HDCN Ask the Professor:

Tubloreticular lesions, FSGS, but no HIV


I presently am taking care of a young African Americal male, who has a history of remote intravenous drug abuse. His hepatitis C serology is positive. He was referred for evaluation of renal insufficiency (SCr of 1.6 mg %) and nephrothic syndrome. His biposy showed FSGS. Interestingly, numerous tubuloreticular inclusions were present in endothelial cells. Biopsy was consistent with HIV associated nephropathy, but the patient is serologicaly HIV negative.

QUESTIONS:
a) Can you have evidence of HIVAN with out serological evidence of HIV infection?
b) Can hepatitis C glomerulonephritis present as FSGS?
c) Is hepatitis C glomerulonephritis associated with tubuloreticular inclusions?

Saul Nurko, M.D., (Case Western Reserve University)

Response by J. Charles Jenette, M.D., University of North Carolina at Chapel Hill

The following are my responses to the questions that were raised concerning the African-American male with a history of IVDA who developed the nephrotic syndrome and was found on renal biopsy to have "FSGS" with features consistent with HIV-nephropathy but negative serology for HIV infection:

a) "Can you have evidence of HIVAN without evidence of HIV infection?"

HIV-nephropathy definitely can occur in HIV infected patients who do not yet have AIDS, but I do not know whether it can occur in HIV-infected patients who are serologically negative for HIV infection. A pattern of renal injury that is virtually identical to HIV-nephropathy by light microscopy does occur and is called by some the collapsing glomerulopathy variant of FSGS or simply collapsing FSGS. In my experience, this pattern of FSGS occurs in three settings: 1) associated with HIV infection, 2) associated with IVDA, and 3) idiopathic. All three categories of the collapsing variant of FSGS (C-FSGS) have a much higher frequency in blacks versus whites, even when other factors are controlled, e.g. HIV infection and IVDA. For example, in our analysis of idiopathic C-FSGS, 81% of 16 patients were black compared to 44% of typical FSGS patients and 33% in our overall renal biopsy population (Kidney Int 45:1416-1424, 1994). C-FSGS, whether associated with HIV, IVDA or idiopathic, tends to have more severe proteinuria (usually greater than 10 g/day) and more rapid progression to renal failure than typical FSGS.

I am not aware of any of our idiopathic C-FSGS patients (i.e., patients with glomerular injury that looks like HIVAN but with no serologic evidence for HIV infection) who have subsequently been found to have HIV infection. Only 1 of the 16 patients that we reported with idiopathic C-FSGS had endothelial tubuloreticular inclusions, and in this patient they were scanty. In the patient under consideration, tubuloreticular inclusions were "numerous". This is the most bothersome feature to me with respect to raising concern that the patient may have occult HIV infection. Endothelial tubuloreticular inclusions are identified in about 80%-90% of HIVAN (e.g., Am J Pathol 126:513-526,1987). The other two setting in which TRI are frequently observed are patients with lupus erythematosus and patients treated with alpha-interferon.

In summary, yes, renal pathologic changes that are indistinguishable from those of HIVAN may occur in patients without evidence for HIV infection, although TRI are usually absent in such patients.

b) "Can hepatitis C glomerulonephritis present as FGS?"

Hepatitis C glomerulonephritis (HepC-GN) is an immune complex GN that often has a cryoglobulinemic or type I membranoproliferative GN phenotype (Kidney Int 46:1255-1263, 1994), but also can manifest other expressions of immune complex injury, e.g. membranous GN, focal or diffuse proliferative GN, or acute diffuse proliferative GN that resembles acute post-infectious GN (Lab Invest 70:157A, 1994). The sclerotic phase of a chronic focal immune complex GN may suggest FSGS by light microscopy, but IF and EM evaluation should reveal this.

In an analysis of the prevalence of hepatitis C seropositivity in patients with various glomerular diseases that has been published only in abstract form (Lab Invest 70:157A,1994), 0/7 patients with the collapsing variant of FSGS were positive, and only 1/28 patients with typical FSGS was positive. My suspicion is that in this patient and in the patient under consideration, the hepatitis C infection is not the cause of the FSGS.

c) "Is hepatitis C glomerulonephritis associated with tubulo reticular inclusions?"

As mentioned above, TRI are frequent in patients with HIV infection, systemic lupus erythematosus and alpha-interferon treatment. They are present in such patients whether or not they have glomerular disease, and are present in renal as well as extrarenal endothelial cells. Therefore, TRI are a systemic expression of a systemic stimulus and are not a purely renal marker of a particular type of renal disease. Current theory, based in part on in vitro observations and observations in patients treated with interferon, is that TRI result from high levels of circulating alpha-interferon.

Because of the high frequency (80%-90%) in patients with HIV and SLE, endothelial TRI are useful ultrastructural markers that raise the level of suspicion for these diseases, but they are not absolutely specific. Although rare (occurring in less than 5% of patients), TRI are observed in patients with virtually any form of renal disease. Therefore, the identification of TRI has a diagnostic sensitivity of approximately 85% for HIV/SLE/interferon-treated patients, and a specificity of >95%.

Endothelial TRI are rare in patients with hepatitis C GN, unless they have been treated with alpha-interferon.

Summary: Based on the description of the renal biopsy findings and the other data, I suspect that this patient has the collapsing variant of FSGS. The most problematic issue is whether this is the idiopathic or the IVDA or the HIVAN category of C-FSGS. This distinction may not matter with respect to the natural history of the renal disease in the patient because, if the patient does have the collapsing variant of FSGS, he is at great risk for rapid progression of renal disfunction whether or not he has HIV infection. The overall management of the patient, of course, will be affected by the presence or absence of HIV infection. Especially because of the "numerous" TRI, I would at least repeat the HIV serology. Seroconversion may not occur for 6 months in HIV infected patients who have viremia. If HIV causes HIVAN, it is at least theoretically possible that HIVAN could begin prior to seroconversion. If the patient under discussion is eventually found to be HIV positive, please let me know.

(April, 1996)

We have seen a number of patients with HCV infection and proteinuria that when biopsied have FSGS. One patient had the collapsing varient. Almost all patients biopsied who had FSGS and HCV infection were black. Most with MPGN and HCV were white. The IF was negative in all patients with FSGS.
Catherine Stehman-Breen, MD (cos@u.washington.edu)
Seattle, WA USA-Wednesday, April 10, 1996 at 11:38:54 (CDT)

The patient in question also had a negative IF, but there were not many glomeruli in that section to study. I wonder if your patients with FGS and HCV had tubulo reticular inclusions.
Saul Nurko M.D. (sxn32@po.cwru.edu)
Cleveland, Ohio USA -Friday, April 26, 1996 at 16:05:20 (CDT)