Prognostic indicators of IgA nephropathy in the Chinese—clinical and pathological perspectives

Philip Kam Tao Li1,, Kelvin Kai Leung Ho1, Cheuk Chun Szeto1, LyMee Yu1 and Fernand Mac-Moune Lai2

1 Departments of Medicine and Therapeutics and 2 Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, People’s Republic of China



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. IgA nephropathy is the most common primary glomerulonephritis in the world. Up to 30% of patients can progress to end-stage renal disease (ESRD) in 10 years.

Methods. We studied 168 Chinese patients with IgA nephropathy followed for an average of 7.4 years in our hospital and tried to identify the clinical and pathological data that were associated with the prognosis of the disease. Clinical features at the time of renal biopsy were reviewed. Severity of histological involvement was scored semi-quantitatively as grade 1–3.

Results. There was a female preponderance in our cohort of patients (male:female ratio 1:1.5). The average age at biopsy was 32.9±10.0 years. Forty-seven of the 168 patients (28.0%) were hypertensive and 47 of 136 patients (34.6%) had a family history of hypertension. A high histological grade of IgA nephropathy was associated with hypertension at presentation, family history of hypertension, a higher serum creatinine, total cholesterol and 24-h urine protein excretion, and a lower serum albumin level. During the follow-up period, four patients died and another 24 progressed to ESRD. The renal survival was 92.0% at 1 year, 87.5% at 5 years and 81.8% at 10 years. With univariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation (plasma creatinine >120 µmol/l), high cholesterol, proteinuria >1 g/day and high histological grading were associated with poor prognosis. With multivariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation, proteinuria >1 g/day and histological grading were independent predictors of renal survival. The relative risks of renal failure for patients were 9.60 (95% confidence interval 4.02–22.92) with hypertension, 1.56 (1.16–2.02) with a family history of hypertension, 15.38 (6.40–36.93) with renal impairment and 5.93 (3.07–11.46) with every increase of one histological grade. Male patients did not show a more adverse outcome compared with females.

Conclusions. Our results suggest that renal biopsy remains useful, even in clinically trivial disease, because of its distinct value in prognosis and risk stratification. The long-term prognosis of IgA nephropathy in Chinese patients is guarded. The prognostic importance of family history of hypertension has not been widely recognized and requires further study.

Keywords: Chinese; IgA nephropathy; renal failure



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
IgA nephropathy was first reported by Berger and Hinglais in 1968 [1]. It is the most common primary glomerulonephritis in the world [2] and is particularly prevalent in Asian countries [35], presumably due to a different policy of health screening and kidney biopsy [6,7]. In Hong Kong, IgA nephropathy accounts for 35% of all forms of primary glomerulonephritis [8].

Nephrologists' perception of IgA nephropathy has changed substantially, with improved understanding of its natural history. Although believed to be benign and non-progressive 30 years ago [1], it is now generally agreed that up to 30% of patients eventually progress to end-stage renal disease (ESRD) [912]. The risk factors of progression are hypertension, proteinuria and impaired renal function at presentation [13,14]. A number of histological findings have prognostic implication [911,15]. However, the relationship between clinical features, pathology and family history of hypertension with renal prognosis has not yet been clearly defined in the Chinese population.

Herein, we studied a large cohort of Chinese patients with IgA nephropathy followed for up to 15 years. We aimed to identify risk factors of progression to renal failure.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Clinical information
All patients with the histological diagnosis of IgA nephropathy in our hospital from July 1987 to June 1996 were reviewed. Patients who suffered from systemic diseases such as systemic lupus erythematosus, Henoch–Schonlein purpura and chronic liver diseases were excluded. Baseline clinical and demographic data at the time of renal biopsy were collected. These included age, sex, presence of hypertension (blood pressure >140/95 mmHg, or requirement for antihypertensive therapy), presence of hypertension in first-degree relatives, plasma creatinine, 24-h urinary creatinine clearance and protein excretion, hepatitis B surface antigen (HBsAg), serum lipid and immunoglobulin A levels. Renal survival was defined as the duration from renal biopsy to ESRD (i.e. required long-term dialysis or kidney transplant), or death.

Renal biopsy
The indications of renal biopsy were persistent microscopic haematuria, proteinuria >0.5 g/day and unexplained renal impairment. The biopsy specimens were processed for light microscopy, immunofluorescence study and electron microscopy. IgA nephropathy was diagnosed by the typical appearance of mesangial proliferative glomerulonephritis with predominant mesangial IgA deposition.

All renal biopsy specimens were reviewed by a single pathologist unaware of the patients’ clinical condition. The biopsies were classified into grade I, II or III in increasing severity as previously described [3,8,16]. In essence, grade I denoted the presence of mild mesangial proliferation (cells, matrix or both) without tubulo-interstitial changes. Grade II indicated a moderate degree of mesangial proliferation and an increase in matrix, with occasional areas of glomerular sclerosis and crescent formation (in <20% of the glomeruli) and 5–15% interstitial changes. Grade III denoted the presence of grade II findings but with >30% glomerular sclerosis and 15% interstitial changes.

Statistics
All numerical data are expressed as mean±SD. The differences in means between groups were compared by {chi}2 test and one-way analysis of variance (ANOVA) as appropriate. Post hoc analysis was performed by the Bonferroni's method. Spearman's rank test was used for correlation analysis. Renal survival was estimated by the Kaplan–Meier method. The effect of prognostic factors was studied as stratifying variable with univariate analysis by log-rank test. Factors of statistical significance by univariate analysis were used for multivariate analysis by the Cox regression method to identify independent factors.



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Demographic and clinical features
There were 168 IgA nephropathy patients and 66 were male. There was a slight female preponderance (M:F ratio 1:1.5). The average age at biopsy was 32.9±10.0 years (range 15–67). Forty-seven percent of all cases presented between 25 and 34 years of age, and 87% between 15 and 45 years old. Clinical presentations of our patients are: asymptomatic proteinuria (23.2%); microscopic haematuria (13.7%); asymptomatic proteinuria and haematuria (31.5%); macroscopic haematuria (19%); nephrotic syndrome (4.8%); nephritic syndrome (1.2%); and advanced renal failure with plasma creatinine >500 µmol/l (6.5%). Thus, asymptomatic proteinuria and haematuria was the most common presentation. Sixty-six patients (39%) had elevated serum IgA concentration (>3.4 g/l); 19 out of 126 patients (15.1%) were HBsAg positive. No patient had depressed serum complement levels. The average duration of follow up was 7.4±2.7 years. Four patients died during that period. Long-term dialysis was required in 24 patients; nine of them subsequently received renal transplant.

The hypertension status of patients and their first-degree relatives was studied. Forty-seven patients (28.0%) had hypertension at presentation. A total of 136 cases had their family history of hypertension available for analysis. Forty-seven patients out of 136 (34.6%) had hypertensive first-degree relatives who included 39 parents (83%) and eight siblings (17%).

Relationship of renal biopsy and clinical feature
There were 167 biopsy specimens (99.4%) available for review. The glomerular, tubular and interstitial damages were scored semi-quantitatively as grade I–III. Their baseline clinical and biochemical data by histological group are summarized in Table 1Go. There was no significant difference in age, sex, serum IgA and triglyceride levels of patients between different grades. A high histological grade was associated with hypertension at presentation, family history of hypertension, higher serum creatinine, total cholesterol and 24-h urine protein excretion, and a lower serum albumin level. Serum creatinine, total cholesterol levels and 24-h urine protein excretion correlated positively and serum albumin level correlated negatively with the histological grading (Spearman's r=0.44, 0.37, 0.27 and -0.26 respectively; P<0.01 for each).


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Table 1. Comparison of clinical characteristics as well as serum and urinary parameters of patients with different histological grading

 

Renal survival
During the follow-up period, four patients died (due to cardiovascular or cerebrovascular disease) and 24 (14.3%) progressed to ESRD. The renal survival was 92.0% at 1 year, 87.5% at 5 years and 81.8% at 10 years. The Kaplan–Meier survival curve is shown in Figure 1Go. With univariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation (plasma creatinine >120 µmol/l), hypercholesterolaemia, proteinuria >1 g/day and high histological grading were associated with worse renal survival (log-rank test, P<0.05 for each). With multivariate analysis, hypertension at presentation, family history of hypertension, renal impairment at presentation, proteinuria >1 g/day and histological grading are independent factors of renal survival (Figure 2aGo–dGo). The relative risks of renal failure for patients were 9.60 (95% confidence interval 4.02–22.92) with hypertension, 1.56 (1.16–2.02) with a family history of hypertension, 15.38 (6.40–36.93) with renal impairment and 5.93 (3.07–11.46) with every increase of one histological grade.



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Fig. 1. The Kaplan–Meier renal survival curve of 168 patients with IgA nephropathy.

 


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Fig. 2. Kaplan–Meier renal survival curves to compare: (a) hypertensive (n=47) vs normotensive patients (n=120); (b) patients with a family history of hypertension (FHHT) (n=47) vs those without (No FHHT) (n=89); (c) patients with renal impairment (plasma creatinine >120 µmol/l) at presentation (RI) (n=37) and those without (No RI) (n=131); and (d) histological grading (grade 1, 71 cases; grade 2, 59 cases; grade 3, 37 cases). See page 68 for (c) and (d).

 
Nine out of the 66 male patients (13.6%) and 17 of the 102 female patients (16.7%) developed renal failure, and there was no significant effect of gender on renal outcome demonstrated.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
IgA nephropathy is not a benign disease. Some authors have reported that up to one-third of patients eventually progresses to ESRD [13]. In this study, we reviewed the clinical features and outcome of a large unselected cohort of primary IgA nephropathy patients. Renal survival after 10 years was 81.8%, similar to the reported figures from Australia, Europe and North America [14]. The major predictors of renal survival in our population were hypertension at presentation, renal impairment at presentation, family history of hypertension, proteinuria >1 g/day and histological grading.

Contrary to common beliefs and most Caucasian series [6,13], there was a female preponderance in our cohort of patients (male:female ratio 1:1.5). Similar female predominance has been reported previously from our locality [3], Japan [4] and Singapore [5]. The reason for this discrepancy is unknown. Nevertheless, local variations in indication for kidney biopsy and health screening practice probably partly explain the difference. In our locality, all pregnant females have careful and repeated urinalysis to detect the presence of any low-grade proteinuria. When proteinuria persists after parturition, renal biopsy is often performed. On the other hand, there is no corresponding screening procedure for the male population. It is interesting to note from a recent meta-analysis looking into the effect of gender on the progression to renal failure in IgA nephropathy that there was a male preponderance with a male to female ratio of 2.21 in the 25 studies with 3125 patients analysed [17]. In fact, all the 25 studies reported from 1977 to 1997 showed a male preponderance. This meta-analysis concluded that male gender is associated with unfavourable renal outcome in IgA nephropathy [17]. Our study in Chinese IgA nephropathy patients did not find such adverse effects in males compared with females.

We found a high prevalence of hypertension in the first-degree relatives of patients with IgA nephropathy (34.6% vs 10% in the age-matched general population in our locality [18]). Furthermore, a positive family history per se was an independent risk factor of disease progression. To our knowledge, our study is the first to suggest the association of prognosis with family history of hypertension. Genetic predisposition of hypertension in IgA nephropathy patients has been suggested [19,20]. Abnormal sodium–lithium countertransport kinetics, a commonly quoted functional defect in essential hypertension, has been reported in IgA nephropathy patients and their first-degree relatives with hypertension [21,22], implying an underlying genetic predisposition. On the other hand, our observation could also be explained by selection bias and recall bias. Even if asymptomatic, relatives of chronic glomerulonephritis patients are more likely to have their blood pressure checked, especially if the index patient has severe disease. Patients are also more likely to remember a positive family history of hypertension when asked. To exclude this possibility, it would be interesting to study the prevalence of hypertension and its relationship to prognosis in the (genetically unrelated) spouses of IgA nephropathy patients.

We found that histological grading has independent predictive value for renal survival, even after correction for clinical factors. The effect of histological severity on renal prognosis has been emphasized by many groups [13,14]. It is not uncommon to find patients with significant histological damage despite the absence of clinical risk factors. Since there is no proven specific therapy for IgA nephropathy, the indication for renal biopsy in patients with low-grade microscopic haematuria and proteinuria has been questioned [13]. Our result suggests that renal biopsy is still worthwhile because of its distinct value in prognosis and risk stratification. However, our study population was unselected, with both mild and severe disease. Further study is required to examine the role of renal biopsy in clinically trivial disease. Proteinuria (>1 g/day) was also a factor for worse renal survival in both univariate and multivariate analyses in our study, similar to previous studies [10,11].

In conclusion, IgA nephropathy is a heterogeneous disease with a substantial risk of progression to ESRD. Patients with hypertension at presentation, a family history of hypertension, renal impairment at presentation, proteinuria >1 g/day and advanced histological involvement are at high risk of progression. The importance of family history of hypertension as a predictor of renal survival is not widely recognized and requires further study.



   Acknowledgments
 
This study is supported in part by the Chinese University of Hong Kong Research Account No. 6900573.



   Notes
 
Correspondence and offprint requests to: Dr Philip K. T. Li, Department of Medicine, Prince of Wales Hospital, Shatin, Hong Kong, People's Republic of China. Email: philipli{at}cuhk.edu.hk Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 3.01
Revision received 11. 9.01.



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