ARTICLE. Abstract. Introduction

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1 163 ARTICLE Primary IgA nephropathy: A ten-year analysis on the renal outcomes and a model for estimating risk of progression B Chacko, GT John, N Neelakantan*, N Balakrishnan, G Meshach, M Kirubakaran, CK Jacob Department of Nephrology, *Department of Biostatistics, Christian Medical College Vellore, India Abstract Background: Characterizing IgA nephropathy (IgAN) from the Indian perspective has been largely speculative, save for a few studies. We aimed to; identify prognostic factors operative at different levels of renal function, calculate cumulative renal survival rates and create a model to estimate the probability of renal survival. Methods: Clinical, laboratory, and histopathological data in 478 patients with biopsyproven IgAN over 10-year duration was analyzed. Patients who had been followed on average for 27 months after diagnosis (n = 347) were divided into 2 groups based on renal function at diagnosis. In group 1 (229 patients), CrCl (creatinine clearance, estimated by MDRD formula) was < 85 ml/min, in group 2 (118 patients) > 85 ml/min. Multivariate analysis by Logistic regression and renal survival by Kaplan-Meier was used. Cox Proportional Hazard model was used to find the factors associated with progression to ESRD on which the final model was constructed. Results: Risk factors for progression by multivariate analysis in patients with decreased renal function at diagnosis (group 1) included hypertension (OR 3.5), nephrotic range proteinuria (OR 3.4), and greater than 50% of sclerosed glomeruli on biopsy (OR 4.1). However, in patents with normal renal function at time of diagnosis (group 2); hypertension (OR 2.3) was the only identified risk factor for progression. The median renal survival time from manifestation of symptoms and renal biopsy was 34 (95%CI: 25, 43) and 18 (95% CI: 10, 26) months respectively Conclusions: Prognostic indices in IgAN depend on renal function at the time of initial assessment. The presence of hypertension, nephrotic range proteinuria, and the degree of interstitial fibrosis and sclerosed glomeruli on biopsy were independent predictors of progression to ESRD. Renal survival after diagnosis was short in our cohort when compared to published information. Key words: IgA nephropathy, progression, survival Introduction Since its original description by Berger and Hinglais 1, Idiopathic IgA Nephropathy (IgAN) has been recognized as the most common form of glomerulonephritis worldwide. Initially considered as a benign disease, the natural history has changed considerably with studies showing an incidence of chronic renal failure ranging Address for Correspondence: Dr. George T. John Professor, Department of Nephrology Christian Medical College, Vellore Tamilnadu India george@cmcvellore.ac.in from 20 to 40% 2,3. The highly variable clinical course has resulted in efforts to determine clinical, laboratory, and histologic features that predict the development of renal failure in IgAN. Characterizing IgAN from the Indian perspective has been largely speculative, save for a few studies 4,7. It remains to be seen whether the prognostic factors and survival rates mentioned in the Western literature for IgAN are applicable to the Indian population also. In the absence of disease specific therapy, this characterization might provide insights into the natural history of IgAN in India. Identifying and aggressive management of patients at risk for progression is imperative, considering the limited resources in developing countries.

2 164 Indian Journal of Nephrology Indian J Nephrol 2004;14: In the present study, we have analyzed the clinical, laboratory, and histopathological data in 478 patients with biopsy-proven IgAN over 10-year duration. We aimed to identify prognostic factors operative at different levels of renal function at time of diagnosis. Distinguishing a progressor from a non-progressor, cumulative renal survival rates and creating a model to estimate the probability of renal survival were the other variables of interest. Patients and Methods Patients The diagnosis of idiopathic IgAN was made at this Institution between January 1994 and December 2003 on 478 adult (age > 15 years) patients, constituting 8.93 % of all native kidney biopsies. The diagnosis was based on the presence of mesangial predominant IgA deposits. Patients suffering from IgAN together with any other type of glomerulonephritis and patients with SLE, HSP or hepatic disease have been excluded from this study. We assessed 347 of the 478 patients who were followedup for at least 3 months, excluding those who presented with end stage renal disease (defined as CrCl < 10ml/ min). Creatinine clearance (CrCl) was estimated in all patients by the abbreviated Modification of Diet in Renal Disease (MDRD) formula 8, using an online calculator. Patients were divided into 2 broad groups, based on the Crcl at time of presentation. Group 1 (n = 229) with CrCl < 85 ml/min and group 2 (n = 118) with CrCl > 85ml/ min. Both groups were divided in 2 subgroups, Progressors [sub-group 1a (n = 139) and 2a (n = 48)] and non-progressors [sub-group 1b (n = 90) and 2b (n = 70)]. Patients were classified as progressor if there was at least 20% decline in renal function at last followup. A schema of the study design is shown in fig.1 Clinical data For all patients, data on sex, age at presentation, blood pressure, the way the disease was discovered (modes of discovery included macroscopic hematuria, acute nephritic syndrome, nephrotic syndrome, incidental and renal failure) were obtained (Table1). Laboratory evaluations included urine examination, 24 hour urine protein, renal functions, serum cholesterol, triglyceride, uric acid and serum albumin. Pathological data The histopathological lesions of the glomeruli were classified according to the Hass s criteria 9. In addition specific histopathological changes such as mesangial hypercellularity, crescents, glomerular sclerosis, interstitial fibrosis, tubular atrophy and vascular involvement were evaluated according to semiquantitative methods as absent, mild, moderate and severe. The Immunofluorescence study included the following antisera conjugated with fluorescein isothiocyanate: IgG, IgM, IgA, C3 and C4. For each type of deposit, a semi-quantitative grading from 0 to 3+ was given according to the observed intensity. For logistic regression analysis, absent and mild was given a value of 0, and moderate to severe a value of 1. Similarly, for Figure - 1 Scheme of study

3 IF, 0 to 2+ was given a value of 0 and 3+ a value of 1. Statistical analyses Between group comparisons for continuous variables was done using independent t-test and Mann Whitney test for normal and non-normal (distribution) data respectively. Pearson Chi-Square test was used for categorical variables. Logistic regression analysis was carried out to find the factors associated with progression in both the groups (1 & 2). Multivariate analyses were carried out on the factors whose Univariate logistic regression test had a p value of < Renal survival was calculated using the Kaplan-Meier method, and compared by Log rank test. Relationship between patient variables and progression to end stage renal disease were examined by Cox regression. We used the Cox proportional hazard model, which is especially designed for multivariate evaluation of factors influencing the actuarial survival curve, taking into account all patients, even censored ones, until their last examination. Briefly, the model assumes that a patient with covariate values X 1, X 2 X n has a cumulative hazard rate related to an unspecified baseline hazard rate seen in the equation: h (t, X) = h 0 (t). exp xβ, where h(t, X) is the patient s hazard at time t, h 0 (t) the baseline hazard rate, and β a regression coefficient that gives the effect of each X covariate on the hazard rate. Values of p < 0.05 were considered to indicate statistical significance. Values are expressed as mean (± SD). All analyses were carried out using SPSS version Figure 2 - The distribution of patients among the grades of Hass classification system IgA nephropathy : outcome and progression Results 165 Clinical presentation Table 1 summarizes the main clinical data in our total series of 478 patients. The mean age at presentation was 32 (±11) months, with a predominant male (65%) cohort. Modes of presentation included nephrotic syndrome (55%), renal failure (serum creatinine > 1.4mg/dl in 56%), hypertension (58%), acute nephritis (28%) and incidental discovery in 5% of patients. On investigation, microscopic hematuria was seen in 60% of patients. The mean serum creatinine and 24 hour urine protein was 2.3mg/dl and 2.9g/day respectively. The distribution of patients among the grades of Hass classification system is shown in Figure 2. Follow-up Follow-up for at least 3 months was possible in 347 (73%) patients. In these 347 patients, during a follow up period of 3 to 140 (mean 27) months, 83 (17.4%) patients progressed to ESRD and a further 99 (29%) had a > 20% permanent decrease in renal function. A complete remission of disease activity with a normal centrifuged urine microscopy, 24 hr urine protein and renal function occurred in 10 (3%) patients. Clinical and laboratory findings among the subgroups are compared in Table 2 and biopsy findings in Table 3. Multivariate Logistic regression analyses of factors associated with progression Risk factors (Table 4) for progression by multivariate analysis in patients with decreased renal function at diagnosis (group 1) included hypertension (Odds Ratio 3.5), proteinuria more than 3gm/day (OR 3.4), and greater than 50% of sclerosed glomeruli on biopsy (OR 4.1). However, in patents with normal renal function at time of diagnosis (group 2); hypertension (OR 2.3) was the only identified risk factor for progression. (Table 5) Progressor Vs Non-progressor Analyzing 347 patients as a whole, with comparable duration of follow-up; hypertension, creatinine clearance at presentation, degree of proteinuria, higher level of serum uric acid and triglyceride, absence of recurrent macroscopic hematuria, degree of interstitial fibrosis, sclerosed glomeruli, and vascular involvement and the presence of crescents on biopsy, delineated a progressor from a non-progressor. (Table 6) Factors associated with progression to ESRD Factors associated with progression to end stage renal disease by Cox regression analysis is detailed in Table.7. On multivariate analysis, 4 factors (hypertension, nephrotic range proteinuria, degree of sclerosed glomeruli and interstitial fibrosis) were found to be significantly associated with progression to ESRD.

4 166 Indian Journal of Nephrology Indian J Nephrol 2004;14: Table1 : Patient demographics at time of diagnosis Variable % Mean ± SD Median (range) Age at presentation (years) 32 ± (15 76) Males 65 Follow up 73 Duration of follow up in months (n = 347) 27 ± (3 140) Nephrotic syndrome 55 Hypertension 58 MAP (mmhg) 105 ± (69 150) Recurrent macro-hematuria 9 Renal failure (creat = 1.4mg/dl) 56 Malignant Hypertension 3 Incidental 5 Acute nephritis 16 Transient Renal failure 3 Micro hematuria 60 Serum creatinine (mg/dl) 2.3 ± ( ) 24 urinary protein (UP) (g/d) 2.9 ± ( ) CrCl (ml/min) 60 ± ( ) Table 2 : Clinical and laboratory findings at time of biopsy Group 1 Group 2 Variable Subgroup Subgroup p Subgroup Subgroup 1a 1b value 2a 2b p value Number of patients Follow-up (months) 26 ( ± 24) 23 (± 29) N S 32 (± 16) 29 (±34) N S Males ( % ) NS NS Age (years) 35 ± ± 10 N S 31 ± 8 27 ± 9 N S Nephrotic syndrome (%) N S N S Hypertension (%) < Mean arterial pressure (mmhg) 112 ± ± 11 < ± ± 11 <0.00 Macroscopic hematuria (%) N S Creatinine clearance (ml/min) t (± 21) 44.4 (± 21) < (±12) 99.7 (± 22) 0.02 Proteinuria (g/d, t 0 ) 3.9 (± 2.8) 2.9 (± 3) < (±1) 2.1 (± 2) N S S. albumin (mg/dl) 3.4 (± 0.6) 3.5 (± 0.5) N S 3.7 (± 0.5) 3.6 (± 0.7) N S S. cholesterol (mg/dl) (± 66) 155 (± 88) N S 130 (± 107) 126 (± 123) N S S. triglyceride (mg/dl) 196 (± 102) 167 (± 110) (±101) 120 (± 116) N S S. uric acid (mg/dl) 7.4 (± 2.6) 6.5 (± 3) (± 2.9) 3.3 (± 3) N S

5 IgA nephropathy : outcome and progression 167 Coloured Page Fig 3: Cumulative probability of renal survival from onset of symptoms and time of biopsy Renal survival rates The cumulative probability of renal survival (that is, not progressing to end stage renal failure) was, from the onset of symptoms, 0.77 at 1 year and 0.25 at 5 years and, from time of renal biopsy, 0.58 at 1 year and 0.15 at 5 years. The median renal survival time from onset of symptoms and renal biopsy was 34 (95%CI: 25, 43) and 18 (95% CI: 10, 26) months respectively. Fig 3 The mean renal survival from time of biopsy was: in patients with and without hypertension (54 and 117 months; p <0.001): in patients with and without nephrotic range proteinuria (52 and 105 months; p <0.001) and in patients who had more than 50% of sclerosed glomeruli on biopsy than in those who did not it was 36 and 97 months respectively (p <0.001). Fig 4: Cumulative probability of renal survival and risk factors. Fig. 5. Cumulative probability of renal survival and year of diagnosis. Patients without identified risk factors (hypertension, nephrotic range proteinuria and > 50% sclerosed glomeruli) had a mean renal survival time of 132 ( 95% CI:120,145) months, while the mean survival time in those with one, two or all three risk factors were 105 ( 95%CI:93,116), 47 (95%CI:35,60) and 28 (95%CI:19,36) months respectively (Fig 4). The median renal survival time in patients who were diagnosed to have IgAN between the year 1994 and 1999 (54 months, 95% CI: 49, 59) was significantly longer than those who were diagnosed between 2000 and 2004 (8 months, 95% CI: 6, 10, p < 0.001). Fig 5 Discussion This study describes the natural history of the largest cohort of patients with IgAN reported to date. The size of the cohort allows meaningful comparison of factors at presentation affecting outcome. The incidence of 8.9 % of IgAN seen in this study is in accordance with those previously reported 4,5. However these figures may represent only the tip of the ice-berg, considering the biopsy policy and availability of immunoflourescence technique, a perquisite for the diagnosis. Although episodic macrohematuria is regarded as the commonest mode of presentation, 10 this study, including those reported from India 4,5, shows that nephrotic syndrome (55%) and renal failure (56%) are the commonest presenting feature of IgAN in India. Restrictive biopsy policies, with consequent selection of the population whose clinical course is closely monitored, might explain this variation in the modes of presentation. Despite the relative paucity of relevant symptoms during the clinical course, the outcome is extremely variable and difficult to predict. The incidence of chronic renal

6 168 Indian Journal of Nephrology Indian J Nephrol 2004;14: Table 3 : Histopathological findings at time of biopsy Group 1 Group 2 Variable (%) 1. a 1. b p value 2. a 2. b p value Hass s staging Stage < Stage 4 & Global sclerosis > 50% < Interstitial fibrosis (mod -sev) < N S Tubular atrophy ( Mod - sev) N S IgA deposition (3 +) IgM deposition N S C3 (3+) N S N S Crescents N S Table 4 : Risk factors for progression by multivariate analysis (Logistic Regression) in patients with decreased renal function at diagnosis (group 1) Variable Regression Standard P Odds 95.0 % C.I. coefficient error value ratio Lower Upper CrCl t o Hypertension Proteinuria Sclerosed glomeruli Interstitial fibrosis Constant Hosmer-Lemeshow test result Table 5 : Risk factors for progression by multivariate analysis (Logistic Regression) in patients with normal renal function at diagnosis (group 2) Variable Regression Standard P Odds 95.0 % C.I. coefficient error value ratio Lower Upper CrCl t o Hypertension Age Macro-hematuria Constant Hosmer-Lemeshow test result 0.322

7 IgA nephropathy : outcome and progression Table 6. Variables among progressors and non-progressors 169 Factors Progressor Non-progressor p value n = 187 n = 160 Duration of follow-up (months) 28 ± ± 32 N S Males (%) N S Age (years) 34 ± ± 11 N S Recurrent macrohematuria Mean arterial pressure (mmhg) 111 ± ± 11 < Creatinine clearance (ml/min) 48 ± ± 35 < Proteinuria (g/d,) 3.4 ± ± 3 <0.001 S. albumin (mg/dl) 3.5 ± ± 0.6 N S S. uric acid (mg/dl) 7 ± ± S. triglyceride ( mg/dl) 190 ± ± Hass stage 4 & 5 (%) Global sclerosis > 50% Mod. interstitial fibrosis Crescents (%) Mod. vascular involvement failure has been reported to range from 20 to 40% 2,3. In our study renal failure as defined by a serum creatinine of greater than 1.3mg/dl was seen in 56% of patients. 17.4% patients progressed to ESRD and a further 29% had a > 20% permanent decrease in renal function. This is in sharp contrast to those observed by Ibels et al 11 where ESRD at follow-up was seen in only 8.6% of their study patients. We analyzed factors associated with progression, separately for groups defined on the basis of level of renal function on diagnosis. This approach, similar to the one used by Rauta et al 12, was chosen since comparisons between pervious studies are difficult because of differences in patient populations, in stages of the disease and follow-up periods and it is known that some factors related to the progression are associated with decreased renal function per-se. In this study only the existence and the degree of hypertension and impaired creatinine clearance at time of diagnosis were associated with progression at all the stages of the disease on biopsy that were defined and studied. This observation is in agreement with those by Okada et al 13 who doubted the significance of histological alterations as prognostic indicators in early stage of the disease. Higher levels of proteinuria, serum triglyceride and serum uric acid were statistically associated with progression in group 1 only. Syrjanen et al 14 also reported similar findings and sought to link the development of glomerulosclerosis to the metabolic disturbances. Macroscopic hematuria was a protective factor for progression in both the groups, however it achieved statistical significance only in group 2 (patients with normal renal function) in univariate analysis. Histopathological changes seen in this study were in concordance with those reported earlier 15,16,17. Grades of interstitial fibrosis, sclerosed glomeruli, tubular changes and the intensity of IgM deposits were significantly related to progression in group 1 but not in group 2 (those with normal renal function). Sakai et al 18 had reported that patients with more severe histological lesions showed more intense IgM mesangial deposits. On multivariate analysis, factors independently predictive of outcome were hypertension, nephrotic range proetinura, and greater than 50% of sclerosed glomeruli on biopsy. This, however, was applicable only to patients with renal failure. In patients with normal renal function, hypertension alone was an independent predictive factor for poor outcome. The existence of hypertension has been reported to be one of the most important factors associated with progression in other multivariate analysis relating to IgAN 19,20. D Amico 21 recently surmised that the existence of hypertension might be the best indicator of likely progression in patients with normal renal function. The results of our study confirm this. On analyzing the entire cohort of 347 patients as a single unit irrespective of the renal function at diagnosis, in addition to the risk factors already mentioned, absence

8 170 Indian Journal of Nephrology Indian J Nephrol 2004;14: Table 7. Factors associated with progression to end stage renal disease by multivariate (Cox regression) analysis Variable Regression Standard P Odds 95.0 % C.I. coefficient error value ratio Lower Upper IgA Hypertension Proteinuria Sclerosed glomeruli Interstitial fibrosis of recurrent macroscopic hematuria, and the presence of crescents on biopsy, delineated a progressor from a non-progressor. We used Cox s proportional hazard model as it estimates the quantitative effect of each significant risk factor and allows the calculation of a relative risk. Nevertheless, this model assumes that the effect of each risk factor remains constant with time, and we do not know if it is true for IgAN. From the analysis of all our patients, Cox s regression model allowed us to find four significant risk factors for the development of ESRD, and gave for each of them their relative weight (β coefficient). In addition to this we can estimate the probability of renal survival with the equation. S (t, X) = exp [-h (t, X)] β coefficients of the 4 significant risk factors are X1 = Hypertension (present - 1; absent - 0); β1 = X2 = Proteinuria (> 3g/d is 1; 0-3g/d is 0); β2 = 0.67 X3 = Global sclerosis (> 50% is 1; < 50% is 0); β3 = 0.59 X4 = Interstitial fibrosis (moderate is 1; mild is 0); β4 = 0.93 Baseline hazard h 0 (t): 0.04 at 1 year S (t, X) = exp [-h (t, X)] [-h (t, X)] = h 0 (t) exp Σβx For example, A patient with IgAN with hypertension, nephrotic range proteinuria, moderate to severe interstitial fibrosis and more than 50 % of sclerosed glomeruli on biopsy. Substituting X and â in the Cox s equation: [-h (t, X)] = h 0 (t) exp Σβx Σβx = (1.139 x 1) + (0.674 x 1) + (0.594 x 1) + (0.933 x 1) = 3.34 Exp Σβx = S (t, x) = s (1, x) = exp [-(0.04 x 28.22)] = 0.31 The probability of a patient with IgAN, having all four risk factors, not progressing to ESRD at 1 year is That is, there is a 69 % probability that he will develop ESRD at 1 year. Kaplan Meier analysis showed that the cumulative probability of renal survival at 5 years form the onset of symptom and biopsy was 0.25 and 0.15 respectively. This was low when compared to the 0.97 and 0.92 observed by Ibels et al 11. The variability at presentation in both duration (lead-time bias) and severity of disease (higher level of mean serum creatinine [2.3mg/dl] at time of presentation in our study) may explain this discordance to a great extent. However, the possibility of other factors (genetic and environmental) contributing to this poor prognosis warrants consideration. Previous observations 22,23 that polymorphisms of the ACE gene and the angiotensinogen gene appear to influence the development of progressive renal failure in IgAN lends credence to this hypothesis. Further genetic studies in our cohort are required to substantiate this view. Environmental factors including dietary differences between countries may also explain differences in the outcome of IgAN as shown by the intake of fish oil 24. A rather disturbing trend observed was the progressive nature of renal dysfunction and poor renal survival, seen in patients diagnosed from year 2000 onward as opposed to those before year Whether the present genetic and environmental milieu and lifestyle changes are responsible for this is highly speculative. The biopsy policy and availability of IF can influence the spectrum of clinical manifestations of IgAN and its apparent incidence. In regions where there is no active urine screening programme or where the biopsy policy is restrictive, the apparent incidence of IgAN correlates inversely with the frequency of severe signs, among those diagnosed with disease, because patients with mild changes are missed. The frequency of severe signs among the present cohort is higher, perhaps, because these patients are being positively selected. Despite these limitations, this study provides insight into the

9 natural history of IgAN in India, thereby, providing a platform for further studies and clinical trials. In conclusion, this study characterizes IgA nephropathy from an Indian perspective. IgAN appears in its clinical and histological manifestations as a continuum, with some features more commonly observed, or more severe, in patients who have a rapidly progressive downhill course. Our model suggests that in an individual patient, a semi-quantitative estimate of both long term outlook and the effectiveness of treatment can be obtained by examining the presence or absence of hypertension, nephrotic range proteinuria, and the degree of interstitial fibrosis and sclerosed glomeruli on IgA nephropathy : outcome and progression 171 biopsy. Renal survival is low; leading to speculation that IgAN is malignant in the Indian context, possibly due to an unfavorable genetic and environmental milieu. Considering that around 50% of patients progressed, including 17% to ESRD, IgAN has serious medical and socio-economic impact. In the absence of disease specific therapy, newer therapeutic modalities, lifestyle changes and rigorous control of hypertension, may go a long way to retard the progressive nature of IgA nephropathy in India. Awarded Rekha Memorial Tanker Award best paper presentation, Annual Conference of Indian Society of Nephrology, 2004, Varanasi. References 1. Berger J., Hinglais: Les depots intercapillaires d IgA IgG. J. Urol. Nephrol. 1968; 74: Kincaid-Smith P, Nicholls K: Mesangial IgA nephropathy. Am J Kidney Dis. 1983;3(2): Lee HS, Koh HI, Lee HB, and Park HC: IgA nephropathy in Korea: a morphological and clinical study. Clin Nephrol. 1987;27(3): Muthukumar T, Fernando ME, Jayakumar M.: Prognostic factors in immunoglobulin-a nephropathy. J Assoc Physicians India. 2002; 50: George J, Ninan VT, Thomas PP, Jacob CK, Shastry JC. Primary IgA nephropathy in adults. 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The clinical course of mesangial IgA associated nephropathy in adults. Q J Med. 1984; 53(210): Sakai O., Kitajima T., Kawamura K., Ueda Y.: Clinicopathological studies on IgA glomerulonephritis. In: Glomerulonephritis, edited by Yoshitoshi Y., Ueda Y., University Park Press, Baltimore, 1979, p Alamartine E, Sabatier JC, Guerin C, Berliet JM, Berthoux F. Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses. Am J Kidney Dis. 1991; 18(1): Beukhof JR, Kardaun O. Toward individual prognosis of IgA nephropathy. Kidney Int. 1986; 29(2): D Amico G, Imbasciati E, Barbiano Di Belgioioso G, Bertoli S, Fogazzi G, Ferrario F, Fellin G, Ragni A, Colasanti G, Minetti L, et al. Idiopathic IgA mesangial nephropathy. Clinical and histological study of 374 patients. Medicine (Baltimore). 1985; 64(1): Harden PN, Geddes C, Rowe PA, McIlroy JH, Boulton- Jones M, Rodger RS, Junor BJ, Briggs JD, Connell JM, Jardine AG. Polymorphisms in angiotensin-convertingenzyme gene and progression of IgA nephropathy. Lancet ; 345(8964): Pei Y, Scholey J, Thai K, Suzuki M, Cattran D. Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients. J Clin Invest ;100(4): Donadio JV Jr, Grande JP, Bergstralh EJ, Dart RA, Larson TS, Spencer DC. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol. 1999; 10(8):