinine ratio was used to estimated proteinuria level [
      • Hogan M.C.
      • Reich H.N.
      • Nelson P.J.
      • et al.
      The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases.
      ]. Each kidney biopsy specimen was independently scored according to the Oxford classification of IgAN score [
      • Trimarchi H.
      • Barratt J.
      • Cattran D.C.
      • et al.
      Oxford classification of IgA nephropathy 2016: an update from the IgA nephropathy classification working group.
      ] by two experienced pathologists blinded to the clinical data. Presence of RBC casts that occluded kidney tubules was recorded as yes or no according to the presence of lesions.

      2.3 Definitions

      For IgAN patients with AKD, baseline (and the beginning of follow-up) was defined as the time after the onset of AKD, if not available, the time of hospitalization was taken instead. In IgAN patients without AKD, baseline was defined as the time of kidney biopsy. The follow-up period was defined as the interval between the baseline and the last outpatient visit, death, or onset of kidney replacement therapy (KRT, maintenance dialysis or kidney transplantation). A serum creatinine level ≤ 1.25 times the baseline creatinine level at the last follow-up was considered to indicate recovery of kidney function [
      • Pannu N.
      • James M.
      • Hemmelgarn B.
      • Klarenbach S.
      Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge.
      ]. The short-term was defined as the first 6 months after the onset of AKD, while for IgAN patients without AKD, it was defined as the first 6 months post kidney biopsy. The long-term was defined as more than 6 months. The main outcome was a composite event including either a permanent reduction in eGFR of > 40% than baseline value, or kidney failure (eGFR <15 ml/min/1.73 m2 or KRT), or death.
      Mean arterial pressure (MAP) was defined as diastolic blood pressure plus one-third pulse pressure. Acute inflammatory cell infiltration was defined as ≥ 50% kidney interstitial edema with substantial infiltration of inflammatory cells, such as eosinophils and neutrophils, regardless of any lesion. Administration of renin-angiotensin-aldosterone system (RAAS) blockers and immunosuppressive agents was defined as any exposure post kidney biopsy.
      Malignant hypertension-related AKD (MHT-AKD) was used to describe malignant hypertensive kidney damage found via biopsy, and combined with a history of malignant hypertension, that is, diastolic blood pressure ≥ 130 mmHg with or without grade III or IV fundus lesions [
      • Rubin S.
      • Cremer A.
      • Boulestreau R.
      • Rigothier C.
      • Kuntz S.
      • Gosse P.
      Malignant hypertension: diagnosis, treatment and prognosis with experience from the Bordeaux cohort.
      ]. Nephrotoxic-drug-exposure-related AKD (NTDE-AKD) was used to describe the conditions of the patients who had been using antibiotics (β-lactams, aminoglycosides, vancomycin, sulfonamides, etc.), non-steroid anti-inflammatory drugs, contrast agents, or herbs containing aristolochic acid within 2 months before the hospitalization, and kidney biopsy pathology showing acute interstitial nephritis and/or acute tubular injury [
      • McCullough P.A.
      • Choi J.P.
      • Feghali G.A.
      • et al.
      Contrast-induced acute kidney injury.
      ,
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ]. Crescentic-related AKD (C-AKD)  [
      • Sevillano A.M.
      • Diaz M.
      • Caravaca-Fontán F.
      • et al.
      IgA nephropathy in elderly patients.
      ] was defined as the presence of crescents affecting ≥ 50% of the glomeruli. Hematuria-related AKD (H-AKD) was defined as the clinical manifestation of gross hematuria within 2 months before the hospitalization and tubular necrosis associated with erythrocyte casts was the major lesions identified via biopsy [
      • Sevillano A.M.
      • Diaz M.
      • Caravaca-Fontán F.
      • et al.
      IgA nephropathy in elderly patients.
      ]. Surgery-related AKD (S-AKD) [
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ] was used to describe the conditions within 2 months before kidney biopsy of the patients who had a clear history of surgery, massive intraoperative blood loss, or a rapid increase in creatinine level within a short period immediately after surgery, and the changes in creatinine level meeting the diagnostic criteria for AKD. The patients who did not meet any of the above-mentioned grouping criteria were included in the "unknown cause" group.

      2.4 Statistical analysis methods

      Continuous variables were presented as mean and SD or median and interquartile range (IQR). Differences between groups were analyzed using independent-samples t- tests. ANOVA or Kruskal–Wallis tests were used for continuous variables, and chi-squared tests were used for categorical variables. Kaplan–Meier method and log-rank test were used to compare the survival rates between groups. Univariate and multivariate Cox regression models were used to analyze independent factors affecting IgAN prognosis. The risk factors for the development of AKD in IgAN patients were analyzed by multivariate logistic regression. All the statistical analyses were performed using IBM SPSS 22.0 (IBM Corp., Armonk, NY) and Graphpad Prism 8.0 (Graphpad Software, San Diego, CA, USA). P < 0.05 indicated a statistically significant difference.

      3. Results

      3.1 Clinical and pathologic data

      As shown in Fig. 1, there were 1320 patients with IgAN between January 2012 and June 2018. Of them, 55.6% were male. The mean age of all the patients was 36.0 ± 11.6 years, and the median follow-up period was 35.0 (IQR, 24.0–49.0) months. A total of 116 (8.8%) newly diagnosed IgAN patients developed AKD during hospitalization (Fig. S1).
      The clinical and pathologic characteristics are summarized in Table 1. The AKD group had more patients with gross-hematuria symptoms or history of nephrotoxic-drug exposure, and had higher MAP, BUN, Scr, UA, TG, urinary protein and urine RBC levels, and lower hemoglobin, eGFR and ALB level compared with the NAKD group. Additionally, compared with NAKD group, AKD group showed higher prevalence of M1, E1, T1-2, C1-2 lesions, and more severe kidney tubules occluded with RBC casts or acute inflammatory cell infiltration lesions. There was no significant difference in S lesions incidence, assessed using the Oxford classification.
      Table 1Baseline clinicopathologic characteristics, treatment and outcomes of IgAN patients.
      CharacteristicTotalAKDNAKDP Value
      (n = 1320)(N = 116)(n = 1204)
      Demographics and clinical History
      Male, n (%)734 (55.6)74 (63.8)660 (54.8)0.059
      Age, yr36±11.638±14.636±11.30.161
      Systolic BP, mmHg135±19.3141±24.3134±18.90.006*
      Diastolic BP, mmHg88±14.491±16.988±14.10.046*
      Mean arterial BP, mmHg104±15.0107.2 ± 18.5103±14.50.024*
      Hypertension history, n (%)497 (37.6)44 (37.9)453 (37.6)0.948
      Gross hematuria history, n (%)97 (7.3)19 (16.4)78 (6.5)<0.001*
      Nephrotoxic drugs exposure history, n (%)116 (8.8)27 (23.3)90 (7.5)<0.001*
      Laboratory Results
      Hemoglobin, g/L130±20.9115±26.7132±19.6<0.001*
      Blood glucose, mmol/L4.7 ± 0.84.6 ± 0.94.7 ± 0.80.332
      BUN, median (IQR), mmol/L5.9 (4.6, 8.1)8.8 (6.0, 13.4)5.8 (4.5, 7.7)<0.001*
      SCr, median (IQR), umol/L89 (68, 131)153 (90, 279)86 (67, 121)<0.001*
      eGFR, median (IQR), ml/min per 1.73 m286 (55, 111)41 (23, 83)89 (59, 111)<0.001*
      UA, median (IQR), umol/L348 (278, 423)393(309, 458)344 (275, 417)<0.001*
      Serum Albumin, g/L37±8.631±8.437±8.5<0.001*
      Total Cholesterol, mmol/L5.5 ± 2.35.7 ± 2.25.5 ± 2.30.273
      Triglyceride, mmol/L2.0 ± 1.62.4 ± 2.01.9 ± 1.50.013*
      Proteinuria, median (IQR), g/d1.7 (0.9, 3.4)3.4 (1.4, 5.9)1.6 (0.9, 3.1)<0.001*
      Urine erythrocyte, median (IQR), /ul34 (8, 121)42 (9, 246)32 (7, 117)0.019*
      Kidney Biopsy Results
      M1, n (%)244 (18.5)36 (31.0)208 (17.3)0.001*
      E1, n (%)331 (25.1)45 (38.8)286 (23.7)0.003*
      S1, n (%)835 (63.2)76 (65.5)759 (63.0)0.597
      T
      T1, n (%)180 (13.6)14 (12.1)166 (13.8)0.61
      T2, n (%)243 (18.4)45 (38.8)198 (16.4)<0.001*
      T1-T2, n (%)423 (32.0)59 (50.9)364 (30.2)<0.001*
      C
      C1, n (%)454 (34.4)39 (33.6)415 (34.4)0.85
      C2, n (%)45 (3.4)17 (14.7)28 (2.3)<0.001*
      C1-C2, n (%)499 (37.8)56 (48.3)443 (36.8)0.015*
      Tubules with RBC casts, n (%)179 (13.6)29 (25.0)150 (12.5)<0.001*
      Acute inflammatory cell infiltration, n (%)301 (22.8)71 (61.2)230 (19.1)<0.001*
      Treatment
      RAAS blocker treatment, n (%)953 (72.2)59 (50.9)894 (74.2)<0.001*
      Immunosuppression treatment, n (%)867 (65.7)98 (84.5)769 (63.8)<0.001*
      Outcome
      Composite outcome, n (%)186 (14.1)48 (41.4)140 (11.6)<0.001*
      40% decline in eGFR, n (%)132 (10.0)39 (33.6)95 (7.9)
      KRT, n (%)103 (7.8)24 (20.7)79 (6.6)
      Death before KRT, n (%)2 (0.2)1 (0.9)1 (0.08)
      aThese rows denote statistical significances.
      Abbreviation: IgAN, IgA nephropathy; AKD, acute kidney disease; NAKD, non-AKD; BP, blood pressure; BUN, blood urea nitrogen; SCr, serum creatinine; UA, uric acid; IQR, interquartile range; M1, >50% of glomeruli show mesangial hypercellularity; E1, any glomeruli show endocapillary hypercellularity; S1, segmental glomerulosclerosis present in any glomeruli; T1, 26−50% of cortical area show tubular atrophy/interstitial fibrosis; T2, >50% of cortical area show tubular atrophy/interstitial fibrosis; T1-T2, > 25% of cortical area show tubular atrophy/interstitial fibrosis; C1, 0%−25% of glomeruli show cellular/fibrocellular crescents; C2, ≥25% of glomeruli show cellular/fibrocellular crescents; C1-C2, any glomeruli show cellular/fibrocellular crescents; RBC, red blood cell; RAAS, renin-angiotensin-aldosterone system; KRT, kidney replacement therapy.

      3.2 Treatment and outcome

      Regarding treatment, 59 patients (50.9%) in AKD group received RAAS inhibitors, and 98 patients (84.5%) received immunosuppressive therapy throughout the follow-up period, whereas in NAKD group, 894 patients (74.2%) received RAAS inhibitors, and 769 patients (63.8%) received immunosuppressive therapy (Table 1).
      Median follow-up period was 28.5 months (IQR, 11.3–43.5) and 36.0 months (IQR, 24.0–50.0), with composite endpoints of 48 events (41.4%) and 140 (11.6%) events, in AKD and NAKD groups, respectively. Kaplan-Meier curve analysis showed that survival rates of the IgAN patients in AKD group were 82.1%, 61.1% and 48.2% at 1, 3 and 5 years, respectively. The short-term (log-rank, χ2=70.6, P < 0.001) and long-term prognosis (log-rank, χ2=101.7, P < 0.001) in AKD group were worse than those in NAKD group (Fig. 2).
      Fig. 2
      Fig. 2The survival rate of the IgAN patients in AKD and NAKD groups at different follow-up periods. (A) In the first 6 months, the survival rate of the IgAN patients in AKD and NAKD groups after the onset of AKD. Solid line indicates IgAN patients in AKD group. Dotted line indicates IgAN patients in NAKD group. (B) The survival rate of the IgAN patients in AKD and NAKD groups until the last follow-up. Solid line indicates IgAN patients in AKD group. Dotted line indicates IgAN patients in NAKD group.
      Abbreviation: IgAN, IgA nephropathy; AKD, acute kidney disease; NAKD, non-acute kidney disease.

      3.3 Risk factors for progression of IgAN

      As shown in Table 2, in cause-specific hazards model 3, after adjustment for age, sex, MAP, eGFR, proteinuria, Oxford classification and RAAS blockers and immunosuppression agents, AKD was found to be an independent risk factor for the short-term composite progression event of IgAN (HR, 7.1; 95%CI, 2.3–22.2; P = 0.001). Results remained consistent in the long-term, indicating that AKD was an independent risk factor for the long-term composite progression event of IgAN as well (HR, 1.8; 95%CI, 1.2–2.6; P = 0.006) (Table 2).
      Table 2AKD as a risk factor for the composite progression event in IgAN.
      Hazard Ratio for Composite Outcomes
      Composite outcomes defined as 40% decline in eGFR or kidney replacement therapy or death before kidney replacement therapy.
      (95% Confidence Interval); P
      UnadjustedModel 1Model 2Model 3
      The short-term progression
      The short-term prognosis was defined as the prognosis of the IgAN patients in the first 6 months after the onset of AKD.
      16.8(6.9–41.1); <0.00110.3(4.1–25.9); <0.0015.4(2.0–14.7); 0.0017.1(2.3–22.2); 0.001
      The long-term progression
      The long-term prognosis was defined as the prognosis of the IgAN patients until the last follow-up.
      4.4(3.2–6.2); <0.0013.1(2.2–4.4); <0.0011.8(1.2–2.6); 0.0031.8(1.2–2.6); 0.006
      Note: Model 1 was adjusted for age, sex and Oxford classification (MEST-C scores), sex was expressed as a dichotomous variable. Model 2 was adjusted for covariates in model 1 plus mean arterial pressure, eGFR and proteinuria. Model 3 was adjusted for covariates in model 2 plus RAAS blockade, steroids and/or other immunosuppressive agents.
      Abbreviation: IgAN, IgA nephropathy; eGFR, estimated glomerular filtration rate.
      a Composite outcomes defined as 40% decline in eGFR or kidney replacement therapy or death before kidney replacement therapy.
      b The short-term prognosis was defined as the prognosis of the IgAN patients in the first 6 months after the onset of AKD.
      c The long-term prognosis was defined as the prognosis of the IgAN patients until the last follow-up.
      In a multivariable logistic regression model, we identified that complicated with malignant hypertension history (OR 38.91; 95%CI, 16.51–91.71; P < 0.001), gross hematuria history (OR 3.51; 95%CI, 1.68–7.36; P = 0.001), nephrotoxic-drug exposure history (OR 3.8, 95%CI, 2.02–7.13; P < 0.001), C2 lesions (OR 2.57; 95%CI, 1.11–5.98; P = 0.03) and acute inflammatory cell infiltration lesions (OR 6.4; 95%CI, 3.24–12.65;
      P < 0.001) were significant independent risk factors of the development of AKD in patients with IgAN (Table 3).
      Table 3Risk factors for the development of AKD in IgAN.
      VariableUnadjustedP ValueAdjustedP Value
      Hazard Ratio (95% CI)Hazard Ratio (95% CI)
      Age, yr1.01 (0.998–1.03)0.08
      Men1.45 (0.98–2.16)0.06
      Malignant hypertension history34.51 (16.63–71.63)<0.00138.91 (16.51–91.71)<0.001
      These rows denote statistical significances.
      Gross hematuria history2.83 (1.64–4.87)<0.0013.51 (1.68–7.36)0.001
      These rows denote statistical significances.
      Nephrotoxic drugs exposure history3.76 (2.32–6.08)<0.0013.80 (2.02–7.13)<0.001
      These rows denote statistical significances.
      UA, umol/L1.003 (1.001–1.005)<0.0011.003 (1.001–1.005)0.012
      These rows denote statistical significances.
      Serum Albumin, g/L0.94 (0.92–0.96)<0.0010.94 (0.91–0.97)<0.001
      These rows denote statistical significances.
      Proteinuria, g/d1.17 (1.11–1.23)<0.001
      M12.16 (1.42–3.28)<0.001
      E12.03 (1.37–3.02)<0.001
      S11.11 (0.75–1.66)0.60
      T1-T22.39 (1.63–3.51)<0.001
      T10.86 (0.48–1.54)0.61
      T23.22 (2.15–4.82)<0.0010.39 (0.18–0.83)0.014
      These rows denote statistical significances.
      C1-C21.60 (1.09–2.35)0.02
      C10.96 (0.64–1.44)0.85
      C21.21 (3.82–13.63)<0.0012.57 (1.11–5.98)0.03
      These rows denote statistical significances.
      Tubules with RBC casts2.34 (1.49–3.69)<0.0011.89 (1.03–3.48)0.04
      These rows denote statistical significances.
      Acute inflammatory cell infiltration6.68 (4.48–9.97)<0.0016.40 (3.24–12.65)<0.001
      These rows denote statistical significances.
      Abbreviation: IgAN, IgA nephropathy; AKD, acute kidney disease; 95% CI, 95% confidence interval; UA, Uric acid; M, mesangial hypercellularity; E, endocapillary hypercellularity; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis; C, cellular/fibrocellular crescents; RBC, red blood cell.
      a These rows denote statistical significances.
      Multivariate Cox proportional hazard regression analysis showed that high baseline MAP (HR, 1.01; 95% CI, 1.002–1.022; P = 0.015), UA (HR, 1.002; 95% CI, 1.001–1.004; P = 0.005) level, T2 lesions on kidney biopsy (HR, 4.35; 95% CI, 2.27–8.36; P < 0.001) and low eGFR (HR, 0.97; 95% CI, 0.96–0.98; P < 0.001), ALB (HR, 0.97; 95% CI, 0.94–0.99; P = 0.007) level were risk factors for the long-term prognosis of IgAN, and IgAN patients who had tubules with RBC casts (HR, 0.36; 95% CI, 0.20–0.67; P = 0.001) on kidney biopsy pathology appeared to have a better long-term prognosis than that of patients without these lesions. Meanwhile, high baseline MAP (HR, 1.03; 95% CI, 1.01–1.05; P = 0.02) and C2 lesions on kidney biopsy (HR, 3.41; 95% CI, 1.05–11.15; P = 0.04) were risk factors for the short-term prognosis of IgAN. In addition, the short-term and long-term prognosis of the IgAN patients treated with RAAS inhibitors were better than those who were not. (Table S1, Table S2)

      3.4 AKD subgroup analysis

      Based on the Table 3 and the clinicopathologic characteristics of the IgAN patients with AKD at admission, the possible causes of the AKD in the IgAN patients were divided into the following six categories (Fig. S2): MHT-AKD (28 cases, 24.1%), NTDE-AKD (14 cases, 12.1%), C-AKD (13 cases, 11.2%), H-AKD (15 cases, 12.9%), S-AKD (6 cases, 5.2%) and unknow cause (40 cases, 34.5%). The clinicopathologic characteristics and treatment strategies in each group are shown in Table S3. Considering the small number of cases in the S-AKD group, we mainly compared the differences among the four groups of MHT-AKD, NTDE-AKD, C-AKD and H-AKD. Overall, MHT-AKD and C-AKD groups showed higher blood pressure, MEST-C scores, Scr and urinary protein levels than the other groups.
      After short-term follow-up, the patients in H-AKD group were found to have better recovery of kidney function (12/15, 80.0%) than those in MHT-AKD (7/28, 25.0%), NTDE-AKD (5/14, 35.7%), C-AKD (7/13, 53.8%), or S-AKD (1/6, 16.7%) group (Fig. 3A). The Kaplan-Meier survival curve analysis revealed that MHT-AKD and C-AKD groups were significantly worse in short-term prognosis than the other groups (Fig. 4A).
      Fig. 3
      Fig. 3(A) The recovery of renal function with the short-term period of the IgAN patients with AKD resulting from different causes. (B) The recovery of renal function with the long-term period of the IgAN patients with AKD resulting from different causes.
      IgAN, IgA nephropathy; AKD, acute kidney disease; MHT-AKD, malignant hypertension-related AKD; NTDE-AKD, nephrotoxic-drug-exposure-related AKD; C-AKD, crescentic-related AKD; H-AKD, hematuria-related AKD; S-AKD, surgery-related AKD.
      Fig. 4
      Fig. 4(A) The survival rate with the short-term prognosis of the IgAN patients with AKD resulting from different causes. (B) The survival rate with the long-term prognosis of the IgAN patients with AKD resulting from different causes.
      IgAN, IgA nephropathy; AKD, acute kidney disease; MHT-AKD, malignant hypertension-related AKD; NTDE-AKD, nephrotoxic-drug-exposure-related AKD; C-AKD, crescentic-related AKD; H-AKD, hematuria-related AKD; S-AKD, surgery-related AKD.
      After the long-term follow-up, we found that the patients in H-AKD group had the best recovery of kidney function (13/15, 86.7%) compared with the patients in MHT-AKD (9/28, 32.1%) group, NTDE-AKD (2/14, 14.3%) group, C-AKD (4/13, 30.8%) group or S-AKD (2/6, 33.3%) group (Fig. 3B). Kaplan-Meier curve analysis showed that the 5 years survival rate for each group were 26.3% for MHT-AKD, 37.4% for NTDE-AKD, 44.0% for C-AKD, and 58.5% for H-AKD groups, respectively (Fig. 4B).
      Noticeably, there were 5 females and 1 male in the S-AKD group, 2 of the 5 women undergoing caesarian section, 3 undergoing abortion, and 1 man undergoing liver transplantation, all under general anesthesia, with a total of 2 patients experiencing significant loss of blood during the procedure. Only 1 patient's kidney function recovered in the first 6 months after the onset of AKD, but none of the them had an endpoint event. At the time of last follow-up, only 2 patients had normalized kidney function, and 2 had endpoint events.

      4. Discussion

      IgAN is the most prevalent primary glomerulonephritis worldwide with different clinical manifestations. Some patients may experience a rapid deterioration of kidney function in a short period, and AKI occurs when this period is < 7 days. Previous studies have found that approximately 8.3–9.7% of IgAN patients develop AKI, and patients with AKI have worse prognosis than those without AKI [
      • Oruc M.
      • Durak H.
      • Yalin S.F.
      • Seyahi N.
      • Altıparmak M.R.
      • Trabulus S.
      A rare presentation of immunoglobulin a nephropathy: acute kidney injury.
      ,
      • Zhang L.
      • Zhuang X.
      • Liao X.
      A proposed Oxford classification-based clinicopathological nomogram for predicting short-term renal outcomes in IgA nephropathy after acute kidney injury.
      ]. A proportion of IgAN patients present with progressive kidney dysfunction, and the duration period < 3 months, meeting the KDIGO criteria for AKD [
      Section 2: AKI Definition.
      ,
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      ]. To date, most studies have mainly focused on the relationship between IgAN and AKI and the short-term prognosis, while few studies on AKD and the short-term and long-term prognosis of IgAN. There is still much confusion as to why AKD occurs in IgAN patients and whether the kidney function can be restored after AKD occurs.
      In our study, we found that the proportion of AKD among the newly diagnosed IgAN patients was approximately 8.8%, and they had more severe clinicopathological features and poorer short-term and long-term prognosis. Because our study only considered Scr or eGFR variations within 3 months before and after hospitalization for IgAN patients with AKD, a few IgAN patients failed to detect the Scr peak or minimum eGFR level in time, these patients failed to meet the diagnostic criterion for AKD and were classified as NAKD group. Therefore, it is possible that the actual prevalence of AKD in newly diagnosed IgAN patients is highly than 8.8%.
      We found that occurrence of AKD was an independent risk factor for both the short-term and long-term prognosis of IgAN patients. Furthermore, we found that high MAP levels and C2 lesions were risk factors for the short-term prognosis of IgAN, while high MAP, UA levels, T2 lesions, and low eGFR, Alb levels were risk factors for the long-term prognosis, and patients with RBC casts in tubules seem to have a better prognosis than those who did not. Fujii et al. have found that AKD patients associated with increased hospital mortality [
      • Fujii T.
      • Uchino S.
      • Takinami M.
      • Bellomo R.
      Subacute kidney injury in hospitalized patients.
      ]. IgAN patients with AKD are undergo constant kidney injury, causing incomplete repair characterized by permanent tubulointerstitial fibrosis, which may cause the poor short-term and long-term prognosis of IgAN patients with AKD [
      • Singbartl K.
      • Kellum J.A.
      AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.
      ].
      AKI is a collection of syndromes, and its pathophysiology usually varies depending on the state and conditions with its development. The term AKD has been proposed to describe the course of the kidney disease among patients with ongoing kidney pathophysiological processes post AKI, which can also include the AKI process. Recent studies suggested that the causes and pathophysiological mechanisms of AKI may be related to a variety of factors, such as renal hypoperfusion, nephrotoxin exposure, rapidly progressive glomerulonephritis, acute interstitial nephritis, major surgery and so on [
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ]. Our findings suggest that IgAN patients are at significantly increased risk of AKD when combined with malignant hypertension history, gross hematuria history, nephrotoxic drugs exposure history, and C2 lesions, tubules with RBC casts and acute inflammatory cell infiltration on kidney biopsy. Therefore, we further subgrouped IgAN patients with AKD according to different causes, mainly into MHT-AKD, NTDE-AKD, C-AKD, H-AKD, S-AKD groups.
      Our study found that malignant hypertension (MHT) is the major cause of AKD in IgAN patients, and the patients with MHT-AKD had poorer recovery of kidney function and prognosis than the other groups both short- and long-term follow-up. Previous studies have found that 55% of patients with MHT may develop kidney involvement [
      • Rubin S.
      • Cremer A.
      • Boulestreau R.
      • Rigothier C.
      • Kuntz S.
      • Gosse P.
      Malignant hypertension: diagnosis, treatment and prognosis with experience from the Bordeaux cohort.
      ], and IgAN is one of the leading causes of MHT, accounting for one-third of all causes in China [
      • Jiang L.
      • Zhang J.J.
      • Lv J.C.
      • et al.
      Malignant hypertension in IgA nephropathy was not associated with background pathological phenotypes of glomerular lesions.
      ]. When IgAN patients are complicated with MHT, the rapidly elevated blood pressure can directly damage the vascular wall and endothelial cells, leading to ischemic changes and fibrinoid necrosis in the arterioles and excessive activation of the RAAS, and finally accelerate the deterioration of kidney function [
      • Howard C.G.
      • Mullins J.J.
      • Mitchell K.D.
      Direct renin inhibition with aliskiren normalizes blood pressure in Cyp1a1-Ren2 transgenic rats with inducible angiotensin ii-dependent malignant hypertension.
      ,
      • El Karoui K.
      • Hill G.S.
      • Karras A.
      • et al.
      A clinicopathologic study of thrombotic microangiopathy in IgA nephropathy.
      ].
      We found that NTDE-AKD mainly affects the long-term prognosis of IgAN patients, while C-AKD mainly affects the short-term prognosis. Previous studies have suggested that some common drugs may lead to kidney dysfunction and are associated with poor short- and long-term prognosis [
      • James M.T.
      • Ghali W.A.
      • Tonelli M.
      • et al.
      Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function.
      ,
      • Rosner M.H.
      • Perazella M.A.
      Acute kidney injury in patients with cancer.
      ,
      • Pistolesi V.
      • Regolisti G.
      • Morabito S.
      • et al.
      Contrast medium induced acute kidney injury: a narrative review.
      ,
      • Perazella M.A.
      Drug-induced acute kidney injury: diverse mechanisms of tubular injury.
      ]. High concentrations of medications and their metabolites may result in haemodynamic changes that affect the kidney function and structure, and cause interstitial inflammatory cell infiltration and thereby ultimately lead to interstitial fibrosis [
      • Couser W.G.
      • Johnson R.J.
      The etiology of glomerulonephritis: roles of infection and autoimmunity.
      ,
      • Makris K.
      • Spanou L.
      Acute kidney injury: definition, pathophysiology and clinical phenotypes.
      ,
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ]. Some scholars found that the prognosis is significantly lower in IgAN patients with crescents than those without crescents, and about 75% had a composite endpoint event [
      • Lee M.J.
      • Kim S.J.
      • Oh H.J.
      • et al.
      Clinical implication of crescentic lesions in immunoglobulin A nephropathy.
      ,
      • Gómez H.
      • Kellum J.A.
      Sepsis-induced acute kidney injury.
      ,
      • Sevillano A.M.
      • Diaz M.
      • Caravaca-Fontán F.
      • et al.
      IgA nephropathy in elderly patients.
      ], which is consistent with our results.
      Hematuria is a typical presentation of IgAN [
      • Wyatt R.J.
      • Julian B.A.
      IgA nephropathy.
      ], and macroscopic glomerular hematuria has been proven to be associated with the development of AKI. Acute tubular necrosis and intraluminal obstructive RBC casts are the most notable histological features of AKI during gross hematuria [
      • Gutiérrez E.
      • González E.
      • Hernández E.
      • et al.
      Factors that determine an incomplete recovery of renal function in macrohematuria-induced acute renal failure of IgA nephropathy.
      ,
      • Moreno J.A.
      • Martín-Cleary C.
      • Gutiérrez E.
      • et al.
      AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences.
      ]. Our study found that gross hematuria history was a risk factor for the development of AKD in patients with IgAN, but compared with other subgroups, the patients in H-AKD group showed the best short-term and long-term renal function recovery and prognosis. Our results were supported by previous literature. The presence or intensity of hematuria associated with worse IgAN prognosis [
      • Rauta V.
      • Finne P.
      • Fagerudd J.
      • Rosenlöf K.
      • Törnroth T.
      • Grönhagen-Riska C.
      Factors associated with progression of IgA nephropathy are related to renal function–a model for estimating risk of progression in mild disease.
      ], but IgAN patients with hematuria-associated AKI seems to have a better outcome compared with other causes [
      • Moreno J.A.
      • Martín-Cleary C.
      • Gutiérrez E.
      • et al.
      AKI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences.
      ].
      In addition to this, we found that 6 IgAN patients with AKD after major surgery under general anesthesia. Preceding studies have suggested that acute kidney failure is independently associated with long-term mortality risk in patients undergoing major surgery [
      • Hobson C.E.
      • Yavas S.
      • Segal M.S.
      • et al.
      Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery.
      ,
      • Gómez H.
      • Kellum J.A.
      Sepsis-induced acute kidney injury.
      ,
      • Gameiro J.
      • Fonseca J.A.
      • Neves M.
      • Jorge S.
      • Lopes J.A
      Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes.
      ,
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ]. The pathophysiological mechanisms may be associated with fluid depletion due to multiple factors and the systemic effects of the anesthetics [
      • Gómez H.
      • Kellum J.A.
      Sepsis-induced acute kidney injury.
      ,
      • Gameiro J.
      • Fonseca J.A.
      • Neves M.
      • Jorge S.
      • Lopes J.A
      Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes.
      ,
      • Ronco C.
      • Bellomo R.
      • Kellum J.A.
      Acute kidney injury.
      ]. Further sample expansion is needed. Therefore, clinicians should be cautioned against the development of AKD and promptly intervene when surgery must to be performed on IgAN patients.
      Our study has limitations due to the retrospective observational design in a single center, and the relatively small number of patients among the subgroups that led to the development of AKD in IgAN patients. Larger samples are needed to confirm our findings.

      5. Conclusions

      AKD is not rare in IgAN patients, and IgAN patients with AKD show more severe clinicopathological features and poorer short- and long-term prognosis than IgAN patients without AKD. Additionally, AKD is an independent risk factor for short- and long-term prognosis in IgAN. For the management of IgAN patients, attention should be paid to strictly managing blood pressure, avoiding nephrotoxic drugs applications, and reducing the occurrence of kidney adverse events. For the IgAN patients with AKD, attention should be paid to promptly diagnosis, identification of the causes, and early aggressive management.

      Disclosures

      All authors have nothing to disclose.

      Funding

      This work was supported by National Natural Science Foundation of China grant 82170721 .

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