Mark, P. B.

Rutherford, E.

Journal of the Royal College of Physicians of Edinburgh

E Rutherford

PB Mark

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The Journal of the Royal College of Physicians of Edinburgh

What does STOP-IgAN tell us about how to treat IgA nephropathy?

Rutherford, Elaine

Mark, Patrick

Enlighten

23clinicalJ R Coll Physicians Edinb 2016; 46: 23–25http://dx.doi.org/10.4997/JRCPE.2016.107© 2016 Royal College of Physicians of EdinburghSUMMARYThe Intensive Supportive Care plus Immunosuppression in IgA Nephropathy (STOP-IgAN) trial was designed to investigate the outcomes of immunosuppressive therapy, when added to maximal supportive care, in patients with IgA nephropathy (IgAN). This was a multicentre, open-label, randomised, controlled trial with a two-group, parallel group design. Following screening, 337 participants were recruited from 32 nephrology centres across Germany. The main inclusion criteria were biopsy confirmed primary IgAN, age 18–70 and a proteinuria level above 0.75 g/day plus hypertension, impaired renal function (estimated glomerular filtration rate [eGFR] <90 ml/min/1.73m2), or both. Patients with eGFR <30 ml/minute/1.73 m2, those with rapidly progressive crescentic IgAN, secondary IgAN and other chronic renal diseases, or who had previously received immunosuppression were excluded. The first stage of the trial involved a six-month run-in phase where all patients received intensive supportive care including renin angiotensin system (RAS) blockade to lower blood pressure (BP) to a target below 125/70 mmHg. If proteinuria persisted above 0.75 g/day once this target BP was achieved, the dose of RAS blocker (either angiotensin converting enzyme inhibitor [ACEI], angiotensin receptor blocker [ARB] or both) was increased as tolerated up to the maximum approved dosage. Participants were seen seven times during this period. In total, 34% of patients had a response to supportive care during this period with proteinuria falling to below 0.75 g/day. These responsive patients were excluded from the randomisation phase of the study.Following the run-in phase, 162 participants with persistent proteinuria more than 0.75 g/day but less than 3.5 g/day were randomised to the 3-year study phase. These participants were randomly assigned either to continue with maximal supportive care alone (80 participants), or to receive maximal supportive care plus immunosuppressive therapy (82 participants).Depending on the eGFR, the immunosuppression given in the immunosuppression arm of the study varied. Patients with eGFR between 30 and 59 ml/min/1.73m2 received cyclophosphamide (1.5 mg/kg/day) for 3 months, followed by azathioprine (1.5mg/kg/day) during months 4–36, plus oral prednisolone initially at dose of 40 mg/day, tapered to 7.5 mg/day by month 6 of the study and continued on this dose until the study end. Those with eGFR of ≥60 ml/min/1.73m2 received glucocorticoid monotherapy for six months. They received intravenous methylprednisolone (1 g/day) as three pulsed doses at the start of months 1, 3 and 5 and oral prednisolone (0.5 mg/kg) every 48 hours on the other days.The primary outcomes of the study were i) full clinical remission defined as proteinuria with a protein:creatinine ratio of <0.2 and stable renal function with decrease in the eGFR of <5 ml/min/1.73m2 from the baseline eGFR at the end of the 3 year trial phase and ii) a decrease in the eGFR of at least 15 ml/min/1.73m2 from baseline eGFR.After three years, 14 participants in the immunosuppression group met the first primary outcome measure of full clinical remission, compared to only four participants in the supportive therapy alone group. This difference was statistically significant (p = 0.01). However, participants who had a full clinical remission had lower baseline levels of proteinuria than those who did not. There was no statistical difference in the number of patients in each group with a decrease in eGFR of at least 15 ml/min/1.73m2 (28% in the supportive What does STOP-IgAN tell us about how to treat IgA nephropathy?Clinical Opinion1E Rutherford, 2PB Mark1Clinical Research Fellow, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK; 2Clinical Reader in Nephrology, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Clinical Research Centre, University of Glasgow, Glasgow, UKTiTle Intensive Supportive Care plus Immunosuppression in IgA NephropathyAUThoRS Rauen T, Eitner F, Fitzner C et al.JoURnAl N Engl J Med 2015; 373: 2225-36. http://dx.doi.org/10.1056/NEJMoa1415463DeclARATion of inTeReSTS No conflicts of interests declaredCorrespondence to E RutherfordDivision of Cardiovascular and Diabetes MedicineMedical Research InstituteNinewells Hospital & Medical SchoolDundee DD1 9SYUKe-mail e.rutherford@dundee.ac.ukcare group vs 26% in the immunosuppression group) with no significant difference in the rate of decline of eGFR between groups.There were more episodes of infection (including one fatal pneumonia) in the immunosuppression group, of which 25% were considered directly related to immunosuppression. There were also more episodes of neoplasia, impaired glucose metabolism and bodyweight gain in the immunosuppression arm.The investigators stated, ‘We could not confirm our hypothesis that additional immunosuppressive therapy would provide substantial kidney-related benefits in patients with high risk IgAN.’ oPinionIgAN is the most common primary glomerulonephritis in the world (including Scotland).1 Approximately one quarter of individuals diagnosed with IgAN with significant proteinuria will progress to end stage renal disease requiring dialysis or a kidney transplant within 20–25 years of presentation.1 The prognosis is worse for those patients with persistent proteinuria.1–3 In this group, approximately 50% may reach end stage renal disease within 10 years.3 RAS blockade to aggressively control BP and reduce proteinuria is the mainstay of treatment. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines also recommend use of immunosuppression with glucocorticoids if proteinuria remains above 1 g/day with maximally tolerated RAS blockade.4 However, with the exception of those with nephrotic range proteinuria (>3.5 g/day),5 the evidence base behind this strategy is relatively weak.6 The STOP-IgAN trial addresses this area of uncertainty.7The first piece of knowledge we gain from this study is that immunosuppression in patients with stage 1–3 chronic kidney disease caused by IgAN without nephrotic range proteinuria is of very limited benefit when added to maximal supportive therapy.7 Previous studies, which inform the KDIGO guidelines, have shown some benefit from immunosuppressive therapy.4,8–12 However, as the STOP-IgAN investigators highlight, these studies lacked a run-in period where RAS blockade was maximised, and RAS blockade was either temporarily stopped pre-baseline or was inconsistent throughout the studies.6–12 Further questions remain unanswered about immuno-suppression in IgAN. First, the follow up in STOP-IgAN was too short to determine if there is longer-term benefit gained from remission of proteinuria, which was achieved in a greater proportion of patients treated with immunosuppression.7 Second, due to the indolent yet progressive nature of IgAN, patients present at different stages in the disease. Some patients may have had haematoproteinuria for years prior to diagnosis. For immunosuppression to be effective there should be minimal irreversible renal fibrosis present. Finally, the individual subgroups treated with the various immunosuppressive regimens were small.7 It is also unclear if more specific future immunosuppressive regimes (e.g. blisibimod, spleen tyrosine kinase inhibition) in the era of ‘precision medicine’ may be more effective than the broad based immunosuppressive regimens employed in STOP-IgAN. The experience of STOP-IgAN highlights the challenges of testing new therapies in IgAN.Perhaps the real success of this trial is the demonstration that traditional supportive therapy for IgAN is effective in the medium term – 34% of participants in STOP-IgAN achieved significant reduction in proteinuria.7 With effective RAS blockade and BP control, proteinuria can be reduced significantly. Furthermore, with reduction in proteinuria one can expect an improved longer-term prognosis with slower rate of decline of eGFR.7,13 Remarkably, mean BP in STOP-IgAN was 126/78 mmHg.7 The investigators must be commended on this achievement; unfortunately real life rarely replicates the controlled environment of a clinical trial. This trial7 does provide further evidence that we should be aggressively pursuing lower BP targets and maximising RAS blockade to reduce proteinuria even if, or when, these BP targets are achieved.It is notable that approximately 42% of randomised participants in STOP-IgAN received both ARB and ACEI therapy simultaneously.7 Subsequent to three recent trials,14–16 the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a warning against this combination, because of increased risk of hyperkalaemia, hypotension and impaired renal function.17 STOP-IgAN had only one serious adverse event (in the supportive arm) associated with increased serum creatinine and potassium.7 The lack of serious complications of simultaneous ARB and ACEI in STOP-IgAN is probably due to intensive study monitoring. In clinical practice, where this level of monitoring is impractical, clinicians pursuing dual RAS blockade in this patient group would be contravening MHRA advice. We recommend maximal single-agent RAS blockade while heeding MHRA guidance.24clinicalJ R Coll Physicians Edinb 2016; 46: 23–25© 2016 RCPEE Rutherford, PB Mark25clinicalJ R Coll Physicians Edinb 2016; 46: 23–25© 2016 RCPERefeRenceS1 Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005; 16; 2088–97.2 D’Amico, G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol 2004; 24: 179–96.3 Bartosik LP, Lajoie G, Sugar L et al. Predicting progression in IgA nephropathy. Am J Kidney Dis 2001; 38: 728–35.4 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter 2012; 2012; 2(suppl): 139–274.5 Kim J-K, Kim JH, Lee SC et al. Clinical features and outcomes of IgA nephropathy with nephrotic syndrome. Clin J Am Soc Nephrol 2012; 7: 427–36. http://dx.doi.org/10.2215/CJN.048205116 Vecchio M, Bonerba B, Palmer SC et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2015; 8: CD003965. http://dx.doi.org/10.1002/14651858.CD003965.pub27 Rauen T, Eitner F, Fitzner C et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med 2015; 373: 2225–36. http://dx.doi.org/10.1056/NEJMoa14154638 Pozzi C, Andrulli S, Del Vecchio L et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol 2004; 15: 157–63.9 Pozzi C, Bolasco PG, Fogazzi GB et al. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 1999; 353: 883–7.10 Praga M, Gutiérrez E, González E et al. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J Am Soc Nephrol 2003; 14: 1578–83.11 Coppo R, Peruzzi L, Amore A et al. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18: 1880–8.12 Manno C, Torres DD, Rossini M et al. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 2009; 24: 3694–701. http://dx.doi.org/10.1093/ndt/gfp35613 Geddes CC, Rauta V, Gronhagen-Riska C et al. A tricontinental view of IgA nephropathy. Nephrol Dial Transplant 2003; 18: 1541–8.14 Yusuf S, Teo KK, Pogue J et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59.15 Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–903. http://dx.doi.org/10.1056/NEJMoa130315416 Parving H-H, Brenner BM, McMurray JJ et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367: 2204–13. http://dx.doi.org/10.1056/NEJMoa120879917 MHRA. Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function—new warnings. Drug Safety Update 19 June 2014. https://www.gov.uk/drug-safety-update/combination-use-of-medicines-from-different-classes-of-renin-angiotensin-system-blocking-agents-risk-of-hyperkalaemia-hypotension-and-impaired-renal-function-new-warnings (accessed 11/2/16).Clinical OpinionThe College Journal Prize 2015, sponsored by the Senior Fellows’ Club, was won by  R Acquah et al for their paper ‘HIV testing in Lanarkshire’. This paper can be read in issue 4, 2014 at http://www.rcpe.ac.uk/sites/default/files/acquah.pdfA prize of £250 will be awarded to the first-named (or corresponding) author of an original research paper on a clinical topic, deemed by a panel of judges to be the best paper by a doctor-in-training (i.e. pre-consultant level) published in the Journal of the Royal College of Physicians of Edinburgh in issues 3 and 4, 2015 and issues 1, 2 and 3, 2016. The paper will be selected by a panel of judges, including a senior Fellow, an active clinician and a member of the Editorial team. The prize-winner will be invited to give a short oral presentation based on his/her paper at the Trainees and Members’ symposium in February 2017.Further details may be obtained from the Editorial Office, RCPE, 9 Queen Street, Edinburgh EH2 1JQ, tel +44 (0)131 247 3666 or email editorial@rcpe.ac.uk.The college JoURnAl PRize

English

Enlighten: Publications

23
clinical
J R Coll Physicians Edinb 2016; 46: 23–25
http://dx.doi.org/10.4997/JRCPE.2016.107
© 2016 Royal College of Physicians of Edinburgh
SUMMARY
The Intensive Supportive Care plus Immunosuppression 
in IgA Nephropathy (STOP-IgAN) trial was designed to 
investigate the outcomes of immunosuppressive therapy, 
when added to maximal supportive care, in patients with 
IgA nephropathy (IgAN). This was a multicentre, open-
label, randomised, controlled trial with a two-group, 
parallel group design. 
Following screening, 337 participants were recruited 
from 32 nephrology centres across Germany. The main 
inclusion criteria were biopsy confirmed primary IgAN, 
age 18–70 and a proteinuria level above 0.75 g/day plus 
hypertension, impaired renal function (estimated 
glomerular filtration rate [eGFR] <90 ml/min/1.73m2), or 
both. Patients with eGFR <30 ml/minute/1.73 m2, those 
with rapidly progressive crescentic IgAN, secondary 
IgAN and other chronic renal diseases, or who had 
previously received immunosuppression were excluded. 
The first stage of the trial involved a six-month run-in 
phase where all patients received intensive supportive 
care including renin angiotensin system (RAS) blockade 
to lower blood pressure (BP) to a target below 125/70 
mmHg. If proteinuria persisted above 0.75 g/day once 
this target BP was achieved, the dose of RAS blocker 
(either angiotensin converting enzyme inhibitor [ACEI], 
angiotensin receptor blocker [ARB] or both) was 
increased as tolerated up to the maximum approved 
dosage. Participants were seen seven times during this 
period. In total, 34% of patients had a response to 
supportive care during this period with proteinuria 
falling to below 0.75 g/day. These responsive patients 
were excluded from the randomisation phase of the study.
Following the run-in phase, 162 participants with 
persistent proteinuria more than 0.75 g/day but less than 
3.5 g/day were randomised to the 3-year study phase. 
These participants were randomly assigned either to 
continue with maximal supportive care alone (80 
participants), or to receive maximal supportive care plus 
immunosuppressive therapy (82 participants).
Depending on the eGFR, the immunosuppression given 
in the immunosuppression arm of the study varied. 
Patients with eGFR between 30 and 59 ml/min/1.73m2 
received cyclophosphamide (1.5 mg/kg/day) for 3 
months, followed by azathioprine (1.5mg/kg/day) during 
months 4–36, plus oral prednisolone initially at dose of 
40 mg/day, tapered to 7.5 mg/day by month 6 of the 
study and continued on this dose until the study end. 
Those with eGFR of ≥60 ml/min/1.73m2 received 
glucocorticoid monotherapy for six months. They 
received intravenous methylprednisolone (1 g/day) as 
three pulsed doses at the start of months 1, 3 and 5 and 
oral prednisolone (0.5 mg/kg) every 48 hours on the 
other days.
The primary outcomes of the study were i) full clinical 
remission defined as proteinuria with a protein:creatinine 
ratio of <0.2 and stable renal function with decrease in 
the eGFR of <5 ml/min/1.73m2 from the baseline eGFR at 
the end of the 3 year trial phase and ii) a decrease in the 
eGFR of at least 15 ml/min/1.73m2 from baseline eGFR.
After three years, 14 participants in the 
immunosuppression group met the first primary 
outcome measure of full clinical remission, compared to 
only four participants in the supportive therapy alone 
group. This difference was statistically significant (p = 
0.01). However, participants who had a full clinical 
remission had lower baseline levels of proteinuria than 
those who did not. There was no statistical difference in 
the number of patients in each group with a decrease in 
eGFR of at least 15 ml/min/1.73m2 (28% in the supportive 
What does STOP-IgAN tell us about how to 
treat IgA nephropathy?
Clinical Opinion
1E Rutherford, 2PB Mark
1Clinical Research Fellow, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK; 
2Clinical Reader in Nephrology, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Clinical Research Centre, University of Glasgow, 
Glasgow, UK
TiTle Intensive Supportive Care plus Immunosuppression in IgA Nephropathy
AUThoRS Rauen T, Eitner F, Fitzner C et al.
JoURnAl N Engl J Med 2015; 373: 2225-36. http://dx.doi.org/10.1056/
NEJMoa1415463
DeclARATion of inTeReSTS No conflicts of interests declared
Correspondence to E Rutherford
Division of Cardiovascular and 
Diabetes Medicine
Medical Research Institute
Ninewells Hospital & Medical 
School
Dundee DD1 9SY
UK
e-mail e.rutherford@dundee.ac.uk
care group vs 26% in the immunosuppression group) 
with no significant difference in the rate of decline of 
eGFR between groups.
There were more episodes of infection (including one 
fatal pneumonia) in the immunosuppression group, of 
which 25% were considered directly related to 
immunosuppression. There were also more episodes of 
neoplasia, impaired glucose metabolism and bodyweight 
gain in the immunosuppression arm.
The investigators stated, ‘We could not confirm our 
hypothesis that additional immunosuppressive therapy 
would provide substantial kidney-related benefits in 
patients with high risk IgAN.’ 
oPinion
IgAN is the most common primary glomerulonephritis 
in the world (including Scotland).1 Approximately one 
quarter of individuals diagnosed with IgAN with 
significant proteinuria will progress to end stage renal 
disease requiring dialysis or a kidney transplant within 
20–25 years of presentation.1 The prognosis is worse for 
those patients with persistent proteinuria.1–3 In this 
group, approximately 50% may reach end stage renal 
disease within 10 years.3 RAS blockade to aggressively 
control BP and reduce proteinuria is the mainstay of 
treatment. Current Kidney Disease: Improving Global 
Outcomes (KDIGO) guidelines also recommend use of 
immunosuppression with glucocorticoids if proteinuria 
remains above 1 g/day with maximally tolerated RAS 
blockade.4 However, with the exception of those with 
nephrotic range proteinuria (>3.5 g/day),5 the evidence 
base behind this strategy is relatively weak.6 The STOP-
IgAN trial addresses this area of uncertainty.7
The first piece of knowledge we gain from this study is 
that immunosuppression in patients with stage 1–3 
chronic kidney disease caused by IgAN without nephrotic 
range proteinuria is of very limited benefit when added 
to maximal supportive therapy.7 Previous studies, which 
inform the KDIGO guidelines, have shown some benefit 
from immunosuppressive therapy.4,8–12 However, as the 
STOP-IgAN investigators highlight, these studies lacked 
a run-in period where RAS blockade was maximised, and 
RAS blockade was either temporarily stopped pre-
baseline or was inconsistent throughout the studies.6–12 
Further questions remain unanswered about immuno-
suppression in IgAN. First, the follow up in STOP-IgAN 
was too short to determine if there is longer-term 
benefit gained from remission of proteinuria, which was 
achieved in a greater proportion of patients treated with 
immunosuppression.7 Second, due to the indolent yet 
progressive nature of IgAN, patients present at different 
stages in the disease. Some patients may have had 
haematoproteinuria for years prior to diagnosis. For 
immunosuppression to be effective there should be 
minimal irreversible renal fibrosis present. Finally, the 
individual subgroups treated with the various 
immunosuppressive regimens were small.7 It is also 
unclear if more specific future immunosuppressive 
regimes (e.g. blisibimod, spleen tyrosine kinase inhibition) 
in the era of ‘precision medicine’ may be more effective 
than the broad based immunosuppressive regimens 
employed in STOP-IgAN. The experience of STOP-IgAN 
highlights the challenges of testing new therapies in IgAN.
Perhaps the real success of this trial is the demonstration 
that traditional supportive therapy for IgAN is effective 
in the medium term – 34% of participants in STOP-IgAN 
achieved significant reduction in proteinuria.7 With 
effective RAS blockade and BP control, proteinuria can 
be reduced significantly. Furthermore, with reduction in 
proteinuria one can expect an improved longer-term 
prognosis with slower rate of decline of eGFR.7,13 
Remarkably, mean BP in STOP-IgAN was 126/78 mmHg.7 
The investigators must be commended on this 
achievement; unfortunately real life rarely replicates the 
controlled environment of a clinical trial. This trial7 does 
provide further evidence that we should be aggressively 
pursuing lower BP targets and maximising RAS blockade 
to reduce proteinuria even if, or when, these BP targets 
are achieved.
It is notable that approximately 42% of randomised 
participants in STOP-IgAN received both ARB and ACEI 
therapy simultaneously.7 Subsequent to three recent 
trials,14–16 the UK Medicines and Healthcare products 
Regulatory Agency (MHRA) issued a warning against this 
combination, because of increased risk of hyperkalaemia, 
hypotension and impaired renal function.17 STOP-IgAN 
had only one serious adverse event (in the supportive 
arm) associated with increased serum creatinine and 
potassium.7 The lack of serious complications of 
simultaneous ARB and ACEI in STOP-IgAN is probably 
due to intensive study monitoring. In clinical practice, 
where this level of monitoring is impractical, clinicians 
pursuing dual RAS blockade in this patient group would 
be contravening MHRA advice. We recommend maximal 
single-agent RAS blockade while heeding MHRA guidance.
24
cl
in
ica
l
J R Coll Physicians Edinb 2016; 46: 23–25
© 2016 RCPE
E Rutherford, PB Mark
25
clinical
J R Coll Physicians Edinb 2016; 46: 23–25
© 2016 RCPE
RefeRenceS
1 Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005; 16; 
2088–97.
2 D’Amico, G. Natural history of idiopathic IgA nephropathy and 
factors predictive of disease outcome. Semin Nephrol 2004; 24: 
179–96.
3 Bartosik LP, Lajoie G, Sugar L et al. Predicting progression in IgA 
nephropathy. Am J Kidney Dis 2001; 38: 728–35.
4 Kidney Disease: Improving Global Outcomes (KDIGO) 
Glomerulonephritis Work Group. KDIGO Clinical Practice 
Guideline for Glomerulonephritis. Kidney Inter 2012; 2012; 
2(suppl): 139–274.
5 Kim J-K, Kim JH, Lee SC et al. Clinical features and outcomes of 
IgA nephropathy with nephrotic syndrome. Clin J Am Soc Nephrol 
2012; 7: 427–36. http://dx.doi.org/10.2215/CJN.04820511
6 Vecchio M, Bonerba B, Palmer SC et al. Immunosuppressive agents 
for treating IgA nephropathy. Cochrane Database Syst Rev 2015; 8: 
CD003965. http://dx.doi.org/10.1002/14651858.CD003965.pub2
7 Rauen T, Eitner F, Fitzner C et al. Intensive supportive care plus 
immunosuppression in IgA nephropathy. N Engl J Med 2015; 373: 
2225–36. http://dx.doi.org/10.1056/NEJMoa1415463
8 Pozzi C, Andrulli S, Del Vecchio L et al. Corticosteroid effectiveness 
in IgA nephropathy: long-term results of a randomized, controlled 
trial. J Am Soc Nephrol 2004; 15: 157–63.
9 Pozzi C, Bolasco PG, Fogazzi GB et al. Corticosteroids in IgA 
nephropathy: a randomised controlled trial. Lancet 1999; 353: 
883–7.
10 Praga M, Gutiérrez E, González E et al. Treatment of IgA 
nephropathy with ACE inhibitors: a randomized and controlled 
trial. J Am Soc Nephrol 2003; 14: 1578–83.
11 Coppo R, Peruzzi L, Amore A et al. IgACE: A placebo-controlled, 
randomized trial of angiotensin-converting enzyme inhibitors in 
children and young people with IgA nephropathy and moderate 
proteinuria. J Am Soc Nephrol 2007; 18: 1880–8.
12 Manno C, Torres DD, Rossini M et al. Randomized controlled 
clinical trial of corticosteroids plus ACE-inhibitors with long-term 
follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 
2009; 24: 3694–701. http://dx.doi.org/10.1093/ndt/gfp356
13 Geddes CC, Rauta V, Gronhagen-Riska C et al. A tricontinental 
view of IgA nephropathy. Nephrol Dial Transplant 2003; 18: 1541–8.
14 Yusuf S, Teo KK, Pogue J et al. Telmisartan, ramipril, or both in 
patients at high risk for vascular events. N Engl J Med 2008; 358: 
1547–59.
15 Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin 
inhibition for the treatment of diabetic nephropathy. N Engl J Med 
2013; 369: 1892–903. http://dx.doi.org/10.1056/NEJMoa1303154
16 Parving H-H, Brenner BM, McMurray JJ et al. Cardiorenal end 
points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 
367: 2204–13. http://dx.doi.org/10.1056/NEJMoa1208799
17 MHRA. Combination use of medicines from different classes of 
renin-angiotensin system blocking agents: risk of hyperkalaemia, 
hypotension, and impaired renal function—new warnings. Drug 
Safety Update 19 June 2014. https://www.gov.uk/drug-safety-
update/combination-use-of-medicines-from-different-classes-of-
renin-angiotensin-system-blocking-agents-risk-of-hyperkalaemia-
hypotension-and-impaired-renal-function-new-warnings (accessed 
11/2/16).
Clinical Opinion
The College Journal Prize 2015, sponsored by the Senior Fellows’ Club, was won by  
R Acquah et al for their paper ‘HIV testing in Lanarkshire’. This paper can be read in issue 4, 
2014 at http://www.rcpe.ac.uk/sites/default/files/acquah.pdf
A prize of £250 will be awarded to the first-named (or corresponding) author of an original 
research paper on a clinical topic, deemed by a panel of judges to be the best paper by a 
doctor-in-training (i.e. pre-consultant level) published in the Journal of the Royal College of 
Physicians of Edinburgh in issues 3 and 4, 2015 and issues 1, 2 and 3, 2016. The paper will be 
selected by a panel of judges, including a senior Fellow, an active clinician and a member of 
the Editorial team. The prize-winner will be invited to give a short oral presentation based 
on his/her paper at the Trainees and Members’ symposium in February 2017.
Further details may be obtained from the Editorial Office, RCPE, 9 Queen Street, Edinburgh EH2 1JQ, 
tel +44 (0)131 247 3666 or email editorial@rcpe.ac.uk.
The college JoURnAl PRize


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                                                                    University of DundeeWhat does STOP-IgAN tell us about how to treat IgA nephropathy?Rutherford, E.; Mark, P. B.Published in:Journal of the Royal College of Physicians of EdinburghDOI:10.4997/JRCPE.2016.107Publication date:2016Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Rutherford, E., & Mark, P. B. (2016). What does STOP-IgAN tell us about how to treat IgA nephropathy? Journalof the Royal College of Physicians of Edinburgh, 46(1), 23-25. https://doi.org/10.4997/JRCPE.2016.107General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 30. Jul. 2023What does STOP-IgAN tell us about how to treat IgA Nephropathy?  E Rutherford1 PB Mark2 1Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom 2Institute of Cardiovascular and Medical Sciences, BHF Glasgow Clinical Research Centre, University of Glasgow, Glasgow, United Kingdom    TITLE: Intensive Supportive Care plus Immunosuppression in IgA Nephropathy AUTHORS: Rauen T, Eitner F, Fitzner C et al. JOURNAL: N Engl J Med 2015; 373: 2225-36. http://dx.doi.org/10.1056/NEJMoa1415463 DECLARATION OF INTERESTS: None declared  SUMMARY  The Intensive Supportive Care plus Immunosuppression in IgA Nephropathy (STOP-IgAN) trial was designed to investigate the outcomes of immunosuppressive therapy, when added to maximal supportive care, in patients with IgA nephropathy (IgAN). This was a multicentre, open-label, randomised, controlled trial with a two-group, parallel group design.   Following screening, 337 participants were recruited from 32 nephrology centres across Germany.  The main inclusion criteria were biopsy confirmed primary IgAN; age 18 to 70; and a proteinuria level above 0.75g/day plus hypertension, impaired renal function (estimated glomerular filtration rate [eGFR] <90ml/min/1.73m2), or both. Patients with eGFR <30ml/minute/1.73m2, those with rapidly progressive crescentic IgAN, secondary IgAN and other chronic renal diseases, or who had previously received immunosuppression were excluded.   The first stage of the trial involved a six-month run-in phase where all patients received intensive supportive care including Renin Angiotensin System (RAS) blockade to lower BP to a target below 125/70mmHg. If proteinuria persisted above 0.75g/day once this target BP was achieved, the dose of RAS blocker (either angiotensin converting enzyme inhibitor [ACEI], angiotensin receptor blocker [ARB] or both) was increased as tolerated up to the maximum approved dosage. Participants were seen seven times during this period. 34% of patients had a response to supportive care during this period with proteinuria falling to below 0.75g/day. These responsive patients were excluded from the randomisation phase of the study.  Following the run-in phase, 162 participants with persistent proteinuria more than 0.75g/day but less than 3.5g/day were randomised to the 3-year study phase. These participants were randomly assigned either to continue with maximal supportive care alone (80 participants), or to receive maximal supportive care plus immunosuppressive therapy (82 participants).  Depending on the eGFR, the immunosuppression given in the immunosuppression arm of the study varied. Patients with eGFR between 30 and 59ml/min/1.73m2 received cyclophosphamide (1.5mg/kilogram/day) for 3 months, followed by azathioprine (1.5mg/kg/day) during months 4-36, plus oral prednisolone initially at dose of 40mg/day, tapered to 7.5mg/day by month 6 of the study and continued on this dose until the study end. Those with eGFR of ≥60ml/min/1.73m2 received glucocorticoid monotherapy for 6 months. They received intravenous methylprednisolone (1g/day) as 3 pulsed doses at the start of months 1, 3 and 5 and oral prednisolone (0.5mg/kg) every 48 hours on the other days.  The primary outcomes of the study were firstly, full clinical remission defined as proteinuria with protein:creatinine ratio of <0.2 and stable renal function with decrease in the eGFR of <5ml/min/1.73m2 from the baseline eGFR at the end of the 3 year trial phase and secondly, a decrease in the eGFR of at least 15ml/min/1.73m2 from baseline eGFR.  After 3 years, 14 participants in the immunosuppression group met the first primary outcome measure of full clinical remission, compared to only 4 participants in the supportive therapy alone group. This difference was statistically significant (p=0.01).  However, participants who had a full clinical remission had lower baseline levels of proteinuria than those who did not. There was no statistical difference in the number of patients in each group having decrease in eGFR of at least 15ml/min/1.73m2 (28% in the supportive care group vs. 26% in the immunosuppression group) with no significant difference in rate of decline of eGFR between groups.  There were more episodes of infection (including one fatal pneumonia) in the immunosuppression group, of which 25% were considered directly related to immunosuppression. There were also more of episodes of neoplasm; impaired glucose metabolism and body weight gain in the immunosuppression arm.  The investigators stated, “We could not confirm our hypothesis that additional immunosuppressive therapy would provide substantial kidney-related benefits in patients with high risk IgAN.”   OPINION  Approximately one quarter of individuals diagnosed with IgAN with significant proteinuria will progress to end stage renal disease (ESRD) requiring dialysis or a kidney transplant within 20-25 years of presentation.1 The prognosis is worse for those patients with persistent proteinuria.1–3 In this group approximately 50% may reach ESRD within 10 years.3 IgAN is the most common primary glomerulonephritis in the world (including Scotland).1 RAS blockade to aggressively control BP and reduce proteinuria is the mainstay of treatment. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines also recommend use of immunosuppression with glucocorticoids if proteinuria remains above 1g/day with maximally tolerated RAS blockade.4 However, with the exception of those with nephrotic range proteinuria (>3.5g/day),5 the evidence base behind this strategy is relatively weak.6 The STOP-IgAN trial addresses this area of uncertainty.7  The first piece of knowledge we gain from this study is that, immunosuppression in patients with stage 1-3 chronic kidney disease caused by IgAN without nephrotic range proteinuria is of very limited benefit in addition to maximal supportive therapy.7 Previous studies, which inform the KDIGO guidelines, have shown some benefit from immunosuppressive therapy.4,8–12 However, as the STOP-IgAN investigators highlight, these studies lacked a run-in period where RAS blockade was maximised, and RAS blockade was either temporarily stopped pre-baseline, or was inconsistent throughout the studies.6–12   Further questions remain unanswered about immunosuppresion in IgAN. Firstly, the follow up in STOP-IgAN was too short to determine if there is longer-term benefit gained by remission of proteinuria, which was achieved in a greater proportion of patients treated with immunosuppression.7 Similarly, due to the indolent yet progressive nature of IgAN, patients present at different stages in the disease. Some patients may have had haematoproteinuria for years prior to diagnosis. For immunosuppresion to be effective, there should be minimal irreversible renal fibrosis present. Finally, the individual subgroups treated with the various immunosuppressive regimens were small.7 It is also unclear if more specific future immunosuppressive regimes (e.g. blisibimod, spleen tyrosine kinase inhibition etc) in the era of “precision medicine” may be more effective than the broad based immunosuppressive regimens employed in STOP-IgAN. The experience of STOP-IgAN highlights the challenges of testing new therapies in IgAN.  Perhaps the real success of this trial is the demonstration that traditional supportive therapy for IgAN is effective in the medium term – 34% of participants in STOP-IgAN achieved significant reduction in proteinuria.7 With effective RAS blockade and BP control proteinuria can be reduced significantly. Furthermore, with reduction in proteinuria one can expect an improved longer-term prognosis with slower rate of decline of eGFR.7,13 Incredibly mean BP in STOP-IgA was 126/78mmHg.7 The investigators must be commended on this achievement. Unfortunately real life rarely replicates the controlled environment of a clinical trial. This trial7 does provide further evidence that we should be aggressively targeting lower BP targets and maximising RAS blockade to reduce proteinuria even if, or when, these BP targets are achieved.  It is notable that approximately 42% of randomised participants in STOP-IgAN received both ARB and ACEI therapy simultaneously.7 On the back of three recent trials14–16 the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a warning against this combination, because of increased risk of hyperkalaemia, hypotension and impaired renal function.17 STOP-IgAN had only one serious adverse event (in the supportive arm) associated with increased serum creatinine and potassium.7 The lack of serious complications of simultaneous ARB and ACEI in STOP-IgAN is probably due to intensive study monitoring. In clinical practice, where this level of monitoring is impractical, clinicians pursuing dual RAS blockade in this patient group would be contravening MHRA advice. We recommend maximal single-agent RAS blockade whilst heeding MHRA guidance.  REFERENCES 1. Barratt, J. & Feehally, J. IgA nephropathy. J. Am. Soc. Nephrol. 16, 2088–97 (2005). 2. D’Amico, G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin. Nephrol. 24, 179–196 (2004). 3. Bartosik, L. P., Lajoie, G., Sugar, L. & Cattran, D. C. Predicting progression in IgA nephropathy. Am. J. Kidney Dis. 38, 728–735 (2001). 4. Abstract. Kidney Int. Suppl. 2, 142 (2012). 5. Kim, J.-K. et al. Clinical features and outcomes of IgA nephropathy with nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 7, 427–36 (2012). 6. Vecchio, M. et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane database Syst. Rev. 8, CD003965 (2015). 7. Rauen, T. et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N. Engl. J. Med. 373, 2225–36 (2015). 8. Pozzi, C. et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J. Am. Soc. Nephrol. 15, 157–63 (2004). 9. Pozzi, C. et al. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet (London, England) 353, 883–7 (1999). 10. Praga, M., Gutiérrez, E., González, E., Morales, E. & Hernández, E. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J. Am. Soc. Nephrol. 14, 1578–83 (2003). 11. Coppo, R. et al. IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria. J. Am. Soc. Nephrol. 18, 1880–1888 (2007). 12. Manno, C., Torres, D. D., Rossini, M., Pesce, F. & Schena, F. P. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol. Dial. Transplant 24, 3694–701 (2009). 13. Geddes, C. C. et al. A tricontinental view of IgA nephropathy. Nephrol. Dial. Transplant 18, 1541–8 (2003). 14. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–59 (2008). 15. Fried, L. F. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 369, 1892–903 (2013). 16. Parving, H.-H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–13 (2012). 17. Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function—new warnings Drug Safety Update - GOV.UK. Drug Safety Update volume 7 issue 11, June 2014: A1.      

                                                              University of DundeeWhat does STOP-IgAN tell us about how to treat IgA nephropathy?Rutherford, E.; Mark, P. B.Published in:Journal of the Royal College of Physicians of EdinburghDOI:10.4997/JRCPE.2016.107Publication date:2016Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Rutherford, E., & Mark, P. B. (2016). What does STOP-IgAN tell us about how to treat IgA nephropathy? Journalof the Royal College of Physicians of Edinburgh, 46(1), 23-25. DOI: 10.4997/JRCPE.2016.107General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 17. Feb. 2017What does STOP-IgAN tell us about how to treat IgA Nephropathy?  E Rutherford1 PB Mark2 1Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom 2Institute of Cardiovascular and Medical Sciences, BHF Glasgow Clinical Research Centre, University of Glasgow, Glasgow, United Kingdom    TITLE: Intensive Supportive Care plus Immunosuppression in IgA Nephropathy AUTHORS: Rauen T, Eitner F, Fitzner C et al. JOURNAL: N Engl J Med 2015; 373: 2225-36. http://dx.doi.org/10.1056/NEJMoa1415463 DECLARATION OF INTERESTS: None declared  SUMMARY  The Intensive Supportive Care plus Immunosuppression in IgA Nephropathy (STOP-IgAN) trial was designed to investigate the outcomes of immunosuppressive therapy, when added to maximal supportive care, in patients with IgA nephropathy (IgAN). This was a multicentre, open-label, randomised, controlled trial with a two-group, parallel group design.   Following screening, 337 participants were recruited from 32 nephrology centres across Germany.  The main inclusion criteria were biopsy confirmed primary IgAN; age 18 to 70; and a proteinuria level above 0.75g/day plus hypertension, impaired renal function (estimated glomerular filtration rate [eGFR] <90ml/min/1.73m2), or both. Patients with eGFR <30ml/minute/1.73m2, those with rapidly progressive crescentic IgAN, secondary IgAN and other chronic renal diseases, or who had previously received immunosuppression were excluded.   The first stage of the trial involved a six-month run-in phase where all patients received intensive supportive care including Renin Angiotensin System (RAS) blockade to lower BP to a target below 125/70mmHg. If proteinuria persisted above 0.75g/day once this target BP was achieved, the dose of RAS blocker (either angiotensin converting enzyme inhibitor [ACEI], angiotensin receptor blocker [ARB] or both) was increased as tolerated up to the maximum approved dosage. Participants were seen seven times during this period. 34% of patients had a response to supportive care during this period with proteinuria falling to below 0.75g/day. These responsive patients were excluded from the randomisation phase of the study.  Following the run-in phase, 162 participants with persistent proteinuria more than 0.75g/day but less than 3.5g/day were randomised to the 3-year study phase. These participants were randomly assigned either to continue with maximal supportive care alone (80 participants), or to receive maximal supportive care plus immunosuppressive therapy (82 participants).  Depending on the eGFR, the immunosuppression given in the immunosuppression arm of the study varied. Patients with eGFR between 30 and 59ml/min/1.73m2 received cyclophosphamide (1.5mg/kilogram/day) for 3 months, followed by azathioprine (1.5mg/kg/day) during months 4-36, plus oral prednisolone initially at dose of 40mg/day, tapered to 7.5mg/day by month 6 of the study and continued on this dose until the study end. Those with eGFR of ≥60ml/min/1.73m2 received glucocorticoid monotherapy for 6 months. They received intravenous methylprednisolone (1g/day) as 3 pulsed doses at the start of months 1, 3 and 5 and oral prednisolone (0.5mg/kg) every 48 hours on the other days.  The primary outcomes of the study were firstly, full clinical remission defined as proteinuria with protein:creatinine ratio of <0.2 and stable renal function with decrease in the eGFR of <5ml/min/1.73m2 from the baseline eGFR at the end of the 3 year trial phase and secondly, a decrease in the eGFR of at least 15ml/min/1.73m2 from baseline eGFR.  After 3 years, 14 participants in the immunosuppression group met the first primary outcome measure of full clinical remission, compared to only 4 participants in the supportive therapy alone group. This difference was statistically significant (p=0.01).  However, participants who had a full clinical remission had lower baseline levels of proteinuria than those who did not. There was no statistical difference in the number of patients in each group having decrease in eGFR of at least 15ml/min/1.73m2 (28% in the supportive care group vs. 26% in the immunosuppression group) with no significant difference in rate of decline of eGFR between groups.  There were more episodes of infection (including one fatal pneumonia) in the immunosuppression group, of which 25% were considered directly related to immunosuppression. There were also more of episodes of neoplasm; impaired glucose metabolism and body weight gain in the immunosuppression arm.  The investigators stated, “We could not confirm our hypothesis that additional immunosuppressive therapy would provide substantial kidney-related benefits in patients with high risk IgAN.”   OPINION  Approximately one quarter of individuals diagnosed with IgAN with significant proteinuria will progress to end stage renal disease (ESRD) requiring dialysis or a kidney transplant within 20-25 years of presentation.1 The prognosis is worse for those patients with persistent proteinuria.1–3 In this group approximately 50% may reach ESRD within 10 years.3 IgAN is the most common primary glomerulonephritis in the world (including Scotland).1 RAS blockade to aggressively control BP and reduce proteinuria is the mainstay of treatment. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines also recommend use of immunosuppression with glucocorticoids if proteinuria remains above 1g/day with maximally tolerated RAS blockade.4 However, with the exception of those with nephrotic range proteinuria (>3.5g/day),5 the evidence base behind this strategy is relatively weak.6 The STOP-IgAN trial addresses this area of uncertainty.7  The first piece of knowledge we gain from this study is that, immunosuppression in patients with stage 1-3 chronic kidney disease caused by IgAN without nephrotic range proteinuria is of very limited benefit in addition to maximal supportive therapy.7 Previous studies, which inform the KDIGO guidelines, have shown some benefit from immunosuppressive therapy.4,8–12 However, as the STOP-IgAN investigators highlight, these studies lacked a run-in period where RAS blockade was maximised, and RAS blockade was either temporarily stopped pre-baseline, or was inconsistent throughout the studies.6–12   Further questions remain unanswered about immunosuppresion in IgAN. Firstly, the follow up in STOP-IgAN was too short to determine if there is longer-term benefit gained by remission of proteinuria, which was achieved in a greater proportion of patients treated with immunosuppression.7 Similarly, due to the indolent yet progressive nature of IgAN, patients present at different stages in the disease. Some patients may have had haematoproteinuria for years prior to diagnosis. For immunosuppresion to be effective, there should be minimal irreversible renal fibrosis present. Finally, the individual subgroups treated with the various immunosuppressive regimens were small.7 It is also unclear if more specific future immunosuppressive regimes (e.g. blisibimod, spleen tyrosine kinase inhibition etc) in the era of “precision medicine” may be more effective than the broad based immunosuppressive regimens employed in STOP-IgAN. The experience of STOP-IgAN highlights the challenges of testing new therapies in IgAN.  Perhaps the real success of this trial is the demonstration that traditional supportive therapy for IgAN is effective in the medium term – 34% of participants in STOP-IgAN achieved significant reduction in proteinuria.7 With effective RAS blockade and BP control proteinuria can be reduced significantly. Furthermore, with reduction in proteinuria one can expect an improved longer-term prognosis with slower rate of decline of eGFR.7,13 Incredibly mean BP in STOP-IgA was 126/78mmHg.7 The investigators must be commended on this achievement. Unfortunately real life rarely replicates the controlled environment of a clinical trial. This trial7 does provide further evidence that we should be aggressively targeting lower BP targets and maximising RAS blockade to reduce proteinuria even if, or when, these BP targets are achieved.  It is notable that approximately 42% of randomised participants in STOP-IgAN received both ARB and ACEI therapy simultaneously.7 On the back of three recent trials14–16 the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a warning against this combination, because of increased risk of hyperkalaemia, hypotension and impaired renal function.17 STOP-IgAN had only one serious adverse event (in the supportive arm) associated with increased serum creatinine and potassium.7 The lack of serious complications of simultaneous ARB and ACEI in STOP-IgAN is probably due to intensive study monitoring. In clinical practice, where this level of monitoring is impractical, clinicians pursuing dual RAS blockade in this patient group would be contravening MHRA advice. We recommend maximal single-agent RAS blockade whilst heeding MHRA guidance.  REFERENCES 1. Barratt, J. & Feehally, J. IgA nephropathy. J. Am. Soc. Nephrol. 16, 2088–97 (2005). 2. D’Amico, G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin. Nephrol. 24, 179–196 (2004). 3. Bartosik, L. P., Lajoie, G., Sugar, L. & Cattran, D. C. Predicting progression in IgA nephropathy. Am. J. Kidney Dis. 38, 728–735 (2001). 4. Abstract. Kidney Int. Suppl. 2, 142 (2012). 5. Kim, J.-K. et al. Clinical features and outcomes of IgA nephropathy with nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 7, 427–36 (2012). 6. Vecchio, M. et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane database Syst. Rev. 8, CD003965 (2015). 7. Rauen, T. et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N. Engl. J. Med. 373, 2225–36 (2015). 8. Pozzi, C. et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J. Am. Soc. Nephrol. 15, 157–63 (2004). 9. Pozzi, C. et al. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet (London, England) 353, 883–7 (1999). 10. Praga, M., Gutiérrez, E., González, E., Morales, E. & Hernández, E. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J. Am. Soc. Nephrol. 14, 1578–83 (2003). 11. Coppo, R. et al. IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria. J. Am. Soc. Nephrol. 18, 1880–1888 (2007). 12. Manno, C., Torres, D. D., Rossini, M., Pesce, F. & Schena, F. P. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol. Dial. Transplant 24, 3694–701 (2009). 13. Geddes, C. C. et al. A tricontinental view of IgA nephropathy. Nephrol. Dial. Transplant 18, 1541–8 (2003). 14. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–59 (2008). 15. Fried, L. F. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 369, 1892–903 (2013). 16. Parving, H.-H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–13 (2012). 17. Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function—new warnings Drug Safety Update - GOV.UK. Drug Safety Update volume 7 issue 11, June 2014: A1.      

                                                                    University of DundeeWhat does STOP-IgAN tell us about how to treat IgA nephropathy?Rutherford, E.; Mark, P. B.Published in:Journal of the Royal College of Physicians of EdinburghDOI:10.4997/JRCPE.2016.107Publication date:2016Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Rutherford, E., & Mark, P. B. (2016). What does STOP-IgAN tell us about how to treat IgA nephropathy? Journalof the Royal College of Physicians of Edinburgh, 46(1), 23-25. https://doi.org/10.4997/JRCPE.2016.107General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 01. Nov. 2025What does STOP-IgAN tell us about how to treat IgA Nephropathy?  E Rutherford1 PB Mark2 1Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, United Kingdom 2Institute of Cardiovascular and Medical Sciences, BHF Glasgow Clinical Research Centre, University of Glasgow, Glasgow, United Kingdom    TITLE: Intensive Supportive Care plus Immunosuppression in IgA Nephropathy AUTHORS: Rauen T, Eitner F, Fitzner C et al. JOURNAL: N Engl J Med 2015; 373: 2225-36. http://dx.doi.org/10.1056/NEJMoa1415463 DECLARATION OF INTERESTS: None declared  SUMMARY  The Intensive Supportive Care plus Immunosuppression in IgA Nephropathy (STOP-IgAN) trial was designed to investigate the outcomes of immunosuppressive therapy, when added to maximal supportive care, in patients with IgA nephropathy (IgAN). This was a multicentre, open-label, randomised, controlled trial with a two-group, parallel group design.   Following screening, 337 participants were recruited from 32 nephrology centres across Germany.  The main inclusion criteria were biopsy confirmed primary IgAN; age 18 to 70; and a proteinuria level above 0.75g/day plus hypertension, impaired renal function (estimated glomerular filtration rate [eGFR] <90ml/min/1.73m2), or both. Patients with eGFR <30ml/minute/1.73m2, those with rapidly progressive crescentic IgAN, secondary IgAN and other chronic renal diseases, or who had previously received immunosuppression were excluded.   The first stage of the trial involved a six-month run-in phase where all patients received intensive supportive care including Renin Angiotensin System (RAS) blockade to lower BP to a target below 125/70mmHg. If proteinuria persisted above 0.75g/day once this target BP was achieved, the dose of RAS blocker (either angiotensin converting enzyme inhibitor [ACEI], angiotensin receptor blocker [ARB] or both) was increased as tolerated up to the maximum approved dosage. Participants were seen seven times during this period. 34% of patients had a response to supportive care during this period with proteinuria falling to below 0.75g/day. These responsive patients were excluded from the randomisation phase of the study.  Following the run-in phase, 162 participants with persistent proteinuria more than 0.75g/day but less than 3.5g/day were randomised to the 3-year study phase. These participants were randomly assigned either to continue with maximal supportive care alone (80 participants), or to receive maximal supportive care plus immunosuppressive therapy (82 participants).  Depending on the eGFR, the immunosuppression given in the immunosuppression arm of the study varied. Patients with eGFR between 30 and 59ml/min/1.73m2 received cyclophosphamide (1.5mg/kilogram/day) for 3 months, followed by azathioprine (1.5mg/kg/day) during months 4-36, plus oral prednisolone initially at dose of 40mg/day, tapered to 7.5mg/day by month 6 of the study and continued on this dose until the study end. Those with eGFR of ≥60ml/min/1.73m2 received glucocorticoid monotherapy for 6 months. They received intravenous methylprednisolone (1g/day) as 3 pulsed doses at the start of months 1, 3 and 5 and oral prednisolone (0.5mg/kg) every 48 hours on the other days.  The primary outcomes of the study were firstly, full clinical remission defined as proteinuria with protein:creatinine ratio of <0.2 and stable renal function with decrease in the eGFR of <5ml/min/1.73m2 from the baseline eGFR at the end of the 3 year trial phase and secondly, a decrease in the eGFR of at least 15ml/min/1.73m2 from baseline eGFR.  After 3 years, 14 participants in the immunosuppression group met the first primary outcome measure of full clinical remission, compared to only 4 participants in the supportive therapy alone group. This difference was statistically significant (p=0.01).  However, participants who had a full clinical remission had lower baseline levels of proteinuria than those who did not. There was no statistical difference in the number of patients in each group having decrease in eGFR of at least 15ml/min/1.73m2 (28% in the supportive care group vs. 26% in the immunosuppression group) with no significant difference in rate of decline of eGFR between groups.  There were more episodes of infection (including one fatal pneumonia) in the immunosuppression group, of which 25% were considered directly related to immunosuppression. There were also more of episodes of neoplasm; impaired glucose metabolism and body weight gain in the immunosuppression arm.  The investigators stated, “We could not confirm our hypothesis that additional immunosuppressive therapy would provide substantial kidney-related benefits in patients with high risk IgAN.”   OPINION  Approximately one quarter of individuals diagnosed with IgAN with significant proteinuria will progress to end stage renal disease (ESRD) requiring dialysis or a kidney transplant within 20-25 years of presentation.1 The prognosis is worse for those patients with persistent proteinuria.1–3 In this group approximately 50% may reach ESRD within 10 years.3 IgAN is the most common primary glomerulonephritis in the world (including Scotland).1 RAS blockade to aggressively control BP and reduce proteinuria is the mainstay of treatment. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines also recommend use of immunosuppression with glucocorticoids if proteinuria remains above 1g/day with maximally tolerated RAS blockade.4 However, with the exception of those with nephrotic range proteinuria (>3.5g/day),5 the evidence base behind this strategy is relatively weak.6 The STOP-IgAN trial addresses this area of uncertainty.7  The first piece of knowledge we gain from this study is that, immunosuppression in patients with stage 1-3 chronic kidney disease caused by IgAN without nephrotic range proteinuria is of very limited benefit in addition to maximal supportive therapy.7 Previous studies, which inform the KDIGO guidelines, have shown some benefit from immunosuppressive therapy.4,8–12 However, as the STOP-IgAN investigators highlight, these studies lacked a run-in period where RAS blockade was maximised, and RAS blockade was either temporarily stopped pre-baseline, or was inconsistent throughout the studies.6–12   Further questions remain unanswered about immunosuppresion in IgAN. Firstly, the follow up in STOP-IgAN was too short to determine if there is longer-term benefit gained by remission of proteinuria, which was achieved in a greater proportion of patients treated with immunosuppression.7 Similarly, due to the indolent yet progressive nature of IgAN, patients present at different stages in the disease. Some patients may have had haematoproteinuria for years prior to diagnosis. For immunosuppresion to be effective, there should be minimal irreversible renal fibrosis present. Finally, the individual subgroups treated with the various immunosuppressive regimens were small.7 It is also unclear if more specific future immunosuppressive regimes (e.g. blisibimod, spleen tyrosine kinase inhibition etc) in the era of “precision medicine” may be more effective than the broad based immunosuppressive regimens employed in STOP-IgAN. The experience of STOP-IgAN highlights the challenges of testing new therapies in IgAN.  Perhaps the real success of this trial is the demonstration that traditional supportive therapy for IgAN is effective in the medium term – 34% of participants in STOP-IgAN achieved significant reduction in proteinuria.7 With effective RAS blockade and BP control proteinuria can be reduced significantly. Furthermore, with reduction in proteinuria one can expect an improved longer-term prognosis with slower rate of decline of eGFR.7,13 Incredibly mean BP in STOP-IgA was 126/78mmHg.7 The investigators must be commended on this achievement. Unfortunately real life rarely replicates the controlled environment of a clinical trial. This trial7 does provide further evidence that we should be aggressively targeting lower BP targets and maximising RAS blockade to reduce proteinuria even if, or when, these BP targets are achieved.  It is notable that approximately 42% of randomised participants in STOP-IgAN received both ARB and ACEI therapy simultaneously.7 On the back of three recent trials14–16 the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a warning against this combination, because of increased risk of hyperkalaemia, hypotension and impaired renal function.17 STOP-IgAN had only one serious adverse event (in the supportive arm) associated with increased serum creatinine and potassium.7 The lack of serious complications of simultaneous ARB and ACEI in STOP-IgAN is probably due to intensive study monitoring. In clinical practice, where this level of monitoring is impractical, clinicians pursuing dual RAS blockade in this patient group would be contravening MHRA advice. We recommend maximal single-agent RAS blockade whilst heeding MHRA guidance.  REFERENCES 1. Barratt, J. & Feehally, J. IgA nephropathy. J. Am. Soc. Nephrol. 16, 2088–97 (2005). 2. D’Amico, G. 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Lancet (London, England) 353, 883–7 (1999). 10. Praga, M., Gutiérrez, E., González, E., Morales, E. & Hernández, E. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J. Am. Soc. Nephrol. 14, 1578–83 (2003). 11. Coppo, R. et al. IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria. J. Am. Soc. Nephrol. 18, 1880–1888 (2007). 12. Manno, C., Torres, D. D., Rossini, M., Pesce, F. & Schena, F. P. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol. Dial. Transplant 24, 3694–701 (2009). 13. Geddes, C. C. et al. A tricontinental view of IgA nephropathy. Nephrol. Dial. Transplant 18, 1541–8 (2003). 14. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–59 (2008). 15. Fried, L. F. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 369, 1892–903 (2013). 16. Parving, H.-H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–13 (2012). 17. Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function—new warnings Drug Safety Update - GOV.UK. Drug Safety Update volume 7 issue 11, June 2014: A1.      

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What does STOP-IgAN tell us about how to treat IgA nephropathy?

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