Abstract
Background and objectives
Current therapy for IgA nephropathy mainly includes renin-angiotensin system inhibitors and adding steroids for patients with persistent proteinuria. This study aimed to evaluate kidney disease progression and its risk factors in a Chinese cohort under current therapy.
Design, setting, participants, & measurements
Patients with IgA nephropathy followed up for at least 12 months from a prospective database were involved. Renal survival and the relationship between clinical parameters and composite kidney failure events (defined as end stage kidney failure or eGFR halving) were assessed.
Results
Overall, 703 patients between 2003 and 2011 were enrolled in this study, with a mean follow-up time of 45 months. Mean eGFR was 84.0 ml/min per 1.73 m2, systolic BP was 124 mmHg, and time-averaged mean arterial pressure was 90.0 mmHg. Median proteinuria at baseline was 1.60 g/d, and time-averaged proteinuria was 0.80 g/d. The mean rate of eGFR decline was −3.12 ml/min per 1.73 m2 per year (95% confidence interval, −19.07 to 11.80), and annual end stage kidney failure rate was 2.3%. Multivariate Cox regression analyses revealed that baseline eGFR (hazard ratio, 0.76 per 10 ml/min per 1.73 m2; 95% confidence interval, 0.66 to 0.91), proteinuria at 6 months (hazard ratio, 1.53 per g/d; 95% confidence interval, 1.27 to 1.84), and systolic BP control at 6 months (hazard ratio, 1.36 per 10 mmHg; 95% confidence interval, 1.05 to 1.77) were associated with composite kidney failure events. Baseline eGFR (regression coefficient, −0.06; 95% confidence interval, −0.07 to −0.04), time-averaged proteinuria (regression coefficient, −0.21; 95% confidence interval, −0.25 to −0.16), and time-averaged mean arterial pressure (regression coefficient, −0.15; 95% confidence interval, −0.21 to −0.09) were independent predictors of the slope of eGFR by linear regression.
Conclusion
Lower proteinuria and lower BP were associated with slower eGFR decline and lower risk of end stage kidney failure in patients currently being treated for IgA nephropathy.
Introduction
IgA nephropathy (IgAN) was described by Berger and Hinglais in 1968 (1), and it is now the most common form of primary GN worldwide, especially in the Asian-Pacific region (2). IgAN is characterized by a highly variable clinical course ranging from a completely benign incidental condition to rapidly progressive renal failure. Most affected individuals develop chronic, slowly progressive renal injury, and many patients develop end stage kidney disease (ESKD) (3). It is estimated that 1%–2% of all patients with IgAN will develop ESKD within 1 year from the time of diagnosis (4). Studies (5–7) have confirmed the prognostic value of some clinical and biochemical parameters for the long-term outcome of patients with IgAN. Among them, impaired renal function, sustained hypertension, persistent proteinuria (especially proteinuria over 1 g/d), and severe renal lesions at initial biopsy constitute poor prognostic markers. Other risk factors are numerous and controversial but not widely confirmed. They include age at disease onset, sex, overweight or obesity, serum albumin, hemoglobin, hypertriglyceridemia or hyperuricemia, and various immunogenetic markers (8–14). Using these factors, several risk scoring systems have been developed (6,9,15) for evaluating the rate of IgAN progression. They are important for patients at risk but have not been validated in most cases. Therefore, we estimate long-term outcome and the effectiveness of treatment by examining risk factors.
A wide variety of treatments has been attempted to slow progression of IgAN, such as immunomodulation with corticosteroids and cytotoxics and modifying glomerular microdynamics with angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), and fish oils (16–19). Based on this evidence, most treatment guidelines relating to IgAN, including the recent KDIGO Clinical Practice Guideline for Glomerulonephritis, recommend optimal BP control using renin-angiotensin system (RAS) inhibitors and suggest adding steroids in patients with persistent proteinuria, regardless of supportive therapy (20). However, few studies have evaluated the progression and risk factors of IgAN under current therapy.
In this observational study, we aim to evaluate if therapy with RAS inhibitors and sequential addition of steroids or other immunosuppressive agents were associated with proteinuria reduction and BP control. We also investigate kidney disease progression and its risk factors for IgAN under current therapy.
Materials and Methods
Patients
All patients were selected from an IgAN database at Peking University First Hospital. This database was established in 2003 and made up of patients biopsied from 1994 to the present. Most patients were from northern China. All patients enrolled in the IgAN database were considered (n=1245). Patients were excluded who presented acute kidney failure (n=61), presented at younger than 15 years of age (n=64), or had less than 12 months of follow-up (n=417). A total of 703 patients were included. The study was approved by the Ethics Committee of Peking University First Hospital, and all participants gave written informed consent.
Data Collection and Patient Follow-Up
Patients had regular follow-up visits at intervals of at least 3–6 months. All data were collected prospectively. Baseline clinical and demographic data were recorded at the time of renal biopsy. Demographic data included age and sex. Clinical and laboratory parameters included were baseline data, such as systolic BP, diastolic BP, mean arterial pressure (MAP), proteinuria, serum creatinine (SCr), and eGFR. MAP was defined as the diastolic pressure plus one third of the pulse pressure. For each patient, an average MAP was determined for each 6-month block during follow-up; the average of MAP for every 6-month period is represented by time-averaged (TA) MAP. Proteinuria was measured by 24-hour urine protein collection. In a similar manner to TA MAP, TA proteinuria represents an average of the mean of proteinuria measurements for every 6-month period (21). The eGFR was estimated according to the Chronic Kidney Disease Epidemiology Collaboration equation (22). The rate of renal function decline is expressed as the slope of eGFR, which was obtained by fitting a straight line through the calculated eGFR using linear regression and the principle of least squares (21). It was plotted and visually examined for each patient. CKD was classified according to the Kidney Disease Outcomes Quality Initiative practice guideline. The composite kidney failure events were based on ESKD or eGFR halving without remission after observation for at least two consecutive follow-up visits.
The treatment regimen in our cohort study was based on completed trials, which were included in one of our prior reviews (23). (1) Full doses of ACEis and/or ARBs were recommended for all patients with proteinuria or hypertension. (2) Steroids were used when there was persistent proteinuria (>1 g/d), despite optimal BP control and RAS inhibitors; a 6- to 8-month course of the oral dose of prednisone or equivalent was started at 0.8–1.0 mg/kg per day for 8 weeks, and the dose was then tapered by 5–10 mg every 2 weeks. (3) Other immunosuppressive agents would be considered in patients with impaired kidney function (SCr>1.5 mg/dl) or rapidly progressive kidney function decline (SCr increase>15% in the year before entry) (24). Renal lesions were graded according to the Haas classification at the time that the database was established (25).
Statistical Analyses
Data were analyzed using SPSS 16.0 software. Continuous variables were expressed as means±SDs. All categorical variables were expressed as frequencies or percentages. The relationship between variables and composite kidney failure events defined as ESKD or eGFR halving was assessed by Cox regression. Parameters significantly associated with composite kidney failure events by univariate analysis were included in the multivariate models. For proteinuria and BP, which was the time-varying covariate, we have used the values at month 6 to predict kidney failure events in the Cox model when patients had entered a relative stable condition (26). Univariate followed by multivariate linear regression was used to determine independent predictors of slope of eGFR (15,21). P<0.05 was considered statistically significant.
Results
Clinical Characteristics
Clinical characteristics at baseline and during follow-up are summarized in Table 1. Mean age at biopsy was 33.9±11.9 years, and 361 (51.4%) patients were men. Mean systolic BP and diastolic BP at baseline were 124±15 and 79±12 mmHg, respectively. Mean eGFR was 84.0±29.1 ml/min per 1.73 m2, and baseline MAP was 93.8±12.2 mmHg. The median and interquartile range (IQR) of initial proteinuria were 1.60 and 0.87–3.09 g/d. Patients were followed for 45.0±28.8 months. Seven patients died, and six of these patients died before reaching ESKD, because of infection (n=3), cardiovascular disease (n=2), and lymphoma (n=1).
Table 1.
Clinical characteristics of patients with IgA nephropathy
| Characteristics | Value |
|---|---|
| Age (yr), mean±SD (median, IQR) | 33.9±11.9 (32, 25–41) |
| Men, n (%) | 361 (51.4) |
| Serum creatinine (mg/dl), mean±SD (median, IQR) | 1.15±0.54 (1.01, 0.81–1.29) |
| eGFR (ml/min per 1.73 m2), mean±SD (median, IQR) | 84.0±29.1 (86.5, 62.3–105.3) |
| CKD stage 1, n (%)a | 326 (46.4) |
| CKD stage 2, n (%)a | 222 (31.6) |
| CKD stage 3a, n (%)a | 77 (11.0) |
| CKD stage 3b, n (%)a | 46 (6.4) |
| CKD stage 4, n (%)a | 32 (4.6) |
| Baseline proteinuria (g/d), mean±SD (median, IQR) | 2.49±2.65 (1.60, 0.87–3.09) |
| SBP (mmHg), mean±SD (median, IQR) | 124±15 (123, 115–130) |
| DBP (mmHg), mean±SD (median, IQR) | 79±12 (80, 70–85) |
| Baseline MAP (mmHg), mean±SD (median, IQR) | 93.8±12.2 (93.3, 85.0–100.0) |
| Haas classification, n (%) | |
| I | 65 (9.2) |
| II | 9 (1.3) |
| III | 309 (44) |
| IV | 242 (34.4) |
| V | 78 (11.1) |
| Follow-up (mo), mean±SD (median, IQR) | 45.0±28.8 (38, 23–59) |
| Proteinuria at month 6 (g/d), mean±SD (median, IQR) | 1.08±1.04 (0.73, 0.32–1.36) |
| SBP at month 6 (mmHg) , mean±SD (median, IQR) | 118±15 (120, 110–125) |
| TA proteinuria (g/d), mean±SD (median, IQR) | 1.12±1.05 (0.80, 0.44–1.47) |
| TA MAP (mmHg), mean±SD (median, IQR) | 90.0±8.7 (89.4, 83.8–95.6) |
| Slope eGFR (ml/min per 1.73 m2 per yr), mean±SD (median, IQR) | −3.12±8.0 (−2.41, −6.34–0.17) |
| Treatment, n (%) | |
| RAS inhibition therapy | 676 (96.2) |
| Glucocorticoids or other immunosuppressive agents | 316 (45.0) |
| Untreated | 14 (1.99) |
| ESKD | 62 (8.8) |
| eGFR decreased >50% or ESKD | 91 (12.9) |
| Death | 7 (0.99) |
IQR, interquartile range; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; TA proteinuria, time-averaged proteinuria; TA MAP, time-averaged MAP; RAS, renin-angiotensin system; ESKD, end stage kidney disease.
CKD stages 1, 2, 3a, 3b, and 4 were divided by eGFR≥90, 60–89, 45–59, 30–44, and 15–29 ml/min per 1.73 m2, respectively.
Treatment and Proteinuria Response
In total, 676 (96.2%) patients received ACEi and/or ARB therapy, and 316 (45%) patients received steroids or steroids plus other immunosuppressive agents. Overall, 262 (37.3%) patients with a median peak proteinuria of 1.33 g/d (IQR=0.89–1.86 g/d) achieved a remission of proteinuria (TA proteinuria<1 g/d) with RAS blockade therapy alone. Steroids were added in 91 (12.9%) patients with persistent proteinuria (>1 g/d), regardless of supportive therapy. The median time of RAS inhibition before adding steroids was 4.4 months (IQR=3.0–7.0 months), and 55 (60.4%) patients achieved proteinuria remission. The combination of steroids with other immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, and leflunomide, was used in 195 patients with impaired kidney function (n=68) or rapidly progressive kidney function decline (n=127), and 79 (40.5%) patients achieved remission of proteinuria. Overall, 111 patients did not receive steroid therapy despite persistent proteinuria>1 g/d, including 7 patients with diabetic mellitus, 2 patients with tuberculosis, 7 patients with hepatitis B virus infection, 2 patients with unstable angina, and 93 patients who refused steroid therapy. Thirty patients had steroids added who presented with nephrotic syndrome or had glomerular necrosis findings in renal biopsy. Fourteen patients received no therapy (namely, patients who were planning pregnancy, were intolerant of RAS inhibitors, or received traditional Chinese medicine treatment).
Among 32 patients with stage 4 CKD, 26 patients were treated with RAS inhibitors and immunosuppressive agents for active lesions in kidney biopsy; the remaining six patients with dominant chronic pathologic lesions were managed with only supportive therapy.
Kidney Progression and Risk Factors
During follow-up, the median of TA proteinuria reduced from 1.60 (0.87–3.09) to 0.80 (0.44–1.47) g/d. Mean TA MAP was 90.0±8.7 mmHg. By the last visit, 91 (12.9%) composite kidney failure events were observed, including 62 ESKD and 29 halving of eGFR events. Patients were followed for 31,635 person-years; the event rate of ESKD was 2.3% per 100 person-years. In multivariate analysis using the Cox stepwise proportional hazards model, three variables were independent risk factors of composite kidney failure events (Table 2): baseline eGFR, proteinuria at month 6, and systolic BP at month 6 (all P values<0.05).
Table 2.
Factors at presentation and during follow-up influencing composite kidney failure events (ESKD or eGFR halving) by univariate and multivariate Cox regression
| Characteristic | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P Value | HR | 95% CI | P Value | |
| Age (per 10 yr) | 1.10 | 0.93 to 1.30 | 0.26 | |||
| Sex (women versus men) | 0.79 | 0.53 to 1.18 | 0.24 | |||
| Haas classification | ||||||
| I/II | 1 | Reference | 1 | Reference | ||
| III | 2.61 | 0.89 to 7.62 | 0.10 | 0.59 | 0.11 to 3.27 | 0.54 |
| IV | 5.02 | 1.76 to 14.37 | 0.01 | 1.99 | 0.43 to 9.24 | 0.38 |
| V | 18.87 | 6.50 to 54.74 | <0.001 | 3.04 | 0.61 to 15.28 | 0.18 |
| Baseline eGFR (per 10 ml/min per 1.73 m2) | 0.67 | 0.62 to 0.73 | <0.001 | 0.76 | 0.66 to 0.91 | 0.002 |
| Baseline proteinuria (per g/d) | 1.13 | 1.07 to 1.18 | <0.001 | 1.02 | 0.92 to 1.13 | 0.79 |
| Proteinuria at month 6 (per g/d) | 1.85 | 1.64 to 2.09 | <0.001 | 1.53 | 1.27 to 1.84 | <0.001 |
| Baseline SBP (per 10 mmHg) | 1.31 | 1.17 to 1.48 | <0.001 | 0.81 | 0.64 to 1.03 | 0.09 |
| SBP at month 6 (per 10 mmHg) | 1.64 | 1.38 to 1.95 | <0.001 | 1.36 | 1.05 to 1.77 | 0.02 |
| Immunosuppressive therapy (yes or no) | 2.37 | 1.55 to 3.60 | <0.001 | 1.73 | 0.88 to 3.38 | 0.11 |
| Uric acid (per mg/dl) | 1.28 | 1.17 to 1.40 | <0.001 | 1.09 | 0.92 to 1.30 | 0.34 |
HR, hazard ratio; 95% CI, 95% confidence interval.
The mean rate of GFR decline, measured by the slope of eGFR, was −3.12 ml/min per 1.73 m2 per year. We evaluated risk factors associated with the rate of GFR decline. All variables that passed univariate testing were used in multiple linear regression (Table 3). Baseline eGFR, TA proteinuria, and TA MAP during follow-up (all P values<0.001) were independently predictive of a faster rate of GFR decline (steeper, more negative slope).
Table 3.
Factors at presentation and during follow-up influencing decline in renal function (ml/min per 1.73 m2 per year) by univariate and multivariate linear regression
| Characteristic | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| Regression Coefficients | 95% CI | P Value | Regression Coefficients | 95% CI | P Value | |
| Age (per 10 yr) | 0.05 | 0.01 to 0.09 | 0.01 | 0.01 | −0.03 to 0.05 | 0.63 |
| Sex (women versus men) | 0.03 | −0.07 to 0.13 | 0.58 | |||
| Haas classification | ||||||
| I/II | 1 | Reference | ||||
| III | −0.01 | −0.16 to 0.15 | 0.94 | |||
| IV | −0.01 | −0.21 to 0.18 | 0.88 | |||
| V | −0.19 | −0.39 to 0.01 | 0.06 | |||
| Baseline eGFR (per 10 ml/min per 1.73 m2) | −0.02 | −0.04 to −0.01 | 0.01 | −0.06 | −0.07 to −0.04 | <0.001 |
| Baseline proteinuria (per g/d) | −0.01 | −0.02 to 0.02 | 0.78 | |||
| TA proteinuria (per g/d) | −0.21 | −0.26 to −0.17 | <0.001 | −0.21 | −0.25 to −0.16 | <0.001 |
| Baseline MAP (per 10 mmHg) | −0.02 | −0.06 to 0.02 | 0.40 | |||
| TA MAP (per 10 mmHg) | −0.19 | −0.24 to −0.13 | <0.001 | −0.15 | −0.21 to −0.09 | <0.001 |
| Immunosuppressive therapy (yes or no) | 0.04 | −0.05 to 0.15 | 0.34 | |||
| Uric acid (per mg/dl) | −0.01 | −0.04 to 0.02 | 0.38 | |||
95% CI, 95% confidence interval; TA proteinuria, time-averaged proteinuria; MAP, mean arterial pressure.
Development of Prediction Model
Based on the regression coefficients, we developed an equation based on the Toronto formula for three independent predictors: slope=[−0.06×eGFR (per 10 ml/min per 1.73 m2)]+[−0.21×TA proteinuria (per g/d)]+[−0.15×TA MAP (per 10 mmHg)]+1.73. The overall model was highly significant (P<0.001), with an adjusted R2 of 0.18. The intercept, partial regression coefficients, and standardized coefficients for baseline eGFR, TA proteinuria, and TA MAP variables are listed in Table 4.
Table 4.
Summary of regression coefficients and standardized β-coefficients for the multiple linear regression model
| Parameter | Regression Coefficients | Standardized β-Coefficients |
|---|---|---|
| Intercept | 1.73 | |
| Baseline eGFR (per 10 ml/min per 1.73 m2) | −0.06 | −0.25 |
| TA proteinuria (per g/d) | −0.21 | −0.33 |
| TA MAP (per 10 mmHg) | −0.15 | −0.19 |
Standardized β-coefficients are a measure of the strength of the association between that individual parameter and rate of disease progression relative to all other independent parameters in the model. TA proteinuria, time-averaged proteinuria; MAP, mean arterial pressure.
Discussion
In this large prospective cohort study with more than 700 patients, we evaluated kidney disease progression and its risk factors under current therapy. Nearly all patients received RAS inhibitors. Sequential steroids were considered in patients with persistent proteinuria, and other immunosuppressive agents were considered in those patients with impaired kidney function or rapidly progressive kidney function decline. Proteinuria declined by approximately 50%, and BP was well controlled among patients treated with our current therapy regimen. Proteinuria and BP were strong risk factors of kidney failure events or the rate of GFR decline. However, the risk of kidney failure events for patients with IgAN remained high, with about 2.3% of patients reaching ESKD each year and an annual rate of GFR decline greater than 3 ml/min per 1.73 m2. These findings suggest that new therapy strategies are urgently needed to reduce kidney burden and the high risk of kidney failure events in this population.
Similar to prior reports, baseline eGFR, proteinuria, and poor BP control during follow-up were the strongest risk factors for the rate of eGFR decline. As in the Toronto GN cohort, we developed a formula to predict GFR decline using eGFR, proteinuria, and BP. This model could explain 18% of all variability shown in the GFR slope based on the adjusted R2 of our model, which suggests that the discrimination capacity of current biomarkers for IgAN progression is limited. New biomarkers should be developed to improve the ability to predict kidney disease progression. Recent studies have shown that serum galactose-deficient IgA1 level (27) and anti-glycan autoantibodies (28) were strongly associated with kidney failure events in patients with IgAN. Additional study is needed to confirm their roles in IgAN progression.
Data from this study suggest current therapy regimen for IgAN was associated with a slower kidney function progression as compared with those in history (9,15). A long-term cohort from the Toronto Glomerulonephritis Registry (15) had recruited a population with similar baseline proteinuria and kidney function; only 53% of patients received RAS inhibitors, and 12.5% of patients were treated with steroids. Urine protein excretion during follow-up was reduced from 2.37 to 2.17 g/d compared with from 2.49 to 1.12 g/d in our cohort. The rate of GFR decline was −4.8 ml/min per 1.73 m2 per year, and the annual kidney failure rate of 4.3% was also much higher than the rate in this cohort. Another interesting finding from this study was that higher baseline GFR was associated with a faster rate of GFR decline. This result contrasts with the Toronto Equation (15,29). Patients with kidney impairment would receive more intensive care in current clinical practice, including more frequent follow-up and higher doses of RAS inhibitors and immunosuppressive agents, which partially explains why patients with lower GFR showed a slower rate of GFR decline.
Another large cohort from south China included 1155 patients, with 90% of patients receiving RAS inhibitors. In that study, the rate of GFR decline was −1.7 ml/min per 1.73 m2 per year, and the ESKD rate was 1.7/100 person-years; however, the median proteinuria at presentation was only 0.89 g/d (14). The largest cohort was from Japan, with 2283 patients followed for 87 months. Only 28.2% of patients received RAS inhibitors. The ESKD rate was 1.7/100 person-years (9). The cohort of IgAN patients from the area of Saint-Etienne comprised 332 homogenous patients from the Saint Etienne area of France, and it included patients with mild proteinuria (0.97 g/d). More than 70% of patients with proteinuria>1 g/d or hypertension received RAS inhibitors, and the annual ESKD rate was only 0.75% (5). Thus, the importance of this study is proven risk and progression of IgAN under current therapy, including RAS inhibition and sequential steroids or other immunosuppressive agents. Most of these cohorts with relatively good prognoses mainly recruit patients with mild proteinuria (less than 1 g/d in more than 50% of patients), which may represent a lead time bias because of different biopsy indications.
In this study, we have shown the association between proteinuria reduction, BP control, and kidney protection in patients with IgAN. Similar to the Toronto Glomerulonephritis Register and the Glasgow cohort, we quantified the association of the rate of GFR decline with baseline eGFR, proteinuria, and BP control. After aggressive therapy, annual ESKD rate declined but was still as high as 2.3%. Therefore, novel therapeutic targets must be confirmed that have already been used in human or animals, such as vitamin D (30,31), α-tocopherol (32–34), and pentoxifylline (35), to slow the rate of renal function decline with time. Other strategies are worth considering, such as selective correction of the intracellular glycosylation pathway, targeted deletion of a small population of Gd-IgA1–producing cells (27), blocking IgA1 interaction with mesangial transferrin receptor (36), or inhibiting production of autoantibodies targeting galactose-deficient IgA1 (28).
The strengths of this study include a large sample size, uniform therapy strategy, and robust database, for which all data were collected at regular 3- to 6-month intervals. One of the major limitations was that this cohort logically included sicker people or those patients on more intensive treatment regimen, and, therefore, the analyses have inherent selection bias for disease severity or treatment choice. Other limitations were the relatively short follow-up and single center study. Thus, more studies are needed to evaluate progression of IgAN in patients under the current therapy regimen.
In summary, our data clearly showed that lower proteinuria and lower BP were associated with slower eGFR decline and lower risk of ESKD event in patients currently being treated for IgAN. However, the risk of kidney failure remained high. New treatment regimens are still needed to retard residual kidney progression in individuals with IgAN.
Disclosures
None.
Acknowledgments
This work was supported, in part, by National Natural Science Foundation (NSF) of China Grants 81322009 and 81270795, Major State Basic Research Development Program of China 973 Program No. 2012CB517700, Program for New Century Excellent Talents in University from the Ministry of Education of China Grant NCET-12-0011, Capital Clinical Research Grant Z12110700100000 (2011-4021-06), and NSF for Innovative Research Groups of China Grant 81021004.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
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