Treatment Options In Goodpastures.

Kidney (Photo credit: Joshua Schwimmer)

Overview of Goodpastures Syndrome.

A rapidly progressive form of kidney disease associated with antibodies directed against the structural components of the functional subunits of the kidney and the lung. The disease therefore gives rise to both lung and kidney pathology a situation termed pulmonary renal syndrome.

The exact cause is unknown. It is considered an autoimmune disorder (other autoimmune disorder's that affect the kidney include Lupus Nephritis). The bodies own immune system is responsible for targeting both lung and kidney tissues. The initial immune system activation may occur in response to viral infection or even the inhalation of toxin from the environment such as inhaling gasoline. Smoking increases the risk of the disease it is most likely to occur in men from ages 16 to 61.

It is possible to be predisposed to good pastures syndrome based solely on your genes. It is therefore possible to have family members with the same problem. The disorder is however relatively rare.


Symptoms of Goodpastures.

The predominant symptoms of Goodpastures syndrome includes cough productive of bloody sputum due to bleeding within the lungs from the inflammation caused there. The kidney disease produced usually has symptoms such as swelling fo the feet or around the eyes retention of fluid and elevated blood pressure with or without headaches. There is lethargy and weakness associated with decreased appetite if the condition has been going on long enough. The nonspecific symtpoms of weakness and lethargy loss of appetite are due to the systemic nature of the disease as well as the anemia associated with it. The anemia is frequently multifactorial, due both to iron loss due to the loss of blood in the lungs as well as kidney disease. Because of episodes of bleeding into the lungs there may be episodic shortness of breath which may be due both to retention of fluid from kidney failure as well as blood filling the spaces within the lung for gas exchange.


Treatment Options.

The mainstay of treatment of Goodpastures is early recognition followed by plasmapherisis (a process of removal of the immune system components of blood) and administration of cytotoxic medication, (medication targeted against rapidly dividing cells of the immune system) and steroid therapy.

Goalfinder immune-system-action (Photo credit: gfinder)

On the horizon are some interesting therapeutic options.


A monoclonal antibody known as ox-8 is the latest experimental drug with efficacy in experimental good pastures disease in rats. It is deemed effective in the prevention and treatment of experimental inflammation of the kidney in rats. We will be hearing more about this one in the future.


Because goodpastures is caused by activity of the native immune system against the collagen forming the structural component of the filtration apparatus of the kidney it is possible to treat the disease by turning off the immune reaction against that specific structural component which is collagen. This has been accomplished in rats utilizing nasally administered collagen which induces tolerance. When tolerance occurs the immune system accepts a previous enemy as a friend and does not attack. This would effectively turn off the immune response against the kidney if it can be achieved in humans


Much basic research is needed and continues to be done looking at goodpasture's disease. Although a rare disease the mechanisms of tolerance and autoimmunity governing the pathology of this condition if properly understood and targetable would herald a new day in the treatment of many other kidney diseases of similar etiology.

Lupus and Kidney disease..What is Lupus Nephritis?

Lupus nephritis
http://www.kidneypathology.com/English_version/Case_8.html

Lupus nephritis an ominous name for a condition that most people would not have heard of. Chances are if you know the entity to which I am referring you either have this disease or know someone who does.

Lupus nephritis is the name given to inflammation of the kidney because of lupus. There are several flavors of Lupus nephritis and they are graded from 1 to 6 based on testing of kidney tissues. The prognosis of lupus nephritis is tied to the class of the disease. With Class I disease having the best prognosis while class 4 and 5 disease and combinations thereof having the worst overall prognosis.

Estimates are that up to 50% of patients who have lupus will have some manifestation of lupus nephritis over the course of their illness. To understand Lupus Nephritis we must first understand some of the key points surrounding lupus itself.

HOW DOES LUPUS OCCUR

Systemic lupus is an autoimmune disease.

The native immune system attacks normal tissue as it would a foreign invading organism.

The reason for this is not yet fully known.

Majority of problems are related to INFLAMMATION within the tissues affected.

The kidney is very vulnerable to inflammation

The organ receives a very high blood flow

Inflammatory cells are easily transported through the blood to the organ.

The consequences of this inflammation, results in several distinct syndromes.

Organ involvement in Lupus

SYNDROMES ASSOCIATED WITH LUPUS NEPHRITIS

Nephrotic syndrome.

Nephritic syndrome.

Acute renal failure

Chronic renal failure

Nephrotic syndrome

A constellation of symptoms and signs which include swelling and passage of high level of protein in the urine associated with high levels of cholesterol.

The nephritic syndrome

The presence of either visible or microscopic amount of blood in the urine in conjunction with elevated blood pressure and fluid retention. There is also usually some retention of waste products in the blood on screening tests of kidney function

Acute renal failure

A sudden decrease in the ability of the kidney to perform its main functions

The excretion of nitrogenous waste products.

The excretion of excess acid.

The excretion of excess fluids.

[caption id="attachment_597" align="alignright" width="300" caption="Lupus antibodies NLM ADAM "][/caption]
Chronic renal failure

This is better termed chronic kidney disease.

A gradual loss of renal function taking place over 3 months or more.

Symptoms of renal failure may be present

Weakness

Lethargy

Fatigue

Vomiting

Fluid retention

Loss of appetite.

If the diagnosis is suspected by your physician it may be confirmed only by a series of tests.

• Measurement of electrolytes and urea and creatinine.


• Measurement of creatinine clearance.


• Measurement of 24 hour protein excretion.


• Analysis of the urine sediment.


• General investigations targetted at the activity of systemic lupus.


• dsDna antibody.


• Complement levels.


• CRP and ESR.

Based on the history and clinical findings plus the results of investigations so far


A clinical syndrome may be diagnosed

• Nephrotic syndrome.


• Nephritic syndrome.


• Acute renal failure.


• Chronic renal failure.

The treatment of lupus nephritis however depends on The HISTOLOGICAL CLASS of disease and the CLINICAL SYNDROME.

Histology is the study of tissues, usually carried out under the microscope.
Samples of tissue are obtained by a procedure known as biopsy. Biopsy may be

1. Open biopsy requiring general anaesthesia and major surgery.


2. Closed biopsy usually done under ultrasound guidance.

CLASS I

Essentially normal.

CLASS II (mesangial)

A localised Mild increase in the cells seen.

CLASS III (focal proliferative)

A diffuse or widespread increase in cells of immune origin and kidney origin. But large areas of normal or mild disease still apparent.
CLASS IV (diffuse proliferative).

As above but almost no areas of mild disease or normal kidney tissue on biopsy.

CLASS V (membranous)

May or may not have an increased number of cells. However there are deposits of abnormal protein apparent within the kidney.

CLASS VI (sclerosing).

Scarring of the kidney usually results when the above classes have progressed beyond the ability to respond to treatment.

TREATMENT OF LUPUS NEPHRITIS

Class I disease
Usually no treatment above what is required to maintain lupus in remission.

Class II disease
May require treatment with increased doses of steroids. Usually responds promptly to therapy and is easily treated.

Class III disease
May behave like Class II disease or Class IV disease.

Class IV disease
Aggressive disease that easily and rapidly progresses without aggressive treatment.

Class V disease.
Pure Class V disease is controversial.
Class V disease with features of class IV is treated as IV
Class V disease with features of III is treated as III or IV.

Class VI disease
Prevent further deterioration of renal function and if signs of chronic renal failure are also present then prepare for dialysis.

• The NIH has the most complete follow up data for severe lupus nephritis defined as Class IV And Class V with features of Class IV.

• Their data suggested that survival with Cyclophosphamide was 90 percent at 10 years.


• With Azathioprine alone 60 percent at 10 years.


• Prednisone alone 20 percent at 10 years.

New treatment options for therapy with lupus are being studied daily.

Patient Education: What is the link between Lupus and Kidney disease.

Diffuse proliferative lupus nephritis (Photo credit: Wikipedia)

Systemic lupus is a disease whose exact cause remains elusive to modern medical research. What is known about lupus is that it is a disease that turns the normal immune system against itself and the rest of the body. The immune system contains several different type of cells. The B and T cells are the brains of the immune system a lot of decision making about what to attack takes place between these cells and the more basic cells such as macrophages.

The macrophages essentially act as a mobile police force travelling throughout your body and tries to envelop all abnormal bacteria and other invaders. Once inside the macrophage the invading organism is imprisoned in its own space within the cell. The cell then injects chemicals that it produces into the area with the invader destroying it, if everything is going according to plan.

The invader once destroyed is then broken down into its constituent pieces and these pieces are presented like trophies on the surface of the cell so that any passing cell can see them. This only becomes important if a passing B cell or T cell happens to notice the trophy. In which case the B cell and T cell communicate with the macrophage examine the trophy and if it is deemed to have arisen from a foreign organism then the B cell designs a perfect weapon to kill it in future called an antibody. If the B and T cells confer and the trophy is thought to have been derived from the self then they USUALLY dont bother to form antibodies.

In lupus there is a defect of one or several of the above processes which are in fact far more complex than outlined. The end result is the B cell is unable to identify self from invader and decides to produce antibodies against anything a macrophage happens to be carrying.

Hence the disease can affect any tissue of the body as macrophages are present within all tissues. When this sequence of events targets the kidney the antibodies produced create an inflammatory reaction at the target site within the specific structure targeted within the kidney.

One of the first signs of this when you go to get your check up is increased protein in the urine. This occurs because the inflammatory reaction affecting the kidneys damage a very important part of the kidney filter that usually produces urine called the "basement membrane" this allows leakage of substances out of the blood where they should have remained. If damage is bad enough blood will also leak through. If You have a significant amount of blood and protein in the urine then you will have what is called glomerulonephritis, which basically means inflammation of the kidney structure known as the glomerulus. The glomerulus being the important filter that starts the process of urine formation.

When this inflammation occurs in patients with lupus it could very well be called lupus glomerulonephritis, instead it is shortened to Lupus nephritis. The severity of the inflammation determines the severity of the nephritis. And as with all things where scientists are involved they have described subsets.

CLASS I disease is mild.
CLASS II disease is also mild.
CLASS III disease can be moderately severe
CLASS IV disease is usually considered the most severe
CLASS V disease may be considered less than class IV in severity but is generally treated the same way.
CLASS VI disease generally represents scarring of the kidney or old inflammation.

The class of disease is not immediately apparent when your doctor asks about your history, examines you or even after the blood tests. The class can only be obtained by taking a tiny piece of the kidney from the body to be analysed in the lab. This is called a renal biopsy.

The treatment options will then be explained to you.

Related articles

• New Targets For Lupus Treatment Inspired By Natural Method For Clearing Cellular Debris (medicalnewstoday.com)

New drugs: A New Option for Lupus Induced Kidney Disease

[caption id="attachment_633" align="alignright" width="250" caption="rituximab.."][/caption]

A new study published in March 2009 comparing the standard treatment of lupus nephritis i.e corticosteroids and cyclophosphamide vs rituximab was published in the clinical journal of the american society of nephrology.

Cyclophosphamide is considered a main stay of chemotherapy where it functions as an " alkylating agent" which is simply a way to express that it binds to DNA (the code that determines the function of the individual cells within the body) and destroys it.

If it were capable of destroying only cancer cells or cells of the immune system involved in lupus then it would be a perfect drug a magic bullet, unfortunately its side effects prove otherwise they include nausea, loss of hair, bone marrow suppression, predisposition to infections, sterility and ironically, with accumulating, doses even cancer. However studies have shown that up to 70% of lupus patients will respond to this drug and the side effects are not guaranteed to occur hence its continued use. Steroids on the other hand are well known to a variety of patients and come with their own problems. The price to be paid is weight gain predisposition to diabetes and recurrent infections, fluid retention, skin changes, hair growth and loss of bone mass to name a few. Steroids however are highly effective at suppressing the entire immune system by turning off the signal in between the sentinel cells that protect the body by searching for foreign invaders on a daily basis. When these cells are unable to talk to each other effectively the immune response is blunted and hence the attack of the immune system against its own body is also blunted. This leads directly to their efficacy in lupus where the immune system is overactive and a major part of the problem.

The fact is however that depending on the genetic make up of each individual patient with lupus and kidney disease these drugs may not work at all to prevent progression of the disease to the end stage. This has led to the search for alternative therapies such as rituximab.

Rituximab is a monoclonal chimeric antibody that targets b cells. Sounds almost like that magic bullet doesn't it?

This drug was designed to perform one task. Locate the cells causing the problem in autoimmune disease (the B cell) and kill it. Unfortunately B cells are also necessary for the normal functioning of the immune system so its expected that there would be increased risk of infection after taking the drug. But the hope is that there would be much less side effects associated with its therapy than the older regime.

This study had 20 test subjects nineteen women and one man side effects included five infections. A complete resolution of kidney disease was seen in 60% of the patients. The investigators concluded that rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis. The study is small however and the findings should be noted, however additional studies will be needed in the future before the drug can become a mainstay of therapy.

Unfortunately the cost of rituximab in jamaica is an issue. The drug is priced out of the reach of many people as a course costs in the region of two hundred thousand dollars.

The verdict? In my opinion try standard therapy first rituximab should only be used as a last line of defense in a patient that has tried everything already and it hasn't worked. Be aware that you are entering unknown territory to some extent.

EDIT: 14th October 2009.

The FDA has issued an advisory re: the use of Rituxan to treat Lupus. The advisory follows the death of two patients who recieved the drug for treatment of lupus. They had a rare complication of therapy known as pleomorphic multifocal leucoencephalopathy or PML.