Abstract
Background and Objectives
Lupus nephritis (LN) is an ominous complication of Systemic lupus erythematosus (SLE) and the risk factors for the disease progression are not very well characterized.
Design, Setting, Participants and measurements
In a retrospective study, we evaluated the mode of presentation and outcomes of 163 consecutive patients with biopsy proven LN, who presented to our center between January 1999 and September 2008. Using stepwise logistic regression analysis we assessed risk factors independently associated with response to treatment as well as to progression to end stage renal disease (ESRD) in proliferative LN (PLN).
Results
Ninety percent of our patients belonged to minority population. Among 122 patients with class III and IV LN (PLN), 76 patients received intravenous cyclophosphamide (IVC) and 38 mycophenolate for induction while 34 patients received IVC, and 63 mycophenolate for maintenance. Thirty six (30%) patients with PLN progressed to ESRD and 3 patients died over a mean follow-up of 37.5 months. On multivariate analysis, chronicity index (CI) (p=0.0007) and hypertension (p=0.042) positively correlated with progression to ESRD and death and CI was associated with increased probability of non-response to treatment (p=0.001). Additionally, mycophenolate as maintenance agent was associated with increased likelihood of sustained complete remission and partial remission [p=0.045].
Conclusions
In patients with LN, Hypertension and a high CI are independent risk factors for progression to ESRD or death. Furthermore, a high CI is associated with poor response and mycophenolate as a maintenance agent may improve the response to treatment.
Keywords: lupus nephritis, outcomes, lupus, SLE, LN
Introduction
Lupus nephritis (LN) is one of the common manifestation of systemic lupus erythematosus (SLE), occurring in about 50–70% of patients, and is a major cause of morbidity and mortality in the SLE population1. The clinical course of LN is heterogeneous and varies from mild subclinical disease to an aggressive course that may rapidly progress to end-stage renal disease (ESRD)1. In fact, LN is the most common secondary glomerulonephritis leading to ESRD2. The nature and severity of the clinical features of LN do not always predict the underlying histological severity3–5. Nevertheless, certain histological and clinical parameters have been associated with poor renal survival6–24. However, results have been diverse due to differences in the population studied, sample size, selection criteria and outcome variables chosen in different studies.
About 15% of patients will develop ESRD despite treatment, with a higher frequency among minority patients24,25. Early diagnosis and prompt treatment of LN are of paramount importance to reduce morbidity and mortality14. While there has been significant improvement in patient and renal survival over the past years, the current immunosuppressive regimens still achieve suboptimal results, with unacceptable high rates of progression to ESRD, disease relapse rate and treatment related complications. Moreover, most of the recent clinical trials exclude severe LN patients (patients with serum creatinine > 3.5 mg/dl or patients with rapidly progressive glomerulonephritis) from their recruitment26–29. Furthermore, barring a few recent studies, the majority of clinical trials in LN patients have not included patients from minority populations. Indubitably, given the high incidence of severe LN in minority populations, there is an urgent need to decipher the risk factors associated with disease progression as well as safer and more effective therapies to improve the outcome of LN in this disproportionally affected group. This prompted us to conduct a retrospective review of biopsy proven lupus nephritis patients at our institution. The purpose of this study was to define the patient population, their clinical presentation, response to treatment and to investigate the risk factors associated with progression of lupus nephritis (LN) in our high risk patient population, predominantly consisting of African Americans (AA) and Hispanics of Mexican origin.
Material and Methods
Study Population
In the present study, we included all the patients with SLE who had a kidney biopsy during the period from January 1999 to September 2008 at our institution. SLE patients with clinical manifestations of LN but without a kidney biopsy were excluded. Medical records were reviewed for demographic, clinical, histological and treatment data. Renal pathology was assessed by our renal pathologist, Xin Jin Zhou, MD, and reported using the International Society of Nephrology/Renal Pathological Society (ISN/RPS) classification30.
Kidney biopsies done prior to 2005 using old WHO classification were re-evaluated and re-classified using ISN/RPS classification. Activity Index (AI) and Chronicity Index (CI) were calculated using well-established guidelines for all patients exhibiting proliferative class III or IV LN6.
The patients with PLN were treated with either 500 to 1000 mg per meter square of cyclophosphamide using NIH protocol or were given MMF (mycophenolate mofetil) or MPS (mycophenolate sodium). The dosing generally ranged from 1500 mg to 3000 mg per day of MMF or 1080 mg to 2160 mg of MMS per day.
The endpoints of the study consisted of 1) the composite of progression to ESRD or death and 2) response to treatment in the form of complete remission, partial remission, non response and relapses.
Definitions
ESRD group comprised of patients whose disease progressed to the level requiring renal replacement therapy.
Complete remission (CR) was defined by all of the following.
Normalization of serum creatinine as evidenced by either serum creatinine less than or equal to the upper limit of normal range of laboratory values or serum creatinine ≤ 15% greater than baseline, if baseline creatinine is within the normal range of the laboratory values. In addition, the patients should have urinary protein to creatinine ratio < 0.5.
Partial remission (PR) was defined as by serum creatinine ≤15% above baseline value and either 50% improvement in urinary protein to creatinine ratio, if the baseline urinary protein to creatinine ratio is ≤3.0, or a urine protein to creatinine ratio of ≤3.0 if baseline protein to creatinine ratio is >3.0.
Those patients who did not achieve complete or partial remission were classified as non responders (NR).
Relapse or renal flare was defined by either a sudden increase in serum creatinine of at least 30% over the last value, associated with nephritic urinary sediment or doubling of proteinuria if at last visit proteinuria was in sub-nephrotic range or an increase in proteinuria by at least 2 grams if value at last visit was in the nephrotic range.
The definitions used to describe various end points were modified from the criteria used in the recently conducted ALMS (Aspreva Lupus Management Study)27 and LUNAR (Lupus Nephritis Assessment with Rituximab)26 trials.
Patient was determined to be non adherent to treatment if it was indicated in physician’s progress notes.
Hypertension was diagnosed if the blood pressure (BP) was consistently ≥140/90 mm Hg on two or more occasions or if the patient was on anti hypertensive medications.
Significant co-morbidities were compared to see if there was any difference in their number among patients achieving various end points. The co-morbidities included for comparison were anemia (Hemoglobin less than 9 gm/dl), coronary artery disease, cerebrovascular accident, congestive heart failure, dyslipidemia, hypothyroidism, pancreatitis, diabetes mellitus, hypertension, asthma, chronic obstructive lung disease, malignancies, depression, deep venous thrombosis and pulmonary embolism.
The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center (UTSW).
Statistical Methods
Student’s t-tests were used to examine if there were significant differences in continuous variables between two groups of patients. Chi square or Fisher’s exact tests were conducted to investigate if there were significant differences in categorical variables between two groups. Stepwise logistic regression analyses were used to identify independent significant risk factors for primary and secondary endpoints. The risk factors described in Table 1 were included as independent variables for stepwise logistic regression analyses. A p value less than 0.05 was considered significant. Statistical analyses were performed with SAS software, version 9.1 (SAS Institute, Inc, Cary, NC).
Table 1.
Presenting features of patients with lupus nephritis.
| Features | All patients (n=163) | Class III and IV (n=122) |
|---|---|---|
| Gender* | ||
| Female | 138 (85%) | 102 (84%) |
| Male: | 25 (15%) | 20(16%) |
| Race* | ||
| African-American: | 78 (48%) | 56 (46%) |
| Hispanics | 68 (42%) | 55 (45%) |
| Caucasians | 12 (7%) | 8 (7%) |
| Others: | 5 (3%) | 3 (2%) |
| Age (Years) at LN diagnosis | 32.3±11.4 | 31.4±11.2 |
| Initial Presentation* | ||
| LN | 23 (14%) | 16 (13%) |
| LN with others | 41 (25%) | 35 (29%) |
| Others | 99 (61%) | 71(58%) |
| Hypertension* | 112 (69%) | 91 (75%) |
| Anemia* | 67 (45%) | 55 (50%) |
| Proteinuria (mg/g) | 3816.8±3459.6 | 4043.0±3395.7 |
| Creatinine (mg/dl) | 1.6±1.5 | 1.7±1.6 |
| Number of co morbidities* | ||
| 0 | 21 (13%) | 16 (13%) |
| 1 | 31 (19%) | 24 (20%) |
| 2 or more | 111 (68%) | 82 (67%) |
| ISN/RPS class of LN* | ||
| II | 18 (11%) | |
| III | 59 (36%) | 59 (48%) |
| IV | 63 (39%) | 63 (52%) |
| V | 22 (13.5%) | |
| VI | 1 (1%) | |
| Treatment induction* | ||
| Mycophenolate | 54 (33%) | 38 (31%) |
| Cyclophosphamide | 77 (47%) | 76 (62%) |
| None | 12 (7%) | 3 (2%) |
| OTHER | 20 (12%) | 5 (4%) |
| Maintenance* | ||
| Mycophenolate | 78 (48%) | 63 (52%) |
| Cyclophosphamide | 34 (21%) | 34 (28%) |
| None | 27 (17%) | 14 (11%) |
| OTHER | 24 (15%) | 11 (9%) |
| Response* | ||
| CR | 62 (38%) | 41 (34%) |
| PR | 23 (14%) | 18 (15%) |
| No response | 37 (23%) | 24 (20%) |
| ESRD | 37 (23%) | 36 (30%) |
| Death | 4 (2%) | 3 (2%) |
| Follow up (months) | 37.5±28.3 | 36.0±27.2 |
| Non adherence* | 34 (21%) | 30 (25%) |
| Relapses* | 32 (20%) | 30 (25%) |
LN: Lupus, nephritis, ISN/RPS (International Society of Nephrology/ Renal Pathology Society),
Indicates that the corresponding values for that feature will be expressed as the number (percent) of patients in each column.
Results
Between January 1999 and September 2008, 277 new patients with lupus nephritis were seen at UTSW affiliated hospitals and clinics. On reviewing their charts, 163 patients were found to be eligible for inclusion. Among 114 patients who were excluded, 81 did not have a kidney biopsy and there was no follow up data on 33 additional patients. The patients’ characteristics at time of initial presentation are shown in Table 1.
Of 163 patients biopsied, 18 (11%) had Class II, 59 (36%) class III, 63(38.6%) class IV, 22 (13.5%) class V and 1 patient was diagnosed with class VI LN.Despite treatment, 41 (25%) patients progressed to ESRD or death. None of the patients with class II or V progressed to ESRD while 1 patient with Class V LN died. The one patient with class VI LN needed renal replacement therapy. Since the majority of patients who progressed to ESRD or death belonged to class III and IV LN, we examined the risk factors for non-response and progression to ESRD and death in the 122 patients with proliferative (Class III and IV) lupus nephritis (PLN). The cause of death in patient with class V LN was unclear. Differential diagnosis included pulmonary embolism versus GI perforation. The etiologies of death in 3 PLN patients were massive CVA, diffuse alveolar hemorrhage and septic shock respectively. Among 122 patients with PLN, 76 patients received IV cyclophosphamide (IVC), 38 mycophenolate, 5 patients received other agents and 3 patients received no treatment for induction. For maintenance, 34 patients received IVC, 63 Mycophenolate, 11 received other agents and 14 received no maintenance therapy. Mean and Median durations of follow-up were 37.5 and 30.0 months respectively. Thirty (25%) patients were considered to be non adherent to treatment during follow up period. (Table 1). The reason for non-adherence to treatment was mainly non-compliance with medication intake. Whether medication side effects played a significant role in inducing non-compliance was unclear.
Risk factors for progression to ESRD or death
Among 122 patients with PLN, 36 (30%) patients progressed to ESRD and 3 patients died. Of 39 individuals who progressed to ESRD or died, 26 (67%) had class IV LN and 13 (33%) had Class III LN. Eight (21%) of the 39 patients were male (Table 2). Mean serum creatinine and mean 24-hour proteinuria at presentation were significantly higher in the group with ESRD and deaths (2.2±1.6 vs. 1.5±1.5, p=0.031; and 5011±3977 mg/24 hrs vs. 3595±3014 mg/24 hrs, p=0.035 respectively) (Table 3). In addition, chronicity index (CI) was significantly higher in ESRD and death group (3.9±2.2 vs.2.3±1.2, p=0.0011). On the other hand, there was no significant difference in the activity index (AI) between the two groups (12.3±3.4 vs. 11.5±4.0, P=0.350) (Table 3). More AA (59%) progressed to ESRD as compared to Hispanics (36%) but the difference was not statistically significant (p=0.218). Thirty seven of the 39 patients who progressed to ESRD or died had HTN as a co morbidity compared to 54 out of 83 patients with proliferative LN who were alive and free of dialysis (p=0.0004) (Table 2). Moreover, patients who progressed to ESRD or died had more co-morbidities compared to those who remained alive and free of dialysis [31(79%) vs. 51(61%) respectively, p= 0.044] (Table 2). There was no statistically significant difference in age at the time of diagnosis of LN (Table 2). The incidence of relapses between the two groups and the mean follow up in both groups (31.1±25.9 months in ESRD and death group vs. 38.4±27.6 months in others, p=0.166), were similar (Table 3).
Table 2.
Comparison of categorical variables for response to treatment and progression to ESRD and death in patients with proliferative lupus nephritis.
| Class III and IV patients | Alive, dialysis free (n=83) |
ESRD or Death (n=39) |
|
|---|---|---|---|
| Variable | Number (%) | Number (%) | p-value |
| Gender | 0.3995 | ||
| Female | 71 (86%) | 31 (79%) | |
| Male | 12 (14%) | 8 (21%) | |
| Race | 0.2184# | ||
| African-Americans | 33 (40%) | 23 (59%) | |
| Hispanics | 41 (49%) | 14 (36%) | |
| Caucasians | 6 (7%) | 2 (5%) | |
| Others | 3 (4%) | 0 (0%) | |
| Hypertension | 54 (65%) | 37 ((95%) | 0.0004 |
| Number of co-morbidities | 0.0442# | ||
| 0 | 15 (18%) | 1 (3%) | |
| 1 | 17 (20%) | 7 (18%) | |
| 2 or more | 51 (61%) | 31 (79%) | |
| Treatment (Induction) | 0.0541# | ||
| Mycophenolate | 29 (35%) | 9 (23%) | |
| Cyclophosphamide | 50 (60%) | 26 (67%) | |
| Other | 4 (5%) | 1 (3%) | |
| None | 0 (0%) | 3 (8%) | |
| Treatment (Maintenance) | 0.0875# | ||
| Mycophenolate | 48 (58%) | 15 (39%) | |
| Cyclophosphamide | 21(25%) | 13 (33%) | |
| Other | 8 (10%) | 3 (8%) | |
| None | 6 (7%) | 8 (21%) | |
| Non-adherence | 19 (23%) | 11 (28%) | 0.5250 |
| Relapses | 21 (25%) | 9 (23%) | 0.7902 |
| Class III and IV patients | Complete or Partial Response(n=59) | No-response (n=63) | |
| Variable | Number (%) | Number (%) | p-value |
| Gender | 0.0723 | ||
| Female | 53 (90%) | 49 (78%) | |
| Male | 6 (10%) | 14 (22%) | |
| Race | 0.3005# | ||
| African-Americans | 25 (42%) | 31 (49%) | |
| Hispanics | 28 (47%) | 27 (43%) | |
| Caucasians | 3 (5%) | 5 (8%) | |
| Others | 3 (4%) | 0 (0%) | |
| Hypertension | 37 (63%) | 54 (86%) | 0.0035 |
| Number of co-morbidities | 0.0094 | ||
| 0 | 12 (20%) | 4 (6%) | |
| 1 | 15 (25%) | 9 (14%) | |
| 2 or more | 32 (54%) | 50 (79%) | |
| Treatment (Induction) | 0.4734# | ||
| Mycophenolate | 19 (32%) | 19 (30%) | |
| Cyclophosphamide | 38 (64%) | 38 (60%) | |
| Other | 2 (3%) | 3 (5%) | |
| None | 0 (0%) | 3 (5%) | |
| Treatment (Maintenance) | 0.1003 | ||
| Mycophenolate | 37 (63%) | 26 (41%) | |
| Cyclophosphamide | 14 (24%) | 20 (32%) | |
| Other | 4 (7%) | 7 (11%) | |
| None | 4 (7%) | 10 (16%) | |
| Non-adherence | 8 (14%) | 22 (35%) | 0.0062 |
| Relapses | 12 (20%) | 18 (29%) | 0.2913 |
p values based on Fisher’s exact test, the other p-values are based on chi-square test
Table 3.
Comparison of continuous variables for response to treatment and progression to ESRD and death in patients with proliferative lupus nephritis.
| Class III and IV patients | Alive, dialysis free | ESRD or Death | |
|---|---|---|---|
| Variable | Mean±Std | Mean±Std | p-value |
| Age (years) | 31.6±10.8 | 31.0±12.0 | 0.788 |
| S. Creatinine (mg/dL) | 1.5±1.5 | 2.2±1.6 | 0.031 |
| Proteinuria (mg/24 hour) | 3595.3±3013.7 | 5011.1±3976.8 | 0.035 |
| Follow-up (months) | 38.4±27.6 | 31.1±25.9 | 0.166 |
| Activity index (out of 24) | 11.5±4.0 | 12.3±3.4 | 0.350 |
| Chronicity Index (out of 12) | 2.3±1.2 | 3.9±2.2 | 0.001 |
| Complete/Partial response | No Response | ||
| Variable | Mean±Std | Mean±Std | p-value |
| Age (years) | 32.4±10.6 | 30.5±11.7 | 0.335 |
| S. Creatinine (mg/dL) | 1.6±1.7 | 1.9±1.4 | 0.274 |
| Proteinuria (mg/24 hour) | 3645.5±3106.0 | 4447.4±3649.5 | 0.203 |
| Follow-up (months) | 37.0±26.2 | 35.1±28.2 | 0.695 |
| Activity index (out of 24) | 11.6±4.1 | 12.0±3.5 | 0.627 |
| Chronicity Index (out of 12) | 2.1±1.3 | 3.4±2.0 | 0.0001 |
Multivariate analysis using stepwise logistic regression was conducted to identify significant independent risk factors of ESRD and death. Chronicity index (p=0.0007, Odds ratio 1.771) and HTN (p=0.042, Odds ratio 5.425) positively correlated with progression to ESRD and death. There was 77.1% increased risk of progression to ESRD or death with each 1 unit increment in CI and patients with HTN were more than 5 times likely to progress to ESRD or die as compared to those without HTN (Table 4).
Table 4.
Multivariate analysis by stepwise logistic regression to assess independent risk factors associated with poor response to treatment, progression to ESRD or death and renal flares (relapses) in patients with Class III and IV (proliferative) lupus nephritis
| Response | Risk Factor | Regression coefficient |
P-value | Odds ratio |
Lower95% CL |
Upper 95% CL |
|---|---|---|---|---|---|---|
| No response | Mycophenolate as maintenance agent | −0.927 | 0.045 | 0.396 | 0.160 | 0.979 |
| Chronicity index | 0.558 | 0.001 | 1.747 | 1.246 | 2.450 | |
| ESRD or Death | Hypertension | 1.691 | 0.042 | 5.425 | 1.066 | 27.612 |
| Chronicity index | 0.572 | 0.0007 | 1.771 | 1.273 | 2.464 | |
| Relapses | Hypertension | 2.334 | 0.027 | 10.322 | 1.310 | 81.308 |
Risk factors for non response to treatment
Of the 122 patients with PLN, 59 achieved CR or PR while 63 patients did not respond to the treatment. Compared to the patients who achieved CR or PR, the patients who did not respond to treatment had significantly higher incidence of hypertension [54(86%) vs. 37(63%), p=0.0035], more comorbidities [50(79%) vs. 32(54%), p=0.0094] and a higher rate of non adherence with treatment [22(35%) vs. 8(14%), p=0.0062] (Table 2). It was also found that mean chronicity index was higher among non responders compared to those who achieved CR or PR (3.4±2.0 vs. 2.1±1.3 respectively, p=0.0001) (Table 3). Again, there was no significant difference in age, race, gender or incidence of relapses between those who achieved CR/PR and the non-responders. (Tables 2 and 3).
On stepwise logistic regression it was observed that higher chronicity index was associated with increased probability of non-response to treatment (p=0.001, odds ratio 1.747) (Table 4). Furthermore, compared to IVC and other immunosuppressive agents, mycophenolate as maintenance agent was associated with increased likelihood of sustained CR and PR (p=0.045, odds ratio 0.396) (Table 4).
A unique opportunity arose for us to compare the efficacy of mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) due to a formulary switch at our county hospital in August 2005. Prior to August 2005, all the patients who were initiated or being maintained on mycophenolate received MMF. After August 2005, the patients started receiving MPS instead of MMF. The switch was made with 360 mg of MPS considered equivalent to 500 mg of MMF. Thus patients on 1000 mg of MMF twice a day were started on 720 mg of MMS two times a day. Hence, we had 2 groups of PLN subjects who received mycophenolate as induction (I) or maintenance (M) agent: Group 1 (pre switch group) who received MMF (n= 19 & 26 for I and M respectively) and a group 2 (post switch group) who received MPS (n= 19 & 37 for I and M respectively). A third group consisted of all PLN patients who received other immunosuppressive agents for induction and maintenance therapy (n= 84 & 59 respectively). Statistical analysis was performed to detect any significant difference in response to treatment between the three groups of patients.
There was no significant difference between the three groups in achieving CR or PR during the induction phase (p=0.6572). For the maintenance therapy, there was a significant difference between MPS (group 2) and other immunosuppressive agents (Group 3) for sustained CR and PR (p=0.0258). However, there was no significant difference between group 1 (MMF) and group 2 (MPS) for maintenance therapy (Table 5).
Table 5.
Pair-wise comparison of various maintenance treatment groups for treatment outcomes in proliferative lupus nephritis. Mycophenolate sodium (MPS), when compared to the others [a group comprising cyclophosphamide and miscellaneous immunosuppressive agents excluding mycophenolate mofetil (MMF)] as a maintenance agent showed a significantly better complete and partial remission rates in proliferative lupus nephritis.
| Outcome variable | Maintenance treatment group | p |
|---|---|---|
| No Relapse vs. Relapse | MPS vs. Others | 0.7246 |
| Alive and not on dialysis vs. ESRD or Death | MPS vs. Others | 0.0777 |
| CR or PR vs. Non-responders | MPS vs. Others | 0.0258* |
| No Relapse vs. Relapse | MPS vs. MMF | 0.2718 |
| Alive and not on dialysis vs. ESRD or Death | MPS vs. MMF | 0.6358 |
| CR or PR vs. Non-responders | MPS vs. MMF | 0.4089 |
| No Relapse vs. Relapse | MMF vs. others | 1.0 |
| Alive and not on dialysis vs. ESRD or Death | MMF vs. others | 0.2759 |
| CR or PR vs. Non-responders | MMF vs. others | 0.285 |
CR; complete remission, PR: partial remission,
indicates statistically significant result.
Relapses
Among 122 patients with class III and IV LN, 30 patients had at least 1 renal flare or relapse. On univariate analysis, lower age at the time of diagnosis of lupus nephritis was associated with higher risk of relapse (P= 0.0035). There was a trend towards higher risk of relapse in patients who had HTN [26(87% vs. 20(70%), P=0.0802]. Mean follow up time in months was higher in individuals who had a renal flare compared to those who did not have a flare (50.17±26.9 vs. 31.42±25.76 months, p=0.0008). In multivariate analysis, HTN was the only variable found to be an independent predictor for relapses (Table 4).
Discussion
This is a large retrospective study from a single center, which attempts to shed light on demographic features, clinical course and the prognostic factors associated with poor renal and patient survivals as well as non-response to treatment in patients with LN belonging mainly to Hispanic and AA ethnicities. This patient population has been shown to have high morbidity and mortality associated with Lupus in general and LN in particular in previous studies15, 31, 32. Austin et al showed AA race increased the risk of progression of kidney disease in lupus nephritis33. Similarly, Dooley studied 89 LN patients with diffuse proliferative glomerulonephritis (DPGN) and found that AA had less renal survival than Caucasians7. Other studies have reiterated the association of increased risk of progression of Lupus nephritis with AA race, which may be related to both genetic and environmental factors15, 31, 32. There have been very few studies comparing outcomes of LN between AA and Hispanics12, 31, 32. These studies have reported that Hispanics and AA are at equal risk of adverse outcomes in Lupus12, 32, 34–37.
Contreras, et al studied the outcomes in AA and Hispanics with LN and found more chronic renal failure and deaths in AA and Hispanics of Cuban descent31.
Our study highlights the importance of various laboratory, biopsy and clinical parameters as prognostic indicators in a population comprising mainly of Hispanics of Mexican origin and African Americans. In concurrence with earlier reports,9,19,20,32,38 our study showed HTN and higher number of associated co-morbidities (two or more) to be significant predictor variables for progression to ESRD and death. This underscores the importance of aggressively treating hypertension and other co-morbidities in patients with LN to improve the outcome.
We also showed that higher serum creatinine and greater proteinuria at the time of renal biopsy were important predictors for poor outcomes of ESRD and death in our patient population. High serum creatinine and greater degree of proteinuria indicate either severe disease presentation or a delay in the diagnosis of the disease, further emphasizing that early diagnosis and prompt and aggressive treatment of PLN in essential to improve outcomes of LN.
Among biopsy features, higher chronicity index (CI) was associated with non response, poor renal survival and death in PLN patients. CI is an indicator of irreversible damage at the time of biopsy and hence portends poor prognosis as shown in previous studies.6,8,18,31,33 Activity index, though it depicts aggressive disease, did not stand out as a significant predictor variable for non response to treatment, since it is potentially reversible if promptly treated.
In a multivariable model, chronicity index and HTN predicted progression to ESRD or death and Mycophenolate as a maintenance agent was associated with improved remission rates. Hypertension is an added insult on top of severe glomerular inflammation in PLN and may hasten the disease progression. This corroborates the findings of previous studies13,32 and highlights the need for effectively treating this risk factor. Our study did not find any significant difference between IVC and mycophenolate when used as an induction agent but mycophenolate was found to be associated with higher remission rates when used as a maintenance agent. Several trials including a recent, large, multicenter, Aspreva Lupus Maintenance Study (ALMS) found no difference in efficacy of these 2 agents27 though Ginzler et al found mycophenolate to be superior to IVC when used as an induction agent29. This could be due to difference in exclusion criteria in the latter study since our patient population included 19 rapidly progressive glomerulonephritis (RPGN) patients who presented with creatinine of >3 mg/dl and showed good treatment response to IVC.
In our study, mycophenolate was found be more effective in maintaining remission as compared to IVC. This supports the results of a randomized trial conducted by Contreras et al31 and suggests that mycophenolate can be used as an effective maintenance agent in treatment of LN. An interesting observation was made in our study when we separated the mycophenolate group into MMF and MPS groups and compared these 2 groups with a third group comprising mainly of cyclophosphamide and azathioprine (Table 5). MMF and MPS showed no statistical difference in maintaining remission when compared to each other but MPS was found to be superior to the third group. It is possible that this difference may be due to better adherence with MPS because of better gastro-intestinal tolerability. However, this needs to be examined further in randomized, prospective trials.
Age, race and gender were not shown to be significant risk factors of disease progression in our patient population consisting mainly of Hispanics and African Americans. In the previous studies, race difference has only been demonstrated when comparing AA with Caucasians or Hispanics with Caucasians24,33,39. Compared to previous studies, our study showed a higher incidence of ESRD and death (25.1%) over mean follow up period of 34.5±25.3 months. This could be due to the fact that most of our patients belonged to a high risk category with low socio-economic status. Non-adherence to treatment must also have contributed to increased morbidity and mortality in this patient group as it was found to be a significant predictor variable of poor outcome in univariate analysis.
There are several limitations of our study. It has inherent flaws of a retrospective study. Only associations can be made by using statistical techniques. Furthermore, we may have excluded several other potential prognostic indicators from our study. For example, we did not look at socio-economic status of the patients as a specific variable. A vast majority of our patients belonged to low-socio-economic class, which has been associated with poor prognosis24,32,40.
Notwithstanding limitations of our study, this study provides insight into several demographic, clinical, and laboratory features of LN and attempts to highlight various risk factors associated with unfavorable outcomes in this large, well-defined, high risk minority patient population with biopsy proven Lupus nephritis from a single center in the US.
Acknowledgement
This study was supported by a research grant (CERL080AUS73T) from Novartis Pharmaceutical Corporation, and a grant from the George M. O’Brien Kidney Research Core Center NIH P30DK079328.
Footnotes
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