A new cause of renal thrombotic microangiopathy: Yttrium 90-DOTATOC internal radiotherapy

A New Cause of Renal Thrombotic Microangiopathy: Yttrium 90-DOTATOC Internal Radiotherapy Solange Moll, MD, Volker Nickeleit, MD, Jan Muel!er-Brand, MD, Felix P. Brunner, MD, Helmut R. Maecke, MD, and Michael J. Mihatsch, MD o The chelator somatostatin analogue dota-o-phe~-tyr3-octreotide (DOTATOC), which is stably labeled with the ~-emitting radioisotope yttrium 90 (90y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses Of 9°Y-DOTATOC approximately 8 weeks apart (mean normalized cumulative dose, 165.4 -+ 36.4 mCi/m2). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m 2 withoutside effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m 2, 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last 9°y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine levet, 300/~mol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of T M A involving g!omeruli, arterioles, and small arteries. Patients treated with high-dose s0y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m 2) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between s°Y-DOTATOC and renal TMA. © 2001 by the National Kidney Foundation, inc. INDEX WORDS: Thrombotic microangiepathy (TMA); dota-o-phe~-tyr3-octreotide (DOTATOC); yttrium 90 (90y); radiation nephropathy; renal failure.

HROMBOTIC microangiopathy (TMA) defines a specific hist0pathologic finding related to endothelial damage and caused by numerous etiologic factors, eg, infectious agents, drugs (mitomycin, cyclosporine, or tacrolimus), or irradiation. We describe a new cause of TMA: yttrium 90-dota2D-phet-tyr3-octreotide (90y_ DOTATOC) therapy. The chelator somatostatin analogue DOTATOC, which is stably labeled with the/3-emitting radioisotope 90y, is used as internal radiotherapy for the treatment of patients with advanced somatostatin receptor-positive neuroendocrine tumors. 1

T

CASE REPORTS

Between October 1996 and November 1999, a total of 29 patients (14 men, 15 women; mean age, 52.3 _+ 13.9 years) with normal renal function before therapy were treated in our hospital (clinical data reported in2). All patients h,ad advanced somat0statin receptor-positive tumors or metastases of neuroendocrine tumors from different primary sites. Only ! patient had been administered external abdominal irradiation in combination with fluoi'ouracil 6 months before 9°Y-DOTATOC therapy. A mean normalized cumulative dose of 165.4 + 36.4 mCilm 2 of 9°y-DOTATOC was admlnistered in divided intravenous doses approximately 6 weeks apart. Stabilization or partial remission Of disease in most patients showed the beneficial effects of DOTATOC therapy. Progression of disease shown on computed tomographic

scans performed at the end of the regular treatment sessions justified one or two supplementary intravenous doses in some patients. Twenty-two of 29 patients administered a normalized cumulative dose of 200 mCi/m 2 tolerated the treatment without side effects (Table 1). Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m~, 5 patients (4 women, 1 man) developed renal failure (Table 2). Increasing serum creatinine levels were observed within 3 months after the last 9°Y-DOTATOC injection (mean, 2.6 + 2.4 months; range, 0.5 to 6 months) and were associated with proteinuria, microhematuria, hypertension of recent onset, and anemia in each case. One patient developed classic hemolytic uremic syndrome. The evolution was rapidly pr0gessive in 3 patients, resulting in end-stage renal 1:allure an 0 hemodialysis within 6 months (mean, 5.6 _+ 4.7 months; range, 2 to 11 months). The outcome was not as poor for the 2 other patients (mean serum creatinine level, 300 t ~ m o ~ an average 16 months after the end of treatment). Renal biopsies performed in three patiei~ts showed typical

From the Institute of Pathology, institute of Nuclear Medicinel and Department of Medicine, University of Basel, Kantonsspital, Switzerland. Received July 24, 2000; accepted in revised form November 3, 2000. Address reprint requests to Michael J. Mihatsch, MD, Institute of Pathology, Kantonsspital, Schoenbeinstrasse 40, CH-4003 Basel, Switzerland. E-mail: [email protected] © 2001 bY the NatiOnal Kidney Foundation, Inc. 0272-6386/01/3704-0022535.00/0 doi: l O.JO53/ajkd.2001.2 285 9

American Journal of Kidney Diseases, Vol 37, No 4 (April), 2001 : pp 847-851

847

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MOLL ET AL Table 1,

Clinical Features of the Control Group Before 90y-DOTATOC Therapy

After 90y-DOTATOC Therapy

122 _+ 13/76 _+ 10 12,6 + 1.7 267 + 95 61 _+ 20

120 _+ 16/73 _+ 11 11.5 + 2.1 201 -+ 86 68 + 26 15 -+ 5

Blood pressure (mm Hg) Hemoglobin (g/L) Platelets (150-450 × 109/L) Creatinine (/~mol/L) Follow-up (mon) NOTE. Mean values given. N = 24.

Table 2.

Clinical Features of the Five Patients Who Developed Renal Failure Patient No. 1

Patient characteristics before 9°Y-DO TA TOC therapy Sex Age (y) Blood pressure (ram Hg) Hemoglobin (g/L) Platelets (150-450 × 109/L) Creatinine (p,mol/L) Tumor and treatment Tumor diagnosis

Previous therapy 9oy-DOTATOC (mCi/m2) Remission Renal failure after 9oY-DO TA TOC therapy Onset (men) Proteinuria Microhematuria Blood pressure (mm Hg) Hemoglobin (g/L) Reticulocytes (%o) RBC morphology Platelets (150-450 × 109/L) LDH (<430 U/L) Evolution creatinine (/~mol/L)/mon* Kidney biopsy

2

3

4

5

F 42 125/75 13.5 325

F 54 130/80 14.1 218

F 63 130/65 11.3 450

F 51 110/75 13.4 263

M 48 130/80 10.8 353

62

60

72

67

79

Neuroendocrine carcinoma

Neuroendocrine carcinoma

Neuroendocrine carcinoma

Thymus carcinoma

None 206 Partial

Rx 4- FU 241 Reduction

Medullary carcinoma of the thyroid None 235 Stable

None 238 Progression

None 241 Progression

2 1.5 g/24 h + 170/105 8.4 ND Anisocytosis, poikylocytosis 118

4 1.37 g/L ÷ 180/100 6.1 32 Fragmentocytes+, anisocytosis 43

6 + + 190/100 8.0 ND ND

1 2.0 g/L + 160/105 8.9 ND Normal

0.5 + + 150/100 9.3 ND ND

315

106

154

557 CRF 230/19 TMA

>430 ESRF 609/11 TMA

ND CRF 370/12 TMA

572 ESRF 516/4 No biopsy

630 ESRF 502/2 No biopsy

Abbreviations: CRF, chronic renal failure; ESRF, end-stage renal failure; ND, not determined; Rx + FU, radiation therapy plus fluorouracil; RBC, red blood cell; LDH, lactate dehydrogenase. * Months after the diagnosis of renal failure.

RENAL INJURY AFTER 9°y-DOTATOCTHERAPY

lesions of TMA involving glomeruli, arterioles, and small arteries. By light microscopy, glomemlar lesions were characterized by capillary loop collapse, focal segmental thrombi of fibrin and other proteins in capillaries, recent and late mesangiolysis, and double contouration of basement membranes (Fig 1A). Arterioles and small arteries showed transmural hyaline deposits and were partially or completely occluded by fibrin and/or protein thrombi, as well as foam cells (Fig 1B). Tubular atrophy and interstitial fibrosis were prominent in all cases. Immunofluorescence showed glomerular deposits of fibrin and nonspecific deposits of immunoglobulin M (IgM), IgA, C3, and C5b-9. Depositions of fibrin, IgM, and IgA was observed in both the lumen and wall of arterioles and arteries. Electron microscopy showed massive thickening of the glomentlar capillary wall with widening of the lamina tara interna, new formation of

Fig 1. Renal biopsy specimens from patients no. (A) 1 ii and (B) 2. (A) Glomerulus with mesangiolysis (arrows). : (B) Small artery with thrombi of fibrin and protein, as well as foam celis in the lumen and transmural hyaline deposRs. (Periodic acid-Schiff; original magnification x 100.)

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lamina densa material, and activation of the endothelial cells.

DISCUSSION

The association of TMA and cancer is well documented in untreated malignant disease, most frequently metastatic carcinoma, and after chemotherapy or radiotherapy. 3,4 Most cases of TMA associated with untreated cancers are reported in patients with adenocarcinoma, primarily gastric adenocarcinoma, followed by carcinoma of the breast and colon and small-cell lung carcinoma. In rare cases, TMA has been observed in association with other tumor types: squamous cancer, 5

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thymoma, 6 prostatic tumor, 7 Hodgkin's disease, s,9 non-Hodgkin's lymphoma, 3 and uterine sarcoma. 1° However, no case report describes TMA associated with neuroendocrine tumors. The association of TMA with antineoplastic drugs is also well known. Among the chemotherapeutic agents, mitomycin is the antiblastic agent most commonly considered responsible for TMA development in cancer patients, 11,12 but other agents have also been implicated.1347 TMA lesions are associated with conventional radiotherapy, leading to radiation nephropathy. Different clinical settings are described according to the administered radiation dose: acute radiation nephropathy following a latent period of 6 to 12 months after abdominal irradiation (>2,000 rads), and chronic radiation nephropathy, usually clinically apparent years after therapy (<2,000 rads).ls-2° The histopathologic lesions observed after 90y_ DOTATOC therapy are identical to those found after external radiotherapy. This suggests a causal relationshiP between 9°y-DOTATOC and renal TMA. Although somatostatin receptors have not been detected in glomeruli and 9°y-DOTATOC is eliminated through ithe kidney and found intact in urine, a significant amount of this drug accumulates in the renal parenchyma. Renal arteritis and radiation nephropathy have been reported in a mouse model treated with the radioisotope 90y21 However, the pathophysiological mechanisms causing radiation nephropathy are unclear. Reactive oxygen intermediates generated within the cell by the ionizing irradiation might interact with DNA, producing double-strand breaks and leading to cell death, or induce apoptosis in the endothelial cells, as reported in hemolytic uremic syndrome :and thrombotic thrombocytopenic purpura.22 The greater sensitivity of endothelial cells to radiation-induced apoptosis might be explained:by their incapacity to spontaneously activate the protein kinase C pathway after irradiationl Protein kinase C activation by cytokines or growth factors was reported to protect endothelial cells against apoptotic DNA degradation and radiation-!nduced :cell killing. 23 Finally, it is interesting tha~ apoptotic endothelial cells were shown to be prod0agulant and thus predispose to plateI . let aggregataon and fibrin formation. 24 An alternative hypothesis might be the direct

MOLL ET AL

effect of tumor burden or tumor lysis syndrome. However, no case report was found describing TMA in association with tumor burden or tumor lysis syndrome. The beneficial effects of 9°y-DOTATOC internal radiotherapy are outweighed by the high rate of severe renal failure caused by TMA lesions, it is essential to elucidate the pathophysiological mechanisms of 90y nephrotoxicity to develop renal protective measures, thus allowing the use of greater doses and improving therapeutic efficacy. One of these renal protective measures might be to block the tubular reabsorption of the radionuclide peptide by the coadministradon of lysine or arginine, known to reduce peptide reabsorption in general 25 and block renal uptake of an indium-labeled somatostatin analogue, a6 Such a clinical trial is currently under way for the patients treated with 9°y-DOTATOC in our hospital. Because more widespread use of internal radiotherapy can be expected in the near future, radiation nephropathy as a serious adverse effect must be considered and systematically looked for. ACKNOWLEDGMENT

The authors thank JtirgA. Schifferli,MD, Departmentof Internal Medicine, Kantonsspital Basel, for helpful comments. REFERENCES

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