Authors: Sidi Liu, Zhenzhen Lu, Zhike Fu, Huijie Li, Chuying Gui, Yueyi Deng
Categories: Research Article, Clinicopathological characteristics, Dyslipidemia, Immunoglobulin A nephropathy, Prognosis, Risk factor
Source: Kidney & blood pressure research
Doi: 10.1159/000529822
Immunoglobulin A nephropathy (IgAN) is one of the most common glomerulonephritic diseases in the world. Several lines of evidence have suggested that dyslipidemia is related to the disease progression and prognosis of IgAN. However, the study is scarce on the clinicopathological characteristics and outcomes of IgAN with dyslipidemia.
This study retrospectively analyzed 234 patients with biopsy-proven idiopathic IgAN at the Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, between January 2015 and June 2021. The participants were divided into dyslipidemia (n = 119) and non-dyslipidemia (n = 115), and the dyslipidemia group was also divided into the following 4 hypertriglyceridemia group, hypercholesterolemia group, mixed hyperlipidemia group, and low high-density lipoprotein cholesterol group. The estimated glomerular filtration rate (eGFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
The prevalence of dyslipidemia in IgAN patients in our center was 50.9% (119/234). The patients with dyslipidemia presented with higher systolic blood pressure (BP), diastolic BP, serum creatinine, uric acid, hemoglobin, proteinuria, and eGFR (p < 0.05). Proportions of males, hypertension, and chronic kidney disease stage 2∼5 were also higher in the dyslipidemia group (p < 0.05). Similarly, the pathological characteristics performed were worse in the dyslipidemia group. Most dyslipidemia patients had a higher percentage of mesangial hypercellularity (M1) and tubular atrophy/interstitial fibrosis (T1∼2) in the Oxford Classification’s scoring system (p < 0.05). Multivariate logistic regression analysis revealed that male gender (odds ratio [OR] = 2.397, 95% confidence interval [CI]: 1.051–5.469, p = 0.038) and proteinuria (OR = 1.000, 95% CI: 1.000–1.001, p = 0.035) were possible risk factors for dyslipidemia. A total of 13 patients (13.8%) in the dyslipidemia group had an endpoint event, of which 6 patients (6.4%) had a ≥50% decrease in eGFR from baseline and 7 patients (7.4%) reached the end-stage renal disease stage. Kaplan-Meier survival curve analysis showed that patients in the dyslipidemia group had a worse outcome than those in the non-dyslipidemia group (log-rank test, p = 0.048).
IgAN patients with dyslipidemia presented more severe clinicopathological characteristics. Male gender and proteinuria are significantly associated with the occurrence of dyslipidemia in IgAN patients. Patients in the dyslipidemia group had a worse prognosis than those in the non-dyslipidemia group, which may be essential for the disease management of IgAN and help identify the high-risk patients.
Keywords: Immunoglobulin A nephropathy, Dyslipidemia, Clinicopathological characteristics, Risk factor, Prognosis
Immunoglobulin A nephropathy (IgAN) is currently the most common glomerulonephritic disease in China and even the world [1], accounting for about half of primary glomerular diseases in China [2, 3]. The long-term renal prognosis of IgAN patients is generally considered to be poor, and about 20–30% of patients with IgAN will progress to end-stage renal disease (ESRD) in 20 years of onset, requiring renal replacement therapy, which brings a huge burden to the family and society [4–7].
Dyslipidemia is present in many chronic kidney disease (CKD) patients, and it is also one of the independent risk factors for the progression of kidney disease [8]. Several lines of evidence have suggested that dyslipidemia is related to clinical symptoms, disease progression, and prognosis of the patients with IgAN [9, 10], and it is also a risk factor for IgAN to enter ESRD [11]. Nevertheless, few studies involve pathological factors (especially the Oxford classification). The association between clinicopathological characteristics and dyslipidemia in IgAN patients is not truly understood and deserves further exploration and research. In this single-center, retrospective study, we summarize the clinicopathological characteristics of IgAN patients with dyslipidemia and set out to identify the possible risk factors of dyslipidemia and prognosis in IgAN patients from China.
Patients with biopsy-proven idiopathic IgAN from January 2015 to June 2021 at the Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, were enrolled in this study. All the participants were older than 14 years and signed an informed consent form. Criteria for excluding the subjects were as secondary IgAN caused by systemic lupus erythematosus, Henoch-Schonlein purpura, and hepatitis-B; IgAN patients with severe malignancy; biopsy sample with fewer than ten glomeruli. At last, a total of 234 patients were included in our study. This project was approved by the Medical Ethics Board of Longhua Hospital, Shanghai University of Traditional Chinese Medicine.
Demographic and laboratory parameters at the time of kidney biopsy were collected, including age, gender, history of hypertension, blood pressure (BP), triglycerides (TG), serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, serum creatinine, blood urea nitrogen (BUN), uric acid, serum albumin, hemoglobin, and proteinuria. The estimated glomerular filtration rate (eGFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [12].
All renal tissue specimens were examined using light microscopy, immunofluorescence microscopy, and electron microscopy. The results of histological slides were independently reviewed by two renal pathologists according to the Oxford classification [13–15], of which the specific scoring rules are as M0/M1 as a mesangial score ≤0.5 or >0.5; absence (E0) or presence (E1) of endocapillary hypercellularity; absence (S0) or presence (S1) of segmental sclerosis or tuft adhesions; T0/T1/T2 as the grade of tubular atrophy/interstitial fibrosis ≤25%, 26–50%, and >50%, respectively; absence of cellular/fibrocellular crescents (C0), exist in at least 1 glomerulus (C1), or exist in >25% of glomeruli (C2). Global glomerulosclerosis, segmental adhesion, interstitial cell infiltration, and vascular lesions were also included in pathological features.
Dyslipidemia was determined by the 2016 “Chinese guideline for the management of dyslipidemia in adults” [16], including 4 clinical hypertriglyceridemia (TG ≥2.3 mmol/L and TC <6.2 mmol/L), hypercholesterolemia (TC ≥6.2 mmol/L and TG <2.3 mmol/L), mixed hyperlipidemia (TG ≥2.3 mmol/L and TC ≥6.2 mmol/L), and low high-density lipoproteinemia (HDL-C <1.0 mmol/L, TC <6.2 mmol/L and TG <2.3 mmol/L). Hypertension refers to a BP ≥140/90 mm Hg in a resting systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg or who has been diagnosed with hypertension before. Proteinuria was estimated using 24-h urine protein collections. CKD [17] was defined as an abnormal renal structure or function or eGFR <60 mL·min^-1^·(1.73 m^2^)^−1^, which has a course of more than 3 months. CKD stage 1 as the eGFR ≥90 mL·min^-1^·(1.73 m^2^)^−1^, CKD stage 2 as the eGFR 60–89 mL·min^-1^·(1.73 m^2^)^−1^, CKD stage 3 as the eGFR 30–59 mL·min^-1^·(1.73 m^2^)^−1^, CKD stage 4 as the eGFR 15–29 mL·min^-1^·(1.73 m^2^)^−1^, and CKD stage 5 as the eGFR <15 mL·min^-1^· (1.73 m^2^)^−1^.
Patients were followed up and evaluated at least every 3 months, with laboratory data and medication administration recorded at each follow-up visit. 53 of 234 patients with IgAN were followed up for less than 12 months and were excluded, leaving 181 patients included in the study analysis. The study endpoint was a ≥50% decrease in eGFR from baseline values or entry into the ESRD phase.
Continuous variables were presented using means ± SD deviation for normal distribution, but for skewed distribution, results were expressed as medians of the 25th and 75th percentiles, which were analyzed by t test, Wilcoxon’s signed-rank test, one-way ANOVA test, or Kruskal-Wallis H test. The results of categorical variables were expressed as the frequency (percentages), which were analyzed by Fisher’s test or χ^2^ test. The Kaplan-Meier method was used to calculate the cumulative renal survival, and the difference between the two curves was tested using the log-rank test. Correlates between dyslipidemia and the variables of clinicopathology in IgAN were identified using multivariate logistic regression, and the results were expressed as odds ratios (ORs) with a 95% confidence interval (CI). All data analyses were performed using SPSS 25.0, and p < 0.05 was considered statistically significant.
The baseline characteristics of 234 IgAN patients were analyzed in this study, including 101 males and 133 females, of which the sex ratio was 1.32 and their median age was 39.06 ± 12.20. The prevalence of dyslipidemia in IgAN patients in our center was 119 (50.9%), and 100 (42.7%) showed hypertension. According to clinical classification, the dyslipidemia group was divided into the following 4 hypertriglyceridemia group, 43 (36.1%); hypercholesterolemia group, 13 (10.9%); mixed hyperlipidemia group, 19 (16%); and low HDL-C group, 44 (37%). IgAN patients with CKD stage 1 and CKD stages 2–5 was 115 (49.1%) and 119 (50.9%), respectively (Table 1).
The clinical and histopathological characteristics of IgAN patients between those who did and did not have an episode of dyslipidemia are presented in Table 1. Compared with people in the non-dyslipidemia group, people in the dyslipidemia group had a higher presentation of systolic BP, diastolic BP, serum creatinine, uric acid, hemoglobin, proteinuria as well as eGFR (p < 0.05). Proportions of males, hypertension, and CKD stage 2–5 were also higher in the dyslipidemia group (p < 0.05). Nevertheless, no significant differences were found in age, the interval between presentation and biopsy, BUN, and serum albumin between the patients in both groups (p > 0.05). IgAN patients in the dyslipidemia group had a higher proportion of M1 and T1∼2 than that in the non-dyslipidemia group (p < 0.05).
Table 2 shows significant differences in uric acid, serum albumin, and proteinuria can be found in the four types of dyslipidemia groups (p < 0.05). However, no significant differences in age, gender, the interval between presentation and biopsy, systolic BP, diastolic BP, serum creatinine, BUN, hemoglobin, eGFR, and CKD stage were found among these groups (p > 0.05). There were also no significant differences detected in the four groups for the histopathological characteristics (p > 0.05).
Table 3 reveals the variables that are independently associated with dyslipidemia. Univariate analysis showed that male (OR = 3.579, 95% CI: 2.072–6.183, p < 0.001), hypertension (OR = 2.050, 95% CI: 1.209–3.473, p = 0.008), systolic BP (OR = 1.025, 95% CI: 1.005–1.046, p = 0.016), diastolic BP (OR = 1.030, 95% CI: 1.000–1.061, p = 0.047), serum creatinine (OR = 1.007, 95% CI: 1.001–1.013, p = 0.019), uric acid (OR = 1.006, 95% CI: 1.003–1.009, p < 0.001), hemoglobin (OR = 1.022, 95% CI: 1.008–1.036, p = 0.002), proteinuria (OR = 1.000, 95% CI: 1.000–1.000, p = 0.015), eGFR (OR = 0.991, 95% CI: 0.982–1.000, p = 0.040), and tubular atrophy/interstitial fibrosis (T1∼2) (OR = 1.880, 95% CI: 1.088–3.247, p = 0.024) were positively correlated with dyslipidemia. Variables with p < 0.05 in univariate analysis were entered into multivariate analysis as covariates. The multivariate logistic regression analysis found that dyslipidemia was most strongly associated with the two clinical male (OR = 2.397, 95% CI: 1.051–5.469, p = 0.038) and proteinuria (OR = 1.000, 95% CI: 1.000–1.001, p = 0.035).
The median follow-up was 29 months (range, 12–68 months) in the dyslipidemia group and 24 months (range, 12–65 months) in the non-dyslipidemia group. Patients with proteinuria levels >0.3 g/24 h were treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. 181 patients with IgAN had a total of 17 (9.4%) endpoint events, of which 8 patients (4.4%) had a ≥50% decrease in eGFR from baseline values and 9 patients (5.0%) reached the ESRD stage. A total of 13 patients (13.8%) in the dyslipidemia group had an endpoint event, of which 6 patients (6.4%) had a ≥50% decrease in eGFR from baseline and 7 patients (7.4%) reached the ESRD stage. Kaplan-Meier survival curve analysis showed that patients in the dyslipidemia group had a worse prognosis than those in the non-dyslipidemia group (log-rank test, p = 0.048), as shown in Figure 1.
Fig. 1. Kidney survival curve in IgAN patients with dyslipidemia and non-dyslipidemia group.
Many previous studies on dyslipidemia have revealed that it is not only a risk factor for the occurrence and development of cardiovascular diseases but aggravates the progression and prognosis of IgAN [10]. Research has shown that the incidence of dyslipidemia in adult IgAN is 45.3–61.1% [9, 18, 19]. At present, there are few studies on the clinicopathological characteristics and renal outcomes of IgAN complicated with dyslipidemia in China. Understanding and analyzing the prevalence, clinicopathological characteristics, risk factors, and outcomes of dyslipidemia in patients with IgAN is of great clinical significance, which is helpful to optimize the prevention and treatment strategies of IgAN and provide meaningful evidence for clinical treatment.
The results obtained from our work revealed that 50.9% of the IgAN patients in our center were accompanied by dyslipidemia, and the proportions of CKD stage 2–5 were higher in the dyslipidemia group. In addition, IgAN patients in the dyslipidemia group had more severe clinical changes than the non-dyslipidemia patients, and a recent clinical investigation from China illustrated similar results [20]. Likewise, pathological features also showed a higher proportion of M1 (mesangial score >0.5) and T1∼2 (tubular atrophy/interstitial fibrosis 26–50% and >50%) in IgAN patients in the dyslipidemia group, which are similar to the previous descriptions of IgAN [20, 21].
These results suggest that dyslipidemia may aggravate the structural and functional damage to the kidneys in IgAN patients. In animal experiments, imaging mass spectrometry analysis found that the molecular distribution of lipids is mainly located in the cortex area, hilum area, and tubular area in hyper-IgA murine kidneys [22]. By the direct toxic effects of lipids on renal cells, dyslipidemia would aggravate the progression of CKD patients [23, 24]. Moreover, clinical and experimental evidence shows that the abnormalities of lipid metabolism can promote the progress of kidney injury by causing inflammatory, oxidative, and ER stress [25, 26].
Multivariate logistic regression analysis revealed that male sex and proteinuria were two risk factors for dyslipidemia in IgAN patients. The research has also shown that the prevalence of dyslipidemia was higher in male IgAN patients than that of females, which is the same as the former findings [27–29], and the reason for this may be that males have more fat deposited viscerally and the differences in sex steroid hormones between the genders [30–32]. In addition, some studies have also revealed that the clinicopathological characteristics of male IgAN patients are worse than those of females, and maleness is seen as an independent risk factor for poor prognosis [33]. These discrepancies in genders may be because of inadequate health awareness and unhealthy lifestyles in male IgAN patients. Men are generally less aware than women of the common symptoms of potentially serious health problems [34]. In terms of unhealthy lifestyles, a retrospective cohort study has reported a higher proportion of male smokers than female smokers (63.7 vs. 36.3%) [35], and higher smoking doses are associated with more severe renal damage and a worse prognosis [36]. Therefore, healthy lifestyle choices and health awareness should be encouraged as part of treatment for IgAN. Numerous clinical data have shown that patients with persistent proteinuria fare poorly. As an independent risk factor, proteinuria is a powerful predictor of the most significant risk for progressive renal loss in those patients [37]. Min Tan et al. [38] also found that proteinuria, as an independent predictor, may help identify the risk of severe renal pathological damage in IgAN patients with benign clinical characteristics. Therefore, it is critical to reduce proteinuria levels to the greatest extent, even in IgAN patient who has a more benign clinical presentation.
Our study showed that patients with IgAN with dyslipidemia have a worse prognosis. Nakamura et al. [39] found that hyperlipidemia was significantly negatively correlated with eGFR, which causes ischemic kidney injury, promotes the inflammatory response, and aggravates oxidative stress, leading to the development of ESRD. In addition, dyslipidemia can lead to glomerular podocyte injury in patients and promote glomerulosclerosis, thus aggravating the disease progression [24]. Therefore, attention should be paid to the management of lipid levels in IgAN patients and early intervention therapy to reduce the harmful effects of lipid metabolism on the organism, thereby delaying the development of the disease and improving the prognosis of IgAN patients.
However, we must acknowledge some potential limitations of our research. First, our retrospective study is single-center. Due to regional restrictions, the patient source is relatively single, leading to a selection bias, and the results may not apply to IgAN patients in other regions. Second, the current study is limited by the relatively small sample, and the data are incomplete. Third, because the data collection has a retrospective nature, the loss of some information is unavoidable, which may have some impact on the reliability of this work. So, more well-designed prospective multicenter cohort studies with larger sample sizes are demanded in the future.
In conclusion, IgAN patients with dyslipidemia showed more severe clinicopathological features, and multivariate analyses in this study revealed that the male gender and proteinuria could be risk factors for IgAN with dyslipidemia. A higher proportion of patients in the dyslipidemia group had a ≥50% decrease in eGFR from baseline values or entered the ESRD stage with a worse prognosis compared to the non-dyslipidemia group. This may be essential for the favorable disease management of IgAN and help identify the high-risk patients.
We would like to thank all the patients included in this study.
This retrospective study complied with the guidelines of the Declaration of Helsinki and was approved by the Medical Ethics Committee of Longhua Hospital of Shanghai University of Traditional Chinese Medicine (2018-008). Written informed consent was obtained from participants (or obtained from the parent/legal guardian of all child participants under 18 years of age) to participate in the study.
The authors declare that they have no conflicts of interest.
This work was supported by Shanghai Municipal Key Clinical Specialty (No. shslczdzk04201), the National Natural Science Foundation of China (No. 82174320), and the National Key Research and Development Program – Research on the Modernization of Traditional Chinese Medicine (No. 2019YFC1709403).
Research idea, study design, and writing – original Sidi Liu; clinical and pathological data Zhenzhen Lu and Zhike Fu; data analysis/ Huijie Li and Chuying Gui; and supervision and writing – review and Yueyi Deng. The authors read and approved the final manuscript.
This work was supported by Shanghai Municipal Key Clinical Specialty (No. shslczdzk04201), the National Natural Science Foundation of China (No. 82174320), and the National Key Research and Development Program – Research on the Modernization of Traditional Chinese Medicine (No. 2019YFC1709403).
Research data are not publicly available for ethical reasons due to participant privacy concerns. The data used and/or analyzed in this study are available from the corresponding author on reasonable request.
Research data are not publicly available for ethical reasons due to participant privacy concerns. The data used and/or analyzed in this study are available from the corresponding author on reasonable request.