Non-infectious complications after bone marrow transplant: other organs toxicity I

Non-infectious complications after bone marrow transplant: other organs toxicity I

What every physician needs to know about complications after bone marrow transplant: organ toxicity I

This section describes and discusses genitourinary system (GUS) complications of bone marrow transplantation (BMT). These complications are very common and caused by various etiology. Herein, we also discuss microangiopathic hemolytic anemia (thrombotic microangiopathy [TMA]), a life-threatening complication, because kidneys are involved frequently in many patients with TMA. Therefore physicians seeing patients with kidney dysfunction after BMT can consider the serious complication in differential diagnosis.Differential diagnosis of GUS complications and thus their appropriate management is critical after BMT. Early and late GUS complications of BMT are different to each other. Knowing the phase of occurrence of these complications of BMT will be helpful in differential diagnosis. Therefore, we have provided common GUS complications and the phases they frequently occur post-transplantation below.

Definition and grade

Kidney complications

Kidney complications (KC) have received more attention over the last decade. Kidney complications can be acute or chronic after hematopoietic stem cell transplantation (HCT).

• Early post-transplant

– Infections, tumor lysis syndrome, veno-occlusive disease (VOD) leading to hepatorenal syndrome (HRS), transplant associated thrombotic microangiopathy (TMA), amphotericin or other drug toxicity, and acute kidney injury/acute tubular necrosis, conditioning regimen toxicity (total body irradiation [TBI], melphalan, high dose cyclophosphamide), calcineurin inhibitors (elevated creatinine is readily reversible with dose adjustments).

• Late post-transplant

– Ongoing TMA, nephrotic syndrome, graft-versus-host disease (GVHD) and volume depletion, calcineurin inhibitor or other drug toxicity, older age, AKI episodes, and radiation nephritis. The burden of chronic kidney disease (CKD) may be significant (e.g., up to 34% over 10 years).

Acute kidney injury (AKI) grading

• Grade 0 (or normal renal function): A decrease in estimated glomerula filtration rate (eGFR) of less than 25% from pre-transplant baseline

• Grade 1: A maximum of a 2 fold rise in serum creatinine, with a decrease in eGFR of greater than 25% of pre-HCT

• Grade 2: A greater than 2 fold rise in serum creatinine, without need for dialysis

• Grade 3: Grade 2 parameters, plus dialysis requirement

Transplant-associated thrombotic microangiopathy Transplant-associated thrombotic microangiopathy has several somewhat differing published definitions as shown below.International Working Group defined TMA as: Increased percentage (greater than 4%) of schistocytes in the blood:

• De novo, prolonged, or progressive thrombocytopenia (less than 50 x 10⁹/L or recent 50% decrease)

• A sudden and persistent increase in serum lactate dehydrogenase (LDH)

• A decrease in hemoglobin (Hgb) or increased red blood cell (RBC) transfusion requirement

• Decreased serum haptoglobin

Notably not including renal dysfunction. TMA is defined by the Blood and Marrow Transplant Clinical Trials Network Toxicity Committee as:

• RBC fragmentation and at least two schistocytes per high power field

• Concurrent increased serum LDH

• Concurrent renal dysfunction (doubling of serum creatinine from baseline or 50% decrease in creatinine clearance from baseline) and/or neurological dysfunction without other explanations

• Negative direct and indirect Coombs test

Hemorrhagic cystitis

Hemorrhagic cystitis (HC) can occur early or late after HCT.Early onset HC occurs during or soon after conditioning. The most common causative agent is cyclophosphamide. Acrolein, a metabolic by product of cyclophosphamide, induces HC by cross-linking epithelial proteins, early post transplant, starting within 72 hours of conditioning.Late onset HC: Although the relationship remains unclear, HC is associated with viruses (for example, BK virus, adenovirus, JC virus, Cytomegalovirus [CMV]). Asymptomatic BK viruria has been reported in 5 to 60% of healthy people and 50 to 100% of patients after HCT. Reactivation of BK virus can lead to hematuria, dysuria, nephritis, renal insufficiency, and HC. Umbilical cord blood transplantation is associated with higher rates of HC. Patients with HC have more often acute graft-versus host disease, fever, and steroids therapy.

Grading of HC:

• Grade 1: microscopic hematuria

• Grade 2: macroscopic hematuria

• Grade 3: hematuria with clots

• Grade 4: macroscopic hematuria with clots and impaired renal function, secondary to urinary tract obstruction

Onset and incidence of KC

AKI after myeloablative (MA) conditioning most often occurs early, between days +7 and +40. Patients with VOD of the liver can develop AKI even earlier, due to intravascular volume depletion, somewhat resembling the HRS. AKI is reported in 30-70% of MA allo-HCT.AKI after reduced intensity conditioning (RIC) can occur later (+20-60 days) similar to other complications, including acute GVHD, and infections, supporting the inference that GVHD, infections and their treatment may result in kidney injury. The incidence is reported as 20 to 50%, mostly in the first 100 days.The need for dialysis is higher after MA (12%) compared to RIC (3%).

Although the early incidence of AKI after MA is higher, after RIC, the cumulative incidence of AKI increases with time (to approximately 50% at 1 year).

The 3 year cumulative incidence of chronic kidney disease (CKD) was similar following MA and RIC allo-HCT (28% versus 29%).

AKI after Auto-HCT: Severe (grade 2 to 3) AKI was reported in 12-20% after auto-HCT.

Polyoma virus nephropathy affects up to 8% of renal transplant patients. Its incidence after HCT may also be frequent.

Thrombotic microangiopathy

Its incidence is reported between 2 and 70% because there is no consensus on its diagnosis. A recent effort to validate both proposed diagnostic criteria found major pitfalls. Although TMA can occur anytime post-transplant, its incidence peaks between days 20 and 100. TMA incidence is similar after RIC (around 10%). A retrospective analysis found 1 year cumulative incidence rates of TMA of 15% and 13% in MA and RIC, respectively. It is rare after auto-HCT.

Hemorrhagic cystitis

BK viruria is similar in allogeneic (range 46-53%) and autologous (range 39-54%) HCT recipients.

Late onset BK-virus-associated HC was reported in 7-40% of HCT recipients.

What features of the presentation will guide me toward possible causes and next treatment steps:

KC: High level proteinuria (e.g., nephrotic syndrome) may present with significant lower extremity edema, periorbital edema or nocturia/polyuria. Patients with nephritis or drug associated renal problems may have hypertension.

Bleeding tendency, jaundice, hepatomegaly, ascites, oliguria, hypotension, or even encephalopathy may indicate hepatic dysfunction and/or VOD.

Neurologic signs and symptoms, bruising or petechiae may suggest TMA.

Gross hematuria with significant dysuria and urinary frequency/urgency suggests HC or urinary tract infection. Asymptomatic microscopic hematuria mostly represents kidney complications such as immunoglobulin A (IgA) nephropathy or TMA.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count with differential

Anemia can be associated with increased red cell distribution width (RDW) (anisocytosis) or macrocytosis (from hemolysis with increased RBC production [reticulocytosis]). Thrombocytopenia may indicate TMA. Reticulocytosis can occur only if post-HCT marrow recovery is robust. Eosinophilia can occur with chronic GVHD.

Comprehensive metabolic panel

Low albumin in nephrotic syndrome, electrolyte abnormalities (for example, hyperphosphatemia, hyperkalemia, hypocalcemia) and high uric acid levels will suggest tumor lysis syndrome.

LDH and haptoglobulin

Increased LDH and decreased haptoglobulin suggest active hemolysis as in TMA, unless tested following frequent RBC transfusions. However, LDH is not RBC specific and haptoglobulin can be low in severe liver dysfunction. Exclude autoimmune or ABO-incompatible alloimmune related hemolysis (Direct Coombs test, presence of recipient antibody against donor RBC antigens.

Coagulations tests

Prolonged prothrombin time indicates liver dysfunction and/or vitamin K deficiency. Nephrotic syndrome can result in urinary loss of clotting and anti-thrombotic factors.

Urinalysis and urine sediment

Proteinuria is the most common abnormality. Heavy proteinuria and RBC casts suggest glomerular disease (with hepatitis C or hepatitis B ). Numerous granular casts suggest ischemic or nephrotoxic acute tubular necrosis. Tubular cell and/or white blood count casts suggest acute interstitial nephritis.

Twenty four hour urine

Twenty four hour urine for total protein, creatinine, and urine protein electrophoresis. Membranous glomerulonephritis (MGN), Minimal Change Disease, and amyloidosis can cause severe proteinuria.

Diagnostic or therapeutic paracenteses

Diagnostic or therapeutic paracenteses may be needed in patients with VOD and significant ascites (to exclude infections or post-transplant lymphoproliferative disorder (PTLD).

Echocardiogram

To exclude cardiac failure as a pre-renal cause of AKI.

Measuring a disintegrin and metelloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) or von Willebrand factor

vWF antigen (Ag) does not help to diagnose post-HCT acquired TMA. ADAMTS13 levels are typically normal in transplant associated microangiopathy.

BK virus and adenovirus in the urine and blood

Note that asymptomatic BK viruria is common. A few studies suggested that HC may be more common if BK virus is greater than 10⁶ copies/ml in urine, or greater than 10⁴ copies/ml in plasma. This remains to be confirmed.

What conditions can underlie non-infectious complications after bone marrow transplant: other organs toxicity I:

Risk factors

For KC

• Pretransplant: Extensive prior chemotherapy or previous HCT may increase risks for VOD. Pre-HCT renal disease may increase risks for subsequent renal insufficiency.

• Membranous glomerulonephritis and IgA nephropathy can rarely be associated with chronic GVHD.

• Drugs: Amphotericin B, intravenous (IV) voriconazole, high dose methotrexate, cyclosporine, or tacrolimus.

• Hepatitis C or B virus: Hepatitis viruses are associated with membranoproliferative glomerulonephritis (MPGN).

For TMA

• Immunosuppression: Calcineurin inhibitors (cyclosporin, tacrolimus), particularly when combined with sirolimus. Radiation nephritis may induce TMA. Proteinuria, high LDH and persistent hypertension might be a sign of TMA.

For HC

• Extensive prior therapy with cyclophosphamide or ifosfamide may increase risks of HC.

• Viral infections (BK viremia and viruria, JC virus, CMV, adenovirus).

Differential diagnosis

TMA

Rule out other causes of hemolysis (drugs, ABO incompatibility, infections), sepsis, disseminated intravascular coagulation (DIC).

MGN

Although MGN can be associated with chronic GVHD, other causes of secondary membranous nephropathy can include viral infections, drugs, and collagen vascular diseases.

HRS

Major diagnostic criteria include chronic or acute liver disease with advanced hepatic failure and portal hypertension, in absence of shock, ongoing bacterial infection or nephrotoxic drugs, corrected gastrointestinal or other fluid losses, no sustained improvement in renal function following diuretic withdrawal, and expansion of plasma volume with infused isotonic saline, proteinuria less than 0.5g/d, and no ultrasound evidence of obstructive uropathy or parenchymal renal disease.

When do you need to get more aggressive tests:

Histopathology

Renal biopsies are rarely done post HCT, but the most common histopathological findings are MGN and thrombotic microangiopathy (TMA). Others may include immune-complex mediated (MGN, IgA nephropathy, MGPN), non–immune complex mediated glomerular injuries in HCT (minimal change disease, focal segmental glomerulosclerosis, and pauci-immune crescentic glomerulonephritis, chronic calcineurin toxicity Polyoma BK virus nephropathy, hypertension related changes, and acute tubular nephrosis.

What imaging studies (if any) will be helpful?

Abdominal ultrasound (US): Useful to exclude obstructive nephropathy (in patients with history of kidney stones or active hemorrhagic cystitis that may cause clot formation and ureteral obstruction); enlarged kidneys may be seen with diabetic nephropathy or amyloidosis; small/atrophic kidneys with hypertensive nephropathy or other parenchymal renal disease.

Non-contrast computed tomography (CT) scan may reveal kidney stones.

Hepatic US with Doppler may help diagnose VOD.

Cystoscopic examination may be needed to exclude urinary tract abnormalities, such as bladder mucosal lesions or cancer.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

TMA

Plasma exchange is generally ineffective. Withdrawal of calcineurin inhibitors and other nephrotoxic medications is essential. Sirolimus can augment risks of TMA when given along with cyclosporin A (CSA) or tacrolimus, particularly with busulfan conditioning. Sirolimus is not associated with TMA when given alone. Complement inhibitors (e.g., eculizumab) are actively investigated in TMA, but their efficacy in post-transplant TMA is uncertain. Their cost is high.

VOD and renal insufficiency (HRS)

Careful monitoring of fluid balance, blood chemistries and urine output are needed. Albumin infusions may be useful. Fluid restriction of 1L per day is recommended in dilutional hyponatremia. The use of diuretics in HRS must be cautious to avoid worsening intravascular volume depletion.

HC

All the following have been used, with variable success:

• Bladder irrigation

– All patients are treated with IV fluids to increase urine output, thus “irrigate”, and therefore debride the inflamed bladder mucosa. Local aggressive bladder irrigations with a large-bore (triple lumen) bladder catheter is needed if clots or urinary urgency and spasms are obstructing bladder outflow.

• Supportive measurement

– Pain control with narcotic drugs and/or urinary tract spasmolytics such as phenazopyridine and oxybutynin. Correcting coagulation abnormalities and keep platelet counts greater than 50 x 10⁹/L.

• Antimicrobial treatment

– Ciprofloxacin may reduce BK virus replication and reactivation.

– Cidofovir is the most common antiviral drug used for BK virus and is also effective for adenovirus (ribavirin is another antiviral agent for adenovirus induced HC or tubular nephropathy), but can itself be nephrotoxic. Concurrent use of probenecid and hydration decrease nephrotoxicity. Intravesical cidofovir has also been used.

• Other agents (published as case series)

– Systemic treatments: ε-amino caproic acid (Amicar) to antagonize urinary tract urokinase induced fibrinolysis. It may be contraindicated if bleeding is from upper urinary system, as it may induce ureteral clotting and obstruction. Estrogen for anti-inflammatory action.

– Intravesical: Prostaglandin E2 or F (to increase platelet function and to improve bladder muscle function), ε-amino caproic acid, silver nitrate or alum for chemical cautery, vitamin E, and sodium hyaluronate have been used.

What other therapies are helpful for reducing complications?

Hemorrhagic cystitis (HC)

Mesna and hyperhydration during high dose cyclophosphamide regimens are well established preventive measures.

What should you tell the patient and the family about prognosis?

AKI was found to be a poor prognostic risk factor for survival. Mortality is two to three times higher in patients with AKI, compared with patients without renal failure. Patients requiring dialysis have a high mortality rate (up to 80%).

TMA has a poor outcome with a mortality rate of 60-90%. Defibrotide seems to be effective in patients with VOD and renal insufficiency, but is more successful if early VOD and no secondary organ dysfunction has occurred.

Although HC affects quality of life in most patients, only severe HC affects survival.

“What if” scenarios.

In severe cases, the following could apply:

VOD-HRS

Transjugular intrahepatic portosystemic shunt (TIPS) or even rare cases of liver transplantation have been reported.

HC

Hyperbaric oxygen therapy, selective embolization of vesical arteries, and cystectomy in patients with intractable life threatening HC have been tried.

Pathophysiology

Pathogenesis

TMA most likely results from multifactorial endothelial damage. Inciting agents include calcineurin inhibitors, chemotherapy, GVHD, and/or TBI. ADAMTS13 levels are not low in post-HCT TMA. Increases in inflammatory cytokines and some coagulation proteins (thrombomodulin, plasminogen activator inhibitor-1 [PAI-1], soluble intercellular adhesion molecule-1, interleukin-1 [IL-1], interleukin-8 [IL-8], tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma, and IL-8) have been reported.

Recent studies suggested that alternative pathway of complement in children with hematopoietic stem cell transplant-associated TMA (thrombotic microangiopathy). High prevalence of deletions in complement factor H (CFH)-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies are detected.

MGN is associated with dysregulated immune responses with glomerular immune complexes, and an association with chronic GVHD.

HC: Alkylator (cyclophosphamide, ifosfamide catabolite acrolein) or radiation damage to urinary epithelium can cause HC. It might be worsened by BK, JC, CMV or adenoviral infection; thus, any conditioning regimen that results in profound immunosuppression can lead to HC.

What’s the evidence?

Worel, N, Greinix, HT, Leitner, G. “ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: close association with transplant-associated microangiopathy”. Transfus Apher Sci. vol. 36. 2007. pp. 297-30. (Describes TMA after RIC HCT.)

Kersting, S, Koomans, HA, Hené, RJ, Verdonck, L. “Acute renal failure after allogeneic myeloablative stem cell transplantation: retrospective analysis of incidence, risk factors and survival”. Bone Marrow Transplant. vol. 39. 2007. pp. 359-65. (Demonstrates incidence and risk factors for AKI after MA HCT.)

Kagoya, Y, Kataoka, K, Nannya, Y, Kurokawa, M. “Pretransplant predictors and post transplant sequels of acute kidney injury after allogeneic stem cell transplantation”. Biol Blood Marrow Transplant. vol. 17. 2011. pp. 394-400. (Describes risk factor of AKI after allo-HCT.)

Lopes, JA, Jorge, S. “Acute kidney injury following HCT: incidence, risk factors and outcome”. Bone Marrow Transplant. vol. 46. 2011. pp. 1399-1408. (Excellent review on kidney injury after allo-HCT.)

Lopes, JA, Gonçalves, S, Jorge, S. “Contemporary analysis of the influence of acute kidney injury after reduced intensity conditioning haematopoietic cell transplantation on long-term survival”. Bone Marrow Transplant. vol. 42. 2008. pp. 619-26. (Demonstrates that AKI is associated with poor overall survival after RIC.)

Ruutu, T, Barosi, G, Benjamin, RJ. “Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: Results of a consensus process by an International Working Group”. Haematologica.. vol. 92. 2007. pp. 95-100. (Proposes diagnostic criteria for TMA.)

Cho, BS, Yahng, SA, Lee, SE. “Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation”. Transplantation. vol. 27;90. 2010. pp. 918-26. (Validation trial for both proposed diagnosis criteria of TMA post transplant.)

Dropulic, LK, Jones, RJ. “Polyomavirus BK infection in blood and marrow transplant recipients”. Bone Marrow Transplant. vol. 41. 2008. pp. 11-8. (Reviews the role of HC virus in HC post transplant.)

Chan, GS, Lam, MF, Au, WY. “Clinicopathologic analysis of renal biopsies after haematopoietic stem cell transplantation”. Nephrology. vol. 13. 2008. pp. 322-30. (This journal describes histopathological findings in patients with renal dysfunction after allogeneic hematopoietic cell transplantation.)

Reddy, P, Johnson, K, Uberti, JP. “Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation”. Bone Marrow Transplant. vol. 38. 2006. pp. 351-7. (Demonstrates association of chronic GVHD and MGN.)

Peyvandi, F, Siboni, SM, Lambertenghi Deliliers, D. “Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation”. Br J Haematol. vol. 134. 2006. pp. 187-95. (Demonstrates that ADAMTS13 or von Willebrand factor measurement are not useful to predict or diagnose TMA post transplant.)

Srinivasan, R, Balow, JE, Sabnis, S. “Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation”. Br J Haematol. vol. 131. 2005. pp. 74-9. (Describes MGN is the most common cause of nephrotic syndrome and progress despite immunosuppressive therapy.)

Megged, O, Stein, J, Ben-Meir, D. “BK-virus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation”. J Pediatric Hematol Oncol. vol. 33. 2011. pp. 190-193. (Demonstrates the incidence and outcome of BK virus in HC after HCT in pediatric population.)

Piñana, JL, Valcárcel, D, Martino, R. “Study of kidney function impairment after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. A single-center experience”. Biol Blood Marrow Transplant. vol. 15. 2009. pp. 21-9. (Demonstrates the risk factors for and incidence of developing AKI after RIC.)

Jodele, S, Licht, C, Goebel, J. “Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy”. Blood. vol. 122. 2013. pp. 2003-2007. (Demonstrates abnormalities in alternative complement system in TA-TMA.)

Shimoi, T, Ando, M, Munakata, W. “The significant impact of acute kidney injury on CKD in patients who survived over 10 years after myeloablative allogeneic SCT”. Bone marrow transplantation. vol. 4891. 2013. pp. 80-84. (Demonstrates CKD can be very frequent in survivors.)

Lunde, LE, Dasaraju, S, Cao, Q. “Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival”. Bone marrow transplantation. vol. 50. 2015. pp. 1432-1437. (Demonstrates umbilical cord blood transplantation is a risk factor and only patients with severe HC have inferior survival.)

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