Nodular Glomerulosclerosis – beyond diabetic nephropathy

A glomerular nodule, i.e. an acellular hyaline structure, can have varied etiologies. Most commonly we see it in the setting of diabetic nephropathy (DN). In these cases, it posesses all the associated features of DN on light microscopy (LM) with glomerular basement membrane (GBM) thickening, mesangial matrix expansion and arteriolar hyalinosis.  These nodules stain well with PAS & silver stains. Immunofluorescence (IF) shows linear IgG deposits along the GBM & tubular basement membrane (TBM) and occasional IgM & C3 trapped in the sclerotic areas. Electron microscopy (EM) shows similar features.
A differential diagnosis is amyloidosis, associated with enlarged glomeruli but poor staining with PAS and silver stain. The striking feature of this condition is red appearance of nodules on Congo staining with characteristic apple green birefringence under the fluorescent microscopy. In the most common form of amyloidosis, the AL type, IF shows light chain restriction with lambda > kappa predominating. EM has the characteristic amyloid fibrils, 7-12 nm in diameter with indefinite length and random orientation.

Among immune mediated glomerulonephritis (GN), MPGN also presents with nodules on biopsy. LM is highlighted by a proliferative morphology with splitting and duplication of the GBM. Cryoglobulinemic GN is associated with pseudo-thrombi in capillaries, which in fact represent large sub-endothelial deposits. IF shows IgG and C3 deposits in GBM. Cryoglobulinemia is associated with IgM and predominance of kappa deposits (Type 1). EM reveals electron dense deposits in sub endothelial, mesangial and sometimes in sub-epithelial locations.

Monoclonal immunoglobulin deposition disease (MIDD) can shows nodules. They stain with PAS and silver stains (see image) and have refractile, PAS-positive deposits in the TBM too. IF is characterized by linear deposits along GBM & TBM with kappa>lambda deposits in LCDD (light chain variant) and IgG in HCDD (heavy chain). EM shows powdery deposits in inner GBM, outer TBM and in the nodules.

Fibrillary and Immunotactoid GN have diffuse a proliferative GN/MPGN pattern, sometimes with crescents. They stain with PAS & silver as well, a feature they share with DN. IF is positive for polyclonal IgG and C3 in Fibrillary GN. The immunotactoid variant has monoclonal IgG with kappa/lambda chains. EM shows large, randomly arranged fibrils (16-20 nm in diameter) in the former, and parallel arrayed microtubules (20-50 nm diameter) in the latter.

Fibronectin glomerulopathy is characterized by nodules positive with PAS and negative with silver. EM shows sub-endothelial electron dense deposits. Immunohistochemistry staining for fibronectin is diagnostic.

The last differential is Idiopathic Nodular Glomerulosclerosis. This entity resembles DN in all aspects except that patient is non diabetic. It is associated with long standing hypertension and smoking. Smoke contains glycation adducts which form AGEs and through oxidative stress is thought to create pathology similar to diabetes.

Thus, a nodule in the glomerulus has a wide differential with definite need for various stains, IF and EM to establish the final diagnosis. The other key feature here is most of the above mentioned diseases can have a similar clinical presentation in the same age group.

Post by Sriram Sriperumbuduri (Images from Paul Phelan)

The Uncertainty of Monoclonal Gammopathies

I spend a lot of time discussing patients with renal disease and monoclonal gammopathies with my haematology colleagues, trying to figure out what is of ‘renal significance’ and ‘undetermined significance’. One of those discussions recently was around a normally well 70 year old lady. She presented with several pre-renal insults including a febrile illness, relative hypotension and NSAID use for joint pains. Her renal function rapidly deteriorated and she became oligoanuric requiring haemodialysis.  

At a routine medical 4 months previously she was normotensive with normal renal function and no proteinuria.  Investigations during this admission revealed nephrotic range proteinuria and an IgG kappa paraprotein at 1g/L with a normal free light chain ratio.  Autoantibodies and cryoglobulins were negative. A renal biopsy showed diffuse endocapillary glomerulonephritis with immunoglobulin pseudo-thrombi in the capillaries and negative Congo Red staining.  Staining was positive for all immunoglobulins and C3. Electron microscopy showed organised sub-endothelial deposits of hollow microtubules of 40-50nm diameter in keeping with immunotactoid glomerulopathy (see image). A bone marrow showed no significant dysplasia, no light chain restriction and no evidence of myeloma. She was treated with high dose steroids and initially plasma exchange whilst results were returned.  Her renal function improved over the following week and she did not require further specific therapy given the absence of overt lymphoproliferative or autoimmune disease.

It is not surprising that we pick up a lot of monoclonal gammopathies in patients with deteriorating renal function or proteinuria as MGUS affects 3% of patients over the age of 50. Recent evidence suggests that MGUS progresses to myeloma or other plasma cell or lymphoproliferative disorders in 10% of patients at 10 years, and higher than this in those with an abnormal serum free light chain ratio or IgM paraprotein.

Monoclonal immunoglobulins or immunoglobulin-derived fragments can be deposited in the kidney in a number of patterns (previous RFN post from Nate):

• Crystalline deposits: cast nephropathy in myeloma
• Organised fibrillar deposits: AL amyloidosis (Congo Red stain positive)
• Organised microtubular pattern: immunotactoid GN or type I cryoglobulinaemia.  Fibrillary GN is from polyclonal IgG deposition (not usually associated with a paraprotein) and on EM has slightly smaller fibrils (approx. 20nm in diameter) than immuntactoid GN.
• Disorganised granular deposits as in LCDD and HCDD 

Immunotactoid GN usually presents in a more insidious pattern with hypertension, haematuria and proteinuria rather than acutely as in this case.  The straight, hollow tubules are over 30nm in diameter and are usually composed of crystallised monoclonal IgG. The diagnosis can be missed when EM is not performed.  It is usually secondary to lymphoproliferative diseases, typically CLL or B cell non-Hodgkin’s lymphoma but also MGUS. Treatment is based on the underlying disease, and in cases as this vigilance for progression is vital.  


Post by Ailish Nimmo

Another Great Masquerader: Amyloidosis

A middle-aged man with a history of microcytic anemia, well-controlled diabetes mellitus (DM)/hypertension (for 15 years), and a 16 month history of diarrhea with a 30-pound weight loss, and a creatinine of 1.9 mg/dL.

Laboratory tests showed a urine protein to creatinine ratio of 0.35 mg/g, hemoglobin of 9.3 g/dL, white blood cell count of 13.5 x 10^9/L, and a platelet count of 662 x 10^9/L. A workup for chronic diarrhea revealed an elevated erythrocyte sedimentation rate and C-reactive protein of 85 mm/hr and 18 mg/dL, respectively. Serologies for systemic lupus erythematosus, mixed connected tissue diseases, tuberculosis, hepatitides, and monocolonal gammoapthies were also unrevealing. Computed tomography of the abdomen, EGD, and colonoscopy were unrevealing – biopsy specimens of both the small and large bowel did not show evidence of inflammation. His urine sediment did not have red blood cells (RBCs) or RBC casts.

Despite his long-standing DM and hypertension, a kidney biopsy was performed – which revealed AA amyloidosis (see immunohistochemistry staining for amyloid A protein and an electron microscopy images below)

Endoscopic biopsies were subsequently stained for amyloid A protein – which was also positive.

Serum amyloid A (SAA) is part of a family of apolipoproteins associated and an acute phase reactant whose production is upregulated by the liver typically in the setting of infection or inflammation, which leads to increased expression of inflammatory cytokines like interleukin (IL)-1, IL6, and TNF-alpha. Increased SAA levels ultimately lead to the formation of amyloid fibrils that are immune to proteolysis.

The differential diagnosis of AA amyloidosis is broad – including autoimmune disorders, inflammatory arthritis, inflammatory bowel disease, lymphoma, familial Mediterranean fever, IgG4-related disease, Castleman disease, and chronic infection. A study of the natural history and outcome in systemic AA amyloidosis of a few hundred patients found that the underlying disorder was inflammatory arthritis in 60%, chronic sepsis in 15%, and periodic fever syndromes in 9%. The underlying disorder was unknown in 6% of cases.

Like most other secondary diseases processes, treatment for AA amyloidosis is treatment of the underlying disease. Other therapies should enhance clearance of amyloid deposits, decrease or interrupt fibril assembly, and decrease fibril deposition. For example, two agents that have been used with some success are a monoclonal antibody to IL-6 (tocilizumab) and the newer agent eprodisate, which directly interferes with amyloid fibril formation and deposition. SAA levels may predict disease progression and prognosis. These therapies would be potential options in this patient who did not have a proven underlying disease process.

To conclude, the presentation of amyloidosis can be nonspecific and the differential is widespread. It is important to remember that kidney biopsy can change management in a significant percentage of cases – even in a case like this, where the urinalysis was misleading and masked underlying amyloidosis.

*This is a fictionalized case based on a true account, details have been modified/changed

Samira Farouk, MD
Chief Fellow, Division of Nephrology
Icahn School of Medicine at Mt. Sinai

Panda Eyes

I recently saw an elderly woman in clinic. She had a background history of migraine headaches and had been investigated over the past 18 months for recurrent syncopal episodes. She had at least 5 episodes that began with palpitations usually on minimal exertion. Apart from these episodes, she was fit and active. Her ECHO showed only mild LV hypertrophy and mild pulmonary hypertension. EKGs were unrevealing.

Two years ago she had been seen by a dermatologist for sun-related skin lesions and had mentioned that she had recurrent bruising around her eyelids. She had taken a photo of these lesions and they were noted to be purpuric. They would come and go and usually last for a couple of months when they were there.

She was referred to my clinic for investigation of mild albuminuria. She had ~500mg albumin for approximately 5 years with no significant change. Her renal function had always been otherwise normal apart from one single increase in creatinine was unexplained and returned to normal in a few days. She had no significant risk factors for kidney disease apart from long term NSAID use for her migraines.

As part of her investigations, she had an SPEP and free light chains. The results showed that she has an IgG lambda paraprotein likely related to an underlying multiple myeloma. Re-review of her ECHO images showed that they were consistent with infiltrative disease and she is currently undergoing work-up for AL-amyloidosis.

Periorbital purpura is a rare finding in patients with amyloidosis occurring in about 15% of patients. It is thought to be a result of Factor X deficiency due to binding of Factor X by the amyloid fibrils. It is generally atraumatic and tends to recur without treatment of the underlying amyloid. It is almost pathognomic of amyloid and its presence should prompt testing for AL amyloid.

Image from NEJM

Treatment of secondary amyloid

Recently I've been dealing with an unfortunate individual with a long history of RA who has developed nephrotic range proteinuria after being stable for many years. Despite the deteriorating renal function, NSAIDs have been continued because without them the patient has no quality of life. Biologics were tried in the past with very severe adverse effects and so we are reduced to treating this much the same as it was treated many years ago. Recently, a review in Nature Reviews Nephrology summarized the most up-to-date thinking on the treatment of systemic amyloid. Similar to my patient, about 50% of patients with AA amyloid have nephrotic syndrome and ~10% have ESRD at diagnosis. More than 40% of patients with AA amyloid eventually progress to ESRD.

For AA amyloid, the primary goal of treatment is to suppress the underlying inflammatory disease and hence prevent further amyloid production.

1. Colchicine: Colchicine has been shown to be effective in the treatment of Familial Mediterranean Fever in particular. It is used as a prophylactic agent to prevent the development of renal amyloid and, in higher doses, can be used to treat nephrotic syndrome although care must be used in patients with decreased renal function. There is less evidence for its effectiveness in rheumatoid diseases.

2. DMSO: This has been shown in small studies to be effective in treating secondary amyloid and in murine studies. However, in one study, there was no effect in patients who had already developed significant renal dysfunction.

3. Cytotoxic Therapy: Cyclophosphamide has been shown to have some effect in AA amyloid in small cases series and retrospective studies. There are no RCTs available. One recent study compared cyclophosphamide with etanercept and found that there was a far higher response rate with etanercept. However, this was a small study and was not an RCT so it is difficult to fully draw conclusions. Methotrexate, chlorambucil and axathioprine have also been shown to have some effect.

4. Anticytokine Therapy: This is currently probably the gold standard of treatment. Anti-TNF treatments has been shown to be effective in preventing the development of AA amyloid and even reversing established disease. More recently, in a small retrospective study, toclizumab, a new IL-6 antagonist was shown to be more effective than TNF antagonists in the treatment of AA amyloid. Other anti-cytokine therapies are being tested for their effectiveness in treating secondary amyloid and this is a field that is advancing rapidly.

Too much protein

An internal medicine resident was presenting a consult to our team on a patient with nephrotic-range proteinuria. During his presentation, he stated that he had already ruled out amyloidosis because the patient had a negative SPEP and UPEP by immunofixation.

To evaluate the validity of his statement, we need to go back to pathophysiology to review the mechanism of amyloidosis.

Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings. Under light microscopy, with hematoxylin and eosin staining, amyloid appears as an amorphous, eosinophilic, hylaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. By electron microscopy amyloid is seen to be made up largely of continuous, non-branching fibrils. This electron-microscopic structure is identical in all types of amyloidosis.

The two major kinds of amyloidosis are:

1)     Primary amyloidosis (AL) (Amyloid Light chain)

The AL protein is made up of light chains, mainly composed of λ light chains or their fragments. Its deposition is associated with certain forms of plasma cell tumors.

Diagnosis: With the use of immunochemical techniques, monoclonal immunoglobulin is found in the serum or the urine in nearly 90% of patients. If you add the serum-free light-chain assay, an abnormal result is found in 99% of patients. A biopsy of an affected organ is usually diagnostic also.

Treatment: Debatable

Patients with severe organ dysfunction should receive repeated cycles of Melphalan/Dexamethasone as first line therapy. Patients with less severe organ dysfunction may benefit from high Dose melphalan followed by stem cell transplant as the first line therapy. For patients with relapsed disease, the use of alternative regimens (thalidomide, lenalidomide, cyclophosphamide, or bortezomib) is a reasonable approach that is growing in popularity.

2)     Secondary amyloidosis (AA)

AA fibrils are derived by proteolysis from a larger precursor in the serum called SAA (serum amyloid–associated) protein that is synthesized in the liver under the influence of cytokines such as IL-6 and IL-1. The production of SAA protein is increased in inflammatory states as part of the “acute phase response”; therefore, this form of amyloidosis is associated with chronic inflammation. However, increased production of SAA by itself is not sufficient for the deposition of amyloid. You need to have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.

Diagnosis: Biopsies of accessory salivary glands, abdominal fat, and rectal mucosa yield positive results in 50% to 80% of patients. Kidney biopsy is positive in almost 100% of symptomatic patients.

Treatment: Treat the underlying source of inflammation. Eprodisate is a member of a new class of compounds that inhibits polymerization of amyloid fibrils potentially slowing the decline in renal function

Getting back to the resident, I think his statement would be correct in AL (primary amyloidosis), but not valid if the patient has AA (secondary amyloidosis).

Posted by Tarek Alhamad

The organization is key

There are a number of glomerulopathies that feature organized deposits of nonbranching fibrils, some more common than others. The diseases make their first major separation into Congo Red positive (amyloid) and Congo Red negative categories. Amyloid fibrils are randomly arranged, and are 8-12nm in diameter. The Congo Red negative fibrillary diseases are more diverse, and since they are more rare but are favored by those who write the boards, I found a review to be helpful. Fibrillary Glomerulonephritis:

• Randomly arranged fibrils 12-30nm in diameter
• Usually polyclonal IgG
• Presents usually with proteinuria. 50% have nephrotic syndrome at presentation.
  
• 50% of patients progress to ESRD within a few years
• Treatment often unsuccessful. Steroids, cytoxan, and rituxan have been used with varying success.
  
• Does not usually recur in transplants
  

Immunotactoid glomerulopathy:

• parallel deposits of straight, hollow-lumen fibrils (microtubules) >30nm in diameter
• usually monoclonal IgG
• usually secondary
• Deposits occur on subepithelial surface of basement membrane, can be indistinguishable from membranous on light microscopy
  
• Presents with nephrotic syndrome, hypertension, hematuria.
  
• Recurs in transplants

Cryoglobulins:

• randomly arranged curved microtubules 25-35nm in diameter

Fibronectin glomerulopathy:

• 10-15nm fibrils
• Hereditary, autosomal dominant
• Presents with proteinuria, hematuria, hypertension
  

Collagenofibrotic glomerulopathy

• Banded collagen fibrils
• Hereditary, autosomal recessive, most cases from Japan
• Presents with edema and nephrotic syndrome
• Progresses to ESRD

Diabetes can also be associated with fibril deposition, usually 5-20nm in diameter. Lupus can cause fibril formation, and these generally are around the same size as the deposits in fibrillary GN and are arranged in a fingerprint pattern.This article contains an outstanding flow chart for the differential diagnosis of glomerular diseases with organized deposits.

For the boards, it may be helpful to remember that the fibril diameter of the more common fibrillary diseases- amyloid, fibrillary GN, and immunotactoid GP are correlated with their position in the alphabet- (A= 8-12nm, F= <30nm, usually 18-20, and I= >30nm, usually 45-55nm).

Don't forget to look for proteinuria!

At Renal Grand Rounds yesterday, we discussed the case of a previously healthy 50 year old man who presented with fulminant hepatic failure and AKI. He was initially thought to have AKI related to either SIRS/hypotension or Hepatorenal Syndrome (which should be a diagnosis of exclusion), but was astutely noted to have significant (about 6 gm/day) proteinuria. The patient was worked up further: his serum electrophoresis revealed a monoclonal immunoglobulin spike and urine Bence Jones protein was present. Serum free kappa light chains were high and the kappa to lambda light chain ratio was significantly elevated. Concomitant liver biopsy revealed AL amyloidosis, which was further confirmed and typed by fat pad and colon biopsies. Unfortunately, the patient succumbed to multi-organ failure.

The teaching point from this case is that the proteinuria was the key to making the correct diagnosis.

By way of quick review, amyloidosis is a group of diseases characterized by extracellular deposition of beta sheet fibrils which, in systemic forms, cause progressive organ dysfunction.

AL amyloidosis is characterized by fibrils that contain fragments of the variable portion of monoclonal light chains. This is the result of a clonal expansion of plasma cells, but interestingly, most patients with AL amyloidosis do not develop the manifestations of multiple myeloma, and most multiple myeloma patients do not have amyloid deposition. What both diseases have in common, however, is renal dysfunction which presents with significant proteinuria. Of note, given the pathophysiology of these diseases, the proteinuria is not related to albuminuria. Therefore, it is important to obtain a spot protein to creatinine ratio on all patients who may have otherwise unexplained or difficult to explain AKI, and subsequently pursue further work-up, including free serum light chain measurement.

In AL amyloidosis, response to therapy correlates with reduction in circulating light chains, so a hematologic response is the first marker in anticipation of renal function recovery or improvement. Interestingly, as well, the degree of baseline proteinuria on presentation correlates with response to treatment. Current treatment options include melphalan (an alkylating agent) plus steroids, Velcade (Bortezomib, a proteasome inhibitor) and rescue stem cell transplantation, which remains controversial.

kappa versus lambda light chains in paraproteinemias

Antibodies are comprised of the structure noted on the left:  they have two immunoglobulin heavy chains (in blue) and two immunoglobulin light chains (in green), covalently linked with one another via disulfide bonds (in red).  The light chains can be one of two types, either kappa or lambda; each individual B-cell (which synthesize and secrete clonal immunoglobulin) expresses either kappa or lambda, but not both, for the entire duration of its lifetime.  

Light chains play an important role in several nephrologic diseases.  They are small enough to be filtered at the glomerulus, but in normal conditions are reclaimed in the tubule.  When the resorptive capacity of the tubules are overwhelmed with extremely large amounts of light chain--as is the situation in paraproteinemias--then the light chains may appear in the urine, and potentially even cause damage as in the cast nephropathy.  Furthermore, certain light chains may accumulate in the glomerular basement membrane, causing glomerular disease (light chain deposition disease, LCDD), and still other light chains may be the underlying cause of AL amyloidosis.  

These different patterns of paraprotein-mediated disease tend to be mediated preferentially by either kappa or lambda light chains:

In cast nephropathy, lambda light chain is the most common.

In light chain deposition disease (LCDD), kappa light chain is the most common.

In AL amyloidosis, lambda light chain is the most common.

The typical kappa-to-lambda ratio in the normal human is about 65:35 (about 1:9), and this ratio is often altered in the above conditions.  It is especially important to look at the K:L ratio (rather than absolute values of K and L light chains) in patients with altered renal function, as the decreased GFR will directly lead to elevation in both K and L light chains.   

On a related note, Waldenstrom's macroglobulinemia is also a paraproteinemia, but rarely causes cast nephropathy or AL amyloidosis.  Interestingly, renal damage in this condition may well be caused by hyperviscosity syndrome.  

T-MINUS 1 DAYS TO THE NEPHROLOGY BOARDS.  GOOD LUCK TO ALL!

Serum Free Light Chain Assay

The dilemma:  there are a subset of patients with some type of paraproteinemia--e.g., light chain deposition disease or amyloidosis, for instance--which are NEGATIVE by SPEP & UPEP.  When there is renal involvement, the diagnosis can potentially be made by renal biopsy. But since we can't always be as invasive as we'd like to be, don't forget about the serum free light chain assay.  

Measuring serum free light chains relies on an assay which quantitates light chains NOT bound to heavy chain. In this 2003 Am J Clin Pathol study by Abraham et al, serum free light chains was found to be much more sensitive than either serum or urine immunofixation, and was successful in identifying several patients with AL amyloidosis who had undetectable paraproteins by SPEP & UPEP. 

Of note, serum light chains are cleared renally--so patients with reduced GFR will have increased values of both kappa and lambda light chain. Thus, for patients with CKD it is essential to look at the kappa:lambda free light chain ratio in order to detect a paraproteinemia. 

Macroglossia

As you may recall, macroglossia (an enlarged tongue) is one of the many manifestations of amyloidosis, the systemic disorder in which a particular protein is deposited as Congo-red positive aggregations. You may also recall that amyloidosis can be divided into subtypes based on the amyloidogenic protein: for instance, there is AL amyloidosis (caused by deposition of Ig light chain, occuring in various paraproteinemias), AA amyloidosis (caused by deposition of serum amyloid A protein, elevated in inflammatory states), beta-2-microglobulin amyloidosis (caused by deposition of beta-2-microglobulin, usually in the joints, as a consequence of reduced middle molecule clearance in dialysis patients), etc. I learned today, however, that macroglossia is a unique complication of AL amyloidosis.

I have learned this, and many other renal factoids, at this year's Massachusetts General Hospital 2009 Nephrology Update. It's free for me (since I'm a fellow at MGH) and about 5 minutes from my house, and a way to force myself into doing at least a little bit of review for the Nephrology Boards. In any case, I have a whole list of new blog topics for the coming weeks...

Differential Diagnosis of Fibrillary Glomerulopathies

The finding of fibrils on electron microscopy of a renal biopsy specimen may be an extremely important clue in establishing the diagnosis.  In fact, for many of the conditions listed below, the diagnosis may be based PURELY on a detailed ultrastructural characterization of the fibril, as in fibrillary or immunotactoid glomerulopathy.  

The first step in the differential diagnosis of fibrillary glomerulopathies is to divide the condition into an IMMUNOGLOBULIN-MEDIATED versus a NON-IMMUNOGLOBULIN MEDIATED process, which is typically done by immunofluorescent staining against different heavy and light chain classes.

IMMUNOGLOBULIN-MEDIATED fibrillary glomerulopathies include:

-AL amyloidosis.

-MIDD (monoclonal immunoglobulin deposition disease).

-type 2 cryoglobulinemia.

-immunotactoid glomerulopathy (see picture)

-fibrillary glomerulopathy.

NON-IMMUNOGLOBULIN-MEDIATED fibrillary glomerulopathies include:

-AA amyloidosis.

-fibronectin glomerulopathy.

-diabetic fibrillary glomerulopathy.

(note:  the latter two on this list are pretty rare).

Another crucial distinction here is whether the biopsy specimen stains negative or positive for CONGO RED (indicating the beta-pleating sheet structure of precipitated amyloid protein).  

New Therapies for Systemic Amyloidosis

Systemic amyloidosis can involve nearly any organ, and the kidney is often involved. Recall that there are two flavors of amyloidosis: AL amyloidosis (in which the amyloid is formed by light chains as a result of a paraproteinemia) or AA amyloidosis (in which a chronic inflammatory condition, such as rheumatoid arthritis, leads to the excess production of the amyloid-forming acute phase reactant serum amyloid A (SAA) protein.

In recent years there have been a few new approaches to treatment of this often deadly disease. One new medication is eprodisate, which functions by interfering with the interaction of amyloidogenic proteins with tissue glycosoaminoglycans. In a randomized, placebo-controlled trial published in a 1997 NEJM article (Dember et al), individuals who received eprodisate exhibited a slower rate of renal decline. This trial was done in patients with AA amyloidosis but the drug may turn out to be useful for AL amyloidosis as well.

In addition, there are numerous immunologic therapies directed at AL amyloidosis. Low-dose oral melphalan and dexamethasone is one mainstay; in younger healthier patients it is also possible to perform high-dose melphalan with autologous stem cell transplant, though the benefit of this approach is controversial.

Beta-2 Microglobulin Amyloidosis

The two major forms of amyloidosis are AL amyloidosis (in which light chains form the amyloid deposits) and AA amyloidosis (in which a variety of inflammatory molecules may adopt a beta-pleated structure to deposit as amyloid.

A specific subset of AA amyloidosis which is secondary to dialysis is beta-2 microglobulin amyloidosis. Beta-2 microglobulin (B2M) is an 11.8 kD protein which is a subunit of the MHC Class I molecule and is normally filtered and catabolized by the kidney. In the absence of renal function, large serum concentrations of B2M may build up and deposit, specifically synovial membranes, tendones, and bone. This leads to a stereotypic syndrome of carpal tunnel syndrome, flexor tenosynovitis, and other musculoskeletal manifestations which may be quite debilitating.

The GOOD NEWS is that this disease is not seen nearly as much as previously. It is hypothesized that the use of high flux dialyzers--which have a larger pore size than previously favored dialyzers and therefore would allow for the clearance of middle molecules such as as B2M--has made B2M amyloidosis a thing of the past.

Hereditary Amyloidosis

I saw a patient in Transplant Clinic today with a strong family history of chronic kidney disease requiring dialysis and periodic fevers. She was coming to the Transplant Clinic because she wants to be considered for a potential renal transplant. Both the patient, her brother, her sister, and her father--a family of English-Irish descent--had a history of high fevers and progressive renal disease. Biopsy of the kidneys previously has revealed nodular deposits with positive apple-green birefringence with Congo Red staining.

It turns out this family has TNF Receptor-Associated Periodic Syndrome (TRAPS), also known as Hibernian Fever, which is due to mutations in the gene encoding for tumor necrosis factor receptor 1. The disease manifests as recurrent fevers and a chronic inflammatory state, similar to other hereditary periodic fever syndromes such as familial Mediterranean fever (FMF) or Muckle-Wells Syndrome, and the reason these individuals may get renal disease is due to AA amyloidosis. Patients with TRAPS can (logically enough) be treated with etanercept (Enbrel), a monoclonal antibody against TNF and prednisone. The patient described is being considered for a cadaveric renal transplant but has been warned that there is a strong possibility that amyloid deposition in her future allograft could occur.