1. Cytostatic drug and radiation associated renal lesions Heinz Regele Department of Pathology

2. Cytostatic drug and radiation associated renal lesions Radiation Clinical: Acute and/or chronic renal failure Histology:Radiation nephritis/nephropathy Cytostatic drugs Cisplatin Clinical: Acute and/or chronic renal failure (Ifosfamide)Histology:Tubulointerstitial injury

3. Renal injury in cancer treatment Radiation Clinical: Acute and/or chronic renal failure Histology:Radiation nephritis/nephropathy Cytostatic drugs Cisplatin Clinical: Acute and/or chronic renal failure (Ifosfamide)Histology:Tubulointerstitial injury Targeted therapies VEGF blockadeClinical: Proteinuria, acute renal failure Tyrosine Kinase Inhibitors (TKI)Histology:Glomerular injury Bisphosphonates Pamidronate, Zoledronate…Clinical: NS, acute or chronic renal failure Histology:Glomerular injury and/or tubular injury

4. Radiation induced kidney lesions TMA like changes in glomeruli and arteries: GBM double contours, mucoid intimal swelling Acute tubular injury Glomerular scarring Intimal fibrosis Interstitial fibrosis and tubular atrophy Radiation nephropathy more appropriate than radiation nephritis

5. Radiation nephropathy Long latency phase after exposure Clinical signs become detectable after months or years Acute radiation nephropathy: 6-12 months Chronic radiation nephropathy:2-10 years (with or without acute phase) Diagnostic features are non-specific Clinical: Hypertension, proteinuria, edema, urinary casts, reduced GFR Histology:TMA like changes in glomeruli and arteries, acute and chronic tubular injury, glomerular scarring, intimal fibrosis, interstitial fibrosis might be due to many other types of injury RT is frequently combined with other nephrotoxic agents/conditions Concomitant cytostatic drug therapy Effects of cytostatic drugs, antibiotics or GvHD might aggravate effects of TBI especially after BMT Diagnostic challenges

6. Kidney injury is dose dependent Dawson LA, Int J Rad Oncol Biol Phys 2010

7. Schematic risk estimation for kidney injury in partial kidney radiation therapy Dawson LA, Int J Rad Oncol Biol Phys 2010

8. Renal injury by radiolabeled peptides and antibodies Radionuclide labeled small proteins Somatostatin analogs (octreotide): Neuroendocrine tumors (NET) Upcoming new agents Glucagon-like peptide 1 receptor (exendin-4):NET Gastrin-releasing peptide receptor (bombesin) :Breast and prostate cancer α v β 3 Integrin (aeg-gly-asp (RGD)):Proliferating endothelial cells CCK2 (gastrin) receptor (gastrin-1): Medullary thyroid carcinoma Vegt E, J Nucl Med 2010 Hydrophilic radiolabeled peptides are excreted mainly via the kidneys and are partially reabsorbed in proximal tubular cells. Renal retention of therapeutic radionuclides causes a relatively high radiation dose to the kidneys, which can lead to kidney failure. Pool SE, Sem Nucl Med 2010

9. Cisplatin induced renal injury Cisplatin and related platinum-based therapeutics are frequently used for the treatment of testicular, head and neck, ovarian, cervical, non-small-cell lung carcinoma and many other types of cancer. Cisplatin nephrotoxicity is a frequent dose limiting side effect which occurs in about one third of patients undergoing cisplatin treatment. Clinical Cisplatin nephrotoxicity is often seen after 10 days of administration with decreasing glomerular filtration rate, increased serum creatinine, and reduced serum magnesium and potassium levels. Pathophysiology Main targets are (predominantly proximal) tubular epithelial cells. Drug induced cell death occurs via apoptosis and necrosis

10. Mechanisms of Cisplatin nephrotoxicity Pabla N, KI 2008, KI 2008

11. Cisplatin induced renal injury Histology is non-specific and renal biopsies are rarely performed during early stages. Renal (tubular) dysfunction may persist over years especially if cisplatin was combined with ifosfamide. Chronic cisplatin nephropathy is however not clearly defined. Effects of multimodal therapy or co-morbidity may be confounders in late biopsies.

12. Bisphosphonates Bisphosphonates are inhibitors of osteoclast mediated bone resorption. They are frequently used in the treatment of post menopausal osteoporosis and against lytic bone lesions in MM or bone metastases Only high dose i.v. application of bisphsponates used in malignacy associated bone disorders is associated with nephrotoxicity Renal lesions typically occur after several months of treatment indication cumulative injury which was also demonstrated in experimental animals

13. Nephrotoxicity of Bisphosphonates Collapsing FSGS Acute tubular injury PamidronateZoledronate

14. Histology and outcome of Bisphosphonate renal injury Perazella MA, Kidney Int 2008

15. Anti-angiogenic cancer treatment Cook KM, CA Cancer J Clin 2010

16. Anti-angiogenic cancer treatment Cook KM, CA Cancer J Clin 2010

17. Receptor Tyrosine Kinase Inhibitors (rTKI) (VEGFR inhibiting) Cook KM, CA Cancer J Clin 2010

18. Renal side effects of VEGF inhibition Kappers MHW, J Hypertens 2009

19. High-grade proteinuria (>3.5g/day) upon VEGF inhibition Wu S, JASN 2010 Incidence of high-grade proteinuria with bevacizumab according to dosage and tumor type

20. Renal lesions during VEGF inhibition Izzedine H, Eur J of Cancer 2010

21. Conditional VEGF gene deletion in podocytes Eremina V, NEJM 2008

22. VEGF is required for normal GEC function Eremina V, NEJM 2008

23. Does VEGF inhibition cause podocyte injury? Sugimoto H, J Biol Chem 2003

24. Does VEGF inhibition directly cause podocyte injury? Normal glomerular function requires paracrine but not autocrine VEGF-VEGFR-2 signaling Sison K, JASN 2010 Studies in whole body and cell specific VEGFR-2 KO mice

25. Summary Renal injury is common in radiation therapy and cytostatic drug treatment especially with platinum based agents and ifosfamide Biopsies are rarely performed in these conditions, histologic lesions are non-specific and an overlap with other pathologies can be diagnostically confounding Antiangiogenic therapy targeting VEGF signaling frequently leads to proteinuria and sometimes cause glomerular TMA. Clinical and experimental findings in VEGF inhibition might provide clues to the mechanisms of other types of TMA (preeclampsia…) I.v. application of bisphosphonates is associated with significant (dose dependent) risk of glomerular (pamidronate) or tubular (zoledronate) nephrotoxicity

27. Proteinuria and TMA may also be caused by receptor tyrosine kinase inhibitors (rTKI)