Introduction

AFib amyloidosis is a rare hereditary disease, affecting people with alterations (mutations) in the gene for fibrinogen.  Fibrinogen is a normal blood protein, made only in the liver, present in everybody and essential for blood clotting. The full name for this condition is “hereditary fibrinogen Aα-chain amyloidosis” because the mutations affect a part of the fibrinogen molecule that is called the “Aα-chain.”  People with these mutations have structurally abnormal, amyloid-forming (amyloidogenic) fibrinogen in their blood, which clumps together and forms amyloid deposits in their tissues, mainly in the kidneys.  The amyloid deposits in the kidneys disrupt kidney structure and cause abnormal kidney function. Abnormal kidney function is usually first diagnosed in this condition in middle age.  Kidney function then tends to become progressively worse over several years until the kidneys stop functioning altogether.  ‘Renal replacement’ treatment (either dialysis or kidney transplantation) is then required.  AFib amyloidosis is equally common in men and in women.  In the UK it is most common in people of British Caucasian ancestry but it may occur in people of any ethnic origin.

AFib amyloidosis is hereditary and “autosomal dominant”.  Nearly half of all patients with AFib amyloidosis seen at the National Amyloidosis Centre have no known family history of the disease at the time of diagnosis.  This may be because some people carrying the mutation never actually develop disease.  This is known as “incomplete penetrance”.  No-one knows why some people with a mutation in the fibrinogen gene develop AFib amyloidosis and other family members with the same mutation do not.

Alternatively, the mutation may have arisen in the patient themselves for the first time, or a parent may have suffered from the disease but not been diagnosed.  AFib amyloidosis was first described in 1993 in the medical literature.  On receiving a diagnosis of AFib amyloidosis, patients and their families may recall that a parent suffered from kidney disease of unknown cause, sometimes in the era before the existence of AFib amyloidosis was known.

Different mutations that can cause AFib amyloidosis

There are ten known amyloidogenic mutations in the gene for the fibrinogen A-α chain.  The mutation that most commonly causes AFib amyloidosis results in production of abnormal (variant) fibrinogen, known as the E526V variant.  A mutation is a permanent change in the sequence of DNA which makes up the genes in all cells in the body.  The DNA acts like a blueprint or recipe for building the proteins that make up the body.  The proteins are made up of strings of amino acids, assembled in a precise order.  The DNA determines the order in which amino acids are assembled.  In people with the E526V variant, an amino acid called glutamic acid is replaced by an amino acid called valine at position number 526 in the fibrinogen molecule.  Several other, less common mutations have been described, often just in members of a single family.

When an amyloidogenic mutation is present, every fibrinogen molecule produced in the body is slightly different from normal, “wild type” fibrinogen.  This different, “variant” fibrinogen is amyloidogenic, meaning that it tends to form amyloid fibrils in the body, whereas normal “wild type” fibrinogen does not.  Fibrinogen amyloid always involves the kidneys but there are often also amyloid deposits in the spleen and sometimes in the adrenal glands, though these do not usually cause any symptoms.

Genetic testing in family members

Genetic testing for mutations in the fibrinogen gene is available at the National Amyloidosis Centre.  The test is performed on blood samples taken from the vein.  Family members of patients with AFib amyloidosis are invited to contact Professor Julian Gillmore  by email or at +44 (0)20 7433 2726 to discuss this possibility.  Genetic testing in a healthy family member without symptoms can provide information on whether a mutation is present, but cannot predict whether the person will go on to develop amyloidosis.  If the relevant fibrinogen mutation is not detected however, that individual will not develop AFib amyloidosis and nor will their offspring.

When a mutation that may cause AFib amyloidosis is detected, careful monitoring of kidney function and blood pressure is always recommended.

It is very important not to have genetic testing for this condition undertaken without prior expert, professional genetic counselling.

Symptoms of AFib amyloidosis

Patients with AFib amyloidosis usually come to medical attention because of abnormalities in kidney function, usually first appearing around age 50 to 60, although onset as early as age 33 and as old as age 83 have been described.  End stage kidney disease, when the kidneys stop functioning altogether, usually develops within about 5 years after the first symptoms.

Protein in the urine (proteinuria) is always present at first.  This may be detected on urine testing, and may cause no symptoms, unless there is a very large amount of protein (one of the signs of nephrotic syndrome) in which case, urine may appear frothy.  Other signs of nephrotic syndrome are swollen ankles and weight gain due to fluid retention and low blood albumin (detected in blood tests).

Most patients with AFib amyloidosis also have hypertension (high blood pressure), either diagnosed before the kidney disease appeared or at the time of its appearance.  Many also have abnormal kidney filtration which is detected on blood tests (urea, creatinine and GFR).

Diagnosis of amyloidosis is often delayed after disease is first detected, sometimes for many years.  This delay occurs because kidney disease is very common, but only rarely caused by amyloidosis.  Doctors have to think of the possibility of amyloidosis in order to make the diagnosis.

How is AFib amyloidosis diagnosed?

Tests used for diagnosing AFib amyloidosis include:

• kidney biopsy
• SAP scanning (only available at the NAC) – amyloid deposits are always seen in the kidneys, often in the spleen and sometimes in the adrenal glands
• genetic testing – mutations in the fibrinogen gene may be detected

Kidney biopsy is the “gold standard” (best available) test for diagnosis of amyloidosis.  Most patients with AFib amyloidosis are diagnosed on the basis of a kidney biopsy.  This is a procedure where a small sample of kidney tissue is obtained, processed and examined under the microscope.  The patient lies on his/her front on a bed and local anaesthetic is injected into the skin of the back, just under the ribcage, over the area where the kidney is situated.  A needle is then inserted into the numbed area of skin, and pushed through till it reaches the kidney, where a small tissue sample is taken.  Ultrasound is often used to help the doctor to insert the needle at exactly the right spot.  There is a small risk of bleeding after the procedure, so the patient is monitored for several hours before going home.

In order to detect amyloidosis in a biopsy, special techniques are necessary at both the processing and the examination stages.  If these techniques are not used, or are used incorrectly by inexperienced laboratory staff, the diagnosis of amyloidosis may be missed.  It is important that the doctor who sends the biopsy to the laboratory requests testing for amyloid.  If the particular techniques needed to detect amyloid are not used, then amyloid deposits may be missed.

AFib amyloid deposits have a very characteristic appearance under the microscope.  Nevertheless, if amyloid is detected on kidney biopsy, further laboratory techniques must be used to definitively identify the type of amyloid, as several other types of amyloid apart from AFib amyloidosis can affect the kidneys.

If all of the following are present, then occasionally AFib amyloidosis may be diagnosed without the need for a kidney biopsy:

·         kidney function abnormalities

·         a known family history of AFib amyloidosis

·         mutation in the AFib gene detected on genetic testing

·         SAP scan showing characteristic AFib appearance of amyloid deposits in the kidneys (and sometimes in the spleen and adrenal glands)

Treatment

Supportive treatment

All patients with kidney disease due to AFib amyloidosis should be seen regularly by a nephrologist.  Important principles of supportive treatment include:

• tight control of blood pressure
• careful monitoring and maintenance of fluid balance
• regular testing of kidney function with blood and urine tests
• use of diuretics when required

Abnormal kidney function due to AFib amyloidosis may affect the ability of the kidneys to produce urine.  This means that the body is unable to cope well with excess fluids.  Patients with fluid overload may develop swelling in the legs (oedema) or difficulty breathing due to a build-up of fluid in the lungs.

Fluid excess can be avoided by careful attention to the 3 Ds:

1. Diet
2. Diuretics
3. Daily weights

1. Diet:

Fluid intake should be steady and should usually not exceed 1.5 litres per day.

Salt intake should be limited.  This includes attention not just to salt added to the food during cooking or eating, but also to food with high salt content such as crisps, bacon, canned meats, sausages, canned soups and smoked fish.  It can be very helpful to meet with a dietician for precise and personalised dietary advice.

2. Diuretics:

Doctors will often prescribe diuretics (water tablets) which help the body to lose excess salt and water.  Taking these drugs is not a substitute for avoidance of excessive dietary salt and water.  Removal of excess body fluid reduces ankle swelling and breathlessness.  Furosemide is usually prescribed first.  Other diuretics such as spironolactone may be added later.  Since diuretics increase the amount of urine produced, they should usually be taken in the morning sometimes with another dose at lunchtime.

3. Daily weights:

Some patients benefit from recording their weight regularly, usually daily or weekly.  It is important that weight should be measured consistently- using the same scales, at the same time of day.  This is usually best done first thing in the morning after passing urine, just wearing underclothes.  Several litres of fluid can accumulate in the body without it being very noticeable.  An increase in weight can be an early sign of fluid excess.  The doctor or nurse can then recommend appropriate measures such as increased diuretic dose, before the patient even feels unwell because of the fluid overload.

Surgery and anaesthesia

It is generally advisable for patients with amyloidosis to avoid undergoing surgery, anaesthesia and other invasive procedures.

If such procedures are necessary, patients should request that the surgeons, anaesthetists and other doctors involved contact the NAC doctors beforehand, to discuss any special considerations involved. For example, it is very important that great care is taken to monitor and maintain blood pressure and fluid balance throughout such procedures. Care should also be taken because of the tendency of tissues with amyloid in them to bleed and to heal poorly.

Renal replacement therapy

In most patients with AFib amyloidosis, kidney function worsens gradually with time and end stage kidney disease, when the kidneys stop functioning altogether, often develops after around 5 years.  Renal replacement therapy is then necessary.  This means either dialysis or kidney transplantation.

Dialysis

Healthy kidneys clean the blood by removing waste products (filtering), maintain a stable balance of fluid, salts and minerals in the blood and control blood pressure.  When the kidneys stop filtering, waste products and fluid build up in the blood.  Dialysis is a treatment that takes over some of these functions that failing kidneys can no longer perform.  There are two types of dialysis:

1. Haemodialysis: The patient’s blood is passed through an artificial kidney machine that removes waste from the blood.
2. Peritoneal dialysis: The blood is cleaned inside the patient’s body.  The abdominal area is slowly filled with dialysis fluid through a tube called a catheter.  Extra fluid and wastes are drawn out of the body through the same catheter.

Dialysis can be done in a hospital, or at home.  Patients can often decide, together with their doctors, which type of dialysis is best for them and where it should take place.

Kidney transplantation

Kidney transplantation is an operation, performed under general anaesthetic, where a healthy, functioning kidney is placed into the body of a person whose kidneys are no longer functioning properly due to end stage kidney disease.

The major advantage of kidney transplantation is that it allows the patient to lead a nearly normal lifestyle, without the inconvenience of spending hours every week on dialysis.  After a transplant, patients often feel stronger and have more energy than they did before.  There is no need to restrict fluid and salt intake.

Patients with kidney failure who decide that they would like to receive a transplant must be assessed to see if this is the best option for them.  Sometimes doctors decide that transplantation is not suitable.  Transplantation is a major operation, so very elderly people or those with heart or lung disease may not be fit enough to undergo the general anaesthetic and the operation itself.  Kidney transplantation may not be recommended to people who have had cancer or serious infections because of the risk of a weakened immune system after the transplant.  All candidates for kidney transplantation must undergo assessment by a nephrologist to determine whether this is suitable treatment for them.

During the transplant operation, the surgeon places the new kidney into the lower abdomen and connects the artery and vein of the new kidney to the patients’ own arteries and veins.  The patient’s blood then flows through the new kidney which starts making urine and takes over all the functions that the patient’s own kidneys no longer perform.  The patient’s own kidneys are left in place.

One healthy kidney is sufficient for a person to live a completely healthy life.  So kidney donations can come from living donors, who donate one of their own kidneys.  The donor then continues to live a completely healthy life with just the one remaining kidney.  When the donor is a close relative there is less risk that the patient’s body will reject the kidney.  The donor must first undergo genetic testing and can only donate a kidney if the mutation causing AFib amyloidosis is not present.

Sometimes a patient who requires kidney transplantation has a relative who is willing to donate a kidney, but who is unable to do so because tissue typing shows that the donor kidney would be incompatible.  This means that the recipient’s body would reject the donor kidney because it has a different tissue type.  Paired donation may be possible under these circumstances.  An incompatible donor/recipient can be matched to another pair in the same situation, so the donor of the first pair gives to the recipient of the second and vice versa.

If a suitable living donor is not available, patients awaiting kidney transplantation are placed on the transplant waiting list to await availability of a kidney from a deceased donor.  Sometimes patients undergo transplantation after they have been treated with dialysis while awaiting a suitable donor.  Waiting periods vary depending on a number of factors including how common their tissue type is.  Suitable donors are usually found more quickly for patients with commoner tissue types.  Sometimes kidney transplantation may be planned while kidney function is deteriorating but before end stage kidney failure develops.  Then it may be possible to perform a pre-emptive transplant without the need for a period of time on dialysis.

Short term risks of kidney transplantation include rejection, infection and blood clots.  Patients need to take medication long term to prevent rejection, and long term risks are usually related to suppression of the immune system due to this medication.  In patients with AFib amyloidosis, amyloid deposits slowly build up in the transplanted kidney, as discussed below.

Results of kidney transplantation in patients with AFib amyloidosis

Overall, the results of kidney transplantation in patients with AFib amyloidosis have been good, with patients enjoying many years of nearly normal quality of life after undergoing transplantation.  Kidney transplants in patients with AFib have continued to function for a similar duration to kidneys transplanted for end stage kidney failure caused by commoner, non-amyloid related diseases.

In 2013, sixteen kidney transplants had been performed in patients with AFib amyloidosis followed at the NAC.  After transplantation, AFib amyloid deposits usually start to build up in the transplanted kidney, and in many cases this eventually leads to failure of the transplanted kidney.  However, the build-up of amyloid is slow, and unpredictable, and most transplant kidneys continue to function for between six and thirteen years.  During this time patients usually enjoy a near normal quality of life.  In two patients, the transplanted kidneys are still functioning well after thirteen years.

Combined liver and kidney transplantation

All the fibrinogen in the body is produced by the liver.  Transplantation of the liver therefore removes the source of the amyloidogenic ‘variant’ fibrinogen and prevents the build-up of new amyloid deposits in a transplanted kidney.  In theory, combined liver and kidney transplantation seems to be a promising treatment for patients with AFib amyloidosis.  However, in practice, this procedure involves major surgery and carries significant risks.

In 2013, ten UK patients had undergone combined liver and kidney transplantation for AFib amyloidosis.  Three of these patients died soon after due to complications related to the operation.  One kidney failed after around 5 years due to chronic rejection, unrelated to amyloid.  In the seven surviving patients, all liver and 6 kidney transplants were functioning well in 2013.  There are no data on the long term survival.

Kidney transplantation versus combined kidney and liver transplantation

Combined kidney and liver transplantation offers the theoretical advantage of removing the source of the amyloidogenic protein.  However, kidney transplantation is probably more suitable for most patients with AFib amyloidosis.

The long term outcomes of kidney transplantation are generally very good, and the procedure is less dangerous than the more complicated combined liver and kidney transplantation.  To date no patients have died as a result of kidney transplantation for AFib amyloidosis.  In contrast, three out of the ten patients who underwent combined liver and kidney transplantation died due to complications of the procedure.

For occasional patients, such as those who are unusually young when diagnosed or those with significant amyloid deposits in the liver, the option of combined liver and kidney transplantation may be considered.  The NAC consultants will recommend the most appropriate treatment for individual patients after considering all aspects of their condition.

Outlook for patients with AFib amyloidosis

Around 60% of patients with AFib amyloidosis followed at the NAC over the last 20 years reached end stage kidney failure.  On average, they started renal replacement therapy at about 60 years of age, about 5 years after the appearance of proteinuria and 2 years after diagnosis of amyloidosis.  The rate of progression of kidney disease varied widely.  The longest follow up without development of end stage kidney disease was over twelve years.  Doctors cannot predict the rate of progression for an individual patient when they are first diagnosed.

Patients with AFib amyloidosis treated with long term dialysis tend to do well, with most surviving for about 10 years, and some for longer.  Their survival is better than that of patients of the same age receiving dialysis for other, non-amyloid related causes of kidney failure.

Average survival from the time of diagnosis of AFib amyloidosis is 15 years, and many patients have survived for longer than this.