1. Renal Problems in the Haematology Patient
Colm C. Magee, MD, MPH, FRCPI
Renal Division
Beaumont Hospital
Dublin, Ireland

2. Disclosures
None

3. Abbreviations AKI: acute kidney injury CKD: chronic kidney disease
HUS: hemolytic uremic syndrome
TTP: thrombotic thrombocytenic purpura
NSAIDs: non-steroidal anti-inflammatory drugs

4. Kidney Problems Encountered in the Hematology Patient
AKI
Nephrotic syndrome
CKD (pre-existing or new)
Electrolyte disturbances
Dosing of meds
Anemia

5. AKI 5

6. Approach to AKI in the Hematology Patient
AKI often multi-factorial
Useful approach: assess causes as:
Prerenal
Intrarenal
Postrenal
Humphreys, Magee at al, J Am Soc Nephrol 16:151-61; 2005

8. Prerenal Common Causes:
Dehydration (diarrhea, vomiting, hypercalcemia)
Drugs (NSAIDs)
Hepatorenal syndrome (after hematopoietic cell transplant)

9. Intrarenal: Glomerular
Relatively rare
Collapsing glomerulopathy (bisphosphonates)

10. Intrarenal: Tubulointerstitial
Common
Causes
Acute tubular necrosis (ischemic / toxic)
Acute cast nephropathy (myeloma kidney)
Tumor lysis syndrome
Infiltration of kidneys (lymphoma)

11. Intrarenal: Vascular
HUS / TTP

12. HUS / TTP Syndromes Causes Cancer + chemotherapy (rarely cancer alone)
Often adenocarcionomas
Clinical Features
AKI and / or neurological - may be delayed
Hypertension
Labs: microangiopathic hemolytic anemia

13. Classic Lab Findings All may not be present! Schistocytes Test Result
FBC
Anemia
Thrombocytopenia
Blood smear
Schistocytes
Plasma LDH
Increased
Plasma creatinine
PT, APTT
Normal
Urine dipstick
Blood, protein
Serum haptoglobin
Decreased / absent
All may not be present!
Schistocytes

14. HUS / TTP Implicated drugs Mitomycin C Cisplatin Gemcitabine
Conditioning regimen for allogeneic HCT
Pathogenesis: presumed direct endothelial damage
Prognosis: variable

15. Postrenal Intratubular obstruction Tumor lysis syndrome
Acute cast nephropathy (myeloma)
Drugs (high dose methotrexate)
Extrarenal obstruction by tumour
Ureters
Bladder

16. 37yr female referred with reduced urine output, creatinine 45016

17. Nephrotic Syndrome 17

18. Nephrotic Syndrome Definition Proteinuria (>3.5g / 24 hrs)
Hypoalbuminemia (<30g/L)
Oedema
Caused by certain forms of glomerular damage

19. Cases 19

20. Case 1 78yr old male referred re creatinine 772
Hx: malaise, fatigue, low back pain
No meds
Exam: P 90, BP 144/88, unremarkable
Urine dipstick: blood 2+, protein 2+
Creat 772, K 5.1, Ca 1.8, Phos 2.6, alb 35, LDH nl
Hb 7.2, WBC 3.1, platelets 102
Renal US: normal sized kidneys

21. Case 1: Renal Biopsy

22. (acute cast nephropathy)
Diagnosis
Myeloma
(acute cast nephropathy)

23. Causes of AKI in Myeloma
Prerenal
Acute cast nephropathy
ATN [NSAIDs, contrast]
(Amyloid / light chain deposition)
High dose bisphosphonates
Hyperviscosity (rare)

24. Mgt of AKI in (presumed) Myeloma
Severe AKI: medical emergency
Rapid investigation: SPE, UPE, (serum free light chains), bone marrow bx
IV fluids+++
Rapid control of hypercalcemia and other nephrotoxins
Early high dose dexamethasone + other Rx
Plasma exchange: probably little benefit (except hyperviscosity)

25. Case 2
Asked to see 39yr old male for rapidly rising creatinine [90290 over 48hrs] and hyperkalemia
Recent dx of ALL (high grade)
Started chemotherapy 36hrs ago; ‘not nephrotoxic’
Exam: P 100, BP 144/84, lymphadenopathy
Urine dipstick: n/a (anuric)
Creat 290, K 7.1, Ca 1.8, Phos 2.9, urate 968
Renal US: echogenic, normal sized kidneys

26. Diagnosis
Tumor Lysis Syndrome

27. Tumor Lysis Syndrome
Metabolic complications of rapid cancer cell turnover or treatment induced cell lysis
Hyperuricemia, hyperphosphatemia, hypocalcemia, hyperkalemia, AKI
Most cases a/w chemotherapy
Intratubular precipitation of uric acid
Intrarenal precipitation of calcium-phosphate

28. Calcium-phosphate precipitation
TLS
Massive cell lysis
Purines
Phosphate
Potassium
Calcium-phosphate precipitation
Xanthine
Allopurinol --
Uric acid
Arrhythmias
Rasburicase +
Allantoin
AKI
Urinary excretion

29. Tumor Lysis Syndrome: Risk Factors
High tumor burden / rapid cell turnover
Certain leukemias / lymphomas (Burkitt’s)
Dehydration
Pre-existing renal disease

30. Tumor Lysis Syndrome: Prevention
IV fluids+++
Role of urine alkalinization unclear
Aim for urine output >200ml/hr
Allopurinol: high dose
Rasburicase in high risk cases (but costly)

31. Calcium-phosphate precipitation
TLS
Massive cell lysis
Purines
Phosphate
Potassium
Calcium-phosphate precipitation
Xanthine
Allopurinol --
Uric acid
Arrhythmias
Rasburicase +
Allantoin
AKI
Urinary excretion

32. Tumor Lysis Syndrome: Treatment
Medical emergency
Treat hyperkalemia
IV fluids++
Diuretic
Rasburicase
Severe / complicated cases: early aggressive dialysis

33. Case 3
Asked to see 65yr old female with rising creatinine over 4 months (baseline 95)
Diagnosed with myeloma 24m before (IgG kappa; minimal light chains)
Treatment included dexamethasone + bortezomib + pamidronate; no recent NSAIDs
In remission (minimal paraprotein)
Exam: P 80, BP 132/84, 2+ leg edema
Urine dipstick: 4+ protein
Creat 224, Alb 29, Ca 1.62, Phos 1.0, LDH nl

34. Presumed Bisphosphonate Nephrotoxicity
Diagnosis
Presumed Bisphosphonate Nephrotoxicity

35. Bisphosphonate Nephrotoxicity
IV bisphosphonates commonly used in cancer pts
2 renal syndromes reported
a) Nephrotic syndrome
Mainly pamidronate
Collapsing glomerulopathy
Prognosis variable
b) AKI
Mainly zolendronate
ATN
Markowitz et al.J Am Soc Nephrol. 2001: 12(6):

36. Bisphosphonate Nephrotoxicity
Risk Factors
Dose (cumulative)
Infusion rate
Myeloma
Clues to Diagnosis
High cumulative dose
Hypocalcemia

37. Bisphosphonate Nephrotoxicity
Prevention
Dose adjust in CKD
Monitor creatinine before each infusion
Slow infusion
Concomitant N / Saline
Treatment of established case
Stop drug
Supportive

38. Case 4 Asked to see 56yr male with relapsing CNS lymphoma
Recent treatment included dexamethasone + high dose methotrexate (MTX)
Falling urine output despite IV isotonic bicarbonate
Cr 88  244 over 48 hrs; LDH nl
Urine dip: trace blood, trace protein, pH 6.0 38

39. Methotrexate induced AKI
Diagnosis
Methotrexate induced AKI 39

40. Methotrexate induced AKI
High dose IV methotrexate is used to treat leukemias, lymphomas
Mainly renal excretion
AKI due to direct tubular toxicity + intraluminal precipitation (obstruction)
Risk factors: high dose methotrexate, low urine pH, renal dysfunction, hypovolemia, other nephrotoxins 40

41. Methotrexate induced AKI
Acute rise in creatinine soon after infusion
Complications:
Life-threatening myelosuppression
Hepatitis
Severe AKI
Death 41

42. Methotrexate induced AKI
Prevention
Dose adjustment for renal dysfunction
Forced alkaline diuresis
Avoidance of other nephrotoxins.
Folinic acid (leucovorin)
Treatment
Further alkalinization of urine + folinic acid
Glucarpidase (breaks down MTX)
High dose dialysis only partly clears MTX; rebound may occur; ‘buys time’ 42

43. Case 5
30 year old male presents 18 months after kidney transplant with malaise, low grade fevers, weight loss
Had received extra immunosuppression for early rejection
Creatinine 180 [baseline 120], LDH 690
CT: enlarged transplant kidney, lymphadenopathy, abnormal small bowel

45. PTLD: post-transplant lymphoproliferative disease
Diagnosis
PTLD: post-transplant lymphoproliferative disease 45

46. PTLD
Important complication of all forms of solid organ transplantation
Sometimes associated with proliferation of EBV infected cells
Sites of involvement often unusual: transplanted organ, small bowel
Treatment involves stopping immunosuppression, rituximab and /or combination chemotherapy
Prognosis variable 46

47. Incidence of non Hodgkin lymphoma in transplant recipients

48. Case 6
57 year old lady presents in 2009 with severe leg oedema, malaise, fatigue
Urine dipstick: 4+ protein
Creatinine 148, albumin <15, cholesterol 12.9, 24 hr urine protein 15g
Aortic thrombosis with embolization to lower limb

49. Nephrotic Syndrome with Hypercoagulable State
Diagnosis
Nephrotic Syndrome with Hypercoagulable State 49

50. SAP Scan

51. Case 6 Treated with CVD then lenalidomide Excellent response
Diagnosed with AL amyloid
Referred to Royal Free Unit – see scan
Treated with CVD then lenalidomide
Excellent response
Seen in clinic on Wed: remains in complete remission

52. Practical Points 52

53. Preventing AKI
Identify the patient at risk of AKI: pre- existing renal disease, nephrotoxic meds etc.
Adequate hydration!
Minimize NSAIDs
Prophylaxis where there is high risk of TLS, methotrexate nephrotoxcity

54. Dosing of meds for pts with renal dysfunction
Complicated!
Consult specialist literature / pharmacist
In general, drugs that have significant renal excretion will need dose reduction
Various formulas (to estimate renal function) available
If pt on dialysis: usually give the drug after dialysis

55. Anemia in the hematology pt with CKD
CKD will worsen the anemia
Treatment: ESAs (epo)
Iron deficiency is common in CKD pts
Remember to replenish iron stores: keep ferritin > 200 and iron saturation >20%

56. Conclusions Spectrum of cancer-associated AKI is changing
Systematic diagnostic approach still applies: prerenal / intrarenal / postrenal
Careful and thorough Hx is essential
Rapid diagnosis and treatment are important
Close co-operation between nephrology and hematology / oncology is important