Membranous Nephropathy (MN) affects men twice as often as women and is more common in adults between the ages of 40 and 70. It develops slowly, over a number of years and people may not realise they have the disorder. Some are identified simply because they are found to have a lot of protein in their urine after a routine test (see Clinicians page).
The first thing a person may notice is that their urine appears very frothy, like the head on a pint of beer. This is due to excess protein in the urine. Normal urine has only traces of protein in it but in MN the kidneys leak a lot of protein into the urine.
Patients often have a puffy face, particularly with swelling of the eyelids first thing in the morning. The tummy may also feel distended and the ankles are swollen, especially in the evenings. These symptoms are due to extra fluid being retained in the body by the kidneys. These are the first symptoms in 8 out of 10 people diagnosed with MN.
These complaints will often trigger a visit to the GP. Simple blood and urine tests will confirm the presence of a nephrotic syndrome. GPs may also find that the patient has high blood pressure.
In people with the severest form of MN or in those who delay seeing their doctor, the disease may have already caused additional damage to the kidneys. This could limit the kidney’s ability to get rid of waste products via the urine so that they build up in the patient. Even so there are few additional symptoms unless kidney failure is advanced. Patients may feel more tired than usual.
A first step is to get the right diagnosis. Once the GP has identified that the person has ‘nephrotic syndrome’ or perhaps just heavy proteinuria, the patient will be referred to a kidney specialist. A range of disorders can present in a similar manner and additional blood tests can help to exclude some of them. However the precise diagnosis can only be made with a kidney biopsy. Characteristic features are found that confirm the diagnosis of MN.
There is a lot that can be done to improve MN patients’ wellbeing even if it does not address the root cause of the problem. Most patients will be treated with medicines called Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARB). These drugs were originally designed to treat high blood pressure. However they also reduce the loss of protein in the urine and allow the level of albumin in the blood stream to improve. Diuretic medicines that get rid of excess fluid from the body can help control swelling. Angiotensin antagonists/inhibitors and diuretics tend to work together, amplifying each other’s effects.
Nutritional support helps to strengthen the bones and muscles. Attention to detail is important and decisions have to be tailored to each person’s needs. Patients with MN need to be closely monitored.
Between 25%-40% of MN patients improve spontaneously.
MN is a disorder of the immune system (see How the disease works below). In patients who do not improve spontaneously, treatment with a wide range of immunosuppressive drugs may be used. There is a lack of good quality trial information about them, particularly the newer medicines such as Rituximab and Benlysta. Responses to these medicines can vary and it is not easy to predict the outcome.
If kidney damage progresses, kidney replacement therapy becomes necessary. This can be undertaken by dialysis or a kidney transplant. In some patients MN can recur in the transplanted kidney. Currently it is not possible to predict which patients are at risk of this. Overall, a kidney transplant remains the best option for most MN patients who have lost kidney function.
I have MN also called glomerulonephritis. I had never heard of either before 1998 when my doctor sent me to the main hospital for a second opinion. At first I felt that it was something I caught. I lived a healthy lifestyle where I didn’t smoke or drink but I did have a lot of salt and sugar in my meals, hence the high blood pressure (all has changed now). When I take the ten or so tablets I’m on I feel fine and know the doctors are doing everything they can to keep the kidneys going, although they are only working at about 9%. I hope that they may find a kidney donor soon and I can get all the energy back I had before this all happened.
Living with this disorder has meant I have to miss out on some things I love, like grapefruit and bananas. It has made me look at what I do eat now and how much salt it has in it. My hair and skin has changed as the kidneys do a major function in the body to keep these things looking and feeling good (never knew that).
I shall more than likely be going on to dialysis soon and not looking forward to this as I will have to give up work during the time I’m on the machine. It’s for the good I suppose.
Maybe one day this illness will be a thing of the past and we will look back and say ‘do you remember membranous nephropathy?’
I was diagnosed with Membranous Nephropathy in November 2012. I had been told to watch my blood pressure for a couple of years and advised to lose weight. However in October 2013, my legs, particularly my calves became swollen and ‘tight’. They were painful at night and very itchy. I went to the doctors, had a blood sample taken and told I would be given diuretics when the results came back. Two days later I was asked to go to my doctors immediately with a urine sample. Protein levels were down in my blood and high in my urine. I had to do a 24 hour urine sample the following Tuesday and by the Friday I was waiting to hear from a specialist at the renal unit. The phone call I received was not from the consultant, but someone from her team informing me that they had a bed for me! Total shock! They couldn’t stabilise my blood pressure so I was admitted on the Sunday for a biopsy on the Monday. I finally met my consultant as I was wheeled into the examining room, where upon she informed me that she had cancelled her training session to fit me in. This began a series of hospital visits, a sense of urgency surrounding all visits. People at my doctors’ surgery kept greeting me with, “I’m sorry to hear you are so ill.” The thing was, I didn’t feel ill at all.
So, I was carefully monitored. So what had caused this to happen? I was tested for HIV, hepatitis, Lupus and had scans to rule out cancer – all possible underlying causes. On the 27th December, I met my consultant who informed me with a sad face that I was clear on all counts. So why the sad face? Because we didn’t know the cause of the disease. Idiopathic – no known cause*. At this time research was being conducted into the presence of an antibody (anti-PLA2R) and I was happy to be part of it. I was still feeling absolutely fine. I had by now noticed the tell-tale sign of frothy urine and swollen legs.
I was advised due to the continued decline of my kidney function, to consider the Ponchelli regime – alternating high dosage steroids and a chemotherapy drug for 6 months. It was made very clear that this was not an easy option, however I did not want to face the alternative of dialysis – within possibly 5 years – so agreed. I was pencilled in for April 2013. During this time, my anti-PLA2R results came back and my marker indicated a higher than normal presence of this antibody – my consultant felt justified at putting me on the Ponchelli regime.
It was a fantastic start – high dose steroids and sunny days during Easter 2013 but it became harder as the chemo started to work – I also had an allergic reaction to Cyclophosphamide, so I had to come off, go back on steroids (numerous trips to the hospital at this point) and start on Chlorambucil, a much heavier drug I was informed.
Six months later, in the October, I finished the regime. It was several months later before I started to gain energy and feel more like myself. February 2014 I received the fabulous news that not only had the treatment worked, (they expect a 30% improvement on results), but that I had had an improvement of around of 98%.
I now see my consultant every 12 months with the proviso that I know the signs, and if any return I have to contact her immediately. Things are still great, and everything is within the normal range,
If it had not been for the quick action of a) my GP and b) the renal consultant she spoke to, I may have not had such a dramatic turn around. There is very little information out there, particularly in the UK so I consider myself a very lucky person.
*No known cause – the levels of protein in my blood had started to decline approximately 6 years before, however they could not see further back into my records. 7 years before I had accidently cut myself on my car exhaust, and had had a very bad reaction where my body seized up after 24 hours – full two weeks for the reaction to stop. My consultant could not confirm that this had caused it due to the length of time however I feel that this was the trigger.
The first meeting of the National Patient Forum for Membranous Nephropathy (MN) was held on Saturday 19th March 2016 at the NOWGEN Centre, 29 Grafton Street, Manchester, M13 9WU. An invitation letter, programme and poster all contain further details of the event.
Slides and photos from the event can be found here.
One task of the kidney is to filter the plasma, the watery fluid of the blood stream. It does this in specialised microscopic blood vessels known as glomeruli. Each kidney can have up to a million of them. These filters allow water and small molecules to leave the blood plasma to be processed by the tubules of the kidney. Larger molecules, like albumin, stay behind in the blood. Albumin is the most common protein dissolved in plasma. If you remember that an egg white is chicken albumin, you will get a picture of human albumin which is very similar.
In MN the filters allow plasma albumin to leak across and end up in the urine where it is wasted. The body tries to make extra proteins but cannot keep up with the losses. Proteinuria means protein in the urine.
The filtration occurs across a special membrane, the glomerular basement membrane. Looked at under a microscope this membrane appears thickened in membranous nephropathy, which is how the condition originally got its name. The thickening is because extra membrane is made around little deposits of antibody.
Antibodies are part of the immune system that defends against infection. They are specialised proteins that recognise very precise chemical patterns on germs, stick to them and help to get rid of them. Sometimes antibodies are produced that target normal tissues by mistake and cause disease. These are autoantibodies (antibodies against the self). Diseases caused this way are autoimmune diseases.
Membranous Nephropathy is an autoimmune disease. Recent work has indicated that in three quarters of patients there is an autoantibody that targets a protein known as PLA2R (phospholipase A2 receptor). In 2014, another autoantibody anti-THSD7A (anti-thrombospondin1 containing 7A) was also shown to be specifically found in some MN patients (in only about 2/100). These receptors occur normally on the cell right next to the glomerular basement membrane, the podocyte. Podocytes are responsible for making and maintaining the glomerular membrane. They also regulate the filtration process. Studies are on-going to see if these autoantibodies are the primary cause of damage to the filters and whether measuring these antibodies can be used as a monitor of disease activity (see Anti-PLA2R Assay Guidance for details).
The events that trigger MN are unclear. In the majority of patients the mechanism was unknown which led to the disease being called ‘Idiopathic MN’, but the recent breakthrough in understanding means we know it is an autoimmune mechanism. Rarely, other diseases can lead to the development of MN. For example infections like viral Hepatitis, other autoimmune conditions like Lupus Erythematosus, Rheumatoid Arthritis, and some cancers. Occasionally drugs can induce it. When MN develops in association with another condition, it is described as ‘Secondary Membranous Nephropathy’. Patients with MN are routinely investigated to see if there is a possible underlying cause.
We have probably learnt more about this disease in the last 7 years than we did in the previous fifty. The breakthrough came in 2009 when the antibody likely to be responsible for the disease and its target (PLA2R) were identified. This antibody occurs in 72-75% of MN patients but not in other people. UK scientists developed and made available the first rapid method of measuring levels of anti-PLA2R antibodies in patients. In 2014, the second autoantibody, anti-THSD7A, was discovered to be specific for MN in a small fraction of the 25% of MN patients who were negative for anti-PLA2R. Anti-THSD7A is found only in about 2% of primary MN patients. It is possible that there may be other autoantigens yet to be discovered
Further work in the UK has identified genetic factors that help explain why some people are susceptible to MN. The results of this extend our understanding of MN as an autoimmune disease. Ongoing work is being funded by the Medical Research Council (2013-2016), Kidney Research UK (2013-2018) and the European Union (2012-2017) to further understand the disease and seek new ways of treating it. A detailed breakdown of the research questions currently being asked appears in the aims of the Membranous Nephropathy Rare Disease Group page.
The MN Rare Disease Group (RDG) is working with international partners with the aim of finding new and improved treatments and to empower patients. To do this the RDG is registering patients with this condition in the National Renal Rare Disease Registry (RaDaR).The registry will be used to find suitable participants for future research trials into the effectiveness of new treatments.
If you are interested in finding out more about the registry RaDaR or the activity of the RDG please visit the Membranous Nephropathy Rare Disease Group page.