Remission of Proteinuria Improves Prognosis in IgA Nephropathy
Heather N. Reich*,
Stéphan Troyanov,
James W. Scholey*,
Daniel C. Cattran* for the Toronto Glomerulonephritis Registry
* Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, and Department of Medicine, Division of Nephrology, Hôpital du Sacré-Coeur de Montréal, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
Correspondence: Dr. Heather Reich, c/o The Toronto Glomerulonephritis Registry, Toronto General Hospital, 12EN-228, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. Phone: 416-340-4187; Fax: 416-340-3714; E-mail: h.reich{at}utoronto.ca
Received for publication May 1, 2007.
Accepted for publication July 4, 2007.
Proteinuria has been shown to be an adverse prognostic factorin IgA nephropathy. The benefit of achieving a partial remissionof proteinuria, however, has not been well described. We studied542 patients with biopsy-proven primary IgA nephropathy in theToronto Glomerulonephritis Registry and found that glomerularfiltration rate (GFR) declined at –0.38 ± 0.61ml/min per 1.73 m2/mo overall, with 30% of subjects reachingend-stage renal disease. Multivariate analysis revealed thatproteinuria during follow-up was the most important predictorof the rate of GFR decline. Among the 171 patients with <1g/d of sustained proteinuria, the rate of decline was 90% slowerthan the mean rate. The rate of decline increased with the amountof proteinuria, such that those with sustained proteinuria >3g/d (n = 121) lost renal function 25-fold faster than thosewith <1 g/d. Patients who presented with 3 g/d who achieveda partial remission (<1 g/d) had a similar course to patientswho had 1 g/d throughout, and fared far better than patientswho never achieved remission. These results underscore the relationshipbetween proteinuria and prognosis in IgA nephropathy and establishthe importance of remission.
Primary IgA nephropathy (IgAN) is the most common form of idiopathicglomerulonephritis (GN) throughout the world and the main causeof ESRD in patients with primary glomerular disease.1 In Toronto,nearly 40% of patients with IgAN progress to ESRD by 10 yr.2Variability in the literature regarding the clinical courseof patients with IgAN3–7 may be related to multiple factors,including patient biologic differences, nephrologists' practicepatterns (e.g., biopsy timing), and geography.7 The abilityto predict outcome in patients with IgAN remains a criticalfeature of patient treatment and has been a primary focus ofprevious studies.2,3,5,6,8–15
Many studies7,16,17 have shown that proteinuria is a predictorof outcome in IgAN. Experimental evidence supports these humandata by clarifying the direct deleterious effect of proteinuriaon renal tissue.18–23 In contrast to other progressivetypes of GN, in which it seems that only sustained nephrotic-rangeproteinuria (>3 to 3.5 g/d) ensures a poor prognosis, studiesin IgAN5,10,17,24,25 and have suggested that much lower levelsof proteinuria adversely affect prognosis. Furthermore, althoughthe concept of achieving "partial remission" is not commonlyassociated with IgAN, recent evidence in other forms of GN hasdetermined its clinical significance and established its prognosticvalue.26,27 The relevance of such a definition and its valuein IgAN would be important for management of this disease.
Accordingly, we examined the effects of proteinuria at diagnosisas well as sustained exposure to proteinuria on outcome in alarge cohort of patients who had primary IgAN and were followedlongitudinally in the Toronto Glomerulonephritis Registry. Wealso assessed the prognostic relevance of achieving partialremission as defined by achieving sustained proteinuria values<1 g/d.
Baseline Characteristics and Clinical Outcome
As described in Table 1, the majority (61%) of the 542 patientsstudied were male and of white or Asian (China, Japan, or PacificRim) descent. Mean initial proteinuria was 2.4 g/d, and creatinineclearance (CrCl) was 77 ml/min per 1.73 m2. Patients were followedfor 6.5 yr. By study completion, one third of patients had reachedESRD. The rate of progression as measured by slope of CrCl was–0.38 ± 0.61 ml/min per 1.73 m2/mo (–4.56ml/min per 1.73 m2/yr).
Table 1. Baseline characteristics and clinical outcome in 542 patients with IgAN
Proteinuria and the Rate of Decline of Renal Function
Clinical variables at onset of disease and during follow-upwere tested for association with the slope of CrCl. Regressionanalysis revealed that several factors, shown in Table 2, werepredictive of a faster rate of renal function decline (steeper,more negative slope).
Table 2. Factors at presentation and during follow-up influencing decline in renal function (slope in ml/min per 1.73 m2/mo) by univariate and multivariate regressiona
The time-average proteinuria (TA-proteinuria; see Concise Methodssection) was a critical determinant of slope by univariate andmultivariate analysis (P < 0.01) and the most important predictorof renal function decline (R2 = 0.162, F = 104.5, P < 0.01).Proteinuria at presentation was not predictive of slope by multivariateanalysis.
The TA-proteinuria was also analyzed as a categorical variable,as illustrated in Table 3. When adjusted for multiple comparisons,the rate of deterioration (slope) of renal function differedsignificantly across the entire range of proteinuria. The greatestdifference in rate of decline occurred between the 1 and >1g/d TA-proteinuria. On the basis of the mean 10-yr slope, patientswith 1 g of TA-proteinuria had stable renal function, and patientswith 1 to 2 g of TA-proteinuria had a projected unadjusted lossof 40 ml/min per 1.73 m2 by 10 yr. Trend test and nonparametrictesting did not establish differences among patients with 1g/d TA-proteinuria: 0 to 0.3 (n = 36) versus 0.3 to 0.6 (n =63) versus 0.6 to 1 g/d TA-proteinuria (n = 72; slopes 0.00± 0.39, 0.02 ± 0.48, and –0.06 ±0.48 ml/min per 1.73 m2/mo, respectively; NS). Proteinuria categoriesdid not overlap (i.e., patients were assigned to only one categoryof TA-proteinuria).
Table 3. Outcome based on categorical grouping of TA 24-h urine protein excretion during follow-upa
Proteinuria and Renal Survival
The TA-proteinuria was the most important predictor of renalsurvival, even when corrected for other parameters (multivariatehazard 1.57; 95% confidence interval 1.39 to 1.77; P < 0.01).The graded effect of TA-proteinuria on renal survival is illustratedin Figure 1. Having <0.3 g/d proteinuria was similar to 0.3to 1.0 g/d, but each gram above 1 g/d (reference group) wasassociated with worse renal survival, with a hazard ratio of3.5 for ESRD with 1 to 2 g/d, 5 with 2 to 3 g/d, and 10 with>3 g/d.
Figure 1. Renal survival by category of TA-proteinuria.
We analyzed the course of patients whose initial proteinuriawas >1 g/d and fell below this level during follow-up. Patientswere divided into groups on the basis of their peak proteinuria:1 to 2, 2 to 3, and >3 g/d. As illustrated in Figure 2, allpatients whose proteinuria reached a "partial remission" of<1 g/d, regardless of the starting point, had a similar,favorable survival (log rank NS) and rate of progression (–0.2± 0.47, –0.14 ± 0.63, and –0.16 ±0.37 ml/min per 1.73 m2/mo respectively; NS). In comparison,the outcome of "nonremitters" (i.e., those who did not achieve<1 g/d) was markedly worse than remitters, with a far morerapid rate of renal decline (–0.76 ± 0.59 versus–0.13 ± 0.41 ml/min per 1.73 m2/mo respectively;P < 0.01). Patients who achieved complete remission of proteinuria(sustained level of <0.3 g/d with preserved CrCl) did nothave a different rate of renal function decline than patientswho achieved partial remission to <1 g/d (–0.17 ±0.47 versus –0.13 ± 0.41 ml/min per 1.73 m2/mo,respectively; NS).
Figure 2. Impact of reduction of proteinuria on renal survival. Patients attaining partial remission (<1 g/d), regardless of peak proteinuria, had a similar favorable outcome (NS). Group 1, 1 to 2 g/d peak proteinuria; group 2, 2 to 3 g/d peak proteinuria; group 3, >3 g/d peak proteinuria.
The course of patients whose initial proteinuria was <1 g/dbut subsequently rose was also analyzed. Change in proteinuriawas calculated by subtracting the final from the initial value.Patients were then grouped into three categories according totheir quantitative increase in proteinuria: 1 to 2 g/d (group1), 2 to 3 g/d (group 2), and >3 g/d (group 3). As illustratedin Figure 3, the opposite of the improvements seen with loweringproteinuria were observed: The greater the rise in proteinuria,the worse the renal survival (log rank P = 0.004 by trend test)and rate of renal function decline (F = 3.8, P = 0.025). Posthoc analysis revealed that although the rate of renal functiondecline of patients in group 1 was similar to that of group2 (–0.23 ± 0.41 versus –0.12 ± 0.79ml/min per 1.73 m2/mo; NS), patients in group 3 had a significantlymore rapid rate of renal function decline than patients in eithergroup 2 (–0.51 ± 0.55 versus –0.12 ±0.79 ml/min per 1.73 m2/mo; P = 0.02) or group 1 (–0.51± 0.55 versus –0.23 ± 0.41 ml/min per 1.73m2/mo; P = 0.03). In terms of renal survival, 20 of the patientswho presented with "low risk" proteinuria levels of <1 g/dhad a subsequent rise in proteinuria and actually progressedto ESRD. These 20 patients had a lower CrCl at presentation(58 versus 81.4 ml/min per 1.73 m2; P < 0.05) and a higherTA mean arterial pressure (TA-MAP; 101 versus 96 mmHg; P <0.05).
Figure 3. Renal survival in patients with 1 g/d proteinuria at presentation differed significantly on the basis of increase in proteinuria from baseline. Group 1, 1 to 2 g/d increase; group 2, 2 to 3 g/d increase; group 3, >3 g/d increase in proteinuria from baseline. P = 0.004 by trend test.
Role of Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker
Because this is not a therapeutic trial, the direct role ofspecific interventions cannot be accurately assessed. It wasobserved that the use of angiotensin-converting enzyme inhibitor/angiotensinreceptor blocker (ACEi/ARB) lowered the rate of decline of renalfunction, even when adjusted for other clinical parameters.A greater proportion of patients who achieved partial remissionof proteinuria were treated with ACEi/ARB, compared with patientswho did not (66 versus 52%; 2 = 12.7, P < 0.01). The beneficialeffects of ACEi/ARB may have been related to effects on bothproteinuria and BP; however, use of other antihypertensive agentsdid not influence loss of renal function by multivariate analysis.The use of ACEi/ARB and GFR at the start of these medicationswere significant determinants of renal survival by univariateanalysis (P < 0.01), however not multivariate analysis. Themajority (86%) receiving ACEi/ARB were treated with ACEi alone,and there were insufficient patient numbers to analyze relativedifferences in ACEi versus ARB versus combination therapy.
Other Determinants of Outcome
Multivariate analysis revealed that only TA-proteinuria, TA-MAP,and quartile of exposure to ACEi/ARB were predictors of renalfunction decline (see Table 2) and were also predictive of renalsurvival by multivariate Cox regression analysis. The complexnature of the interaction between MAP and proteinuria is illustratedin Figure 4; patients with the highest quartile of TA-MAP alsohad high levels of proteinuria and the greatest rate of lossof renal function; however, TA-proteinuria was still the mostimportant predictor of outcome, independent of BP. Neither bodymass index (BMI; continuous variable) nor high BMI (>27)was a predictor of slope by univariate analysis. As a continuousvariable, BMI related to renal survival only by univariate (notmultivariate) Cox regression, which may have been driven bya higher risk for ESRD in patients with BMI >29 (hazard ratio2.1; 95% confidence interval 1.2 to 3.6). No other factor (initialrenal function, smoking, gender, ethnicity, fish oil, or immunotherapy)was predictive of the rate of loss of kidney function.
Figure 4. Relationship between TA-proteinuria group, quartile of MAP, and loss of CrCl. Group 1, TA-proteinuria <1 g/24 h; group 2, 1 to 2 g/24 h; group 3, 2 to 3 g/24 h; group 4, >3 g/24 h.
The purpose of this study was to quantify the value of proteinuriareduction on outcome in patients with IgAN. We also sought todetermine whether by defining partial remission and by assessingthe impact of change in proteinuria on outcome we could confirmthe importance of the definition by quantifying its value inrelationship to both rate of disease progression and renal survival.
Although proteinuria is a known risk factor for progressionof IgAN,2–6,8,9,14,28 important questions regarding itsrole in the prognosis of IgAN remain. First, timing of measurementrequires clarification; proteinuria at diagnosis often is nota predictor of outcome by multivariate analysis,2,17 whereasproteinuria at 1 yr or later may better indicate prognosis.2Second, although many studies suggest that patients with 1 g/dat presentation have a favorable prognosis,5,29 this observationis not uniform,10 and it is not known whether patients who achievethis target from higher values have the same prognosis as patientswho present with and maintain low-level proteinuria. Finally,the importance of defining partial remission in proteinuriawas established recently for other forms of GN26,27; it hasnot been confirmed or quantified in IgAN and would representimportant information for clinicians.
We have confirmed that in IgAN, proteinuria exposure over time(TA-proteinuria) is the strongest predictor of the rate of renalfunction decline. The relationship between TA-proteinuria andoutcome is dramatically altered down to levels as low as 1 g/d,which is in marked contrast to the other progressive types ofprimary nephropathy, including membranous GN and FSGS. A quantitativeestimate of the impact of proteinuria has been determined: Eachincremental gram per day above 1 is associated with a 10- to25-fold more rapid rate of renal function decline and similardifferences in renal survival. Although we could not determinea difference in outcome below 1 g/d, this may reflect inadequatestatistical power because the benefit is likely continuous;however, even if power were improved, the clinical relevanceof improved slope below this level will be minor given the overallslow rate of decline observed in the patients with <1 g/dTA-proteinuria.
Patients who reached <1 g/d proteinuria regardless of theirstarting point, whether "partial remission" was reached spontaneouslyor with intervention, had an excellent prognosis, similar topatients whose proteinuria never exceeded 1 g/d. This is strongsupport for using this partial remission definition as a goalfor clinicians and provides new insights regarding the valueof proteinuria reduction as a therapeutic target. Although previouslyrecognized as important, the magnitude of the effect of proteinuriareduction on progression and renal survival has not been describedin IgAN. By determining the quantitative value of partial remission,intensive therapy targeting significantly lower levels of proteinuriathan in the other primary glomerulopathies is justified. Providingthis information to the patient—that is, the substantialvalue of small reductions in proteinuria—should also aidcompliance in these largely asymptomatic individuals.
This study was not a therapeutic trial and not designed to assessthe benefit of therapeutic interventions in the course of IgAN.The most important conclusion derived is that the reductionof proteinuria by whatever means (medication, MAP reduction)is of great clinical benefit. The use of ACEi/ARB was the onlyintervention associated with a slower rate of renal functiondecline and prolonged renal survival, in keeping with both publishedrandomized, controlled trials and retrospective reviews demonstratingthe renoprotective effect of renin-angiotensin-aldosterone systemblockade.30–39 These beneficial effects may reflect bothhemodynamic and nonhemodynamic antiproteinuric effects of ACEi/ARB24,35,40–42or alterations in glomerular permselectivity43; however, thisstudy was not designed to determine causality or mechanism.Similarly, although MAP was an important determinant of outcomeand patients with the highest quartile of MAP had the highestlevels of proteinuria, this is not necessarily a causal relationship.
The results of this study may not be generalizable to otherpopulations. We previously demonstrated differences across geographicregions of the world in patients with IgAN.7 Although the majorityof the difference was due to practice patterns, we could notexplain all of the regional differences. In addition, becauseof the dominant effect of protein reduction on outcome, theeffects of interventions and clinical parameters (fish oil,BMI) may have been obscured. Finally, this study was not designedto assess the role of renal biopsy findings in predicting outcome.Our aim was to measure factors during the course of diseasethat relate to outcome (e.g., TA-proteinuria), as opposed toimplications of cross-sectional factors, such as biopsy gradeat the time of diagnosis. As demonstrated in our previous study2of a large cohort of patients with IgAN, although biopsy findingsare clinically important, we do not believe that the findingsat the time of biopsy provide additional information that isnot captured by time-dependent variables. Although many studieshave found a relationship between sclerosis/fibrosis and outcome,these studies did not include sequential measurements of MAP/proteinuriaover time5,44,45 or had shorter follow-up.3 Indeed, a relationshipbetween biopsy class and final follow-up data has been noted15;however, the value of adding the pathologic information to repeatedsequential clinical measurements over time has not been demonstrated.
In summary, sustained proteinuria >1 g/d was the strongestpredictor of the rate of progression of renal disease and thedevelopment of renal failure in IgAN. We demonstrated that witheach sustained gram-per-day increment of proteinuria above 1,fold differences in progression rate and renal survival wereobserved. More important, patients who were able to achieveand sustain reduction in proteinuria to <1 g/d had an excellentprognosis regardless of the level of initial proteinuria. Thisstudy quantifies the impact of proteinuria reduction in IgANand the clinical relevance of defining partial remission inthis disease as a valuable prognostic indicator for both theclinician and the patient.
Patient Selection
As described previously,26,27,46 the Toronto GlomerulonephritisRegistry was started in 1974 and includes all biopsy-provencases of GN from the greater Toronto area. Patient informationis documented from first clinical presentation and collectedon a periodic prospective basis by registrars.
All patients who had biopsy-proven IgAN and were enrolled inthe Toronto Glomerulonephritis Registry were considered (n =1373) and were excluded only when clinical data were incomplete(37 lacked proteinuria data, 18 lacked weight data), they wereyounger than 16 yr at presentation (n = 54), they had <12mo of follow-up (n = 713), or they had a secondary cause ofIgA deposition (n = 9). A total of 542 patients were included.
Gender, ethnicity, age, and BMI were recorded at the time offirst assessment suggestive of GN. Weight; BP; exposure to medications;and laboratory parameters recorded, including creatinine, albumin,urinalysis results, and 24-h urine protein and creatinine excretion,were collected prospectively.
Definitions
CrCl was estimated using the Cockroft-Gault method adjustedfor body surface area.47,48 The GFR was also estimated usingthe abbreviated Modification of Diet in Renal Disease (MDRD)equation,49 and the results of the analysis were the same interms of relative importance of predictors in determining outcome.Start of follow-up was defined as the first assessment suggestiveof renal disease. A CrCl <15 ml/min per 1.73 m2, initiationof dialysis, or transplantation defined ESRD. MAP was definedas the diastolic pressure (in mmHg) plus one third of the pulsepressure. For each patient, an average MAP was determined foreach 6-mo block during follow-up; the average of every 6-moperiod's MAP is represented by the TA-MAP. Proteinuria was measuredby 24-h urine protein collection. In a similar manner to MAP,the TA-proteinuria represents an average of the mean of every6-mo period's proteinuria measurements.
The rate of renal function decline is expressed as the slopeof CrCl, which was obtained by fitting a straight line throughthe calculated CrCl using linear regression and the principalof least squares. This was plotted and visually examined foreach patient. Periods of reversible acute renal failure (a rapidreduction and recovery in CrCl of 40% within a 1-mo time frame)were removed from the calculation.
Statistical Analyses
Data were analyzed using Microsoft Excel (Redmond, WA) and SPSSsoftware (SPSS, Chicago, IL). Normally distributed variablesare expressed as means ± SD and compared using t testor ANOVA as required. Nonparametric variables are expressedas median and range and compared using either Mann-Whitney Uor Kruskal-Wallis test. Categorical variables were comparedusing a 2 test. All P values were two-tailed; P < 0.05 wasconsidered statistically significant. Univariate followed bymultivariate linear regression was used to determine independentpredictors of slope. Clinically relevant parameters or variablessignificantly associated with slope by univariate analysis wereincluded in the multivariate models. Because proteinuria distributionwas skewed (at presentation and time averaged), log-transformedvalues were used in the regression analysis, and similar resultsin terms of the significance of proteinuria were obtained withnontransformed data (data not shown). Multivariate regressionmodels were assessed by stepwise and block entry of variables.Renal survival times were calculated from the first clinicalassessment suggestive of renal disease to last follow-up. Therelationship between parameters and renal survival was assessedusing Cox regression.
Exposure to ACEi or ARB was considered as both a dichotomousvariable and a continuous TA measurement of ACEi/ARB exposure.This variable had a skewed distribution and was considered inquartiles of exposure to ACEi/ARB for multivariate regression.For assessment of the role of ACEi/ARB on survival, these factorswere considered as time-dependent variables for Cox regressionanalysis to account for time of initiation as well as residualGFR at that moment.
H.N.R. is the recipient of a KRESCENT clinician-scientist fellowshipfrom the Kidney Foundation of Canada and the Canadian Instituteof Health Research (CIHR). J.W.S. holds the Amgen-CIHR ResearchChair at University Health Network/University of Toronto. Fundingfor this study was supported by operating grants from the KidneyFoundation of Canada and CIHR, in addition to the CIHR Genes,Gender, and Glomerulonephritis New Emerging Team grant. S.T.'sresearch efforts are supported by the Fonds de la rechercheen santé du Quebec.
We thank the glomerulonephritis registrars N. Ryan and P. Lingfor help in the collection and management of data and the followingnephrologists for contributing patients and support to the registry:Drs. S. Albert, J. Bargman, M. Berall, W. Berry, H. Bornstein,G. Buldo, C.J. Cardella, C. Chan, P. Chan, S. Chow, E.H. Cole,S. Donnelly, I.O. Elkan, S.S.A. Fenton, M.B. Goldstein, R. Golush,G. Hercz, M. Hladunewich, M.R. Hockley, V. Jassal, K. Kamel,A. Kang, S.Y. Karanicolas, D. Kim, L. Lam, A.G. Logan, C.E.Lok, M.E. Manuel, P. McFarlane, H. Mehta, D. Mendelssohn, D.Naimark, B. Nathoo, P.S.Y. Ng, M. Oliver, D.G. Oreopoulos, S.Pandeya, Y. Pei, Y.A. Pierattos, V. Poulopoulos, R. Prasad,B. Reen, R.M. Richardson, J. Roscoe, D. Ryan, J. Sachdeva, C.S.Saiphoo, D. Sapir, J. Sasal, M. Schreiber, M. Silverman, A.Steele, E. Szaky, P. Tam, D.S. Thompson, R. Ting, S. Tobe, A.Wadgymar, L. Warner, C. Wei, C. Whiteside, G. Wong, G. Wu, andJ. Zaltzman. We also thank participating pathologists T. Feltis,A.M. Herzenberg, S. Jothy, G. Lajoie, L. Sugar, and J. Sweet.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had 
1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission. 
2 = 12.7, P < 0.01). The beneficial effects of ACEi/ARB may have been related to effects on both proteinuria and BP; however, use of other antihypertensive agents did not influence loss of renal function by multivariate analysis. The use of ACEi/ARB and GFR at the start of these medications were significant determinants of renal survival by univariate analysis (P < 0.01), however not multivariate analysis. The majority (86%) receiving ACEi/ARB were treated with ACEi alone, and there were insufficient patient numbers to analyze relative differences in ACEi versus ARB versus combination therapy. 
