Case 5 -

Gemcitabine-associated Thrombotic Angiopathy Helmut G. Rennke

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Clinical History: 61-year-old man was diagnosed Stage IIIB non-small-cell carcinoma of the lung (T2, N3) in 2002. He received carboplatin and Taxol chemotherapy followed by concurrent chemoradiotherapy. In April 2003 a right supraclavicular node was noted and treated with radiation. At the time he had received Taxotere with ZD6474, Iressa, Navelbine, and beginning February 2004, gemcitabine was started. He tolerated the treatment well, and on 2 subsequent scans he showed improvement. On July 5, 2004 he was admitted to BWH with increasing dyspnea, edema, pleural effusions, which showed no malignant cells. He was discharged, the edema got worse, and he developed systemic hypertension. He was re-admitted to the renal service. His PE remained unchanged with marked edema, his UA showed 4+ protein, and a 24-hour collection revealed 10 g of protein. The sediment was bland. His serum creatinine was 1.6 mg/dl. Case 5 - Slide 1 - H&E Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 2 - Jones Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 3 - PAS Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 4 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 - This low power image of the renal cortex shows well-preserved parenchyma without signs of glomerulosclerosis or tubular atrophy. Two small arteries on the right show prominent walls. PAS. Case 5 - Figure 2 - The glomerulus depicted on this H&E reveals capillaries largely occluded by swollen cells, although with this stain it is difficult to know if there are also changes of the capillary wall that are contributing to this appearance. Significant hypercellularity of the tuft is not present. Case 5 - Figure 3 - This PAS-stained section of a glomerulus reveals thickening of the capillary walls with numerous irregular "double contours", especially noticeable in the center and on the right side of the image. Swollen cells appear to occlude several capillaries. The tuft shows mild mesangial expansion and slight increase of cells at these sites. Case 5 - Figure 4 - This glomerulus reveals changes similar to those seen in Figure 3. One arteriole at the vascular pole of the glomerulus is occluded by foamy material. The wall of the arteriole also reveals indistinct cell borders. PAS Case 5 - Figure 5 - This image depicts kidney cortex with few tubules showing necrotic debris in the lumen and one small artery with a moderately thickened vascular wall. PAS. Case 5 - Figure 6 - The immunofluorescence microscopy reveals diffuse and irregularly distributed granular deposits reactive predominantly for IgM (and C3, not illustrated). Direct immunofluorescence microscopy with anti-IgM Case 5 - Figure 7 - There is also dull reactivity for fibrin-related antigens along the glomerular capillary walls. Direct immunofluorescence microscopy with antibodies against fibrin-related antigens. Case 5 - Figure 8 - This low power electron micrograph shows three glomerular capillary loops with prominent thickening of the wall. Small fragments of cells in the urinary space include prominent lysosomes. Case 5 - Figure 9 - This electron micrograph shows the details of the thickened capillary wall. The endothelial cells show marked loss of fenestrations. There is prominent expansion of the subendothelial space by electron-lucent debris and interposition of cells and cell projections. There is also widespread effacement and simplification of foot processes. The epithelial cells show microvillous degeneration of the cell surface. Several small and ill-defined aggregates of electron dense material is also present in the markedly expanded subendothelial space. Case 5 - Figure 10 - This high power electron micrograph shows the details of the glomerular capillary wall changes. Notice the multi-layered basement membrane under the endothelium, the cell projections in the expanded subendothelial space, and the aggregates of ill-defined dense material. The lamina densa proper is maintained, and the foot processes of the epithelium are well preserved in this capillary. Differential Diagnosis Chronic thrombotic angiopathies and other forms of primary vascular injury results endothelial injury followed by mild inflammation and repair. In the arterial vessels results in arterial and arteriolar sclerosis, with subintimal accumulation of connective tissue, especially when this process goes through repeated cycles. In larger arteries the end result is progressive and often asymmetric narrowing and obliteration of the lumen and secondary ischemic injury of the parenchyma. In smaller arteries and arterioles this pattern of injury and repair results in the so-called "onionskin" lesions. The same process of injury and repair in the glomeruli leads to the formation of double contours, often with entrapment of by-products of the coagulation and fibrinolytic processes; this includes fibrin-related antigens, IgM, complement components, and cellular and platelet debris often referred to as subendothelial "fluff" visualized by electron microscopy. The cell debris or protein complexes prevent the regenerating endothelial cells from anchoring to a matrix normally represented by the basement membrane. A new basement membrane is generated by the endothelium, resulting in a remodeled capillary wall, now with a double contour pattern. The absence of electron dense deposits in capillaries with double contours strongly suggests that a primary endothelial injury or a chronic or healed thrombotic angiopathy is the mechanism of the glomerular pathology. Although vascular sclerosis with parenchymal atrophy and sclerosis is often described under the misleading term of "benign nephrosclerosis" and ascribed and dismissed as secondary to hypertension, many other well-recognized forms of primary vascular injury can result in such changes and are more likely to represent the cause of the vascular sclerosis seen in this patient's biopsy. The case presented here represents an example of a drug-induced thrombotic angiopathy, a complication seen in association with the use of several chemotherapeutic and anti-rejection agents. The vascular and glomerular capillary wall changes seen are rather non-specific and can be observed in several diseases associated with a primary form of vascular injury, including: Pro-coagulant states (thrombophilia) Autoimmune disorders Paraproteinemia Toxic injury affecting components of the vascular wall Physical factors such as irradiation Smoking Metabolic diseases with an important vascular component. 1. Procoagulant conditions associated with this pattern of vascular injury include the renal involvement of the lupus anticoagulant (APS, the primary or idiopathic variant and APS associated with SLE), the healed phase of an E. coli- associated hemolytic-uremic syndrome (HUS), and the thrombotic thrombocytopenic purpura (TTP). Possibly several coagulation factor abnormalities associated with thrombophilia (thrombophilic dysfibrinogenemia, prothrombin gene mutation, and the factor V Leiden mutation and other forms of resistance to activated protein C, protein S or C deficiency, etc.) may also contribute to this type of primary vascular injury. The kidney involvement in pregnancy-related complications such as eclampsia, pre-eclampsia, HELLP syndrome, and post partum acute renal failure (or post-partum HUS or cortical necrosis also referred to as post-partum angiosclerosis) clearly fall into this category of diseases. The association of these and other pregnancy-related complications such as fetal wastage or habitual abortion, low birth weight, and abruptio placentae with thrombophilia is well established in the literature, and the similarities of the vascular changes in the placenta of women with these complications and in the kidney is striking. 2. Autoimmune disorders with a primary vascular injury include the already-mentioned primary and SLE-associated antiphospholipid antibody syndrome, systemic sclerosis (scleroderma), and the so-called undifferentiated connective tissue disorder or overlap syndrome. These disorders are sometimes difficult if not impossible to differentiate from each other on the basis of the renal biopsy findings alone. In a very general sense, the condition known as transplant glomerulopathy probably falls into this category; the endothelial damage in these cases is likely to be cause by antibodies and/or specific T cells directed against antigens expressed on the endothelium and other elements of the vascular wall. 3. Some patients with paraproteinemias do not manifest a paraprotein deposition disease, amyloidosis, or cast nephropathy, but instead, present with vascular and glomerular lesions similar to those observed in thrombotic angiopathies. Although this complication for the kidney has not been reported in the literature (see abstract at this meeting), several related studies have suggested an interference of certain paraproteins with the coagulation or fibrinolytic pathways, so that the inclusion of paraproteins in the differential diagnosis of patients with chronic thrombotic angiopathies is certainly justified, and a search for a circulating paraprotein is often indicated, if clinically relevant. Cases of kidney involvement in patients with the POEMS syndrome probably represent examples of this category. 4. Among the toxic forms of endothelial and vascular injury we include biological agents such as the vero cytotoxin and Shiga-like toxins, and various chemotherapeutic and immunosuppressive agents. The latter include the combination of cisplatin, bleomycin, mitomycin C, Gemcitabine, Cyclosporine, tacrolimus or FK506, OKT3, and potentially some cytokines and cytokine- or growth factor receptor-blockers used as adjuvants in some forms of cancer therapy. Also agents with marked vasoactive effects, such as cocaine, decongestants (ephedrine and related drugs), amphetamines, etc. can cause or trigger the development of lesions in the kidney indistinguishable from other forms of chronic thrombotic angiopathies. 5. Physical factors that can induce identical vascular changes are irradiation (radiation nephritis) and hypertension, especially malignant hypertension. The kidney disease post-bone marrow transplantation is probably in part due to irradiation and in part due to toxic injury. 6. Patient with a strong history of smoking can also present with similar vascular sclerosis and glomerular capillary wall lesions indicative of a primary form of endothelial injury. 7. Several metabolic diseases, such as diabetes, hyperuricemic disorders, and hyperhomocysteinemia, a well-recognized general risk factor for vascular disease, may play a key role in some forms of primary vascular injury in the kidney and contribute to progressive vascular and glomerular sclerosis. In the absence of diabetes mellitus and chronic immune complex diseases, the differential diagnosis of a nodular glomerulosclerosis should include not only light chain and other paraprotein deposition diseases but also chronic thrombotic angiopathies since these mesangial nodules can be the result of healed mesangiolysis. Mesangiolysis is often seen in patients with any of the acute thrombotic angiopathies. FINAL Diagnosis: Gemcitabine-associated Thrombotic Angiopathy References : Flombaum CD, Mouradian JA, Casper ES, Erlandson RA, Benedetti F. Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kid Dis. 1999;33(3):555-562. Fung MC, Storniolo AM, Nguyen B, Arning M, Brookfield W, Vigil J. A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy. Cancer. 1999;85: 2023-2032. Green MR. Gemcitabine safety overview. Semin Oncol. 1996:23: 32-35. Harrell RM, Sibley R and Vogelzang NJ. Renal vascular lesions after chemotherapy with vinblastine, bleomycin, and cisplatin. Am J Med. 1982;73: 429-433. Lesesne JB, Rothschild N, Erickson B, et al. Cancer-associated hemolytic-uremic syndrome: Analysis of 85 cases from a national registry. J Clin Oncol. 1989;7: 781-789. Moake JL: Thrombotic microangiopathies. N Engl J Med. 2002;347: 589-600. Murgo AJ: Thrombotic microangiopthy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol. 1987;24 (3): 161-177. Pham PT, Peng A, Wilkenson AH, Gritsch HA, Lassman C, Pham PC and Danovitch GM. Cyclosporine and tacrolimus-associated thrombotic microangiopathy. Am J Kid Dis. 2000;36: 844-850. Raife TJ and Lager DJ: Chronic thrombotic microangiopathy associated with antineoplastic therapy with minimal hematologic effects. Mayo Clin Proc. 2002;77: 323-328. Walter RB, Joerger M, Pestalozzi BC: Gemcitabine-associated hemolytic-uremic syndrome. Am J Kidney Dis. 2002;40 (4): E16. Humphreys BD, Sharman JP, Henderson JM, Clark JW, Marks PW, Rennke HG, Zhu AX, Magee CC. Gemcitabine-Associated Thrombotic Microangiopathy: Cancer 2004; 100:2664-70.