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  Wednesday, 10 August 2011
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73 year-old man with 7.5 grams of urinary protein per day.
[b]Past Medical History:[/b]
[list="1"] [*]Hypertension x decades [*]Diabetes (HbA1C 6%, no complications) [*]Hypercholesterolemia [*]Prostate cancer PSA now, on hormonal replacement Apparently in 'remission' [/list]
[list] [*]ACE inhibitor [*]DRI [*]Statin [*]ASA [*]Metformin [/list]
[b]Presenting Illness:[/b]
Presented to family doctor complaining of edema. Otherwise asymptomatic.
[b]Physical Exam:[/b]
Blood pressure 160/70, hypervolemic with bilateral lower limb edema
Creatinine 175 umol/L, electrolytes normal. Blood glucose normal with HbA1C 6%. LDL 7.2 mmol/L, normal triglycerides. SPEP, calcium normal. Serum albumin 20 g/L. 24 hr urine protein 7.5 grams, normal urine protein electrophoresis. ANCA, ANA, AntiGBM normal, Hep B/C/HIV negative. Chest xray normal. Ultrasound shows normal kidneys, 10 cm bilaterally. Chest xray normal. Colonoscopy normal.
MICROSCOPIC DESCRIPTION Sections show kidney tissue consisting of cortex. Up to 16 glomeruli are present in the specimen. No glomeruli are globally sclerosed. Most glomeruli are enlarged and have mild mesangial hypercellularity. There are no crescents. The mesangial matrix is increased in some glomeruli, with no lobular changes. The capillary wall thickness is increased. The silver stain does not show spikes on the outside of the glomerular basement membrane. There is moderate interstitial fibrosis. Interstitial fibrosis has a diffuse distribution. The juxtaglomerular arterioles are normal. Arteries are present in the specimen and show no abnormalities. The tubules are atrophic in some areas. Immunofluorescence shows peripheral granular deposits of IgG (2+) and C3 (2+). ELECTRON MICROSCOPY shows conspicuous subepithelial electron dense deposits surrounded by spikes extending from the GBM.
[b]Clinical Question:[/b]
This patient was observed for a 3 month period with a trial of dose escalation in ACE and ARB. Despite this, proteinuria persisted and renal function gradually deteriorated. I considered him to be high risk for progression to end-stage renal disease.
[b]My concern of course is that:[/b]
[list] [*]He has a recent malignancy [*]He has impaired renal function [*]He is relatively elderly with significant comorbidity. [/list]
[b]Would you[/b]
[list="1"] [*]Treat with immunotherapy [*]If yes, which agent? [*]Or, would a recent malignancy dissuade you [/list]
Help is appreciated!
12 years ago

I suppose part of the issue is, does this patient have idiopathic membranous and if not, do conventional treatments apply here?
12 years ago
Hi KidneyCop (nice handle :)),

It is often difficult to differentiate idiopathic from secondary membranous; the biopsy was suggestive of primary (not not unquestionably). And so I agree with your comment, that if truly secondary, the treatment is cessation of the offending cause. In this case, prostate cancer is an obvious thought but according to his treating Urologist, he is in remission.

I do share you anxieties, but given the severity of the presentation and appearance that he might progress rapidly to ESRD, I decided to treat. More on that later.
12 years ago
He does not seem like a great candidate for immunotherapy given the recent malignancy.
12 years ago
Thanks for your responses.

I had a discussion with the patient about these issues and we decided that:

Since his prostate CA was in remission
He had very high risk to progress disease
Had normal sized kidneys on ultrasound
Only mild fibrosis on biopsy

We proceeded with treatment. Given the choice to proceed, what would you consider using? Options:

Cyclophsphamide + steroids
Cyclosporine +/- steroids
12 years ago
Hi Dr. Weinstein,

Well I'm not certain that this man should be treated. But if he should, of course each has problems:

Cytoxan and cancer is not ideal. Cyclosporine in the setting of renal dysfunction is problematic. The evidence of rituxan with membranous is limited and among the evidence, treating those with renal insufficiency is also of questionable benefit (let alone possible harm).

Having said all this, my vote would be for cyclosporine.
12 years ago
Hi Dr weinstein
I think still we can wait , he might recover spontaniously (up to 6 m) , sodium restriction , blood pressure control might help , i will vote for CSA later if he dosnt respond . I am not sure if he is realy cured from ca prostate ?
12 years ago
Dear Dr J. W.
Membranous glomerluonephrits secondary to malignancy is the most accepted scenario in this situation
and treatment of the cause rather than immunosuppressive medications is the backbone of therapy
and even if it is Primary membranous , a trial of conservative therapy is meritted
So , my answer is simpley is ACEI or ARB , Statin , Asprin
Immunosuppression is not indicated for the timebeing
By the way stop metformin (Poor Kidney functions )
Best of wishs
Dr Sherif El Shazly
12 years ago
As pointed by Ronco, (Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int 1999; 56: 355–377) only few MN regress after ytreatment of the malignancy. However it would be wise to check that he is not developing another neoplasm (?lung)
12 years ago
Lets put the aggressive view more explicitly. He has severe membranous with declining function. The only good evidence is for alkylating agents. There is little long term evidence for calcineurin inhibitors. Rituximab is expensive and in SLE/vasculitis trials is not less toxic than cyclophosphamide. I doubt that controlled prostate Ca will be much affected by the therapy. So I discuss a modified Ponticelli regimen with him (alternating months of high dose steroid and oral cyclophosphamide) for six months.
12 years ago
Great discussion.

It really does seem like there is no one correct answer, like most cases of GN ;)
12 years ago
I would treat this patient with CyA + small dose of steriods ( 10mg/d ) , treatment of NS is mandatory to avoid complications . I would observe his malignancy by frequent PSA testing
12 years ago
Can you go into specifics of what the biopsy showed:
1. Did it show any specific IgG subtypes for helping us figure out secondary or primary
2. Were there any mesangial deposits?
3. Any TRI noted on EM?

All above suggesting perhaps a secondary cause. Also, if you empirical start treatment for now, and then send a Anti phospholipase AB testing at Boston to get some idea about it being primary, might help.
I would avoid treatment given recent cancer. Just ACEI.ARB and conservative management. Re eval by oncology might be needed perhaps to make sure no metastatic lesions and or a new neoplasm. If I had to choose a potential treatment, I would do steroids with rituxan perhaps.
12 years ago
Take a look at a recent Nature Nephrology paper by Lien Y and Lai L titled Pathogenesis diagnosis and management of Paraneoplastic glomerulonephritis in Feb 2011 issue this year. pages 85-95
12 years ago
My personal 2 cents worth here is to start T. Cyclophosphamide and Prednisolone. I tend not to use the alternate month Ponticelli regime but combine the two for a total of months. Is Ca Prostate associated with Secondary Membranous?
12 years ago
Yes, Prostate Cancer is associated with Secondary Membranous.
The biopsy you have is showing some mesangial proliferation. I think appears more secondary.
Can you have pathologist look at IgG subtypes on IF? Any pathologists thoughts on this case?

12 years ago
This is difficult descion. 1st of all this case need treatment.2nd he is in remission,if more than 6 monthes this will be in favour of starting rituximab for him as membraous not responding to other treatment.
12 years ago
Hi there Jordan, I am not english speaking so there might be a few things I missed with abbreviations; are there deposits anywhere else other than sub epithelial? That would suggest secondary etiology. Also, how was the prostate cancer treated, surgery or only medical treatment and do you have a bone scintigraphy? After all prostate cancer might be silent in treatment and "remission" but in many cases it's still there, so the antigen is still present. Also, even if it ends up being a primary membranous nephropathy immunosupression would be contraindicated if the prostate cancer wasn't completely eradicated, which seems to be the case since the patient is under hormonal therapy.
What to do?
Check again on the presence of the neoplasia and if it's still there maybe just try steroids.
Good luck
Tough case
12 years ago
Hello. Really a tough decision but I still think we have to go with classical teaching. This patient has renal dysfunction along with proteinuria of more than 6 gram / day, so I will go with alkylating agent and steroids and to follow closely in terms of progression of his malignancy and other complications.

12 years ago
The biopsy report is suggestive of secondary with the presence of mesangial proliferation. IgG subclass would be helpful. Personally I would wait for a few months and start looking hard for other potential sites of malignancy. Difficult!!!:
12 years ago
danny sapir

he is elderly with advanced renal disease and interstitial fibrosis, given his overall pic i would not treat aside from statin, aceI/arb and a dri, and a statin.

given he has interstitial fibrosis im more concerned for lack of benefit and increased risk.

thank you< D
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