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
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: 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 %
Focal segmental GS %
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
The differential diagnosis includes IgA nephropathy in early diabetic nephropathy. IF and EM would be needed to exclude IgA nephropathy

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
The PAS stain is very useful to identify and accurately assess the percentage of globally sclerotic glomeruli (global glomerulosclerosis). Also, the PAS stain if done routinely will remind you to closely evaluate the non-neoplastic kidney.

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
I recommend counting at least 50 (preferably 100) glomeruli and assessing the percentage of global glomerulosclerosis for every tumor nephrectomy specimen.
Bijol V, et al. Am J Surg Pathol, 2006; 30:

34. I recommend counting at least 50 (preferably 100) glomeruli and assessing the percentage of global glomerulosclerosis for every tumor nephrectomy specimen.
Extent of global glomerulosclerosis correlates with the rate of renal function decline in radical nephrectomy specimens
J Urol 2010, 184:

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
Crescent formation involving more than 50% of the glomeruli is a critical value in surgical pathology. While this is likely a rare phenomenon in tumor nephrectomy specimens,

42. Pitfall – JGA hyperplasia

43. Pitfall – Collapsing Glomerulopathy
Collapsing glomerulopathy is also known as collapsing variant of focal segmental glomerulosclerosis. The example shown on this slide is from a patient with acute HIV infection and these findings are consistent with HIV-associated nephropathy, but the glomerular changes could easily be mistaken for crescentic glomerulonephritis.

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)
____ 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 50

51. Summary Chronic Kidney Disease / End-stage renal disease is important
Non-neoplastic renal diseases are common
Diabetic nephropathy
Arterionephrosclerosis
Examine the non-neoplastic kidney carefully, especially with benign tumors!
Order PAS/Jones silver stains 51

52. Questions?