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American Society of Nephrology Annual Scientific Meeting October, 2000 The Dysproteinemias Part Two of Two | ||||
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Stephen M. Korbet, M.D. Professor of Medicine, Associate Director of Nephrology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL. |
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Now one of my favorite topics:
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Initial reports of Congo-red negative fibrillary GN
In 1977, Dr. Rosenmann and his colleague, Dr. Eliakim, reported a 46-year old woman who presented with a nephrotic syndrome.
00:00
When they biopsied her, they found she had amyloid-like glomerular deposits. But in fact, they were Congo red negative. The lesion she had... and this is not her biopsy but this is a representative biopsy... was primarily one of mesangial expansion, as you can see here.
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The immunofluorescence was IgG with C3, again in a mesangial pattern.
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Electron microscopy appearance of Congo Red-negative fibrillary GN
By electron microscopy, she had these randomly oriented fibrils, which in her case were only about 9 or 10 nm in diameter. That is why they felt it looked so much like amyloid-- because the size was even the same. Yet they were Congo red negative. They identified, in fact, that that was a distinction. These actually represent 18 to 20 nm diameter fibrils.
What they found was this young woman had amyloid-like deposits that were Congo red negative, but they also recognized that this woman did not have cryoglobulinemia, she did not have a paraproteinemia, and had no evidence of any systemic disease at least to their exam and work up.
00:00
Early report of ITG
Three years later, Mel Schwartz and Ed Lewis saw a patient who presented at almost the same age. It was a 47-year old male who had 15 grams of proteinuria. On biopsy there was marked thickening of the capillary walls with marked mesangial expansion. This patient's immunofluorescence actually had IgG-3 kappa, and it fluoresced in a granular pattern around the capillary wall with marked mesangial involvement. In contrast, this patient had parallel bundles, if you will.
If you can see some of the cross-sections here, there are these fairly distinct microtubules which had a diameter of about 35 nm.
00:00
They chose to name this glomerular process in this patient immunotactoid glomerulopathy to emphasize the immunoglobulin content of these microtubules and the ultrastructural appearance of what looked very much like a tactoid. If you look at the ultrastructure of a tactoid of sickle cell disease, it looks very similar to this.
00:00
ITG in relation to other variants of fibrillary glomerulopathies
What these two patients had very much in common was that not only were the Congo red negative, immunofluorescence positive, neither one had cryoglobulinemia, neither one had monoclonal gammopathies, and neither one had lupus. In fact, the patient that Ed and Mel saw they followed for almost 15 years. That gentleman had, I think, at least two or three bone marrow biopsies, never developed a plasmacytosis or myeloma, never developed a cryoglobulinemia, and never developed a monoclonal gammopathy, and ultimately went on dialysis and died after a total course of 15 to 16 years without having developed any systemic disease per se.
00:00
We choose to call these patients immunotactoid glomerulopathy. Since these original cases have been described, there are at least close to 200 cases now that have been described, and there have been a number of synonyms that have been used to describe this lesion. We have chosen immunotactoid glomerulopathy for the reasons that I stated. Others choose to call it fibrillary glomerulopathy, and there are other names that apply as well. I personally don't care what you call it. I am not proprietary, as Mel would say.
00:00
Different tubule / fibril sizes in ITG
But what I do care about is whether you split it up or not. If you want to call them all fibrillary GN, that is fine with me. If you want to call them all immunotactoid, that is even more fine with me. But the fact of the matter is that there is a big push or there has been a push to try to divide these up based upon the ultrastructural differences. Again, the majority of these patients have ultrastructural features that are microtubules or microfibrils, if you will, that are anywhere from 18 to 22 nm in diameter. The minority fall into this larger category. It is somewhere in the range of maybe 10 to 15 percent of all the cases that have been reported.
00:00
In an excellent review... we reviewed this in '91 and again in '94 and more recently Pronovost, Brady, and I think Dr. Rennke was involved as well, reviewed the literature as well as their experience and published this in Nephrology, Dialysis, and Transplantation in 1996. Then there was a Nephrology Forum in Kidney International in 1998.
They defined fibrillary glomerulopathies not dissimilar from the way we do. There are those that are amyloid associated, there are those that are Congo red negative, there are those that are Congo red negative with a cryoglobulinemia, those with a monoclonal gammopathy, and then there is this group that don't appear to have a measurable cryoglobulin or monoclonal gammopathy.
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Division of ITG based on microtubular diameter
When they looked at these patients, they found that the incidence of malignancy may be affected by microtubular diameter. One of the reasons people have brought up that it is important to divide ITG is, because the patients who have microtubules greater than 30 nm have a higher incidence of malignancy versus those less than 30 nm.
But when they used the definition I just showed you, they found that if you look at all the cases that have been reported thus far, the likelihood of a malignancy associated with this glomerulopathy was about 3 percent in patients who had the smaller microtubules and none of the ones... again a small population of patients... with the larger microtubules.
When they looked at their orientation, random or bundles, again they found no significant clinical differences whatsoever.
00:00
Presenting features of patients with ITG
They also compared the presenting features of these groups. This is the composite data. These patients present anywhere from the age of 10 to 81. On average, most of these patients are between the ages of 45 and 50. Proteinuria, obviously in all of these patients because it is the renal presentation that they present with. Nephrotic syndrome in 71 percent; hematuria, hypertension, renal insufficiency are common, not unlike other primary glomerulopathies. They are not responsive to therapy. What I meant to say on this slide is, that when they broke down the patients into less than 30 and greater than 30 nm microtubular diameter and then looked at these presenting clinical features, they found no clinical differences between the two groups.
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Treatment for ITG
There is a paucity of information on the treatment of these patients. But in fact what there is is about 33 patients who have been treated with prednisone, cytotoxics, the combination, plasmapheresis, nonsteroidals. Partial remissions, at best, were seen in three patients. The majority of these patients appear to be very nonresponsive, at least with these therapies.
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Survival of patients with ITG
Patient survival over the course of 5 to 10 years, greater than 75 percent--almost 80 percent. Renal survival--not unlike what we see in FSGS. Over the course of 5 to 10 years, 50 percent or more of these patients progress to renal failure.
Organs involved with ITG
These patients don't appear to have a systemic disease and there have only been a few case reports of patients who have extrarenal manifestations. Dr. Rennke had one patient with, I believe, pulmonary hemorrhage. That was reported in The New England Journal of Medicine.
There was one other case of a patient where there were deposits found in the liver. But in general, these patients do not appear to have an infiltrative disorder to the best of our knowledge. We had an autopsy on one of our patients who we reported who had no evidence of involvement in the heart or the spleen or the liver. Again, there are not a lot of these patients out there. But to the best of our ability to determine it, they don't appear to have a systemic disease.
00:00
Renal transplant results in patients with ITG
A number of patients with ITG have been transplanted after they have progressed to renal failure. Thus far, there are about eight reported cases. Four of these come from the Pronovost paper. Four of these patients have had recurrence, clinical as well as histologic recurrence. Interestingly the histology in the transplant looks almost identical to that in the native kidney. In one of our patients, the recurrence lead to end- stage renal disease. In the other patients, they had some progressive renal insufficiency, but hadn't progressed to end-stage renal disease. This is over a follow-up of 2 to 11 years.
00:00
What are the deposits in ITG?
The real issue here I think when it is all said and done at the end of the day is what is this? Or what are these things that lead to these highly organized deposits? This may be many different diseases with this ultrastructural manifestation. We don't know. Are these immune complexes? Are they monoclonal proteins?
00:00
Results of specific staining of the fibrils in ITG
For sure Gloria Gallo and her group did some excellent studies with immunoelectron microscopy and did at least show that in fact these fibrils, and these are markers for IgG as well as C3, and she also looked at amyloid P component, and they line up right along the fibrils. The ground substance in-between was actually negative for evidence of immunoglobulin.
00:00
The fibrils themselves were positive for the things that they were looking for and negative for some other things. The amyloid P component, interestingly, was found in all of these fibrils. Amyloid P component apparently is found in the basement membrane normally. But it is just found in extremely high concentration in patients with amyloid and may in fact have something to do with the formation of the amyloid fibrils.
They suggested that maybe they have something to do with the formation of the fibrils in people with immunotactoid glomerulopathy. All of the patients that she studied had IgG, all of them had both kappa and lambda and C3. They didn't have fibronectin or fibrillin or other compounds that might lead to microtubular formation.00:00
When we reviewed the data, we found that most cases have both kappa and lambda along with IgG or other heavy immunoglobulins. But there are anywhere from 19 percent in my review, others have found 20 percent, where the deposits have only IgG kappa, if you will, suggesting that there might be in some cases a monoclonal abnormality leading to the deposition of these proteins.
Dr. Iskandar and Dr. Jennette looked at a group of these patients as well and actually found that in their patients with fibrillary GN, they all had IgG4 subclass. Now interestingly, the patients who had idiopathic membranous also had a predominance of IgG4. So I don't quite know how that plays in, but nonetheless it still gives you the suggestion that they all have one subclass and there may be something to this issue of some monoclonal abnormality in the plasma cells. But the fact of the matter is we are unable to measure it in most of these patients.
We are unable or have not been able by the techniques available to isolate a paraprotein or a cryoglobulin in most of these patients. Now whether they have a forme fruste of paraproteinemia or cryoglobulinemia is yet to be seen.00:00
Immunotactoid glomerulopathy: Summary
These patients with immunotactoid or fibrillary glomerulopathy have deposits with organized ultrastructure, they are Congo red negative, they appear to be immunoglobulin mediated, and they have no evidence, to my knowledge, of a systemic process to the best of our ability to measure it. I include them in the differential primary glomerular diseases, per se.00:00
Source: Brady HR. Kidney Int. 1998 May;53(5):1421-9.
Premature to subdivide patients with ITG at the present time
The whole issue of whether to split them up--should these patients be subclassified, I think was summed up fairly nicely by Dr. Brady. The clinical presentation is similar for these patients if you look at the patients with fibrils greater than 30 nm versus less than 30 nm. The incidence of malignancy is similar. The pathogenesis is unknown. It would be folly to subclassify patients on the basis that the variants look different.
I think that is where we are at right now, and I will end there. Thank you for your attention.
References
1. Kyle RA. Treatment of chain amyloidosis (AL). Adv Nephrol Necker Hosp. 1998;28:383-99. Review.
2. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7.
3. Heilman RL, Velosa JA, Holley KE, Offord KP, Kyle RA. Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis. 1992 Jul;20(1):34-41.
4. Rosenmann E, Eliakim M. Nephrotic syndrome associated with amyloid-like glomerular deposits. Nephron. 1977;18(5):301-8.
5. Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant. 1996 May;11(5):837-42.
6. Brady HR. Fibrillary glomerulopathy. Kidney Int. 1998 May;53(5):1421-9.
7. Korbet SM, Schwartz MM, Lewis EJ. Immunotactoid glomerulopathy. Am J Kidney Dis. 1991 Mar;17(3):247-57. Review.
8. Korbet SM, Schwartz MM, Rosenberg BF, Sibley RK, Lewis EJ. Immunotactoid glomerulopathy. Medicine (Baltimore). 1985 Jul;64(4):228-43.
9. Yang GC, Nieto R, Stachura I, Gallo GR. Ultrastructural immunohistochemical localization of polyclonal IgG, C3, and amyloid P component on the congo red-negative amyloid-like fibrils of fibrillary glomerulopathy. Am J Pathol. 1992 Aug;141(2):409-19.
