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TITLE:
Intravenous Pulse cyclophosphamide and steroids induce
immunological and clinical remission in New-incident and relapsing
Primary Membranous Nephropathy
AUTHORS:
Durga Anil K Kanigicherla MRCP1, Patrick Hamilton MRCP1, Krystyna Czapla1, Paul EC Brenchley
PhD1
AFFILIATIONS:
1 Manchester Institute of Nephrology and Transplantation, Central Manchester University
Hospitals NHS Foundation Trust, UK
Key Words: Primary Membranous Nephropathy, Immunosuppression, Nephrotic Syndrome,
Biomarkers
ADDRESS FOR CORRESPONDANCE
Corresponding Author: Dr Durga Anil K Kanigicherla
Address: Department of Renal Medicine, Manchester Royal Infirmary,
Oxford Road, Manchester,
United Kingdom M13 9WL
Abstract
Aim: Primary membranous nephropathy (PMN) is associated with progression to end stage
renal disease in some patients. Standard immunosuppressive therapy with cyclical
cyclophosphamide and corticosteroids can be associated with significant adverse effects. We
aimed to assess immunological and clinical response with intravenous pulse cyclophosphamide
and oral steroids in patients with severe nephrotic syndrome – in a prospective observational
cohort study at our centre.
Methods: 17 consecutive patients (9 New-incident and 8 relapses) with severe nephrotic
syndrome received intravenous pulse cyclophosphamide and daily oral steroids after failure to
achieve remission with supportive therapy alone. Immunosuppressive therapy was
discontinued at 6 months or earlier if proteinuria regressed to <100mg/mmol and patients
were followed for at least 12 months. Achievement of partial remission was primary outcome;
changes in proteinuria, eGFR, serum albumin and anti-phospholipase A2 receptor antibodies
were secondary outcomes.
Results: Dose of cyclophosphamide received was 5.4gm in New-incident patients and 4.2gm in
patients with relapses. All 17 patients achieved partial remission within 6 months: proteinuria
improved from 656 to 102mg/mmol at 6-months and 55mg/mmol at 12-months (p<0.001);
eGFR improved from 31 to 48ml/min/1.73m2 at 6-months and 45ml/min/1.73m2 at 12-months
(p<0.05). Anti-PLA2R levels reduced from 244 to 10U/L at 6-months and 10U/L at 12-months
(p<0.001). 2 out of the 9 patients in the New-incident group developed subsequent relapse.
Cumulative dose of cyclophosphamide and steroids received was about half of conventional
regime.
Conclusion: Monthly intravenous pulse cyclophosphamide with oral steroids induced
immunological and clinical partial remission at significantly reduced cyclophosphamide and
steroid doses in PMN.
Introduction
Primary Membranous Nephropathy is a common cause of nephrotic syndrome in adults and
progresses to end stage renal disease (ESRD) in a proportion of patients (1). Evidence and
current guidelines recommend therapy with cyclophosphamide based regimes in patients at
risk of progression or in those with severe and persistent nephrotic syndrome (2-4). Achieving
partial remission provides good prognosis in the long term (5, 6) and is considered a useful end
point during therapy. Therapy with cyclophosphamide is associated with potential short term
and longer term toxicity which is more widely reported in literature from lymphoma and ANCA
associated vasculitis (7-9). This may lead to reluctance on part of physicians and patients to use
such therapy in some individuals (5, 10) which could lead to under-treatment of the disease
process, increasing the risk of progression to ESRD and its consequences. Search for alternative
therapies that can reduce drug toxicity profile without reducing efficacy continues (11-13).
Patients with PMN can progress to ESRD primarily following persistent active disease; however
relapse of nephrotic syndrome after an initial remission occurs in a significant proportion of
patients which could add to further burden in outcomes (5). Management of relapses is less
well studied, with previous reports from 1990s showing good response with therapy with
various agents including steroids alone, or with combination of immunosuppressants including
cytotoxic agents (14, 15). Repeated courses of therapy for relapses potentially increase the
cumulative dose of alkylating agents with its attended risks.
Since the breakthrough discovery of PLA2R and anti-PLA2R (16) and their specificity in PMN,
there has been accumulating evidence into immunological aspects and effects of these
antibodies on outcomes. Retrospective and prospective data (17, 18) showed that anti-PLA2R
response precedes response in proteinuria. It is speculated that targeting therapy to
immunological response may achieve better outcomes by reducing prolonged exposure to
immunosuppressive agents (19). However immunological response with cyclophosphamide
based therapy is not well studied.
Experience and trials in ANCA associated vasculitis over the past two decades showed that
intravenous pulse therapy with cyclophosphamide could reduce the cumulative dose thereby
contributing to reduction in adverse effect profile; this was seen without reducing clinical
effectiveness in achieving disease remission (20). A similar approach is used in some centres,
including ours, to treat PMN to reduce the cumulative dose thereby limiting potential drug
toxicity (5, 10). Use of Intravenous pulse cyclophosphamide with steroids in idiopathic
membranous nephropathy was reported with variable success in previous studies (21-23). The
aim of this study is to evaluate and report the clinical and immunological course of the disease
in patients receiving pulse cyclophosphamide based therapy, for New-incident episodes and
relapses of nephrotic syndrome from PMN.
Methods:
This is a single centre study of adult patients aged ≥18 years with Primary Membranous
Nephropathy who were referred with nephrotic syndrome. All New-incident patients had
diagnosis of PMN based on clinical and histological criteria; and did not receive any previous
immunosuppressive therapy. Patients with diabetes mellitus and previous history of malignancy
were excluded. In those with relapses, immunosuppressive therapy was used only for the initial
episode following their New-incident diagnosis. Biopsy was not undertaken routinely in patients
with relapses (but patients had previously confirmed biopsy proven PMN during their first
presentation). Secondary causes were excluded as per standard policy – screening for occult
malignancy was undertaken if patients had no clinical features of such a cause, were aged >60
years and if serum was negative for anti-PLA2R. Written informed consent was obtained and all
patients were recruited into the AutoMN study (Medical Research Council, UK, MR/J010847/1),
exploring the immunological mechanisms and genetic control involved in PMN.
Supportive therapy included (unless contraindicated) – standard therapy of BP, diuretics as
necessary, Renin-Angiotensin inhibitors and statins for up to 6 months before therapy,
anticoagulation with warfarin or Low molecular weight heparin for the period of severe
nephrotic syndrome (if uPCR>300mg/mmol AND serum albumin <20g/L).
Immunosuppressive Therapy:
a) Intravenous pulse cyclophosphamide at a dose of 600mg/m2 every 4 weeks – for up to 6
months; in conjunction with
b) Oral Steroids: Prednisolone at a dose of 0.75mg/Kg daily (up to 60mg/day) – with
gradual tapering to 0.5mg/kg/day by 3 months and 0.1mg/kg/day by 6 months.
Cyclophosphamide pulses were discontinued either after 6 doses or earlier if proteinuria
regressed to <100mg/mmol during therapy.
Azathioprine: Incremental increase of Azathioprine was used after induction of partial
remission, (upto 50-100mg/day), if patients had persistent proteinuria (>100mg/mmol) after 6
months of induction therapy AND either a) poor renal function (MDRD eGFR <30ml/min) or b)
persistent elevation of Anti-PLA2R antibodies. Azathioprine was discontinued after a total
duration of 12 months.
Prophylaxis with co-trimoxazole and fluconazole was undertaken in all patients for the duration
of cyclophosphamide therapy and gastric prophylaxis was undertaken with proton pump
inhibitors. Monitoring for toxicity and effectiveness was undertaken 2-weekly for 6 months
after initiation of cyclophosphamide therapy and 3-monthly thereafter. Clinical and serological
data were collected prospectively as patients were followed up for at least 12 months.
End Points: The primary end point was partial remission of proteinuria throughout the study in
both groups. Secondary end points were eGFR at 1 year, anti-PLA2R response throughout the
observation period and complete remission.
Clinical indicators and definitions
Partial Remission: At least 50% reduction in proteinuria from baseline and uPCR <300mg/mmol
with stable renal function (<15% drop in eGFR). Decline in proteinuria was confirmed on repeat
measurements.
Complete Remission: Proteinuria less than 30mg/mmol and stable renal function.
Relapse: Recurrence of proteinuria with ≥ 300mg/mmol.
CKD-5: 4-variable MDRD eGFR<15mls/min/1.73m2 (24) or initiation of renal replacement
therapy.
Anti-PLA2R: Serum was assayed for anti-PLA2R by ELISA at New-incident presentation and at
relapse, as per previous descriptions (25). Serial assays were undertaken monthly during the
course of therapy and at 3 monthly intervals following induction therapy.
Continuous data was summarised as median (with range or interquartile range) and groups
compared using Mann-Whitney test. Categorical data was expressed in percentage and
compared using Fisher’s Exact tests. 2 tailed p-values <0.05 were considered statistically
significant. Analyses were performed in the R statistical environment (Ref: R Core team (2014).
R: A language and environment for statistical computing. R Foundation for Statistical
Computing, Vienna, Austria. URL http://www.R-projgect.org/).
Results
From January 2013 until June 2015 – 40 patients were diagnosed with biopsy proven New-
incident nephrotic syndrome from PMN. 13 patients with previously diagnosed PMN who were
under regular follow up of the unit developed relapse of NS during the same time (Fig 1). 17
patients received immunosuppressive therapy with combined pulse intravenous
cyclophosphamide and daily oral prednisolone - 9 patients with New-incident diagnosis of PMN
and 8 patients with relapses of nephrotic syndrome. Tables 1-3 include features at baseline and
during follow up respectively for all these patients divided into 2 groups – New-incident
patients and patients presenting with relapses. 7 out of 8 patients with relapses were men. All
patients had severe nephrotic syndrome at presentation that showed no sign of improvement
up during non-immunosuppressive anti-proteinuric therapy alone. Patients received such
therapy for a median of 6 months in New-incident group and 4 months in relapse group before
initiation of immunosuppressive therapy. Most of the patients had abnormal renal function at
presentation which, during follow up with lone supportive therapy reduced in both subsets of
patients (51ml/min at presentation to 35ml/min at initiation of therapy in New-incident
patients, 46ml/min at presentation to 30ml/min at initiation of therapy in relapses). The
median duration of follow up was 32 months in New-incident patients and 19 months in
relapses of nephrotic syndrome.
Doses of cyclophosphamide: In New-incident cohort – median dose of cyclophosphamide
received was 5.4 grams over 4 to 6 monthly pulses, and in patients with relapses – 4.2 grams
over 3 to 6 monthly pulses (Table 4). In New-incident cohort, one patient did not receive renin-
angiotensin inhibitors because of decline in renal function ascribed to the drug by physician
(major renal arterial stenosis was excluded). All patients received loop diuretics to help manage
oedema and statins for hypercholesterolemia. 5 out of 9 patients in New-incident cohort
received prophylactic anticoagulation. 1 patient with relapse had serum albumin <20 at
presentation and so received prophylactic anticoagulation.
2 patients in the New-incident group (one with eGFR<30ml/min + moderate proteinuria and
one with elevated anti-PLA2R at end of 6-months induction therapy + moderate proteinuria)
received Azathioprine for a total duration of 12 months. 1 patient in relapse group had
eGFR<30ml/min + moderate proteinuria and received Azathioprine for a duration of 12 months.
End Points:
All 9 patients in New-incident cohort and 8 patients in relapse cohort achieved partial remission
by the end of induction therapy (Fig 2). The median duration of time to partial remission from
initiation of immunosuppression was 2.1 and 2.3 months respectively. Complete remission was
seen in 4 (44%) patients in New-incident cohort and 4 patients (50%) in relapse cohort during
follow up. In the whole cohort, median proteinuria improved from 656mg/mmol at initiation of
therapy to 102mg/mmol at 6-months and 55mg/mmol at 12-months. Median eGFR improved
from 31ml/min/1.73m2 at initiation of therapy to 48ml/min/1.73m2 at 6-months and
45ml/min/1.73m2 at 12-months.
There was no significant difference in proteinuria between time at presentation to the time at
initiation of therapy (750 vs 656mg/mmol, p=0.59); no significant difference in serum albumin
during this time (23 vs 20g/dL, p=0.46); but there was decline in renal function during this time
of observation although not statistically significant (51 v 31ml/min/1.73m2, p=0.07).
Temporal response with clinical parameters and immunological response is shown in Fig 3
according to the subgroups (New-incident & relapsed patients). There was significant
improvement in these parameters by month 6 and month 12 and up until last follow up,
compared to time at initiation of therapy (Table 3).
Immunological response (Anti-PLA2R antibodies):
8 out of 9 patients in New-incident cohort were seropositive for anti-PLA2R at presentation and
through the course of active disease, and all 8 patients in relapse cohort were seropositive.
However, there was a distinct difference in Anti-PLA2Rab profile in the 2 groups. Quantitative
anti-PLA2R levels at presentation were significantly higher in New-incident group in comparison
to patients with relapses (median of 2772 vs 60U/ml, p<0.05). There was significant decline in
anti-PLA2R levels following immunosuppressive therapy in the 8 patients in New-incident group
– 726 to 24U/mL (p<0.001). In these 8 New-incident patients with anti-PLA2R positivity, anti-
PLA2R IgG4 subclass constituted 72% of total anti-PLA2R IgG (47-86%).
Adverse Events:
1 patient had chest infection that improved with antibiotics (no hospital admission). 1 patient
had CMV syndrome and viremia that improved with oral Valganciclovir (no hospital admission).
1 patient needed hospital admission for severe fluid retention, 1 month after initiation of
immunosuppressive therapy that was managed with intravenous diuretics and albumin
infusion. 1 patient died 7 months after completing immunosuppressive therapy, because of a
spontaneous intracerebral stroke. He remained in partial remission at the time of this event. 5
out of 17 (29%) patients developed diabetes mellitus during therapy, and needed hypoglycemic
agents. Two of these patients recovered subsequently following steroid withdrawal needing
only dietary management of diabetes mellitus during follow up.
Discussion
There has been increasing interest in the pathogenesis and management strategies in PMN.
This has been spurred by the discovery of PLA2R and anti-PLA2R in patients with PMN. It is well
recognised that declining renal function in the context of persistent or severe nephrotic
syndrome in primary membranous nephropathy portends poor prognosis and progression to
renal failure (26, 27). Our data suggests that pulse cyclophosphamide based therapy in patients
with severe nephrotic syndrome reverses progression of disease and achieves partial remission
with improvement of renal function. Similar clinical response was seen in both New-incident
nephrotic syndrome as well as relapses of severe nephrotic state in patients with previous
PMN. This study shows further insight into the immunological window during therapy for
severe disease. Understanding the role of Anti-PLA2R in pathogenesis as well response to
therapy could hold the key in stratifying patients and could be incorporated into future trials.
Knowledge of such response in prospective studies will help in designing future trials.
The regime with alternating monthly cyclophosphamide and high dose steroids (4), Ponticelli
regime, is the current recommended therapy for use in regular clinical practice. Efficacy of this
regime was widely demonstrated and is shown to be the commonly used approach in a recent
survey of renal centres in UK (10). Ponticelli et al (4) found that 40 of 43 patients with New-
incident NS who received alternating monthly cyclophosphamide and high dose
methylprednisolone (followed by daily oral steroids; and followed up for at least 1 year)
achieved remission. In the randomised controlled trial reported by Jha et al (3) 34 out of 47
patients (72%) achieved remission during follow up. Although not seen significantly in these
two studies, toxicity of these therapeutic agents at a high dose could limit its wider use despite
the potential persistence of disease activity in PMN. In addition, it is unknown if patients
achieve partial remission during the period of intensive therapy and if so could be spared of
exposure to full doses of immunosuppression. Although CNIs have been shown to be effective
in inducing remission, their use is limited in patients with declining renal function (28).
Therefore further studies are underway to look for alternative therapies and approaches; and if
found effective could help in improving outcomes whilst reducing toxicity (29).
The pulse intravenous therapy allows for approximately 50% reduction of cumulative
cyclophosphamide and steroid dose over a 6-month period that patients would have received
with the conventional 6-month regime. This is similar to the findings of CYCLOPS study in ANCA-
associated vasculitis (20). Efficacy of this pulse regime appears similar in both New-incident and
relapsed patients with 100% achievement of partial remission. All patients in both the groups
achieved partial remission 6 months from initiation of therapy.
2 out of the 9 patients in New-incident group developed relapse (9 and 24 months after initial
therapy) of nephrotic syndrome. We could not comment if their risk of relapse would have
been different if they received conventional 6-month regime. However, relapse of nephrotic
syndrome was noted to be high in previous reports using a selective approach for identifying
patients who needed therapy (30). In one of the 2 patients with subsequent relapse anti-PLA2R
was undetectable in serum for 2 months before therapy was stopped; whilst in the other
patient anti-PLA2R was still detectable above the normal range (at a lower level – 54u/ml) at 6
months when therapy was stopped. This patient particularly had an early relapse 3 months
after stopping therapy. This patient’s relapse responded after 5 additional months of therapy.
This raises the question if therapy should take serological status into account along with clinical
status. Bech et al showed that elevated anti-PLA2R levels predict rate of subsequent relapse
(31). Larger scale studies are warranted to explore this effect.
In a recent study, we reported longer term effects of relapse on patient outcomes (5). Therapy
of relapses has not been systemically studied so far. Our study shows good response and
achievement of partial remission following therapy of relapses with this pulse regime.
Moreover, in this study we find that some patients with relapsed nephrotic syndrome achieved
significant improvement in proteinuria by 3 months and therefore did not need full 6 months of
therapy. This approach allowed for individualisation of therapy and merits further evaluation.
Similar to cumulative dose of cyclophosphamide, the dose of prednisolone was approximately
50% less than the conventional 6-month alternating regime. Contrary to our experience,
previous studies have not shown such a high incidence of diabetes mellitus and it may be
related to patient factors or to increased vigilance in our study. Other adverse effects, in terms
of infection, included chest infection and CMV viremia which were managed with interim
measures although interruption of further dosing of cyclophosphamide was necessary.
Therapy with cyclophosphamide has bearing on subsequent morbidity including bladder related
toxicity (including transitional cell carcinoma), myeloid dysplasia and non-melanoma skin
cancer (32).This is in addition to increased risk of infections in the short term and bone health
and fertility in longer term (9). In PMN, the study by van den Brand et al showed an increase in
incidence of malignancy in cyclophosphamide-treated patients by 3-fold (annual cancer risk
from 0.3% to 1.0% in a 55-year old patient) (33). Dose-response relationship between
cyclophosphamide therapy and malignancy risk was reported in some studies (8) although not
in the van den Brand study. This variation may have been contributed by numbers in each
group in reported studies. It is suggested that in ANCA associated vasculitis, less extensive use
of immunosuppressants in current treatment protocols might result in a lower cancer risk
compared to historical studies (34). We speculate that similar approach in PMN has potential to
reduce the lifetime cumulative dose and toxicity of cyclophosphamide exposure.
This study shows other findings that may be relevant in future trials and clinical practice. Anti-
PLA2R levels in serum were significantly higher in New-incident patients compared to relapsed
patients. This could be a consequence of a) earlier diagnosis in relapse; b) different biological
responses in relapse such as antibodies to different epitopes (35); c) reduced reservoir of
actively secreting plasma cells post immunosuppression or d) previous immunosuppression in
patients with relapses. 6 out of 8 patients with relapses received immunosuppression during
the first nephrotic presentation from PMN, and there was a median interval of 65 months
between the 1st presentation with nephrotic syndrome and their relapse episode (range of 13-
210 months). Also this data suggests that utility of monitoring of anti-PLA2R and therapy
directed at serology may be different in New-incident and relapsed patients. There is significant
improvement in quantitative serum anti-PLA2R levels in New-incident patients – reduction by
approximately 75% at 1 month after initiation of therapy whilst proteinuria is reduced by about
50% by month 2 in all 9 patients. This is in comparison to clearance after 9 months with
Rituximab (in 18 out of 25 patients who cleared to undetectable level) (17). Also in the same
study only about 50% of patients achieved clinical remission at 12 months. In our study all 8
patients who had high anti-PLA2R with New-incident nephrotic syndrome cleared the antibodies
(to undetectable level) before month 4 (at which point median uPCR was still 189mg/mmol).
This clinical-immunological dissociation was reported in previously reported retrospective and
prospective (17,18) studies and raises the important question of appropriate therapy
(withholding vs continuation of further immunosuppressive therapy) that warrants further
study. This study makes a case for individualisation of therapy based on close immunological
and clinical monitoring.
Limitations
Our study has several limitations. The study is relatively small and is from an unselected
population from a single centre, although describing all patients who received the regime for
persistent active disease in PMN. There is no control group and improvements seen could be
spurious or attributed to ‘regression to the mean’ phenomenon. However multiple
measurements in the group over a period of over 12 months consistently showing trends
towards improvement in disease activity makes this less likely. We could not undertake
multivariate analyses for outcomes of interest given small number of patients in the study. Also
because of lack of control group comparisons are drawn from previously published studies.
Duration of follow up in the ‘New-incident’ group is more than the relapse group, but there was
no plausible reason that could be noted. Despite the limitations, to our knowledge this is the
only study showing comparable clinical and immunological outcomes with reduced doses of
cyclophosphamide and steroids. Also it provides prospective view into immunological status
much more closely than previously reported. Patients were monitored as part of visits to
hospital fortnightly during the induction therapy. This may have had an impact in rates of
adverse events such as infections. Further evidence of such regime in a controlled and larger
study would be necessary to influence patient outcomes in the wider context.
Conclusions:
This prospective study in PMN demonstrates the efficacy of intravenous pulse
cyclophosphamide with daily oral steroids with significant improvement in clinical and
immunological status in both New-incident and relapsed patients. Further studies are needed
to explore individualisation of therapy to improve efficacy and adverse effect profile for
patients with PMN.
Acknowledgements
PB acknowledge financial support from Medical Research Council, UK (Project MR/J010847/1)
and from EU FP7 Programme (contract 305608 “Eurenomics”). DK, PH, PB acknowledge
financial support from Kidneys for Life Charity, UK (charity no 505256). All authors acknowledge
support from Manchester Academic Healthcare Science Centre (MAHSC).
We declare that the results presented in this paper have not been published previously in
whole or part, except in abstract format.
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Table 1: Baseline Characteristics of patients grouped by New-Incident Nephrotic Syndrome &
Relapses of Nephrotic Syndrome*
Characteristics at presentation Incident NS Relapse NS
n 9 8Caucasians 6 7Males 5 7Age 58 (55-64) 58 (49-63)Previous immunosuppression 0 6 (75%)SBP (mm Hg) 170 (150-195) 154 (150-164)DBP (mm Hg) 94 (74-102) 79 (77-95)BMI 30.2 (23.9-33.2) 30.3 (24.7-34.3)Renin-Angiotensin inhibitors (prior
to episode)
0 (0%) 4 (50%)
Statins (prior to episode) 1 (11%) 5 (63%)
Proteinuria (uPCR – mg/mmol) 831 (732 – 956) 515 (332 – 724)Serum Albumin (g/L) 20 (15–24) 25 (14–28)Serum Creatinine (umol/L) 153 (119-331) 176 (85-633)eGFR (ml/min/1.73m2) 51 (20-68) 46 (20-90)Cholesterol (mmol/L) 8.6 (5.2-13.3) 5.9 (5.1-9.4)Anti-PLA2R (U/mL) 2544 (10–3000) 60 (26–931)
*Values represented as median with ranges, percentages or number as noted
Table 2: Outcomes during follow up of patients grouped by Incident Nephrotic Syndrome &
Relapses of Nephrotic Syndrome*
Characteristics New-incident NS Relapse NS
Total Follow up time 32 (17-39) 19 (12-39)Time to immunosuppressive therapy
(months)
6 (0-15) 4 (2-13)Follow up time, from start ofImmunosuppression
23 (12-36) 14 (12-36)
During follow upPartial Remission n (%) 9 (100) 8 (100)Time to Partial Remission (months) 2.1 (2.0–6.0) 2.3 (2.0–6.0)Complete Remission n (%) 4 (44) 4 (50)Time to Complete Remission
(months)
9.3 (8.1 – 9.8) 9.9 (9.2 – 10.6)Relapses n (%) 2 (22.2) 0 (0)CKD-5 n 0 0Death n 1 0
*Values represented as median with ranges, percentages or number as noted; time
represented in months
Table 3: Clinical and immunological status at presentation and during various time points relative to initiation of immunosuppressive therapy
At presentationAt initiation of
immunosuppression6-months from IS therapy
12-months from IS
therapyAt last follow up
New-incident NS
Proteinuria (mg/mmol) 831 (732-956) 853 (445-1350) 102 (23-260) 61 (5-330) 38 (10-506)
Serum Albumin (gm/L) 20 (15-24) 20 (8-28) 31 (30-39) 35 (24-43) 35 (19-45)
eGFR (ml/min/1.73m2) 51 (20-68) 35 (16-58) 48 (27-68) 46 (24-81) 48 (27-75)
Anti-PLA2R (U/mL) 2544 (10-3000) 701 (10-3000) 20 (10-115) 11 (6-61) 13 (10-68)
Relapse NS
Proteinuria (mg/mmol) 515 (332 – 724) 554 (380-808) 96 (41-275) 36 (10-226) 34 (32-39)
Serum Albumin (gm/L) 25 (14–28) 23 (14-28) 35 (30-36) 33 (30-35) 36 (32-39)
eGFR (ml/min/1.73m2) 46 (20-90) 30 (8-79) 45 (11-77) 41 (11-75) 46 (13-78)
Anti-PLA2R (U/mL) 60 (26–407) 125 (26-931) 10 (5-17) 10 (6-20) 10 (8-20)
*Values represented as median with ranges
Table 4: Characteristics at treatment and during follow up for patients grouped by Incident Nephrotic Syndrome & Relapses of Nephrotic Syndrome
Group /No
Age Sex Months(cyclophosphamide pulses)
Creatinine (µmol/L)(initiation of therapy)
Creatinine (µmol/L)(12 months)
eGFR(initiation of therapy)
eGFR(12 months)
uPCR(mg/mmol)(initiation of therapy)
uPCR(mg/mmol)(12 months)
Anti-PLA2R(U/mL)(initiationof therapy)
Anti-PLA2R(U/mL)(12 months)
Outcome(12 months)
Outcome(last follow-up)
New-Incident1 58 F 6 130 86 36 59 685 61 254 10 PR Relapse
2 63 M 6 195 108 30 46 853 108 701 61 PR CR
3 54 M 6 290 238 20 26 445 102 750 13 PR Death
4 56 M 6 112 85 58 81 1204 5 >3000 10 CR CR
5 70 M 6 331 234 16 24 860 49 >3000 11 PR PR
6 55 F 6 230 112 23 56 1350 98 259 21 PR PR
7 64 F 6 132 112 35 42 1188 330 >3000 11 Relapse CR
8 53 M 5 153 110 41 58 729 30 685 10 CR CR
9 62 F 4 119 106 40 45 656 17 10 6 CR CR
Relapse
10 65 M 3 218 166 29 36 808 17 128 10 CR CR
11 53 M 6 196 161 31 39 460 226 134 10 PR PR
12 65 M 6 150 124 41 51 607 22 124 10 CR CR
13 51 M 3 633 494 8 11 710 108 153 8 PR PR
14 65 F 5 155 122 29 43 656 25 228 20 CR CR
15 78 M 3 309 17 25 29 500 46 223 6 PR PR
16 68 M 6 93 88 70 75 393 10 931 4 CR CR
17 63 M 3 85 106 79 61 380 64 44 20 PR PR
