Focal and Segmental Glomerulosclerosis:

Definition and Relevance of a Partial Remission

Stéphan Troyanov, Catherine A. Wall, Judith A. Miller, James W. Scholey, and
Daniel C. Cattran, for the Toronto Glomerulonephritis Registry Group
Department of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

Focal and segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases to terminate in ESRD.
A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR)
have not been defined. This study evaluated the rate of renal function decline (slope of creatinine clearance) and renal survival
in nephrotic FSGS patients with CR, PR, or no remission. It also examined relapse rate from remission and its impact on
outcome. Multivariate analysis included clinical and laboratory data at presentation and over follow-up, BP control, the agents
used, and immunosuppressive therapy. The study cohort was 281 nephrotic FSGS patients who had a minimum of 12 mo of
observation and were identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 65 mo, 55
experienced a CR, 117 had a PR, and 109 had no remission. A PR was independently predictive of slope and survival from renal
failure by multivariate analysis (adjusted time-dependent hazard ratio, 0.48; 95% confidence interval, 0.24 to 0.96; P ⴝ 0.04).
Immunosuppression with high-dose prednisone was associated with a higher rate of PR and CR. Relapse from PR was
frequent (56%) and associated with a more rapid rate of renal function decline and worse renal survival compared with
relapse-free partial remitters. Only female gender and the nadir of proteinuria during remission were associated with a
sustained remission. A PR in proteinuria and its maintenance are important therapeutic targets in FSGS, with implications for
both slowing progression rate and improving renal survival.
J Am Soc Nephrol 16: 1061-1068, 2005. doi: 10.1681/ASN.2004070593

F
ocal and segmental glomerulosclerosis (FSGS) is one of cludes all biopsy-proven cases of glomerulonephritis from the Toronto
the most common causes of primary glomerular disease area. Patient information at onset is compiled using a standard form,
that terminates in renal failure (1,2). In most series, its and registrars perform a periodic prospective assessment of the pa-
10-yr survival is in the 40 to 60% range (3–7). tients’ clinical status, medications, and laboratory results (15). We re-
viewed all previous medical and surgical history recorded as well as
Severity of proteinuria at onset and during follow-up have
results from all blood tests and radiologic evaluation to rule out po-
been associated with a poor outcome in several series (3– 8).
tential secondary cases, such as other types of glomerulonephritis or
Although there is strong evidence that nephrotic patients who causes such as reflux nephropathy. Only patients with definite patho-
experience a complete remission (CR) have a very favorable logic findings of FSGS (focal and segmental consolidation of the tuft by
prognosis (9 –11), the long-term outcome in adults with only a increased extracellular matrix obliterating the capillary lumen ⫾ hya-
reduction in proteinuria has seldom been reported (11,12). De- linosis ⫾ glomerular adhesions with either negative immunofluores-
spite the lack of evidence of its value as a valid surrogate for cence or only segmental IgM or C3) were considered for this study. In
improved renal survival in FSGS, it is often reported as a addition, only nephrotic FSGS patients who were older than 16 yr at
positive finding in clinical studies (11–14). presentation and had at least 12 mo of observation were included.
This study addresses the long-term implications of a partial
remission (PR) in nephrotic FSGS patients. It compares the rate Parameters Collected
of renal function decline, relapse, renal failure, and treatment Demographics were gender, ethnicity, age, and body mass index (BMI)
effects among patients with a PR, CR, and no remission (NR). at the first clinical assessment suggestive of renal disease. Laboratory
parameters collected included both initial and follow-up information on
systolic and diastolic BP, weight, serum creatinine, and 24-h urine protein
Materials and Methods and creatinine. Also recorded was exposure to immunosuppressive agents
All FSGS patients from the Toronto Glomerulonephritis Registry
and antihypertensive medications, including the angiotensin-converting
were considered for this study. This database began in 1974 and in-
enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) classes of
drugs. Finally, biopsy reports were reviewed to identify those with the
features of glomerular capillary collapse associated with visceral epithelial
Received July 23, 2004. Accepted November 18, 2004. cell hyperplasia or hypertrophy suggestive of the collapsing variant of
FSGS as well as those with only features of the tip lesion variant (16).
Published online ahead of print. Publication date available at www.jasn.org.

Address correspondence to: Dr. Daniel C. Cattran, University Health Network,

Toronto General Hospital, NCSB 11-1256, 585 University Avenue, Toronto, On-
Definitions
tario M5G 2N2, Canada. Phone: 416-340-4187; Fax: 416-340-3714; E-mail: Creatinine clearance (CrCl) values were calculated using the Cock-
[email protected] croft-Gault method adjusted for body surface area (BSA) (17,18). Ne-

Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1602-1061

1062 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 1061-1068, 2005

phrotic patients were identified by a proteinuria value ⱖ3.5 g/d at any used only information preremission for PR and CR. Finally, the impact
point during follow-up. A CR was defined by a proteinuria value ⱕ0.3 of relapse from PR was evaluated.
g/d. A PR was defined by a ⬎50% reduction in peak proteinuria and to All P values were two-tailed, and values ⬍0.05 were considered
subnephrotic levels (⬍3.5 g/d) (13). A relapse was defined by a single statistically significant. Confidence intervals (CI) included 95% of pre-
proteinuria value ⱖ3.5 g/d after any remission. Patients who had both dicted values. Analyses were carried out using SPSS software (version
a PR and a CR were included only in the CR group. Time to remission 11; SPSS Inc., Chicago, IL).
was calculated from the time the patient was first defined as being
nephrotic. Renal failure was defined by a CrCl ⬍15 ml/min per 1.73 m2,
the start of dialysis, or renal transplantation. Remissions in proteinuria
Results
were not ascribed when the CrCl was ⱕ15 ml/min per 1.73 m2 at that
Patient Selection
proteinuria time point. Mean arterial pressure (MAP) was defined as
A total of 528 patients had a diagnosis of primary FSGS and
the diastolic plus one third of the pulse pressure. For each patient, an clinical information available in the Toronto Glomerulonephri-
average MAP was determined for each 6-mo period of follow-up. tis Registry from 1974 to the end of March 2003. Exclusions
Time-average MAP represents the average of every period’s mean. were 96 patients who were younger than 18 yr at presentation,
Immunosuppressive treatment is reported as intention to treat re- nine with probable secondary FSGS on detailed review, 13 with
gardless of the duration of therapy. It was further divided into high- neither proteinuria nor weight measured, and 49 with ⬍12 mo
dose steroid therapy defined as either a minimum of 0.7 mg/kg or 50 follow-up. In the remaining 361 patients, 80 were never ne-
mg daily of prednisone and into exposure to other immunosuppression phrotic and 281 were nephrotic at some time during their
regimens: ⬎10 mg/d of prednisone, 1.5 mg/kg per d of azathioprine or follow-up. The latter cohort is the subject of this report.
cyclosporine, 1 mg/kg per d of cyclophosphamide, or 1000 mg/d of
mycophenolate mofetil in single or combined therapy. Therapy with
ACEi or ARB is presented as any exposure to either or both classes of Cohort Description
agents. The patient’s baseline characteristics, follow-up, and out-
comes are summarized in Table 1. The average age at presen-
Statistical Analyses tation was 43 ⫾ 16 yr with a predominance of men (66%) and
Normally distributed variables were expressed as mean ⫾ SD and whites (70%) and a small percentage of black patients (9%).
compared using t test, one-way ANOVA, or Pearson test. Nonparamet- Seventy-three patients reached renal failure, 10 died of causes
ric variables were expressed as median and range and compared using not associated with renal failure, and 68 were still followed as
either Mann-Whitney or Kruskal-Wallis test. Categorical variables were of the end of March 2003. A total of 130 patients had no clinical
expressed in percentages and compared using ␹2 test. information recorded since March 2000 and were considered
The rate of renal function decline (slope of CrCl) and renal failure lost to follow-up. The median duration of observation in the
were the two definitive outcomes used to validate PR as a valid sur-
latter group was 61 mo; their average slope was ⫺0.39 ⫾ 0.76
rogate for outcome in FSGS. The slope was determined by fitting a
ml/min per 1.73 m2/mo compared with ⫺0.29 ⫾ 0.45 ml/min
straight line through the calculated CrCl using the principle of least
per 1.73 m2/mo in those who were still followed by the registry
squares. This was plotted and visually examined in each patient. Peri-
ods of reversible acute renal failure defined as a rapid reduction and (NS, t test). Overall, 55 patients had at least one CR, 117 had a
recovery in CrCl of ⱖ40% within 1 mo were censored. PR with a nadir proteinuria after remission of 1.2 g/d (0.33 to
Univariate analysis followed by multiple linear regression was used 3.49), and 109 had NR.
to determine independent explanatory variables of slope. Only vari- Seventy-one patients had their renal biopsy ⬎12 mo after the
ables that were associated by univariate analysis were included in a baseline assessment. These patients had a median initial pro-
multivariate model. teinuria of 3.0 g/d (0.2 to 23.0) as opposed to 5.0 g/d (0.2 to
Survival analysis was performed to test the association between renal 98.3) in the remaining patients (P ⬍ 0.001, Mann-Whitney).
failure and each parameter collected. Survival times for each patient They were otherwise comparable in regard to baseline variables
were obtained from first clinical assessment suggestive of renal disease
and outcome. In addition, 90 of 281 had a first proteinuria value
to last follow-up. Univariate comparisons of renal survival were done
⬍3.5 g/d and developed nephrotic-range proteinuria after a
by Kaplan-Meier curves and Cox regression. A multivariate model
median of 28 mo (range, 1 to 292 mo). Again, these patients
using only the variables associated by univariate analysis was con-
structed to determine independent variables associated with this out- were otherwise comparable to the rest of the cohort and had a
come. Because remissions were time-dependent variables, i.e., were not similar rate of renal function decline and renal failure.
present at onset but appeared during follow-up, our Cox proportional
hazard model was repeated using time-dependent expressions of these Predictors of the Rate of Renal Function Decline and
variables to account for the survival time of patients before the event to Renal Survival
confirm that any survival benefit seen with remission is accounted for Clinical and laboratory variables at onset and over follow-up
by the time after remission.
were tested for association with either the rate of renal function
Different methods of variable entry (backward or block entry) and
decline or renal survival. The univariate determinants of slower
testing models with clinically relevant variables not associated by uni-
progression (flatter slope) were a BMI ⬎27 kg/m2; lower initial
variate analysis were also examined to determine whether the interac-
tion between our variable of interest (PR) and outcome (slope and renal proteinuria; and time-average BP, PR, CR, and ACEi or ARB
failure) was congruent (19). We also studied PR defined by various exposure (Table 2). The slope in those with a PR was signifi-
nadirs in proteinuria. cantly flatter than in the NR group (⫺0.47 ⫾ 0.65 versus ⫺0.88 ⫾
Patients with PR were compared with those with CR and NR to 1.00 ml/min per 1.73 m2/mo; P ⬍ 0.001). By multivariate
identify variables that predicted the type of remission. This analysis analysis, severity of proteinuria at onset, BMI, time-average BP,
J Am Soc Nephrol 16: 1061-1068, 2005 Partial Remissions in FSGS 1063

Table 1. Baseline characteristic and outcome of 281 patients who reached a minimum proteinuria ⬍1 g/d (n ⫽ 43),
nephrotic FSGS patientsa between 1 and ⬍2 g/d (n ⫽ 48), and between 2 and ⬍3.5 g/d
(n ⫽ 26). The renal survival was not statistically different
At onset among these three groups, but the rate of renal function decline
age (yr) 43 ⫾ 16 was slower with a lower proteinuria nadir (⫺0.29 ⫾ 0.36,
gender (% female) 34 ⫺0.52 ⫾ 0.71, and ⫺0.69 ⫾ 0.83 ml/min per 1.73 m2 in the low,
ethnicity (%) mid, and high nadir groups, respectively; P ⫽ 0.01, trend test).
white 70 These three groups had a similar delta in terms of reduction in
black 9 proteinuria: The peak to nadir was ⫺6.0 g/d (⫺2.6 to ⫺27.4) in
Asian 11 those who reached a PR with a nadir ⬍1 g/d, ⫺5.3 g/d (⫺2.0
other 10 to ⫺17.3) in those with a nadir between 1 and ⬍2 g/d, and ⫺5.8
BMI 27 (15–49) g/d (⫺2.3 to ⫺95.8) in those who reached between 2.0 and ⬍3.5
MAP (mmHg) 107 ⫾ 15 g/d (NS, Kruskal-Wallis). Renal survival in the high remission
CrCl (ml/min per 1.73 m2) 73 ⫾ 31 nadir group still remained superior to the NR patients (data not
Proteinuria (g/d) 4.7 (0.2–98.3) shown). Finally, within the NR group, the patients who had a
Follow-up 50% reduction in proteinuria but did not reach ⬍3.5 g/d (n ⫽
duration of follow-up (mo) 64 (12–346) 19) did not have a better renal survival or slower rate of
MAP (mmHg) 101 ⫾ 10 progression compared with the rest of the NR group (data not
peak proteinuria (g/d) 7.2 (3.5–98.3) shown).
immunosuppressionb (%)
high-dose corticosteroids 50 Predictors of a PR
cytotoxic 19 Patients with PR were compared with CR and NR groups to
cyclosporin 12 identify predictors of this outcome (Table 4). Compared with
any form 66 NR, patients with a PR had a higher proportion exposed to
ACEi or ARB therapy (%) 54 high-dose prednisone and maintained a lower preremission
Outcomes MAP despite similar antihypertensive medication. When com-
remission (%) pared with CR, the PR group had lower proteinuria at onset,
CR/PR/NR 20/41/39 had a lower percentage exposed to high-dose prednisone, and
rate of renal function declinec ⫺0.54 ⫾ 0.83 maintained a higher follow-up MAP despite more antihyper-
renal failure (%) 26 tensive drugs. Race was not identified as a predictor, i.e., blacks
aBMI, body mass index; MAP, mean arterial pressure; had a similar rate of remission as whites.
CrCl, creatinine clearance; ACEi, angiotensin-converting
enzyme inhibitor; ARB, angiotensin receptor blocker; CR, Relapse from a PR
complete remission; PR, partial remission; NR, no remission. Of the 117 PR patients, 47 never relapsed, 61 relapsed after a
b
One patient received plasmapheresis.
c median time of 7 mo (range, 1 to 66), and nine had no protein-
Measured as change in slope of CrCl (ml/min per 1.73
m2/mo). uria measurement after their remission. Thirty-two of the re-
lapsers (32 of 61) had a second remission either spontaneously
(n ⫽ 15) or after immunosuppressive therapy (n ⫽ 17), and 19
PR, and CR independently predicted slope (R2 ⫽ 0.25; stan- of these (19 of 32) had multiple relapses and remissions. The
dardized ␤ ⫽ 0.22 and 0.40 for CR and PR, respectively; P ⬍ median maximum proteinuria during the first relapse was 6.5
0.001 for both). g/d (3.8 to 22.8), a peak similar to that seen before remission
The univariate determinants that predicted better renal sur- (Table 1). Duration of follow-up after remission was 44 mo (4 to
vival at presentation were a higher initial CrCl, a BMI ⬎27 207 mo) in relapsers compared with 30 mo (1 to 164 mo) in
kg/m2; younger age; and, during follow-up, PR, CR, lower nonrelapsers (P ⫽ 0.01, Mann-Whitney). Male gender and the
time-average MAP, and exposure to ACEi or ARB treatment nadir in proteinuria in remission were significantly associated
(Figure 1, Table 3). Multivariate Cox regression identified CrCl with the risk of relapse: 64% of men versus 41% of women
and BMI at onset, PR, and CR as independent predictors (Table relapsed (P ⫽ 0.03, ␹2), and the nadir proteinuria after remis-
3). The adjusted time-dependent hazard ratio of renal failure sion was 1.6 (0.7 to 3.4) in those who relapsed versus 0.9 (0.4 to
for PR in reference to NR was 0.48 (95% CI, 0.24 to 0.96; P ⫽ 2.4) in the nonrelapsers (P ⬍ 0.001, Mann-Whitney). A relapse
0.04). We also repeated these analyses without using time- from a PR was significantly associated with outcome. Patients
dependent variables and found an adjusted hazard ratio for PR who had a PR and relapsed had an overall rate of renal function
of 0.23 (95% CI, 0.12 to 0.44; P ⬍ 0.001). Using different methods decline significantly worse than those who did not (⫺0.59 ⫾
of entry of variables into the models for both multivariate linear 0.69 versus ⫺0.31 ⫾ 0.61 ml/min per 1.73 m2/mo; P ⫽ 0.03, t
and Cox-proportional regressions and controlling for variables test), and it was associated with a higher risk for renal failure
not predictive by univariate analysis (e.g., race) did not alter the compared with the PR group without a relapse (time-depen-
statistically significant association between PR and outcomes. dent hazard ratio adjusted for the clearance at the time of
We also examined the difference in outcome between PR relapse, 2.90; 95% CI, 1.09 to 7.72; P ⫽ 0.03). However, patients
1064 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 1061-1068, 2005

Table 2. Univariate and multivariate determinants of slope (ml/min per 1.73 m2/mo)a
Univariate Multivariate

Mean/Standardized ␤ P Standardized ␤ P

Presentation
proteinuria (g/d) ⫺0.17 0.005 ⫺0.25 ⬍0.001
BMIb
low ⫺0.44 ⫾ 0.85 0.03 – NS
mid ⫺0.70 ⫾ 1.10 High⬍Mid Reference
high ⫺0.37 ⫾ 0.55 0.18 0.006
Follow-up
MAP ⫺0.24 ⬍0.001 ⫺0.20 0.003
remission
NR ⫺0.88 ⫾ 1.00 ⬍0.001 Reference
PR ⫺0.47 ⫾ 0.65 NR⬍PR⬍CR 0.22 0.003
CR ⫺0.02 ⫾ 0.36 0.40 ⬍0.001
ACE
yes ⫺0.44 ⫾ 0.53 0.03 – NS
no ⫺0.67 ⫾ 1.07
a
Gender, ethnicity, age, CrCl, and MAP at onset as well as immunosuppressive therapy were not predictive of slope.
b
BMI divided into three categories low (BMI ⬍20), normal (BMI 20 to 27), and high (BMI ⬎ 27).

CR
A total of 55 patients had a CR, 20 relapsed after a median
time of 20 mo (range, 4 to 112), six had no proteinuria mea-
surement after their remission, and 29 never relapsed, although
three of these developed a minor relapse (proteinuria between
1 and ⬍3.5 g/d after their CR). Three patients in the CR group
progressed to renal failure. On closer examination, one relapsed
and did not remit a second time, and the other two patients had
an adjusted CrCl of 25 and 40 ml/min per 1.73 m2 when their
proteinuria was documented as ⱕ0.3 g/d and both slowly
progressed to renal failure after 7 and 8 yr, respectively. Six of
55 patients experienced a CR without immunosuppressive
treatment. These patients had a median peak proteinuria of 4.2
g/d (3.8 to 4.8) in contrast to the rest of the cohort, whose peak
was 9.9 g/d (4.0 to 41.0).

Figure 1. Survival from renal failure in patients with complete Histology Findings
(CR), partial (PR), and no remission (NR). One patient in the We reviewed the pathology reports of all patients. Twenty-
NR group had a creatinine clearance ⬍15 ml/min per 1.73 m2 nine biopsies had visceral epithelial cell hyperplasia or hyper-
at presentation and was excluded from the survival analysis. trophy, and 14 had coexisting capillary wall collapse in that
area. When we examined these 29 cases, there was a dispro-
portionate percentage of black origin (29%). Overall outcome
was 14 NR, 10 PR, and five CR, with eight of 14 of the NR, one
who had a PR and relapsed still had a better renal survival than
of 10 of the PR, and zero of 5 of the CR progressing to renal
the NR group (Figure 2).
failure. If we consider those with both collapse and hyperplasia,
36% were of black origin and outcome was six NR, four PR, and
Benefits of ACEi or ARB Therapy four CR, with one patient (NR) progressing to renal failure. Five
The median time from first clinical assessment to the intro- patients had a clear histologic description of a tip lesion as the
duction of these drugs was 17 mo (0 to 289 mo), and during that only lesion of FSGS seen on light microscopy. None of these
period, patients had lost an average 8 ⫾ 20 ml/min per 1.73 m2 progressed to renal failure.
(P ⬍ 0.001, paired t test). The use of ACEi or ARB therapy was
associated with a slower progression and a better renal survival Patients Who Were Followed for Less Than 12 Months
by univariate analysis but not by multivariate linear regression A total of 49 patients had ⬍12 mo of follow-up. Eight of this
or time-dependent Cox regression (Tables 2 and 3). group had a fall in clearance ⬎30 ml/min per 1.73 m2 during
J Am Soc Nephrol 16: 1061-1068, 2005 Partial Remissions in FSGS 1065

Table 3. Univariate and multivariate determinants of renal failurea

Univariate Multivariate

Hazard Ratio Hazard Ratio

P P
(95% CI) (95% CI)

Onset
CrCl (ml/min per 1.73 m2) 0.97 (0.96–0.99) ⬍0.001 0.97 (0.95–0.98) ⬍0.001
BMIb
low 0.73 (0.17–3.05) NS 1.12 (0.25–5.06) NS
normal 1 1
high 0.39 (0.21–0.71) 0.002 0.35 (0.19–0.65) ⬍0.001
age (yr) 1.02 (1.01–1.04) 0.002 1.01 (0.98–1.07) NS
Follow-up
MAP (mmHg) 1.04 (1.01–1.06) 0.009 1.02 (0.98–1.07) NS
remission
NR 1 1
PR 0.27 (0.16–0.45) ⬍0.001 0.48 (0.24–0.96)c 0.04
CR 0.07 (0.02–0.21) ⬍0.001 0.23 (0.07–0.77)c 0.02
ACEi or ARB therapy 0.43 (0.27–0.67) ⬍0.001 0.85 (0.46–1.57)c NS
a
Gender, ethnicity, proteinuria, and MAP at onset as well as immunosuppressive therapy were not predictive of renal
survival by univariate analysis. CI, confidence interval.
b
BMI divided into three categories low (BMI ⬍20), normal (BMI 20 to 27), and high (BMI ⬎ 27).
c
Expressed as a time-dependent variable. For PR and CR, the multivariate analysis used clearance at time of remission.

the follow-up period (seven NR and one PR). Five of these of our cases with a shorter follow-up and found eight patients
patients had a biopsy with epithelial cell hyperplasia accompa- who lost ⱖ30 ml/min per 1.73 m2 within 1 yr, and only one of
nied by capillary collapse. Eight others had ESRD at time of these experienced a PR. Five of these patients had features of
biopsy. the collapsing variant FSGS, supporting the poor prognosis
associated with this histology. At the other extreme, five pa-
Discussion tients had a clear histologic description of a tip lesion as the
The long-term outcome in FSGS has been associated with the only lesion of FSGS seen on light microscopy. Because this
level of initial proteinuria and creatinine clearance, tubuloin- description was not commonly reported or labeled as a specific
terstitial disease on histology, and CR (3– 8,20). Although a lesion before 1990, it is possible that other cases existed and
partial reduction in proteinuria has also been linked with an were not reported as such. Because the number was small, these
improved outcome, the definitions used have varied and the cases were included in our cohort.
description of this cohort has been very limited (11,12). This The primary thrust of the study was to examine outcome in
analysis of FSGS patients from the Toronto Glomerulonephritis those who did achieve a PR, regardless of their histology or
Registry was undertaken to determine whether PR in protein- treatment. We found that in addition to a CR, achieving a PR
uria was a valid surrogate end point predictive of both survival was independently associated with a slower rate of renal func-
from renal failure and the rate of progression of renal disease. tion decline and a reduced risk for renal failure. We deliberately
This review included 281 patients with a median follow-up of did not include stable creatinine in the definition of PR to avoid
⬎5 yr, and although 124 of the cohort were lost to follow-up, introducing a bias that would inevitably lead to a greater renal
this was only after 5 yr of observation and the majority of them survival in that group because stable renal function and renal
were nonnephrotic at their last observation point. survival are clearly strongly associated. However, we did ex-
We reviewed all of the clinical, laboratory, and histologic clude the diagnosis of PR once the CrCl permanently dropped
information to ensure that patients had primary FSGS. Al- below 15 ml/min because proteinuria is often reduced at such
though we did find nine secondary cases, it is possible that low GFR. We also found by univariate analysis that BP and
others were missed. Such misclassification is unlikely to have ACEi or ARB therapy were associated with our main outcomes,
an impact on the main purpose of this study, which is to but the impact of either a PR or a CR overwhelmed these in the
quantify the benefits associated with a partial reduction in multivariate analysis (21,22). We used the same definition of PR
proteinuria. We excluded patients who had ⬍12 mo follow-up, as in our trial (13) and confirmed that a more clinically mean-
because small variations in creatinine can have an important ingful benefit is achieved when the 50% reduction in protein-
impact on the slope estimation if the points used for linear uria is combined with a nadir ⬍3.5 g/d. We further found that
regression are close together. However, because it is recognized the nadir proteinuria in the subnephrotic range in the PR group
that FSGS can follow a very malignant course, we reviewed all correlated with the rate of renal function decline. Whether
1066 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 1061-1068, 2005

Table 4. Comparison of CR, PR, and NRa

NR PR CR P Post Hoc

N 109 117 55
At onset
gender (% female) 29 32 45 NS
ethnicity (% white/black/Asian/other) 75/8/8/9 66/11/9/13 67/8/17/8 NS
age 45 ⫾ 17 42 ⫾ 16 40 ⫾ 16 NS
BMI 27 (15–47) 27 (17–49) 26 (18–45) NS
MAP (mmHg) 108 ⫾ 15 107 ⫾ 15 104 ⫾ 16 NS
CrCl (ml/min per 1.73 m2) 67 ⫾ 30 76 ⫾ 32 77 ⫾ 30 NS
proteinuria (g/d) 4.0 (0.4–19.6) 4.7 (0.2–98.3) 6.6 (0.2–41.0) ⬍0.001 NR,PR⬍CR
Follow-up
duration of follow-up (mo) 50 (12–273) 64 (12–346) 93 (14–315) ⬍0.001 NR⬍PR⬍CR
time to remissionb (mo) – 12 (1–153) 14 (2–197) NS
peak proteinuriac 7.5 (3.5–43.5) 6.9 (3.5–98.3) 7.2 (3.8–41.0) NS
MAPc (mmHg) 104 ⫾ 11 101 ⫾ 8 96 ⫾ 8 ⬍0.001 NR⬎PR⬎CR
antihypertensive medicationsc (n) 1.1 (0–4.2) 1.3 (0–3.8) 0.8 (0–2.9) ⬍0.001 NR,PR⬎CR
immunosuppressionc (%)
high-dose corticosteroidsc 33 49 75 ⬍0.001 NR⬍PR⬍CR
cytotoxicc 15 11 17 NS
cyclosporin 9 11 8 NS
any form 51 66 89 ⬍0.001 NR⬍PR⬍CR
ACEi or ARB therapyc (%) 43 50 31 NS
Outcome
slope (ml/min per 1.73 m2/mo) ⫺0.88 ⫾ 1.00 ⫺0.47 ⫾ 0.65 ⫺0.02 ⫾ 0.36 ⬍0.001 NR⬎PR⬎CR
relapsed (%) – 56 41 NS
renal failure (%) 45 18 6 ⬍0.001e NR⬎PR⬎CR
a
Normally distributed variables (expressed as mean ⫾ SD) are compared using one-way ANOVA with post hoc analysis
using the least significant difference method for significant results. Nonparametric variables (expressed as median and range)
are compared using Kruskal-Wallis with post hoc analysis using the Mann-Whitney test for significant results. Categorical
variables were expressed in percentage and compared using ␹2 test.
b
Measured from first nephrotic measurement.
c
Information from first clinical assessment up until remission for PR and CR groups.
d
Patients with no proteinuria measurements after remission were excluded from the denominator.
e
Log-rank test.

further immunosuppressive therapy or high-dose ACEi and/or

ARB therapy is warranted to gain this additional benefit cannot
be answered by this study, but these findings suggest that
lower nadir proteinuria targets should be considered important
outcomes in future studies.
BMI was also found to be independently associated with a
better renal survival and a slower rate of renal function decline.
Studies have suggested that obesity might be an important risk
factor for progression of renal disease (23,24). It is interesting
that a case-control study from a large cohort of FSGS patients
did find differences in clinical presentation (less nephrotic) and
a better outcome in obese patients compared with those with
normal BMI (25). It may be that the pathogenesis of the disease
is different in obese patients with perhaps a greater role for
hemodynamic and less for immunologic factors in their disease
progression (23).
Figure 2. Survival from renal failure in patients with NR and a
PR with a relapse. One patient in the NR group had a creatinine Our study found a greater proportion of patients who were
clearance ⬍15 ml/min per 1.73 m2 at presentation and was exposed to high-dose prednisone in the PR group (before re-
excluded from the survival analysis. mission) compared with NR patients and an even higher pro-
J Am Soc Nephrol 16: 1061-1068, 2005 Partial Remissions in FSGS 1067

portion in the CR group, suggesting a relationship between receive treatment. The greater proportion in the CR group who
exposure to these drugs and outcome. Studies on immunosup- received high-dose corticosteroids supports this notion. Also of
pressive treatment of FSGS have been sparse and centered on interest was that six of 281 patients achieved a CR without
high-dose prednisone, cyclosporine, or cytotoxics (10,13,26 –33). immunosuppressive therapy. These had a relatively low peak
Although our findings do support the association between proteinuria contrary to the others, and perhaps they represent
high-dose corticosteroid therapy and CR or PR, it is underpow- another causative variant. This study has shown that a PR is a
ered in regard to any conclusions about the benefits of other valid and important therapeutic goal for clinician to target
immunosuppressive agents. We recognize the many deficits of because its achievement and maintenance are strongly corre-
ascribing a value of treatment in this type of data analysis but lated with both a reduction in the rate of renal disease progres-
have included it knowing the intense interest in this area. Our sion and a better renal survival.
major point, however, remains not how to get a PR but the
clinical relevance of achieving this goal. Acknowledgments
There was a high rate of relapse and subsequent remissions This study was supported in part by a grant from the Canadian
after PR. Those who relapsed from a PR had a significantly Institutes of Health Research, Net Grant on Genes, Gender and Glo-
faster rate of renal function decline and lower renal survival merulonephritis (no. 452773L).
than those who never relapsed. This emphasizes the impor- We thank the glomerulonephritis registrars N. Ryan and P. Ling for help
tance of maintaining non–nephrotic-range proteinuria. It also in the collection and management of data, and the following nephrologists
for contributing their patients and support to the registry: Drs. S. Albert, J.
raises the issue of maintenance therapy rather than targeting
Bargman, M. Berall, W. Berry, H. Bornstein, G. Buldo, C.J. Cardella, C.
complete withdrawal of treatment after a short exposure pe-
Chan, P. Chan, S. Chow, E.H. Cole, S. Donnelly, I.O. Elkan, S.S.A. Fenton,
riod, especially when the remission is only partial. It is evident
M.B. Goldstein, R. Golush, G. Hercz, M. Hladunewich, M.R. Hockley, V.
that FSGS is more a pattern of injury than a specific disease. Jassal, K. Kamel, A. Kang, S.Y. Karanicolas, D. Kim, L. Lam, A.G. Logan,
Recent findings have identified multiple genetic mutations cod- C.E. Lok, ME Manuel, P. McFarlane, H. Mehta, D. Mendelssohn, D.
ing for different proteins involved in the slit diaphragm that Naimark, B. Nathoo, P.S.Y. Ng, M. Oliver, D.G. Oreopoulos, S. Pandeya, Y.
lead to heavy proteinuria and a histologic picture similar to Pei, Y.A. Pierattos, V. Poulopoulos, R. Prasad, B. Reen, R.M. Richardson, J.
idiopathic FSGS (34), and some of these cases could be included Roscoe, D. Ryan, J. Sachdeva, C.S. Saiphoo, D. Sapir, J. Sasal, M. Schreiber,
in our cohort. Nevertheless, the percentage of adult nephrotic M. Silverman, A. Steele, E. Szaky, P. Tam, D.S. Thompson, R. Ting, S. Tobe,
patients with FSGS caused by these mutations is currently A. Wadgymar, L. Warner, C. Wei, C. Whiteside, G. Wong, G. Wu, and J.
unknown; these markers are not readily available; and their Zaltzman, and participating pathologists T. Feltis, A.M. Herzenberg, S.
Jothy, G. Lajoie, L. Sugar, and J. Sweet.
capacity to predict outcome better than clinical variables such
as renal function, proteinuria, and BP has not been demon-
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