Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy
Jaana Syrjänen,
Jukka Mustonen and
Amos Pasternack
Department of Medicine, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
Correspondence and offprint requests to:
Jaana Syrjänen MD, Medical School, University of Tampere, PO Box 607, FIN-33101 Tampere, Finland.
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Abstract
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Background. The prognosis of IgA nephropathy (IgAN) is variable and about 1020% of patients progress to end-stage renal disease (ESRD) in 10 years. Hypertension, proteinuria and renal insufficiency at the time of diagnosis are risk factors associated with poor prognosis. Lipid abnormalities may have a role in the progression of glomerulonephritides, and glomerulosclerosis and atherosclerosis may have similar pathophysiological mechanisms. We therefore evaluated factors associated with cardiovascular diseases, especially hypercholesterolaemia, hypertriglyceridaemia, and hyperuricaemia, as predictors of the progression of IgAN.
Methods. A total of 223 patients with IgAN (141 men, 82 women; median age 41 years, range 878 years) were studied. The following parameters were recorded at the time of renal biopsy: presence of hypertension or diabetes, smoking habits, body mass index (BMI), serum creatinine, total and HDL-cholesterol, triglycerides, and urate and 24-h urinary protein excretion. The patients were followed up for 0.217 years (median 10 years) with respect to progression of renal disease defined as elevation of serum creatinine above 125 µmol/l in men or 105 µmol/l in women, and over 20% elevation from baseline.
Results. Forty-one patients (18%) showed progression. Hypertriglyceridaemia and hyperuricaemia were significantly more common at the time of renal biopsy in patients with progressive than in those with stable disease. In patients with normal renal function at the time of diagnosis initial hypertriglyceridaemia, hyperuricaemia, hypertension and proteinuria were independent risk factors for progression of IgAN in the Cox regression hazard model.
Conclusions. Our results show that hypertriglyceridaemia and hyperuricaemia at the time of diagnosis are important, previously underestimated predictors of poor outcome in IgAN, although causality between these factors and progression cannot be inferred from the present study.
Keywords: glomerulonephritis; hypercholesterolaemia; hyperlipidaemia; hypertriglyceridaemia; IgA nephropathy; uric acid
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Introduction
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There is an increasing body of evidence to indicate that lipid abnormalities may have a role in the progression of renal diseases. This has been well established in experimental studies [14], and lipid-lowering agents have been found to reduce glomerular injury in animal models [3,5]. It has been suggested that analogous mechanisms lead to atherosclerosis and glomerulosclerosis [6,7].
In clinical studies, lipid abnormalities have predominantly been seen as modulators rather than as primary initiators of progressive renal disease. Patients with the most common forms of primary hyperlipidaemia do not generally develop renal insufficiency without coexisting renal disease [8,9]. However, two primary lipid disorders, namely the familial lecithincholesterol acyltransferase deficiency and the so-called lipoprotein glomerulopathy, lead to renal failure [10,11]. Dyslipidaemia may also be implicated in a decline in renal function in patients without renal disease [12].
Chronic renal failure and the nephrotic syndrome are accompanied by disturbances in lipoprotein metabolism [13], and it has been hypothesized that these lipid abnormalities may mediate the progression of renal failure [14]; some preliminary data indeed suggest a relationship between lipids and the rate of progression of renal disease. In patients with diabetic nephropathy, hypercholesterolaemia has been associated with the rate of decline in the glomerular filtration rate [15,16], and cholesterol-lowering therapy may retard this [17]. In a study involving 43 patients with chronic glomerulonephritis and renal failure the entry levels of plasma lipids correlated with the rate of progression [18]. In children with idiopathic focal segmental glomerulosclerosis and the nephrotic syndrome, the higher the serum cholesterol at presentation the more rapid was the progression to ESRD [19].
Hyperuricaemia is a common finding in hypertension and in hyperinsulinaemia [20,21]. Hyperuricaemia has also been held to contribute to the progression of renal disease in hypertension [20] and to play a role in the development of cardiovascular diseases [22,23].
The course of IgAN is variable. Some 1020% of patients develop ESRD over the first 10 years of follow-up [24,25] and the number of those with progressive disease increases with further follow-up. The strongest known risk factors associated with poor prognosis are renal insufficiency, hypertension, and proteinuria at the time of diagnosis [25,26].
The aim of the present study was to establish whether factors associated with cardiovascular diseases, especially hypercholesterolaemia, hypertriglyceridaemia, and hyperuricaemia at the time of diagnosis, also play a role in the progression of IgAN. The approach adopted consisted in measuring the levels of serum lipids and serum urate at the time of the diagnosis of IgAN and following the patients for several years.
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Subjects and methods
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Patients
All patients in whom IgAN was diagnosed in Tampere University Hospital between January 1980 and December 1990 were included in the study. IgAN was defined as glomerulonephritis with IgA as the sole or main glomerular immunofluorescence finding [27]. Of the 223 patients in question, 141 (63%) were men and 82 (37%) women. Their median age at the time of renal biopsy was 41 years, ranging from 8 to 78 years. They were resident in Pirkanmaa, an area with about 440000 inhabitants.
Clinical data
Table 1
shows the clinical profile of the patients at the time of renal biopsy. There were no cases of systemic lupus erythematosus or liver cirrhosis. Eleven had purpura; in two of them this was associated with arthritis and abdominal pain (HenochSchönlein purpura), in one with arthritis, and in three with abdominal pain. Both primary and secondary IgAN were thus included [28].
Data on medication, diabetes, smoking habits, body mass index (BMI), blood pressure, 24-h urinary protein excretion, serum lipids and serum urate at the time of renal biopsy were recorded. For the present analyses the criterion for hypertension was the use of antihypertensive medication at the time of renal biopsy or systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg measured during hospitalization for renal biopsy. Fifty-three patients were using antihypertensive medication (37 ß-blockers, 25 diuretics, eight ACE inhibitors and five calcium-channel blockers). None was taking lipid-lowering agents. Ten patients had diabetes (two insulin-dependent and eight non-insulin-dependent diabetes mellitus). A variable of smoking habits was defined as current smokers, past smokers, and non-smokers. Proteinuria was defined as 24-h urinary protein excretion
1 g. Hyperuricaemia was defined as a level of serum urate >0.45 mmol/l in men or >0.34 mmol/l in women. Urate values above these cut-off points are considered elevated in our laboratory. Two patients were using allopurinol for gout.
Follow-up
The median follow-up time after renal biopsy was 10 years, range 0.217 years. A total of 197 (88%) patients have been followed up for at least 5 years, 119 (53%) for at least 10 years and 46 (21%) for at least 15 years. The median follow-up time from the first signs of IgAN (episode of macroscopic haematuria, discovery of microscopic haematuria, or proteinuria or renal insufficiency) was 13 years, range 0.557 years.
Thirty patients (13%) died during the follow-up: five of uraemia, 12 of vascular diseases, three of malignancy, two of chronic obstructive pulmonary disease, two in accidents, and six of various other causes. Causes of death were confirmed from patient files and from death certificates kept by Statistics Finland. Fifteen patients (7%) had moved away from the area of Pirkanmaa. The remaining 178 were invited to attend for assessment between October 1996 and January 1997; 168 (94%) consented to participate in the study. The patients concerned have been continuously under the control of our hospital or local health care centre, but all those included made an assessment visit for the purposes of the present study.
In 55 patients, antihypertensive medication was started during the follow-up: 49 ß-blockers, 34 diuretics, 55 ACE inhibitors, and 47 calcium-channel blockers. Thus, 108 patients were on antihypertensive medication at the end of the follow-up. During the follow-up lipid-lowering agents were prescribed in seven patients with dyslipidaemia (5 statins, 2 fibrates) and allopurinol in 11 patients with gout. During the follow-up four patients with nephrotic syndrome were treated with corticosteroids for about 1 year. Two of these patients had HenochSchönlein purpura and one of them was also given cyclophosphamide for 6 weeks.
Definition of progression of IgAN
The initial measurement of serum creatinine was made at the time of renal biopsy. The serum creatinine measured at the assessment visit, or the last known serum creatinine value before death or loss from follow-up, was used when defining progression of IgAN. Serum creatinine values were considered normal if they were <125 µmol in men or <105 µmol in women. Progression of IgAN during the follow-up was defined as elevation of serum creatinine above the normal levels and over 20% elevation from the baseline level. Serum creatinine values were measured at about 1-year intervals during the follow-up. These were used when studying the time interval in years until impaired renal function developed, this interval being needed in survival analysis and in the Cox proportional hazard regression model.
Lipid determinations
Blood samples for determination of serum lipids were obtained after an overnight fast at the time of renal biopsy. Serum lipid concentrations were determined enzymatically. In 191 patients (86%) the concentration of triglycerides, in 188 patients (84%) the concentration of total cholesterol, and in 101 patients (45%) that of HDL-cholesterol (HDL-c) were available. HDL-c was measured systematically after the year 1985. LDL-cholesterol (LDL-c) was calculated using the formula LDL-c=total cholesterol-HDL-c-(triglycerides/2.2) [29], provided that the triglyceride values were <4.0 mmol/l. The LDL-c concentration could be calculated in 96 (43%) patients. The age and sex distribution and the follow-up time in patients in whom triglycerides and cholesterol were measured did not differ from those in the whole patient population: the median age was 39 years (range 876 years), 63% were men and 37% women, median follow-up time was 10 years (range 0.217 years).
In statistical analysis, lipid values were studied in two ways: as continuous variables and dichotomized. Cut-off points in dichotomizing lipid values were total cholesterol, 5.0 mmol/l and triglycerides, 1.7 mmol/l. Values above these cut-off points are considered elevated in our laboratory.
Definition of patient groups
As chronic renal failure is accompanied by disturbances in lipoprotein and urate metabolism, a separate analysis was made of patients with normal serum creatinine values at the time of renal biopsy when the role of dyslipidaemias and hyperuricaemia in the progression of IgAN was assessed. For the present study, this subgroup of patients was defined as subgroup N.
Statistical methods
The SPSS package was used for statistical analysis. Differences in proportions in different patient groups were compared by the chi-square test. Estimated relative risks (odds ratio) for progression were computed as quantitative measures of discrepancy together with their 95% confidence intervals (CI) [30]. Non-normally distributed data in the two groups with different prognosis were compared by non-parametric MannWhitney U-test. Survival analysis for stable renal function in relation to hypertriglyceridaemia or hyperuricaemia was carried out by the KaplanMeier technique [31]. Differences between survival curves were tested by log-rank test [31]. The Cox proportional hazard regression model was used to assess the effects of individual factors on the progression of IgAN, controlling for differences in other factors possibly affecting the progression [31]. The 95% CI for hazard ratio is expressed. Two-sided P values are reported, with 0.05 taken as the level of statistical significance.
Approval of ethics committee
This study was approved by the Ethics Committee of Tampere University Hospital. In the assessment visit all patients gave their informed consent to participate in the study.
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Results
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Progression of IgAN
Altogether 181 patients (81%) had normal (subgroup N) and 42 (19%) elevated serum creatinine at the time of renal biopsy. Out of the 181 patients in subgroup N, 27 (15%) progressed during the follow-up. Fourteen out of the 42 patients (33%) with elevated serum creatinine at biopsy showed progression of IgAN. In 14 of these 42 (33%), serum creatinine normalized, and in 14 (33%) it remained elevated without further rise over 20%. Thus, 41 of the study patients (18%) evinced progression of IgAN according to the definition, in 34 of these 41 the last measured serum creatinine was >150 µmol/l. The median increase in serum creatinine was 106% in patients with progressive disease. At minimum, serum creatinine had elevated from 75 to 106 µmol/l in one female patient and from 75 to 129 µmol/l in one male patient. Eighteen out of all patients (8%) and nine of those in subgroup N (5%) developed ESRD (i.e. serum creatinine >700 µmol/l or requiring dialysis).
Univariate association between serum lipid levels, serum urate, and progression of IgAN
In all patients and in subgroup N, the median serum level of triglycerides at the time of renal biopsy was significantly higher in those with progressive as compared to those with stable disease (Table 2
). Prognosis of IgAN and the dichotomized lipid values in all patients and in subgroup N are shown in Table 3
. Survival rate curves for stable renal function both in all patients and in subgroup N differed significantly in relation to hypertriglyceridaemia (Figure 1
).
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Table 2. Serum lipid and serum urate values at the time of renal biopsy in IgAN patients with stable and progressive disease
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Table 3. Univariate analysis for progression of IgAN with respect to dichotomized serum lipid and serum urate values at the time of renal biopsy
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Fig. 1. Survival rate curves for stable renal function in relation to hypertriglyceridaemia (serum triglycerides >1.7 mmol/l) at the time of renal biopsy. The upper graph represents all patients and the lower those with initially normal renal function (subgroup N). The differences in the cumulative proportion of patients with stable renal function between patients with or without hypertriglyceridaemia are statistically significant, P<0.001 and P<0.01 for all patients and for subgroup N respectively.
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Both in all patients and in subgroup N, the median serum urate level was significantly higher in those who progressed as compared to those who did not (Table 2
), and hyperuricaemia was associated with poor prognosis (Table 3
). Survival rate curves for stable renal function also differed significantly in relation to hyperuricaemia (Figure 2
).

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Fig. 2. Survival rate curves for stable renal function in relation to hyperuricaemia (serum urate >0.45 mmol/l in men or >0.34 mmol/l in women) at the time of renal biopsy. The upper graph represents all patients and the lower those with initially normal renal function (subgroup N). The differences in the cumulative proportion of patients with stable renal function between patients with or without hyperuricaemia are statistically significant, P<0.01 and P<0.02 for all patients and for subgroup N respectively.
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All these results of hypertriglyceridaemia or hyperuricaemia and progression of IgAN remained unchanged when patients who had developed more severe renal insufficiency (elevation of serum creatinine >150 µmol/l and over 20% elevation from the baseline level) were compared to those with stable disease (data not shown).
In addition to renal insufficiency, the use of antihypertensive medication such as diuretics and ß-blockers is also known to increase levels of serum lipids and urate. We therefore studied the effect of hypertriglyceridaemia or hyperuricaemia on the progression of IgAN in patients not using antihypertensive medication, and separately in such patients in subgroup N. The association remained unchanged (Table 4
). In addition, the associations between hypertriglyceridaemia or hyperuricaemia and progression of IgAN were similar in spite of the exclusion of the 11 patients with secondary IgAN.
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Table 4. Univariate analysis for progression of IgAN in patients without antihypertensive medication at the time of renal biopsy with respect to dichotomized serum triglyceride and serum urate values at the time of renal biopsy
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Univariate association between other factors and progression of IgAN
Hypertension, proteinuria, and diabetes were significantly associated with poor prognosis both in all patients and in the patients in subgroup N (Table 5
). The proportion of patients older than 40 years was significantly higher among those who had progressive as compared to those with stable disease (Table 5
). The median age was also higher in those who progressed as compared to those with stable disease: 52 years (range 2476 years) vs 37 years (range 878 years), P<0.001. Smoking habits did not differ significantly between the groups (Table 5
). The median BMI was higher among patients who progressed as compared to those who did not: 26 (range 1745) vs 25 (range 1544), P<0.05. The occurrence of macroscopic haematuria did not differ between patients with stable or progressive disease.
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Table 5. Univariate analysis for progression of IgAN with respect to various clinical and laboratory findings at the time of renal biopsy
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Independent risk factors for progression of IgAN
The implication of hypertriglyceridaemia and hyperuricaemia in the progression of IgAN was investigated by the Cox proportional hazard model. Hypertriglyceridaemia increased the risk of progression 3.3- and 3.0-fold and hyperuricaemia 2.4- and 2.6-fold in all patients and in the patients in subgroup N respectively (Table 6
). The association between hypertriglyceridaemia and progression of IgAN remained significant even after adjustment for proteinuria, hypertension, diabetes, hyperuricaemia, hypercholesterolaemia, age, gender and BMI (Table 6
). Hyperuricaemia remained a significant risk factor in subgroup N after adjustment for proteinuria, hypertension, diabetes, hypertriglyceridaemia, hypercholesterolaemia, age, gender and BMI (Table 6
). In this multivariate model the independent risk factors for progression of IgAN were proteinuria, hypertriglyceridaemia, hypertension and hyperuricaemia in subgroup N. The hazard ratios (95% CI) for proteinuria, hypertriglyceridaemia, hypertension, and hyperuricaemia were 14.8 (4.153.2), 7.3 (1.731.4), 6.3 (1.233.8), and 4.6 (1.119.4) respectively.
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Table 6. Unadjusted and adjusted hazard ratios for hypertriglyceridaemia and hyperuricaemia to progression of IgAN (Cox regression model)
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Discussion
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Our results show that hypertriglyceridaemia and hyperuricaemia constitute risk factors for the progression of IgAN. Both factors are subject to interference by diuretics and ß-blockers as well as renal insufficiency. However, the association between hypertriglyceridaemia or hyperuricaemia and progression of IgAN remained significant even in a subgroup of patients without any antihypertensive medication or without elevated serum creatinine at the time these parameters were measured. The progression of chronic glomerulonephritis is a multifactorial process and the Cox proportional hazard model was used to assess whether hypertriglyceridaemia or hyperuricaemia are independent risk factors for progression when other risk factors are controlled for. The effect of diuretics or ß-blockers was also taken into account in this model, as hypertension was defined as elevated blood pressure or the use of any antihypertensive medication. Hypertriglyceridaemia remained a statistically significant risk factor for progression. In addition, hyperuricaemia emerged as an independent risk factor for progression in patients with initially normal renal function. The observation that hypertriglyceridaemia and hyperuricaemia are independently predictive of poor prognosis does not necessarily imply that hypertriglyceridaemia or hyperuricaemia per se are pathogenic, since it is possible that they are markers of other factors not considered in the Cox model. However, the present findings emphasize the prognostic value of these factors although a causal relationship between them and progression cannot be inferred from the present study.
The patient population in this study was representative of IgAN. It consisted of all new patients with biopsy-proven IgAN treated in Tampere University Hospital, which is the only hospital in the region where renal biopsies are performed. The rate of participation in the assessment was high (94%) and files were available on all patients, making possible the follow-up of most for at least 5 years. The prognosis of our patients was similar to that reported in another European study [32]. The definition of impaired renal function was based on the level of serum creatinine, which was used routinely in the follow-up of all patients. This made it possible to include even patients who had died or were otherwise lost from the follow-up. However, it is well established that substantial reductions in renal function may occur before serum creatinine becomes abnormal. We used the cut-off points 125 µmol/l in men and 105 µmol/l in women when defining elevated serum creatinine. These values are somewhat higher than the normal upper limits in our laboratory (115 µmol/1 in men and 100 µmol/l in women) and it is possible therefore that some patients in subgroup N actually had decreased renal function. We also included an elevation of creatinine of over 20% in the definition of progression of IgAN to avoid misclassification of patients with stable disease. It may thus be assumed that all patients classified as having progressive disease had actually progressed. In most of them the last measured serum creatinine was >150 µmol/l and also the minimum change in serum creatinine among them was clinically relevant.
Hyperlipidaemia has long been recognized as a complication of chronic renal failure [13,33,34], and more recently it has also been implicated in the progression of renal disease [8,14]. In contrast to earlier studies, we did not find a relationship between hypercholesterolaemia and the rate of progression of renal disease [15,16,18,19,35,36]. The patient population here was homogeneous; all were suffering from only one class of chronic glomerulonephritis, whereas many earlier studies have covered a variety of renal diseases [15,16,18,19,35,36]. In the earlier studies, the majority of patients have had renal insufficiency from the beginning of follow-up [15,18,19,35,36] in contrast to the present study where only 19% had elevated serum creatinine at that time. In the present study, an association was observed between hypertriglyceridaemia and progression of IgAN also in patients in whom renal function was normal at the time of diagnosis. the observation of an association between hypertriglyceridaemia and progression of IgAN is in agreement with the findings of Samuelsson et al. [18,36], who also studied patients with chronic glomerulonephritis. As in the present series no relationship emerged between reduced levels of HIDL-c and progression of renal disease [36].
It has been reported that glomerulosclerosis increases in IgAN when studied by repeated renal biopsies [37,38] and that progression of disease is characterized by progression of extraglomerular lesions [39]. Analogous pathophysiological mechanisms have been proposed to be operative in both glomerulosclerosis and atherosclerosis [6,7], and lipids may also have a role in the progression of tubulointerstitial changes [14]. The role of hypertriglyceridaemia in the development of atherosclerosis has been a subject of controversy. However, hypertriglyceridaemia is associated with elevated levels of VLDL remnants, which are known to be atherogenetic [40]. In recent studies, hypertriglyceridaemia has also been found to be an independent risk factor for ischaemic heart disease and atherosclerosis [4143].
Similar to hyperlipidaemia, hyperuricaemia has been shown to be a predictor of coronary heart disease and stroke [22,23,44,45], and it may play a role in the pathogenesis of atherosclerosis [23]. Hyperuricaemia, which is common in essential hypertension, has also been thought to contribute to the deterioriation of renal function associated with hypertensive vascular disease [20]. Serum urate levels have been reported to be inversely related to renal blood flow and directly related to renal vascular resistance in both normotensive subjects and in patients with essential hypertension [46,47]. There is evidence that at least prolonged hyperuricaemia may induce chronic renal disease, in which a number of histological changes, including arteriosclerosis, arteriolosclerosis, glomerulosclerosis, and tubular changes, can be detected [20,48]. Although plausible underlying mechanisms remained undetermined, hyperuricaemia at the time of renal biopsy was found to be a predictor of poor prognosis in patients with normal renal function at that time. There are no earlier reports of an influence of hyperuricaemia on the progression of IgAN.
Hypertriglyceridaemia and hyperuricaemia are risk factors clustering with hyperinsulinaemia together with increased levels of small, dense LDL-c particles, low levels of HDL-c, hypertension and glucose intolerance in patients with the metabolic syndrome [21,4951]. Insulin resistance and concomitant hyperinsulinaemia are found in patients with IgAN and polycystic kidney disease very early in the course of renal disease, even when glomerular filtration rate values are still within the normal range [52]. Hyperinsulinaemia causes release of free fatty acids from adipose tissue, leading to high levels of triglyceride-rich VLDL particles. Plasma insulin may enhance renal sodium retention and decrease urinary uric acid clearance, contributing to the development of hypertension and hyperuricaemia [53]. The risk of atherosclerosis is increased in patients with the metabolic syndrome and metabolic disturbances may also play a role in the development of glomerulosclerosis. This may explain the association between hypertriglyceridaemia, hyperuricaemia, and the progression of IgAN. The question whether triglyceride- or uric-acid-reducing drugs should be used in these patients cannot be answered at this time. Further studies are needed to assess the effect of treatment of hypertriglyceridaemia or hyperuricaemia on the progression of IgAN.
We conclude that in addition to the well-known risk factors, hypertension and proteinuria, hypertriglyceridaemia and hyperuricaemia are important and previously underestimated or unrecognized risk factors for poor prognosis of IgAN.
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Acknowledgments
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This work was supported by grants from the Medical Research Fund of Tampere University Hospital and the Finnish Kidney Foundation. Part of this work was presented in the 31st Annual Meeting of the American Society of Nephrology, Philadelphia, 2528 October 1998. We thank Anna-Maija Koivisto MSc for her help in statistical analyses and Mrs Heidi Hällström for her skilful technical assistance.
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Received for publication: 12. 4.99
Accepted in revised form: 21. 7.99