Slide 1

 In this presentation I will provide recommendations about the management of IgA nephropathy, the commonest pattern of glomerulonephritis.

Slide 2

I will describe the wide variations in the clinical and pathological features of IgA nephropathy, and discuss the available data which assist in predicting individual prognosis in IgA nephropathy, before reviewing available data on drug therapy.

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I will start with the many phenotypic variations in IgA nephropathy.

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IgA Nephropathy is the commonest pattern of glomerulonephritis in the world.

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And I used the word pattern deliberately.

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We define it on the basis of mesangial IgA.

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But of course, it’s a pattern with very many variants for example, great variation in pathology.

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Here are 4 glomeruli all from patients with IgA nephropathy; one normal, one with segmental and diffuse mesangial hypercellularity and one with marked increase in mesangial matrix.

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There is great variation in clinical presentation too. I’ll show you a series of slides pointing this out.

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Henoch-Schonlein purpura, IgA nephropathy with a small vessel vasculitis is typically a disease of children. I won’t discuss that further.

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Recurrent macroscopic hematuria with mucosal infection is a disease of young adults and young people.

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As is nephrotic syndrome as a presentation.

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Patients who are asymptomatic and picked up with blood and protein in the urine are typically older.

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And even older are those who already have proteinuria, hypertension and a falling GFR when first identified. That means there must be variations in process also.

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IgA with IgG and C3 is deposited in the glomerulus in this condition and causes inflammation which can go on to scar glomeruli and the interstitium and cause renal failure.

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But of course, it is not inevitable you may have IgA deposition and no injury.

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You may have segmental injury even though the IgA is diffusely deposited.

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The glomerulonephritis may resolve.

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There may or may not be recurrence in transplant.

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There’s enormous geographical variation too. These percentages are the percentage of patients with primary glomerular disease who have IgA nephropathy in different parts of the world. 40% and 50% in the Pacific Rim, 25% in Europe, very much lower in blacks including in blacks in North America strongly suggesting a genetic influence which we do not yet understand.

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Marked gender differences as well.

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So we have variations in pathological pattern, in clinical pattern, in transplant recurrence, in geographical prevalence and gender prevalence.

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So we have no proof that IgA nephropathy is a single disease or indeed that IgAN is the same disease in all parts of the world and we have to bear that in mind.

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We also need to be able to predict prognosis in individual patients.

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Now this is an old slide, 25 years old but very typical showing a cohort of patients with IgAN and this is the proportion with independent renal function after 20 years of follow up.

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And I usually teach people to think in terms of 20% have ESRD at 20 years because it’s easy to remember. But of course, it depends who is in your cohort to start with.

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Here for example, are data from India with a completely different outcome, 60% in renal failure by 10 years.

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Is it a different disease in India? Well, it might be but this is a tertiary referral centre and half the patients were nephrotic and half the patients had a reduced GFR when they arrived in the unit. So they are a completely different group of patients.

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Here we have 4 cohorts from white Caucasian background which appeared to have different outcomes and much of this is in fact, explained by the different sorts of patients who were in the cohort to begin with.

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We also have some evidence that those who have visible hematuria are less likely to get renal failure than those who do not.

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It seems likely this is a phenomenon of lead time bias that if you have visible hematuria, you’re diagnosed very much earlier in a course than if you’re picked up asymptomatic.

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Suggesting perhaps that these patients are the same as these patients. But simply not detected earlier although we do not know that.

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We’re very familiar with the idea of a number of prognostic factors which influence outcome, which are present when the patient presents.

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Particularly severity of proteinuria,

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hypertension

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and a low GFR.

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Histological features including glomerulosclerosis

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and tubulointerstitial fibrosis.

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What happens if you have none of those however? Here’s a cohort from Canada of people with IgAN who have microscopic hematuria but no proteinuria and normal blood pressure.

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Their 10 year risk of developing renal failure is 0. Now, of course, 10 years is a very short time for a young person with IgAN but that appears reassuring. However, a cohort from Hong Kong of patients with microscopic hematuria and only very low grade proteinuria are completely different.

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In a 7 year follow up many of them developed proteinuria, hypertension or renal impairment. Does this tell us that this is a different disease in Chinese people? I do not think we yet know.

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What we do know is that proteinuria is extremely important and right across the severity of proteinuria there is progressively increased risk of developing renal failure. However, even if you have little proteinuria at presentation, what happens during follow up is equally important.

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These are 3 groups of patients who over 10 years developed worse proteinuria and the more proteinuria developed during follow up. Even if you had little to start with, the more likely you are to get renal failure.

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The reverse is true. If you get a patient into even a partial remission and get proteinuria to less than 1g, then what your proteinuria was at presentation does not matter. So these are 3 groups of patients all of whom went into partial remission during follow up who had completely different baseline proteinuria.

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So if you can achieve remission of proteinuria, the prognosis improves. It’s clear that your risk of losing renal function is strongly affected both by your time average proteinuria and also by your mean arterial blood pressure. These recent data are all from Toronto.

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If you know the clinical features at presentation, does the biopsy add any information?

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Well, in that Toronto Registry study the answer was no that in multivariate analysis if you knew proteinuria and mean arterial blood pressure, the histological grade did not improve your prognostic accuracy.

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Now other studies show different things and I think what this reflects is the problems we have with many different pathological classifications of IgAN, none of which are ideal and all of which are opinion based.

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The reason I mentioned that is that later this year you are going to see published a new classification which is an international evidence based clinicopathological classification of IgAN.

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I cannot show you the data today but you will see that both pathological and clinical features at presentation do indeed influence outcome. Such a classification is going to be very important not just to help us with individual patient advice but I think potentially to identify those more and less likely to respond to others treatments and certainly to improve our ability to recruit people into clinical trials.

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Let’s talk about choosing drug therapy.

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There are many ways in which patients with IgAN will present to you.

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And in this short time I’ve chosen to focus on the most difficult problem; the patient with proteinuria, hypertension and who is at high risk of an aggressive fall in GFR. I’ve set proteinuria at more than 1 g because most of the trials we have use that as a recruitment threshold.

Slide 54

We have no specific treatments for this condition.

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We’re reliant on generic treatments and many different generic treatments have been tried.

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They’re very likely applicable to other chronic glomerular diseases although we think of them as being treatments for IgAN.

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Before I review some of those studies, let me make a point to you about trial design. 10 years ago we looked at some data from 3 European centres, took patients with IgAN, more than 1 g of proteinuria and hypertension and established there was a 20% risk of doubling creatinine in 3 years.

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Now, if you use that to inform a power calculation for a trial to try to find a 50% relative reduction in getting renal failure, you have a sample size requirement of 550 and that is much bigger than any trial we have in the literature. It is likely that that is a bigger problem now because of course, we’re much better at controlling blood pressure and blocking the renin-angiotensin system than we were when this study was done. So you will only get a smaller study unless you’re better at picking patients likely to progress and you have better surrogate markers and don’t need to wait for ESRD.

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The other problem is that it is likely there are patients beyond a point of no return through whom you will never gain by treatment.

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So we do have trials but they’re small, not all are well designed, many have insufficient follow up.

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And for the reasons I’ve told you they mostly use clinical and not pathological entry criteria.

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Let’s look at some trials dealing with these four agents.

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Now, there is data which suggests that if you have well preserved renal function very high risk of progression that you should be treated with corticosteroids.

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And the main basis for that is this Italian study which shows a --- impressive benefit from treatment with steroids compared to those who were not treated.

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This is a regimen which used 9 g of methylprednisolone and a large dose of alternate day oral prednisolone which in this study had no side effects or drop outs although it’s certainly not a regimen which we could use in our patients without such problems.

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Interestingly there is another trial of steroids and this trial gave a much smaller dose of prednisolone and when the authors got much less effect, they concluded they had not given enough steroids. I will come back later to why I think that may be incorrect.

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So a suggestion that steroids benefit this group of patients.

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If you have more advanced renal dysfunction, then the evidence really is based around fish oil.

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And is relied upon this old study now from the MAYO clinic which appears to demonstrate a clear benefit for fish oil against placebo after 2 years of treatment with prolonged follow up. It’s very curious that proteinuria was not reduced in the fish oil treated patients and this study has never been replicated.

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Whilst I’m suspicious of metanalysis with only 3 studies, nevertheless you need to take account of the fact that there are two other negative studies.

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And this Forest plot would suggest that there is no proven benefit for fish oil.

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Another group of patients is those with more severe disease who are clearly progressing rapidly to renal failure and here there is a suggestion that cyclophosphamide maybe justified. This is a study from the UK in which a regimen of prednisolone and cyclophosphamide followed by azathioprine was used.

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And appears very successfully to prevent the renal failure which developed in all patients within 5 years in the control group.

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So those 3 options appear to have some evidence.

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Let me deal with mycophenolate because it’s extremely fashionable. We have 4 small studies.

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And I think they should be called pilot studies because they’re all small.

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We can discard two for methodological reasons and I’ll discuss that later if you wish and we’re left with two studies one of which shows no benefit from mycophenolate and one that shows reduction in proteinuria. Is this another phenomenon that the disease is different in different parts of the world? We simply don’t yet know.

Slide 79

So we have these data

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But what I want to do now is interpret them in the context of blood pressure control because I think then we will put these studies into their appropriate position.

Slide 81

Most of us I think would agree with these blood pressure targets for patients with glomerular disease with and without substantial proteinuria.

Slide 82

And I think you would agree that to block the angiotensin system would be the right approach. Let me just emphasise with one small study that there is good evidence that even modest benefits in blood pressure are important in IgAN as in many other renal diseases. Here’s a trial in which patients with IgAN were controlled to two different targets with an ACE inhibitor and a calcium channel blocker and even this modest difference in blood pressure from 129 – 136, from 70-76 protected this group from loss of creatinine clearance over 3 years but not this group.

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We do have data that ACE inhibitors have a special role in these patients as in other proteinuric diseases. This is the most recent study from Rosanna Coppo and her colleagues demonstrating benefit from ACE inhibitors in protecting you from progression.

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We also have the COOPERATE study which is a study in non-diabetic proteinuric renal disease demonstrating here where the upward trend is more endpoints that combination of an ACE inhibitor and an ARB gave more protection than either alone.

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This study achieved that protection with excellent blood pressure where the combination produced a greater reduction in proteinuria.

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And more than a third of the patients in this study had IgAN, that’s the largest IgAN study we have.

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With that information in hand let me go back to the trials I told you about. The trial of a large dose of corticosteroids, the Italian study produced respectable but not ideal blood pressure control and only a proportion of patients had an ACE inhibitor. The Japanese study where a smaller dose of steroid had little effect produced superb blood pressure control without an ACE inhibitor. The study suggesting cyclophosphamide was justified in people with progressive disease produced poor blood pressure control without any data on ACE inhibitor use.

Slide 88

Only among the mycophenolate studies which are more recent do we have excellent blood pressure control and full use of ACE inhibitors. I do not criticise those who designed and delivered the earlier studies but they were designed before we understood about blood pressure targets and renin-angiotensin blockade.

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This is the excellent blood pressure control in the COOPERATE study.

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This is the blood pressure control in the Italian high dose steroid study.

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This is the blood pressure control in the cyclophosphamide study.

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This is the blood pressure control in the mycophenolate studies which you and I would regard as a standard to aim for.

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So in my view the patient with proteinuria of more than 1 g and hypertension must have aggressive renin-angiotensin blockade and immaculate blood pressure control.

Slide 94

And only then I would suggest to you if you achieve a blood pressure target and the patient still has more than 1 g of proteinuria should you consider other additional treatments.

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Many other patients will have their proteinuria very well controlled by that regimen.

Slide 96

You might on the basis of the literature consider each of those but let me remind you that we have very little evidence whether those agents are effective in those circumstances. We don’t have trials where immaculate blood pressure control and vigorous blockade of the renin-angiotensin system was the basis upon which other agents were tried. That’s nobody’s fault, it’s simply a result of history and when these studies were done.

Slide 97

What that means is that we’re still very short of evidence and so there’s plenty of room for you to have your own opinion.

Slide 98

Let me simply end by saying that we have an IgAN Satellite Meeting of the World Congress of Nephrology next year in Italy immediately after the World Congress and I hope very much we’ll see you there. Thank you very much for your attention.