IgA nephropathy (IgAN) is one of the most common primary kidney diseases, and 20%–25% of patients have cases that result in kidney failure over time. Independent predictors of progression to kidney failure include a low eGFR, proteinuria >1 g/d or persistent proteinuria, hypertension, and glomerular or interstitial sclerosis at biopsy (1–9). However, these predictors have been shown to occur in advanced stages. More studies are needed to identify early-stage predictors that provide more detailed prognostic information.
The current working model for the pathogenesis of IgAN indicates that, after mesangial deposition of galactose-deficient IgA1, IgA1/IgG, or IgA/IgA immune complexes, these deposits (via interaction with specific mesangial receptors or via direct activation of complement) induce activation, proliferation, increased mesangial matrix synthesis, and eventually, cell injury. Several studies have shown that mesangial IgA deposits can activate complement via two pathways that are not mutually exclusive (1,8–10). In the majority of patients, the presence of mesangial IgA deposits colocalizes with C3 but not with IgG or C1q deposits, suggesting that activation occurs through the alternative pathway. Between 25% and 30% of patients have mesangial mannose binding lectin (MBL) deposits that are colocalized with IgA, C3, and C4d deposits, indicating complement activation through the lectin pathway, which is a pathway associated with a higher degree of kidney damage, a lower eGFR, and proteinuria at diagnosis (11–13).
Recent studies indicate that mesangial C4d deposits are an independent predictor for progression to ESRD (14–19). However, the prognostic value of complement activation via the lectin pathway remains incomplete for several reasons. First, the criteria used to classify patients as C4d positive or C4d negative were arbitrarily defined without external validation (16,17). Second, it is unknown if mesangial C4d deposits change during the course of the disease. Third, the predictive role of C4d has been analyzed in patient cohorts with established but variable stages of CKD, thus excluding C4d analysis as a potential early prognostic factor. Fourth, there are few data analyzing whether the response to treatment with angiotensin II blockers (ARBs) or corticosteroids is associated with the presence of mesangial C4d deposits.
In this study, we included a cohort of patients with idiopathic IgAN and normal kidney function at diagnosis. The objectives were to analyze the association between C4d deposits and response to treatment, analyze the reproducibility of C4d staining in repeated kidney biopsies, and investigate the predictive value on long-term kidney function of the presence of mesangial C4d deposits after adjusting for histopathologic variables and clinical variables (including mean proteinuria and treatment with ARBs, corticosteroids, or other immunomodulatory drugs).
Materials and Methods
We included 190 patients with idiopathic IgAN diagnosed by kidney biopsy (1988–2005). Inclusion criteria were eGFR calculated by creatinine (Cr) clearance GFR = [urine Cr (milligrams per deciliter) × volume (milliliters)]/[serum Cr (milligrams per deciliter) × time (minutes)] ≥80 ml/min per 1.73 m2 at diagnosis, absence of any disease resulting in IgAN, and availability of paraffin-embedded kidney biopsy (more than eight glomeruli).
All patients gave written informed consent. The study protocol was approved by the institutional review board of the referral center, and the study was performed in accordance with the ethical standards of the Declaration of Helsinki.
Follow-Up and Treatment
Demographic data, hypertension status, macroscopic hematuria, eGFR, urinary protein excretion, smoking status, and body mass index were recorded at kidney biopsy and before treatment. Serum creatinine was measured using the Jaffe method. GFR was estimated by endogenous creatinine clearance (patients ≥14 years old) and the Schwartz Equation (20) (patients <14 years old). To standardize the measurements between children and adults, proteinuria was expressed in grams per square meter per 24 hours in <14-year-old patients and as protein-to-creatinine ratio (grams per gram) in ≥14-year-old patients.
Treatment protocols were not uniform over follow-up. Between 1988 and 1994 (n=90), hypertension was treated using different drugs, including ARBs (n=70; 78%), whereas patients who were normotensive with proteinuria >1 g/d or protein-to-creatinine ratio >1 g/g did not receive ARBs routinely. Furthermore, corticosteroids were indicated whenever the protein-to-creatinine ratio was >1 g/g, regardless of ARB prior treatment.
Between 1994 and 2005 (n=100), all patients with proteinuria >1 g/24 hours per 1.73 m2 or protein-to-creatinine ratio >1 g/g used ARBs, regardless of BP. In patients who were normotensive, the dose was increased up to the maximum without inducing hypotension. In patients who were hypertensive, the dose was adjusted to maintain target BP <140/90 mm Hg, and other antihypertensive drugs were used when necessary. Eighteen patients received therapy with angiotensin-converting enzyme inhibitors plus ARBs, and 16 patients received triple therapy with angiotensin-converting enzyme inhibitors, ARBs, and spironolactone due to a protein-to-creatinine ratio >1 g/g, despite double blockade of angiotensin II. No patient received treatment with pentoxifylline or paricalcitol. Patients with protein-to-creatinine ratio >1 g/g after 6 months of ARB treatment at the maximum tolerated dose were treated with corticosteroids at 1 mg/kg per day for 4 weeks and a gradual reduction up to 6 months after treatment discontinuation. Patients with a protein-to-creatinine ratio >1 g/g associated with microhematuria 6 months after corticosteroid treatment were treated with mycophenolate mofetil for 6–16 months (n=29), high-dose Igs for 12 months (n=15), or both (n=26). During follow-up, every time a >1-g/g protein-to-creatinine ratio increase was observed in association with >15 red blood cells per microliter for >3 months, patients received additional courses of treatment with prednisone and mycophenolate for 3–6 months.
Histopathologic Analyses of Kidney Biopsies
All biopsies were evaluated by three independent pathologists blinded to clinical outcomes. Paraffin-embedded kidney tissues (4- to 5-mm sections) were stained with hematoxylin-eosin, Masson trichrome, periodic acid–Schiff, and Jones methenamine. They were classified according to the Oxford criteria (21–25). C4d inmunohistochemical staining was performed on 3-μm deparaffinized and rehydrated sections of formaldehydefixedrenal tissue using rabbit polyclonal anti-human C4d (Biomedica, Vienna, Austria) as the antibody diluted 1:30 in PBS. To block nonspecific staining, antigen retrieval was performed in advance of slide treatment by pressure cooking (10 minutes [1 bar], 10 mM citrate buffer, pH 6.0). The detection system used was Dako EnVisionHRP (Dako A/S, Copenhagen, Denmark) according to the following protocol: block endogenous peroxidase with 3% H2O2 in PBS for 10 minutes, wash sections in PBS, apply anti-C4d antibody for 20 minutes at room temperature, wash in PBS, apply diamino-benzene chromogen for 5 minutes, wash sections in tap water for 10 minutes, and coverslip using an aqueous mounting medium.
During follow-up, 35 (18%) patients were rebiopsied due to nephritic flares (n=20) or persistent proteinuria >1 g/g associated with hematuria (n=15), despite treatment with corticosteroids and ARBs. Thirty-one of these biopsies (89%) contained more than eight glomeruli and were used to analyze the concordance of mesangial C4d staining in repeated biopsies.
Hypertension was defined as BP>140/90 mm Hg. Nephritic flare was defined as acute increase in serum creatinine of at least 30% over the last available value associated with protein-to-creatinine ratio >1 g/g and hematuria >15 cells per microliter. C4d-positive biopsies were those with deposits limited to the mesangium in at least one nonsclerotic glomerulus.
The kidney outcomes were analyzed using two different measures: (1) the slope of GFR during the total observation period, and (2) the cumulative percentage of patients who developed ESRD, which was defined as the need for dialysis or transplantation during follow-up. The response to both ARBs and corticosteroids was analyzed using two outcome measures: (1) the quantitative reduction of the protein-to-creatinine ratio and (2) the number of patients with reduction of the protein-to-creatinine ratio to values <1 g/g or <1 g/m2 per 24 hours 6 months after starting treatment.
Quantitative variables are expressed as mean±1 SD for normally distributed variables or the median with the interquartile range (IQR) for non-normal distributions. Qualitative variables are expressed as proportions. Comparisons of means between groups were performed using t tests, and comparisons between proportions were performed using chi-squared tests. Correlation analysis between quantitative variables was performed using the Pearson correlation test. The concordance of mesangial C4d staining patterns between the kidney biopsies obtained at diagnosis and during-follow-up was analyzed using the weighted κ index. Weighted κ was also used to evaluate the interobserver reproducibility of mesangial C4d staining observed by the three independent pathologists. The GFR reduction was used as a criterion for the loss of kidney function, the least squares method was used with at least 20 GFR measurements, and a linear regression model was performed with the GFR slope logarithm as the dependent variable.
A multiple regression model was created using the variables that had significant associations in the univariate analysis to analyze the independent predictors of eGFR slope. For each patient, mean time-averaged proteinuria, systolic BP, and diastolic BP were determined for every 12 months during follow-up. Kaplan–Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d status on kidney survival.
Univariate survival comparisons were made using the log rank test. The Cox model was used to estimate the adjusted relative risk of each parameter with regard to kidney survival. For statistical analyses, categorical variables were transformed into dummy variables.
A P value <0.05 was considered statistically significant. Statistical analyses were performed using SPSSv20.0.
The study group included 190 patients; the mean (SD) follow-up was 15.8 (±4.1) years, median (IQR) was 15 (12–22) years, and range was 10–26 years. At the time of diagnosis, 170 (89%) patients were adults (≥18 years old).
Table 1 shows the clinical and histopathologic characteristics at the time of diagnosis in the whole group and stratified by the presence/absence of mesangial C4d deposit in the kidney biopsy. All biopsies showed mesangial deposits of IgA and C3. C1q staining and IgG staining were negative in all patients. There was no classification discordance for mesangial C4d staining among the three pathologists. Mesangial deposits of C4d were observed in 38 (20%) patients. Among C4d-positive patients, the mean number of glomeruli showing positive mesangial staining was 4.5±1.9 (median [IQR]: 4 [3–6]). C4d-positive patients exhibited greater proteinuria without significant differences in other variables. In this group of patients, there were no statistically significant associations between the percentage of affected glomeruli and any of the clinical, biochemical, or histopathologic variables analyzed. Supplemental Figure 1 shows representative examples of IgA biopsies with positive and negative C4d staining.
Table 1. -
Clinical and histopathologic characteristics at diagnosis according to the presence or absence of mesangial C4d deposits in the kidney biopsy
|Age, yr, mean±SD
|Body mass index, kg/m2, median [IQR]
|Smoker, n (%)
|Macroscopic hematuria, n (%)
|Systolic BP, mm Hg, mean±SD
|Diastolic BP, mm Hg, mean±SD
|Hypertension, n (%)
|Serum creatinine, mg/dl, median [IQR]
|eGFR, ml/min per 1.73 m2, median [IQR]
eGFR categories, n (%)
|Protein-to-creatinine ratio, g/g, median [IQR]
Histopathologic Oxford classification, n (%)
| T0: <25%
| T1: 25%–50%
| T2: >50%
|Glomeruli with crescents median [IQR]
IQR, interquartile range; M, mesangial cellularity; S, segmental sclerosis; E, endocapillary hypercellularity; T, interstitial fibrosis and tubular atrophy.
aFor protein-to-creatinine ratio (grams per gram) median [IQR], the P value among all variables was statistically significant at P=0.04.
Changes of Clinical and Biochemical Characteristics during Follow-Up
Table 2 summarizes the changes of clinical and biochemical variables during follow-up in both patient groups, the number of patients treated with ARBs and corticosteroids, the response to treatment, and the eGFR slope during the total period under observation in the complete patient cohort and both groups of patients. Nine (5%) patients underwent tonsillectomy (all <18 years old). There were no significant changes in protein-to-creatinine ratio after tonsillectomy.
Table 2. -
Change of clinical and biochemical variables during follow-up in C4d-positive and C4d-negative patients
Treatment with ARBs, n (%)
| Protein-to-creatinine ratio <1 g/g after treatment with ARBs, n (%)
| Protein-to-creatinine ratio reduction 6 mo after ARBs, median [IQR]
Treatment with prednisone, n (%)
| Protein-to-creatinine ratio <1 g/g after treatment with prednisone, n (%)
| Protein-to-creatinine ratio reduction 6 mo after treatment with prednisone, median [IQR]
|Other immunosuppressive or immunomodulatory treatments, n (%)
|Time-averaged protein-to-creatinine ratio, median [IQR]
|No. of nephritic flares, median [range]
|Rebiopsy during follow-up
|Time-averaged systolic BP, mm Hg, mean±SD
|Time-averaged diastolic BP, mm Hg, mean±SD
|Smoker, n (%)
|Hypertension, n (%)
|No. of antihypertensive drugs, median [range]
|eGFR slope, ml/min per 1.73 m2 per year, median [IQR]
ARB, angiotensin II blocker; IQR, interquartile range.
aPatients who underwent more than one biopsy.
One hundred fifty-five (82%) patients received treatment with ARBs. These patients exhibited significant reductions in both systolic BP (123±11.8 versus 119±8.7; P=0.02) and diastolic BP (69±10.1 versus 65±7.6; P=0.04). Six months after ARBs were started, the average reduction in protein-to-creatinine ratio was 1.04 g/g (median [IQR]: 1.0 [0.1–1.9]). In 103 (66%) patients, protein-to-creatinine ratio diminished below <1 g/g after treatment. In ten patients who developed symptomatic hypotension at low doses, ARBs were withdrawn.
Fifty-three (28%) patients were treated with corticosteroids. The average reduction of protein-to-creatinine ratio after 6 months of corticosteroid treatment was 0.83 g/g (median [IQR]: 1.3 [0.6–2.4]). In 34 (64%) patients treated with corticosteroids, the protein-to-creatinine ratio declined below <1 g/g. Among these patients, 13 (38%) persisted with a <1-g/g protein-to-creatinine ratio, whereas 21 (62%) were recorded to maintain a >1-g/g protein-to-creatinine ratio during follow-up. Ten (48%) of them were treated with two or more repeated prednisone courses, and 20 (95%) received alternative immunosuppressive or immunomodulatory treatments, including mycophenolate mofetil for 6–12 months (n=20), high-dose Igs (n=18), or both (n=16).
During follow-up, C4d-positive patients had higher numbers of nephritic flares, received more immunosuppressive drugs or alternative immunomodulator treatments, and had higher levels of protein-to-creatinine ratios compared with C4d-negative patients.
Concordance between Mesangial C4d Staining in Repeated Biopsies
Among the 31 patients with repeated kidney biopsies who were included in the analysis, ten (32%) were C4d positive and 21 (68%) were C4d negative in the biopsies obtained at diagnosis. Follow-up biopsies showed C4d-positive staining in all C4d-positive patients (100%) and four of 21 (19%) C4d-negative patients. The concordance κ index between repeated biopsies was 0.73 (95% confidence interval, 0.48 to 0.97).
Response to Treatment with ARBs and/or Corticosteroids According to C4d Deposits
Both the number of patients treated with ARBs and the reduction of proteinuria after angiotensin blockade were similar in C4d-positive and C4d-negative groups. The quantitative reduction of proteinuria and the proportion of patients reaching a protein-to-creatinine ratio <1 g/g after the first cycle of prednisone were similar in both groups (Table 2).
Independent Predictors of eGFR Slope
Table 3 summarizes the variables associated with the eGFR slope in the multivariate analysis. Baseline eGFR, body mass index, smoking status, time-averaged proteinuria, and mesangial C4d deposits were identified as independent predictors for the eGFR slope, together accounting for 67% of variability. This multivariate model was analyzed after reclassifying the four patients who changed from C4d negative at diagnosis to C4d positive at follow-up, and results did not significantly differ compared with the original model.
Table 3. -
Independent predictors of the GFR slope in the multivariate regression model
||0.67, F: 31.38, P<0.001
|Body mass index
Baseline eGFR is in milliliters per minute per 1.73 m2, body mass index is in grams per meter2, smoking is yes or no, age is per year, time-averaged proteinuria is in grams per gram, C4d positive is versus C4d negative, and β indicates β error.
Independent Predictors of Kidney Survival
Fifty (26%) patients reached the primary end point of ESRD. Kidney survival rates at 10, 15, and 20 years were 82%, 76%, and 75%, respectively. Table 4 summarizes the multivariable adjusted hazard ratios for ESRD. Basal eGFR, time-averaged proteinuria, and C4d staining were identified as independent predictors of ESRD.
Table 4. -
Independent predictors of ESRD in the multivariate Cox regression analysis
||Cox Multivariate Analysis
|HR (95% CI)
||0.69 (0.57 to 0.84)
||1.04 (1.01 to 1.06)
||3.12 (1.97 to 4.95)
||2.07 (1.16 to 3.71)
Baseline eGFR is in milliliters per minute per 1.73 m2, smoking is yes or no, time-averaged proteinuria is in grams per gram, and C4d positive is versus C4d negative. HR, hazard ratio; 95% CI, 95% confidence interval.
The results of our study indicate that the presence of mesangial C4d deposits is one of the earliest prognostic variables in patients with IgAN and normal kidney function at the time of diagnosis. These deposits were observed to be associated with kidney outcomes using two different outcome measures after adjusting for histopathologic classification and variables, such as mean proteinuria, angiotensin II blockade, and immunomodulatory treatment. Both predictive models of outcome included eGFR, smoking, time-averaged proteinuria, and the presence of C4d mesangial deposits as independent predictors of progression. However, there were some differences between them, because the predictive model of the change of the slope of glomerular filtration also included age and body mass index. These differences can be justified, because both variables relate to the prognosis in a different way. The slope of eGFR provides a direct measure of the rate of loss of kidney function over time, whereas kidney survival involves a dichotomic classification, with the risk of including as nonprogressors patients who suffer a progressive loss of kidney function but still do not meet the criteria defined by the outcome measure. The quantitative reduction of proteinuria 6 months after starting treatment with angiotensin blockers or prednisone was not influenced by the presence of mesangial C4d deposits.
Our results in patients with normal renal function provide new information that complements previous research that analyzed the prognostic value of C4d mesangial deposits in patients with different degrees of renal failure (12–14,16,17). However, the analyses accounting for clinical data and potential treatment influence are scarce (19). Our data indicate that, even in patients with normal kidney function, there are significant differences in both the presentation and evolutionary course of the disease between C4d-positive and C4d-negative patients. At the time of the kidney biopsy, we observed higher proteinuria in C4d-positive patients. We did not observe significant differences in kidney function or kidney lesion severity among C4d-positive and C4d-negative patients. These differences can be explained by all patients in our cohort having normal kidney function and low degrees of interstitial fibrosis and tubular atrophy lesions. Thus, the prevalence of biopsies with C4d deposits in our cohort was less than that described in other studies that included patients with varying degrees of ESRD (16,17).
The reduction of proteinuria after angiotensin blockade or the first cycle of corticosteroids was similar in C4d-positive and C4d-negative patients, suggesting that treatment response was independent of the presence of mesangial C4d deposits, at least in the short term. However, the change after diagnosis was different in both groups of patients. The most notable difference between the two groups was persistent disease activity in the group of C4d-positive patients over time, expressed as a greater number of nephritic flares, a higher level of proteinuria, a greater frequency of rebiopsy and repeated treatment with corticosteroids and/or other immunomodulators due to persistent proteinuria and active urinary sediment, a greater reduction in eGFR slope, and eventually, higher incidence of ESRD. These data suggest that C4d-positive mesangial staining was associated with a higher level of disease activity. The reason for this higher activity is unknown; however, we postulate that it may be related to the intensity and/or number of pathways through which the complement system is activated (16,17). The sum of complement activation through different pathways could explain, at least in part, why patients with mesangial C4d deposits eventually develop more extensive glomerular and tubulointerstitial lesions and greater loss of kidney function.
The reason why only some IgAN biopsies exhibit C4d mesangial deposits remains unclear. In our patients, in the repeated biopsies performed during the nephritic flares or because of persistent activity, the mesangial deposit pattern tended to remain constant. However, four of 21 patients who were classified as C4d negative at diagnosis showed mesangial C4d deposits in repeated biopsies, suggesting that the mesangial deposition of C4d may not be limited to a particular and exclusive group of patients but rather, could reflect a dynamic process that would occur in any patient under the appropriate conditions. At present, these conditions have not been yet identified. Experimental evidence indicates that only degalactosylated IgA is able to activate the MBL pathway (10–12). This raises the hypothesis that both MBL deposits and activation of the complement via this pathway (and the ensuing C4d deposits) could be related to the degree of IgA1 glycosylation. However, to date, the level of galactose-deficient IgA1 has not been shown to be elevated in patients with C4d deposits (compared with patients without C4d deposits), and it is unknown whether the same patient may or may not have mesangial MBL and C4d deposits depending on the degree of galactosylation or sialization of the IgA1 molecule.
Our study is retrospective and presents methodologic limitations that must be taken into account. First, neither the treatment indication criteria nor the treatments used were homogeneous over time. The treatment protocols were on the basis of different standards and clinical guidelines and sometimes, the in-house experience of the center, and therefore, they were not free from potential bias. Second, because in IgAN, C4d mesangial deposits may be focal, it is not possible to rule out that some C4d-positive patients have been incorrectly classified as C4d negative. Third, the classification of patients as C4 positive or negative was on the basis of data obtained at diagnosis, assuming that the staining pattern was invariable along the whole clinical course of the disease. This fact, however, does not seem to affect our results, because when the four patients who were C4d negative at diagnosis and C4d positive in follow-up biopsies were reclassified as C4d positive, the results of the multivariate predictive models did not change significantly. Fourth, because the rebiopsies were indicated by clinical criteria of persistent activity and not indicated systematically, we do not have any data on rebiopsies in patients in the remission phase, and therefore, we cannot analyze whether the staining pattern for C4d can change after immunomodulatory treatment.
In conclusion, data from our study provide evidence for mesangial C4d deposits being one of the earliest prognostic variables for patients with idiopathic IgAN and normal kidney function. This deposit pattern is associated with increased and persistent activity as well as worse kidney outcomes. Remarkably, these deposits did not necessarily identify two different groups of patients but rather, could reflect a dynamic process that can occur in any patient under certain conditions. Understanding the reasons why only some biopsies have mesangial C4d deposits and why these patients exhibit a worse prognosis could open the window to find more specific therapies.
Medical writing assistance was provided by Juan Martín Alonso (Trial Form Support).
This work was partly funded by the Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias) and cofunded by European Union (European Estructural and Investment Funds) project PI14/01831. C.M. is supported by Juan de la Cierva Ministerio de Economía y Competitividad grant IJCI-2015-26099.
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