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

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

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

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

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

“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.”

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)

“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?”

“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

Non-Neoplastic Renal Diseases & Kidney Cancer

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

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.)

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

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

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%

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

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

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

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

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

Vessels Intimal fibrosis Hyalinosis Thrombus Atheroembolus Vasculitis

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

Diffuse Mesangial Sclerosis The differential diagnosis includes IgA nephropathy in early diabetic nephropathy. IF and EM would be needed to exclude IgA nephropathy

Nodular Mesangial Sclerosis

Capsular Drop

Arteriolar Hyalinosis

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

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

Amyloidosis

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

Glomerulosclerosis

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.

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: 575-584..

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: 1872-1876.

Interstitial fibrosis / tubular atrophy

Arteriosclerosis

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

Focal Segmental Glomerulosclerosis

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.

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

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,

Pitfall – JGA hyperplasia

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.

Pauci-immune crescentic GN

Actual Parameter

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): ___________________

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

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

Questions?