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1. Focal segmental glomerulosclerosis (collapsing variant). 2. Prominent tubular epithelial cell damage. Tubular atrophy and interstitial fibrosis, unspecific accompanying inflammation.
65 years
65 yrs old female patient with multiple myeloma (IgG kappa) known for years, progressive tumor disease. Now nephrotic syndrome (proteinuria 12g/day). Serum creatinine increase up to 664 mol/l.
Renal biopsy with 12 glomeruli, 2 of which are completely obsolescent. The others are enlarged. The mesangium of one glomerulus shows slight mesangial matrix increase. Glomerular collapse is also present.Glomerular hypercellularity is lacking. In five glomeruli perihilar or peripheral segmental sclerosis and hyalinosis with synechia formation to Bowman’s capsule is present. In one glomerulus a prominent activation and cell crowding of podocytes (pseudo-crescent) is present.The peripheral glomerular basement membranes are slightly thickened. The arterioles exhibit severe arteriolar hyalinosis. In the tubulo-interstitial space mild diffuse fibrosis, accompanied by scattered infiltration of lymphocytes and histiocytes was present. The tubules showed early signs of atrophy in some areas or luminal dilatation with epithelial cell damage of variable degree: irregular vacuolization, loss of brush border, irregular nuclear distribution and increased mitotic activity. No myeloma casts.
Immunohistochemistry showed massive focal and segmental deposits of IgM and complement factors (C1q, C3, C4, C5b-9) in glomeruli with segmental lesions. All other immunoglobulins were absent. The arterioles showed severe circular hyalinosis and were positive by immunohistochemistry for IgM, complement C3 and C5b-9. Electron microscopy confirmed segmental sclerosis, mild collapse and activation of podocytes and hyalinosis. Complete foot process fusion was present in the less severely affected glomerular segments. The diagnosis of FSGS with minor lesions compatible with the collapsing variant was made.
Under Bisphosphonate therapy for treatment of malignant metastizing tumors (in particuar multiple myeloma and breast cancer with bone metastesis) or M.Paget, two forms of nephrotoxicity can be observed. 1) Toxic tubular necrosis 2) Focal segmental glomerular sclerosis (nos or collapsing variant) or glomerular minimal change with nephrotic syndrome Both patterns of injury can occur together. 1. Toxic tubular necrosis Following a variable therapy period of months to years, progressive renal failure appears. Clinically progressive renal insufficiency is noticable, which is however not accompanied by relevant urinary findings (normal sediment, low proteinuria (< 1.5g/day). When treatment is discontinued, renal function can stabilize or improve. Histologically, in the foreground, are the changes in the tubulo-interstitial space. The tubuli are changably widened, they contain a variable number of of hyaline and Tamm-Horsfall protein casts as well as shedded tubular epithelial cells. Cell nuclear polymorphism in the the tubular epithelium is striking, accompanied by variable numbers of mitosis. The interstitium is partly edematous, partly slightly fibrotic and lympho-histiocytic infiltrates are discrete. Glomeruli and vessels (arterioles and arteries) exhibit no characteristic lesions. Characteristic immunohistochemical or electron microscopic findings are absent. 2. In most cases focal segmental glomerular sclerosis (nos or collapsing variant) is found, more rarely glomerular minimal changes with nephrotic syndrome. Nephrotic syndrome is the cardinal symptom, accompanied by renal insufficiency. The nephopathy can, even following discontinuation of the drug, rapidly progress to terminal renal failure. In renal biopsy variable numbers of glomeruli exhibit FSGS, which can either show FSGS (not otherwise specified) or the picture of the collapsing variant. In advanced cases, obsolescent glomeruli are also found. The tubulo-interstitial space shows signs of tubular epithelial injury (as above) and the results of glomerular injury with tubular atrophy and and interstitial fibrosis. There are no characteristic immuno-histochemical findings. The FSGS can be confirmed by electron microscopy. The changes described above do not occur after oral ingestion of biphosphonate or injection of the drug once or twice a year for treatment of osteoporosis. Renal side effects are rare in tumor patients (< 10% of patients) . The various drugs on the market (zolrdonic acid (Zometa), pamidronate (Aredia), ibrandonate (Bondronat) may cause the same lesions. There is a clear cut dosage effect. The reason for tubular toxicity (mainly of proximal tubules) is the limited secretion of bisphosphonates in the tubular lumens. In our own and consultation cases, nephrotoxicity always occured when bisphosphonate was infused together with cytostatic agents. All drugs with tubulo-toxic potential may favor development of FSGS as well. Whether a pathogenetic connection exists between the tubular toxicity of the drugs and the development of FSGS is unclear.
Am J Kidney Dis 39: 1118-22, 2002. Nephrotic syndrome after treatment with pamidronate. Markowitz GS, Fine PL, D'Agati V D.

J Am Soc Nephrol 12: 1164-72, 2001Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate.Markowitz GS, Appel GB, Fine PL.

Biopharm Drug Dispos 20,193-198,1999. Renal handling of bisphosphonate aalendronate in rats. Kino I, Kato Y, Lin JH, Sigiyama Y.
Michael Mihatsch, Institute for Pathology Basel
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