Original ArticlesClinical Immunology and Pathology

Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis

Emilie C. Rijnink, Y.K. Onno Teng, Suzanne Wilhelmus, Mathilde Almekinders, Ron Wolterbeek, Karlien Cransberg, Jan A. Bruijn and Ingeborg M. Bajema
CJASN May 2017, 12 (5) 734-743; DOI: https://doi.org/10.2215/CJN.10601016

Abstract

Background and objectives The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in LN outside the framework of the classification.

Design, setting, participants, & measurements Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft–Gault (normalized to a body surface area of 1.73 m2) and Schwartz formulas were used to calculate eGFR for adults and children, respectively.

Results During median follow-up of 9.9 years (25th–75th percentile, 5.9–13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio [HR], 1.04 per %; 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m2 per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (−0.4 ml/min per 1.73 m2 per %; 95% CI, −0.6 to −0.2) and age (−0.8 ml/min per 1.73 m2 per year; 95% CI, −1.2 to −0.4).

Conclusion The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

classification;

Introduction

The disease manifestations and outcomes in lupus nephritis (LN) are heterogeneous, but 10%–30% of patients progress to ESRD within 15 years (1,2). The prognosis can usually be improved by immunosuppression; although, there are severe and sometimes lethal adverse effects (3). There is a constant need for refined and novel indicators to help clinicians predict outcomes and determine when intensive immunosuppression should be initiated for individual patients with LN.

Currently, clinical guidelines for LN (4–6) reserve intensive immunosuppression primarily for patients with class III/IV (±V) LN according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (7). Although the ISN/RPS classification is useful in terms of standardization and reproducibility of diagnosis (8–10), studies concerning the power of this classification in predicting disease outcome reported conflicting results (9,11–18). Conflicting results may be due to the grouping of a wide variety of prognostically, pathogenically, and chronically different glomerular lesions in broad classes, thereby assuming that the prognosis of individuals within classes is equal regardless of the type of lesions.

A revision of the ISN/RPS classification is called for (19,20). An evidence-based approach, similar to the Oxford classification of IgA nephropathy, would be the resolution for a future classification (21,22). In this study, we aimed to identify evidence-based clinical and histopathologic predictors of renal outcome in LN outside the framework of the ISN/RPS classification.

Materials and Methods

We collected a cohort of patients, who underwent biopsy from 1987 to 2011, with biopsy-confirmed LN from the pathology archives at the Leiden University Medical Center (LUMC). Inclusion criteria were: patients with a first renal biopsy available for re-evaluation with ≥5 scorable glomeruli, fulfilling ≥4 of the revised American College of Rheumatology (23,24) or Systemic Lupus International Collaborating Clinics (25) classification criteria for SLE, and with clinical follow-up at the LUMC, Bronovo hospital (The Hague, The Netherlands), or Erasmus Medical Center (Rotterdam, The Netherlands). In accordance with the ethics committee guidelines at the LUMC, all patient data were coded and kept anonymous. Biopsy specimens were processed for light and immunofluorescence microscopy according to standard techniques in our center, including hematoxylin and eosin, periodic acid–Schiff, and methenamine-silver staining. Immunofluorescence reports were originally prepared by four experienced nephropathologists who consistently scored immunofluorescence intensity on a 0–3+ scale.

Histopathology Definitions and Scoring

Definitions of histopathologic lesions are shown in Supplemental Material 1. Slides were scored by an experienced nephropathologist (I.M.B.). All glomerular variables were determined for each scorable glomerulus separately and tubulointerstitial parameters were scored categorically (Supplemental Material 1). We treated glomerular parameters as continuous variables and expressed them as the percentage involved of all scorable glomeruli. We considered 50 histopathologic variables (Figure 1). To reduce the number of candidate variables, we excluded lesions with low prevalence (occurring in ≤5 patients) and included only one of two strongly correlated variables (Pearson's r/Spearman's rho >0.8). The decision on which of the correlated variables to be included was on the basis of relevance and ease of scoring.

Figure 1.
Figure 1.

Histopathologic variables that were assessed. For definitions of histopathologic lesions, see Supplemental Material 1. Percentages represent the proportion of involved scorable glomeruli. Crescent score: a multiplication factor of 1 was used for segmental crescents, and 2 for circumferential crescents. *Excluded from analyses because of low prevalence (≤5 patients). †Excluded from analyses because the variable was strongly correlated with another variable (r/rho>0.8). ‡Interstitial fibrosis and tubular atrophy were combined to form the composite variable “IF/TA” (interstitial fibrosis/tubular atrophy; whichever was the higher value). +/−, scored as either present or absent.

Clinical Dataset

The following clinical parameters were recorded for each patient at the time of biopsy: age, sex, race, mean arterial pressure (MAP; diastolic BP + 1/3 pulse pressure), antihypertensive medication, previous immunosuppression, induction immunosuppression, time since SLE diagnosis, eGFR, 24-hour proteinuria, erythrocyturia, and the presence of antinuclear, antidouble-stranded DNA, and antiphospholipid antibodies. The Cockcroft–Gault (normalized to a body surface area of 1.73 m2 [26]) and Schwartz formulas were used to calculate eGFR for adults and children, respectively (27–29). The eGFR and 24-hour proteinuria were registered at 1, 5, and 10 years (±0.5 year) and at the last follow-up. Clinical data were studied throughout follow-up for the occurrence of renal flare and/or ESRD.

Brief Study Outcomes and Statistical Methods

A complete outline of this section is given in Supplemental Material 2. Outcomes were studied in two settings: (1) the complete cohort of patients with all observed LN classes who received various therapies and (2) a subset of patients with class III/IV (±V) LN who received induction immunosuppression including cyclophosphamide (CYC), mycophenolate mofetil (MMF), or azathioprine (AZA). Prespecified variables for multivariable analyses were: variables from the reduced histopathology dataset; interaction terms of these with race, age, and induction immunosuppression; and the clinical variables sex, race, time since SLE diagnosis, age at the time of biopsy (age0), proteinuria at the time of biopsy, erythrocyturia at the time of biopsy, MAP at the time of biopsy (MAP0), induction immunosuppression, and decade during which the patient underwent biopsy.

Renal Flare and ESRD.

Time to first LN flare was calculated for patients who achieved (partial) remission from the date of biopsy until the date of flare for patients who reached this endpoint; the remaining patients were censored at the last follow-up or at the time of ESRD. Time to ESRD was calculated analogously. Patients who reached ESRD before 10 years’ follow-up were regarded as having eGFR=0 ml/min per 1.73 m2 at the remaining time points. Multivariable Cox proportional-hazards models included the prespecified variables and were simplified by stepwise removal of the least significant variables.

eGFR During Follow-Up.

The extent by which variables were associated with irreversible nephron loss was investigated by modeling eGFR during follow-up. The prespecified variables were tested for their potential to predict a change in the intercept of the adjusted average level of decline in multivariable random intercept/slope linear mixed-effects models, which were simplified by removing the least significant variables (Wald test) and comparing the goodness of fit of nested models (maximum likelihood ratio test).

Progressive eGFR Decline.

To investigate progressive eGFR decline that did not necessarily result in ESRD and/or renal flare, variables were analyzed in association with progressive eGFR decline over 1, 5, and 10 years relative to its linear prediction based upon eGFR at the time of biopsy (eGFR0).

Normally distributed data were expressed as mean±SD. Non-normally distributed data were expressed as median (25th–75th percentile). Correlations between clinical and histopathologic variables were assessed using Pearson and Spearman tests, as appropriate. Given the chance of false positives by multiple correlations of histopathologic variables, Bonferroni correction was performed (Supplemental Material 3). All other P values were two-tailed and considered significant at P<0.05. All analyses were performed using SPSS 23.0 (IBM, Armonk, NY).

Results

We retrieved 293 reports of patients with LN from the pathology archives at the LUMC. Of these, 134 patients were not followed at any of the specified centers, and 54 did not have a retrievable renal biopsy specimen or their biopsy specimen was of insufficient quality. Thus, 105 patients were included. Baseline clinical and laboratory findings are summarized in Table 1 and histopathologic findings in Table 2. A complete overview of histopathologic findings and assessment of scorable glomeruli are found in Supplemental Material 4. The histopathology dataset (Figure 1) was reduced from 32 to 27 glomerular and 18 to 9 tubulointerstitial variables by excluding lesions occurring in ≤5 patients, excluding one of two strongly correlated variables, and combining interstitial fibrosis and tubular atrophy (IF/TA; see Supplemental Material 3). Correlations between histopathologic variables and MAP0, eGFR0, and proteinuria at the time of biopsy are shown in Supplemental Material 5.

View this table:
Table 1.

Clinical characteristics of 105 patients with lupus nephritis at the time of renal biopsy

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Table 2.

Distribution of selected histopathologic findings in 105 patients with lupus nephritis

Treatment and Outcome

The median follow-up was 9.9 years (25th–75th percentile, 5.9–13.8). Induction immunosuppression was given to 102 patients (Table 1). Patients who underwent biopsy before 2000 received significantly more frequently AZA and less often CYC or MMF than patients who underwent biopsy after 2000 (all P<0.001). Five patients required dialysis at the time of renal biopsy and did not regain renal function during follow-up. Of 100 patients without ESRD at the time of biopsy, 99 achieved (partial) remission; of these, 47 experienced a renal flare during follow-up. Fifteen of the patients who experienced a renal flare eventually developed ESRD. In addition to the five patients with ESRD at the time of biopsy, 16 patients progressed to ESRD and did not regain renal function (Figure 2). Five patients died during follow-up due to renal failure (n=1), infection (n=2), cardiovascular disease (n=1), and trauma (n=1). A comparison between patients who underwent biopsy before and after 2000 revealed no difference in renal survival (P=0.34) and renal flare rate (P=0.66).

Figure 2.
Figure 2.

Probabilities of renal survival and renal flare among patients in the cohort. Time to ESRD (A, n=105) and time to first renal flare (B, n=99) are depicted according to the Kaplan–Meier method. (A) During follow-up, 21 patients progressed to ESRD. The probability of renal survival was 93% at 1 year, 90% at 5 years, 85% at 10 years, and 71% at 20 years of follow-up. (B) Patients were only considered who achieved (partial) remission after renal biopsy and were not censored because they already reached ESRD. During follow-up, 47 patients experienced a renal flare. The probability of renal flare was 8% at 1 year, 35% at 5 years, and 48% at 10 years.

Predictors of Renal Outcome

Predictors of renal outcome were similar for the complete cohort and the subset (Supplemental Material 6, Tables 3 and 4). Below, parameter estimates refer to the complete cohort.

View this table:
Table 3.

Multivariable prediction models for renal flare and ESRD

View this table:
Table 4.

Multivariable prediction model for the course of eGFR during follow-upa

Renal Flare and ESRD.

Nonwhite race (hazard ratio [HR], 2.23; 95% confidence interval [95% CI], 1.23 to 4.04) and fibrinoid necrosis (HR, 1.04 for each percent of glomeruli; 95% CI, 1.00 to 1.07) independently predicted renal flare (Table 3). The following variables independently predicted ESRD (Table 3): nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91), eGFR0 (HR, 0.98 for each ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), fibrous crescents (HR, 1.09 for each percent of glomeruli; 95% CI, 1.02 to 1.17), fibrinoid necrosis (HR, 1.08 for each percent of glomeruli; 95% CI, 1.02 to 1.13), and the presence of IF/TA≥25% (HR, 3.89; 95% CI, 1.25 to 12.14).

eGFR During Follow-Up.

The adjusted mean eGFR at the time of renal biopsy was 116.5 ml/min per 1.73 m2, with an average change of −0.7 ml/min per 1.73 m2 per year (Table 4). Cellular/fibrocellular crescents independently predicted an overall lower eGFR (i.e., lower adjusted mean eGFR at baseline and during follow-up) of −0.4 ml/min per 1.73 m2 per % glomeruli (95% CI, −0.6 to −0.2), as did fibrous crescents (−1.4 ml/min per 1.73 m2 per % glomeruli; 95% CI, −2.4 to −0.5) and the presence of IF/TA≥25% (−40.5 ml/min per 1.73 m2; 95% CI, −56.2 to −24.8). Conversely, each percent of normal glomeruli, including glomeruli with 1–3 leukocytes, independently predicted an overall higher eGFR (+0.27 ml/min per 1.73 m2 per % glomeruli; 95% CI, 0.1 to 0.4). Clinically, nonwhite race and age0 independently predicted an overall lower eGFR (−11.4 ml/min per 1.73 m2; 95% CI, −21.9 to −0.8; and −0.7 ml/min per 1.73 m2 per year; 95% CI, −1.2 to −0.4, respectively).

Progressive eGFR Decline.

Briefly, a decline of eGFR over 1 and 5 years was independently predicted by nonwhite race, age0, fibrinoid necrosis, fibrous crescents, and IF/TA≥25%. Contrastingly, wire loops and endocapillary lymphocytes were associated with eGFR recovery over 10 years’ follow-up (Supplemental Material 6).

Influence of Therapy, Race, and Age on the Predictive Values of Histopathologic Variables

In the complete cohort, cytotoxic immunosuppression and/or angiotensin-converting enzyme inhibition were not associated with any of the renal outcomes (Supplemental Material 2). Of the histopathologic variables, only segmental/global endocapillary hypercellularity (P=0.03) and cellular crescents (P=0.05) were associated with cytotoxic immunosuppression (CYC, MMF, or AZA). Therapy showed no interactions with histopathologic variables for the different outcomes, with the exception of global glomerulosclerosis with ESRD (HR, 1.03 for each percent glomeruli; 95% CI, 1.00 to 1.06; P=0.01) only in patients treated with AZA within the class III/IV subset (Supplemental Material 7). Spikes/vacuoles and tubular reabsorption droplets were associated with a lower eGFR during follow-up in patients with Afro-Caribbean race compared with other races (Supplemental Material 7). None of the prespecified clinical variables were correlated both with spikes/vacuoles or tubular reabsorption droplets and race. Age0 showed no interactions with histopathologic variables for the different outcomes (Supplemental Material 7).

Immunofluorescence in Relation to Outcome

The intensities of the individual immunoglobulins (IgA, IgG, and IgM) and C factors (C3 and C1q) were not associated with ESRD, renal flare, or eGFR during follow-up (data not shown); neither were different immunofluorescence patterns, including <1 + IgG and C1q or the full house pattern.

ISN/RPS Classes in Relation to Outcome

ISN/RPS classes were not significantly associated with overall renal survival (P=0.72) and renal flare (P=0.29). LN classes were significantly associated with eGFR during follow-up (P<0.05), with the lowest eGFR in class IV-S LN. For detailed results, see Supplemental Material 8.

Discussion

Controversies surrounding the prognostic significance of histopathologic (sub)classes in the classification of LN indicate that the prognosticators should be restructured from scratch (19,20). Without preconceptions, we analyzed clinical and histopathologic predictors of renal outcome in 105 patients with class I–V LN, including a subset of 91 patients with class III/IV (±V) LN treated relatively uniformly with cytotoxic immunosuppression. Essentially, our analysis of the different outcomes in the complete cohort and its subset revealed two categories of clinical and histopathologic predictors: (1) variables predictive of the level of eGFR during follow-up and (2) variables predictive of renal flare, progressive eGFR decline, and ultimately ESRD. The variables that emerged as independent predictors in the complete cohort were consistent with the predictors in the class III/IV (±V) LN subset. Here, we discuss the clinicopathologic predictors of renal outcome as identified among patients with class I–V LN.

In our study, the percentage of normal glomeruli with <4 leukocytes, in the absence of other abnormalities, was the only independent histopathologic predictor associated with a higher eGFR during follow-up. The prognostic significance of glomeruli that are normal by light microscopy most likely indicates that the relatively unaffected part of the kidney is vital in determining renal function. This notion is well known in the setting of ANCA-associated GN, where biopsy specimens in which ≥50% of glomeruli are normal using identical definitions have been incorporated in a well validated “focal class” in the classification (30–35). On the basis of our results, glomeruli that are normal by light microscopy may similarly transcend the LN classes and warrant incorporation into a separate index.

Only a limited number of active glomerular lesions had adverse prognostic value. Of the endocapillary lesions, wire loops and endocapillary lymphocytes were associated with eGFR recovery rather than decline over 10 years’ follow-up (Supplemental Material 6), suggesting that the treatment of active endocapillary lesions was successful and damage was largely reversible for most patients. This result reflects the suggestion of the Oxford study on IgA nephropathy that endocapillary hypercellularity is a lesion more responsive to immunosuppression given the lack of its association with renal function decline among patients who received immunosuppression (22). In contrast with active endocapillary lesions, the association of cellular/fibrocellular crescents with a lower eGFR during follow-up suggests active extracapillary lesions may result in irreversible damage. Yet, like active endocapillary lesions, active extracapillary lesions were not associated with progressive eGFR decline. The prognostic significance of extracapillary lesions also implies a treatment effect, but more in terms of halting the progression. In the current classification of LN, active endocapillary and extracapillary lesions contribute equally to the assignment of class III/IV LN. Our findings indicate that more weight should be given to extracapillary lesions.

In contrast with other active glomerular lesions, fibrinoid necrosis was not associated with eGFR0, but rather with renal flare, progressive eGFR decline, and ESRD. Interestingly, fibrinoid necrosis was correlated with segmental, but not global, endocapillary hypercellularity. This finding is consistent with the notion that global and segmental lesions represent distinct entities in class IV LN (13,14,36), and that segmental lesions, with emphasis on fibrinoid necrosis, may have a different immunopathogenesis than global lesions (13).

Apart from fibrinoid necrosis, chronic glomerular lesions were generally better predictors of eGFR and progressive eGFR decline than active lesions. Fibrous crescents were independently associated with lower eGFR during follow-up, progressive eGFR decline, and ESRD. Correspondingly, it has been demonstrated that the composite chronicity index devised by Austin et al. (37), as well as its components individually, are excellent predictors of ESRD; whereas, the activity index and its components are weaker predictors (37–42).

Currently, primarily the histopathologic class on the basis of glomerular pathology determines the recommended clinical management of LN (4–6). Our results confirm that, in addition to glomerular variables, tubulointerstitial variables including IF/TA, interstitial infiltrates, tubular casts, and arterial intimal fibrosis (38,39,41–44); as well as clinical variables including nonwhite race, age, MAP0, and eGFR0, are also valuable predictors of renal outcome in LN (39,40,45,46).

Our study has some limitations. First, the predictors we identified apply to patients with the spectrum of clinical and histopathologic features observed in our cohort, in which the biopsy specimens were scored by an experienced nephropathologist using our definitions. Indeed, a number of lesions, including microthrombi and vasculitis, were excluded from our analyses due to a low prevalence. These lesions may well have prognostic significance and should be evaluated in other cohorts. Second, we did not analyze electron microscopy, which, if at hand, is the usual complement to light and immunofluorescence microscopy to comprehensively study LN pathology. Whereas in our study immunofluorescence microscopy did not confer prognostic significance, electron microscopy studies may reveal additional prognosticators. Third, our study is retrospective, whereas an ideal prognostic study would be prospective and standardize diagnostic and therapeutic procedures for all patients. However, our design allowed us to identify a cohort that could be followed to determine long-term outcomes.

Inherent to any histopathologic study investigating active LN, our results must be interpreted in the light of immunosuppression. Most patients (68%) in the class III/IV (±V) subset were treated relatively uniformly with regimens including CYC or MMF according to guidelines. Importantly, 29 (31%) patients were treated with AZA. Within the subset, no interactions between pathology variables and treatment were found, with one exception: global glomerulosclerosis was significantly associated with ESRD for patients treated with AZA, whereas in patients who received CYC or MMF, it was not. AZA has been associated with increased risk of renal flare and inferior efficacy compared with CYC in terms of delaying the progression of chronic lesions (47,48). The adverse prognostic significance of global glomerulosclerosis among patients treated with AZA and of chronic lesions in general provides circumstantial evidence that AZA should not be recommended as induction therapy in case of chronic lesions.

In conclusion, our results show that although ISN/RPS classes were poorly associated with the clinically relevant outcomes, prognostication in LN may benefit from the specific assessment of clinical variables and lesions currently obscured in the classification. Normal glomeruli, cellular/fibrocellular crescents, fibrous crescents, and IF/TA were potent predictors of eGFR during follow-up. Importantly, particularly active endocapillary lesions were likely responsive to immunosuppression because they were not associated with renal function deterioration. Contrastingly, fibrinoid necrosis, fibrous crescents, and IF/TA predicted progressive renal dysfunction even in the uniformly treated subset, implying that these lesions are unlikely to benefit from immunosuppression and thereby correspond to the clinically most relevant category of predictors. An evidence-based era of classifying LN is on the horizon, with an international effort to refine the histopathologic classification already on its way. Our results suggest that LN classes should be expanded with an evidence-based index, analogous to the mesangial and endocapillary hypercellularity, segmental sclerosis and IF/TA (MEST) score in the Oxford classification, with special attention to defining clinically important categories of predictors. Awaiting further validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

Disclosures

None.

Acknowledgments

Y.K.O.T. was supported by the Dutch Kidney Foundation (KJPB12.028) and a Clinical Fellowship by The Netherlands Organization for Scientific Research.

Footnotes

  • Received October 9, 2016.
  • Accepted February 1, 2017.

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Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis
Emilie C. Rijnink, Y.K. Onno Teng, Suzanne Wilhelmus, Mathilde Almekinders, Ron Wolterbeek, Karlien Cransberg, Jan A. Bruijn, Ingeborg M. Bajema
CJASN May 2017, 12 (5) 734-743; DOI: 10.2215/CJN.10601016
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