Chronic Kidney Disease in Kidney Cancer Patients

1. Chronic Kidney Disease in Kidney Cancer Patients Anthony Chang, MD University of Chicago Medical Center

2. Outline • Non-Neoplastic Kidney Diseases in Kidney Cancer • Harmful • Common • Underappreciated • Review common medical renal diseases associated with renal cancer

3. Chronic Kidney Disease (CKD) Previously known as “chronic renal failure” Defined as GFR <60 ml/min per 1.73 m2 May progress to end-stage renal disease Involves 25% of renal cell carcinoma (RCC) patients prior to nephrectomy Diabetes and hypertension are independent risk factors for RCC

4. Chronic Kidney Disease (CKD) ↑ risk of CKD after radical compared with partial nephrectomy ↑ risk of cardiovascular and non-cardiovascular death

5. American Urological Association 2009 - T1 tumors (<7 cm) should be treated with partial nephrectomy Emerging data that T2 tumors should also be treated with nephron sparing surgery

6. “Despite mounting evidence that PN is an effective and preferable approach to the T1 renal mass, it remains markedly underutilized in the USA and abroad. The overzealous use of radical nephrectomy for T1 tumors must now be considered detrimental to the long term health of the kidney tumor patient.”

7. 2004 US Renal System Data Expected life span on dialysis: 20 – 24 years: 14.6 years 60 – 64 years: 4.3 years 70 – 74 years: 3.1 years 80 – 84 years: 2.2 years RCC 5 year survival rates Stage 1 = >90% Stage 2 = 75-90% Stage 3 = 59-70% Stage 4 = <10% (median: 16-20 mos)

8. “As I spoke, the family seemed to relax visibly, and began to break into smiles. “Oh, that’s wonderful news, wonderful news!” I smiled too, automatically, although I did not think my news—a biopsy finding of advanced glomerulosclerosis, irreversible kidney failure—had been so wonderful. It was true that this particular kidney biopsy had been done because of heavy proteinuria and newly diagnosed kidney failure in a man with a lung nodule; the working diagnosis had been a paraneoplastic membranous nephropathy, and the specter of lung cancer had been hanging over the scene for the last few days. My news made the possibility of cancer recede. The nodule eventually was found to be benign, and we were left to deal with the aftermath of the not-cancer diagnosis, the good news that wasn’t. If the one-year mortality for new end-stage kidney failure exceeds that for most new cancer diagnoses, why is it that this family, like many others, dreaded the latter more than the former?”

9. “I became very close with the patient who reacted with such relief to the diagnosis of advanced kidney disease rather than cancer. I saw him progress, quickly and inexorably, to dialysis-requiring kidney failure. I watched him suffer with infections, fatigue, confusion, and cramps. He lost his appetite, and became weak and bedbound. He died less than a year after I met him. To the end, I don’t think that he or his family ever understood that the news I had brought was bad, or that kidney failure itself had been the final blow to his fragile health. Perhaps it was for the best that they did not really understand. Then again, that’s what oncologists used to say, in whispers, outside the rooms of patients who were pretending not to listen.” Dena E. Rifkin, MD, MS La Jolla, California

10. Non-Neoplastic Renal Diseases & Kidney Cancer

11. Non-Neoplastic Kidney Disease & Cancer • 24 cases (9.8%) • 19 Diabetic nephropathy • 3 Thrombotic microangiopathy • 1 Focal segmental glomerulosclerosis • 1 Sickle cell nephropathy • 21 (88%) – not originally diagnosed • Of 147 pathology residency programs, 98 responded – only 35 (36%) require renal pathology rotation

12. Non-Neoplastic Kidney Disease & Cancer • Cedars Sinai Medical Center – LA (2010 USCAP online abstract) • 311 nephrectomies • 66% nephrosclerosis (41% or 24% of total were mild) • 7.4% - Diabetic nephropathy • 4.8% - Focal segmental glomerulosclerosis • 3% - Miscellaneous (amyloid, GN, atheroemboli, etc.)

13. Non-Neoplastic Kidney Disease & Cancer • Weill Cornell Medical College (2011 USCAP abstract) • 216 nephrectomy cases • 47 (21.7%) new pathologic diagnoses • 21 – diabetic nephropathy • 11 – hypertensive nephropathy • 6 – focal segmental glomerulosclerosis • 2 – collapsing glomerulopathy • Arteriolar sclerosis predictive of renal function decline

14. Non-Neoplastic Kidney Disease & Cancer • 110 tumor nephrectomy (60 prospective) • 38% - Normal • 24% - Diabetic nephropathy • 28% - Severe scarring • Misc (IgA, collapsing GP, amyloid, etc)

15. Incidence in TN specimens Arterionephrosclerosis >20% Diabetic nephropathy 10-20% Focal segmental GS 2-9% Thrombotic microangiopathy 3-5% AA amyloidosis 3% Atheroembolic disease 2% IgA nephropathy 2% Membranous nephropathy <1%

16. Grossing Nephrectomy Specimens • Should you obtain a fresh tissue sample for IF and EM? • Order the PAS/Jones silver stain on the non-neoplastic kidney tissue block

17. Algorithm Identification of glomerular abnormalities First, light microscopy! Glomeruli Tubules Interstitium Vessels

18. Glomeruli Normal Mesangial sclerosis Mesangial hypercellularity Crescent / fibrinoid necrosis Segmental Sclerosis Endocapillary hypercellularity

19. Algorithm If glomerular abnormalities present, Consider Congo red Immunofluorescence microscopy (IgG, IgA, IgM, kappa/lambda light chains, albumin) on paraffin tissue sections Decreased sensitivity compared with frozen tissue Immunohistochemistry Electron microscopy from paraffin block Preservation/processing artifact

20. Tubules / Interstitium Normal Interstitial fibrosis / tubular atrophy Interstitial inflammation Acute tubular injury

21. Vessels Intimal fibrosis Hyalinosis Thrombus Atheroembolus Vasculitis

22. Diabetic Nephropathy Diabetes is a risk factor for RCC 8% of American adults c diabetes 10-20% of RCC patients have diabetes DN in up to 8-20% of TN specimens Diabetic nodular glomerulosclerosis predicts progression of CKD Treatment: Strict blood glucose control

23. Diffuse Mesangial Sclerosis

24. Nodular Mesangial Sclerosis

25. Capsular Drop

26. Arteriolar Hyalinosis

27. Nodular Glomerulosclerosis Differential diagnosis Diabetic nephropathy Amyloidosis Monoclonal Immunoglobulin Deposition Disease Light chain deposition disease Light and heavy chain deposition disease Fibrillary GN Immunotactoid glomerulopathy Idiopathic nodular glomerulosclerosis Associated with hypertension and smoking

28. Amyloidosis ~3% of RCC with AA amyloidosis Rare cases of AL amyloid and other amyloid forming proteins Treatment: removal of neoplasm Proteinuria may indicate recurrent or metastatic disease

29. Amyloidosis

30. Arterionephrosclerosis AKA Hypertensive nephropathy / nephrosclerosis Hypertension in 25-60% of RCC pts Tumor nephrectomy (TN) specimens 40% with arteriosclerosis and no TI scarring 20% with arteriosclerosis and TI scarring >20% global glomerulosclerosis predicts progression of CKD

31. Glomerulosclerosis

32. Underestimating global glomerulosclerosis

33. Significance of Global Glomerulosclerosis Bijol V, et al: Presence of >20% global glomerulosclerosis or nodular diabetic glomerulosclerosis predicted an increase of 0.5 mg/dL in serum creatinine 6 months after surgery Bijol V, et al. Am J Surg Pathol, 2006; 30: 575-584..

34. Extent of global glomerulosclerosis correlates with the rate of renal function decline in radical nephrectomy specimens J Urol 2010, 184: 1872-1876.

35. Interstitial fibrosis / tubular atrophy

36. Arteriosclerosis

37. Focal Segmental Glomerulosclerosis • 2 to 9% of TN specimens • Often associated with hypertension, arteriosclerosis, and parenchyma scarring • May be secondary to reduction of functional nephrons • Proteinuria, nephrotic-range (>3 g/day) • IF: negative • EM: podocyte foot process effacement

38. Focal Segmental Glomerulosclerosis

39. Crescentic GN Etiologies Pauci-immune (ANCA-associated) GN Anti-glomerular basement membrane (anti-GBM) GN Immune complex-mediated GN IgA nephropathy Lupus nephritis Membranoproliferative GN Post-infectious GN Etc.

40. Pauci-immune crescentic GN Uncommon in the setting of kidney cancer 80% with positive ANCA titer Clinicopathologic entities Churg-Strauss syndrome Granulomatosis with polyangiitis (Wegener) Microscopic polyangiitis

41. Crescentic GN

42. Pitfall – JGA hyperplasia

43. Pitfall – Collapsing Glomerulopathy

44. Pauci-immune crescentic GN

48. Actual Parameter

49. Proposed Parameter Non-Neoplastic Kidney (evaluate using PAS and/or Jones methenamine silver stain; check all that apply) ____ Insufficient tissue (partial nephrectomy specimen with <5 mm of adjacent non- neoplastic kidney ____ Sufficient tissue __ No significant pathologic alterations of the glomeruli, tubules, interstitium, or vessels __ Significant pathologic alterations Glomeruli (fill all that apply) ____ % of glomeruli with global sclerosis (0-100%) ____ Glomerular disease (specify): ________________ ____ Other Tubulointerstitial compartment (check all that apply) ____ No significant abnormalities ____ Interstitial fibrosis/tubular atrophy, mild (5-25%) ____ IF/TA, moderate (26-50%) ____ IF/TA, severe (>50%) ____ Other tubulointerstitial diseases (specify): ______________ Vessels (check all that apply) ____ No significant abnormalities ____ Arteriosclerosis (mild; <25% occlusion) ____ Arteriosclerosis (moderate; 26-50% occlusion) ____ Arteriosclerosis (severe; >50% occlusion) ____ Other vascular injuries (specify): ___________________

50. Future Directions • Improve coordinated care between urologists and nephrologists • Refine therapeutic implications of pathologic parameters of the non-neoplastic kidney • % Global glomerulosclerosis • Severity of interstitial fibrosis / tubular atrophy • Severity of arteriosclerosis or arteriolosclerosis