Diagnosis and Management of Kidney Injury Following HSCT Refined

Sangeeta R. Hingorani, MD, MPH

Kidney complications often occur following successful hematopoietic stem cell transplantation (HSCT) from a myriad of underlying etiologies, according to up-to-date information provided during an educational session at the 2019 European Society for Blood and Marrow Transplantation Annual Meeting.

Sangeeta R. Hingorani, MD, MPH, professor of pediatrics at the University of Washington, and director of Nephrology at Seattle Children’s Hospital, charted the course of kidney injury from the toxic lesion to transplant-associated thrombotic microangiopathy (TA-TMA).

She began her discussion of kidney injury with a case study of a 25-year-old man who gained 8 kg between days +3 to +7 following myeloablative allogeneic HSCT for acute myeloid leukemia (AML). Day +7 saw a bilirubin rise to 2.1 mg/dL, which continued to rise. The patient showed jaundice and had right upper quadrant tenderness plus ascites. An ultrasound of the liver showed reversal of flow; however, urinalysis was negative but creatinine had doubled from baseline.

“We’re concerned about sinusoidal obstruction syndrome (SOS), acute kidney injury (AKI), and volume overload,” she said, while asking the audience to give their diagnosis, which turned out to be AKI.

According to Hingorani, the incidence of AKI varies from 6% in autologous transplants to 79% in patients admitted to ICU. The time of onset also shows extreme variance from day +1 to days +60 through +100. AKI. AKI is characterized by 3 stages, which are defined by creatinine 1.5 to 1.9 times baseline, (stage I), creatinine 2.0 to 2.9 times baseline (stage II), and by creatinine 3.0 or ≥4.0 mg/dL or renal replacement therapy (RRT; stage III). Chronic kidney disease has 5 stages and is determined using different criteria, including glomerular filtration rate (GFR) ≥90 mL/min/1.73 m² (stage I), GFR 60 to 89 mL/min/1.73 m² (stage II), GFR 30 to 59 mL/min/1.73 m² (stage III), GFR 15 to 29 mL/min/1.73 m² (stage IV), and GFR <15 mL/min/1.73 m² or dialysis (stage V).

The diagnosis workup for AKI includes urinalysis, renal ultrasound assessment with Doppler, detection of lactate dehydrogenase (LDH) and haptoglobin, as well as checking the serum levels of medication.

“The presence of graft-versus-host disease, SOS, sepsis, and viral infections must also be considered,” said Hingorani.

The mechanisms that contribute to AKI include intravascular volume depletion, which often arises from vomiting and diarrhea occurring in acute graft-versus-host disease (GVHD), systemic vasodilation associated with sepsis, renal vasoconstriction resulting from SOS or CNIs, and interstitial injury due to viral infections. Calcineurin-inhibitor (CNI)-related toxicities, as well as acute GVHD, total body irradiation (TBI), and TMA, may also affect the kidney by causing endothelial injury. Conditioning chemotherapy and medications such as amphotericin and vancomycin may cause tubular injury leading to AKI.

Survival following allogeneic HSCT has been shown to be decreased by the presence of AKI compared with no AKI, and kidney failure has been reported to decrease cumulative survival by approximately 55%.¹

New toxicity criteria for fluid overload were established in a retrospective study that was conducted in patients undergoing HSCT at a single center in Texas; of these, 145 patients were in the study cohort and the validation cohort contained 449 patients.² Fluid overload status was collected during rounds through time points from the date of admission to resolution or discharge. The primary study endpoints were non-relapse survival (NRS) and overall survival (OS). Based on the toxicity criteria listed below, cumulative NRM was significantly increased (P = .001) and OS was decreased (P = .001) in patients with a fluid overload score ≥2 compared with those with a score <2. In the validation cohorts, similar rates of increased NRM (P&thinsp;<.01) and decreased OS were observed (P&thinsp;<.001).

Toxicity criteria for determination of the 4 grades of fluid overload include:

• Grade 1: Weight gain <10% from baseline,
• Grade 2: Symptomatic, with weight gain ≥10% to <20% from baseline
• Grade 3: Weight gain ≥20% from baseline and organ dysfunction,
• Grade 4: Progression dysfunction of >1 organ system or requiring intensive care.

Once fluid overload is determined, the patient is managed by administering diuretics, consulting nephrology and, potentially, early initiation of renal replacement therapy (RRT). Fluid overload >10% and further nephrotoxins should be avoided, said Hingorani.

Regarding TA-TMA, which is a major cause of transplant-associated kidney injury, the incidence of TA-TMA depends largely upon the diagnostic criteria used and was established as 0.5% to 76% in older reports, according to Hingorani who added that newer studies show larger studies of 10% to 39%. TA-TMA is more common in hematopoietic stem cell transplants.³

The clinical and laboratory parameters that define TA-TMA include anemia with red blood cell count fragmentation and the presence of >2 schistocytes per field, thrombocytopenia, elevated LDH, negative Coombs test (direct and indirect), elevated serum creatinine >50% of baseline, neurologic involvement, proteinuria, and hypertension. Acute and refractory GVHD account for 46.52% of the conditions preceding TA-TMA, with systemic infection (20.47%), idiopathic/drug (12.0%), disease recurrence (10.7%), and alveolar hemorrhage (10.23%) making up the remaining conditions that contribute to TA-TMA development.

Risk factors for TA-TMA include preclinical parameters, such as receipt of a prior autologous or allogeneic transplant (HR, 2.24), myeloablative regimen (HR, 2.21), and a mismatched donor (HR, 2.13). Post-transplant risk factors are alveolar hemorrhage (HR, 7.28), acute GVHD (HR, 4.73), BK virus (HR, 2.67), invasive aspergillosis (HR, 2.23; all P <.001) and bacteremia (HR, 1.52; P = .010). These risk factors were established in a single-center retrospective study of 2145 transplant patients, wherein TA-TMA was detected in 192 patients.⁴

Hingorani continued with a discussion of the individual risk factors for TA-TMA. Specifically regarding the risk factor of acute GVHD, Hingorani said that TA-TMA develops at a median of 39 days after diagnosis of GVHD and risk varies dramatically, according to GVHD clinical grade and the organ involved. For example, regarding the risk of TA-TMA and GVHD grade, the risk associated with grade 2 GVHD was a hazard ratio of 2.65 (P <.01), grade 3 (HR, 9.54; P <.01), and grade 4 (HR, 26.74; P <.01), whereas, the risk of developing TA-TMA associated with acute GCHD of the skin was a hazard ratio of 1.23 (P = .21), liver (HR, 2.93; P <.01), and gut (HR, 13.26; P ≤.01).

The risk of developing TA-TMA following transplant also varies with the class of immunosuppressants used as GVHD prophylaxis at baseline from the lowest with tacrolimus, HR_adjusted 1, cyclosporine, HR_adjusted of 1.44 (95% CI, 0.97-2.15), cyclophosphamide HR_adjusted of 1.51 (95% CI, 0.47-4.88), to sirolimus plus CNI, HR_adjusted of 1.59 (95% CI, 0.82-3.07).

She stressed the importance of monitoring the immunosuppressant blood levels, as both an increase in trough level over the prior 7-day average and the time the trough level is elevated contribute to higher risk of TA-TMA. The greatest risk is associated with elevated sirolimus levels; every 1 ng/mL over the previous 7-day average (HR, 1.44; 95% CI, 1.16-1.79; P = .001), and discrete time above trough >10 ng/mL (HR, 3.23; 95% CI, 0.62-16.80; P = .164).

Complement activation has been described as a leading factor in the pathophysiology of TA-TMA,⁵ and a recent study has indicated that there may be a genetic component involving a gene in the complement pathway in pediatric patients.⁶

Laboratory evaluation of TA-TMA begins with a complete blood count, and detection of markers of non-immune hemolysis (LDH, haptoglobin, negative Coombs test, and ADAMTS13), and markers of normal coagulation (normal partial thromboplastin time/prothrombin time), and urinalysis for albuminuria. Markers of complement activation must be looked for, including increased sC5b5-9 and decreased CH50/AH50.

Moreover, Hingorani stressed the importance of biopsying the affected organ and suggested following the procedure established by prior data.⁷

The survival of patients following diagnosis of TA-TMA varies according to the underlying etiology, from idiopathic drug affecting survival the least, with survival lower following acute GVHD, and systemic infection decreasing survival and with the poorest survival observed in patients with a underlying etiology of alveolar hemorrhage.⁸

Therapeutic interventions for TA-TMA include:

• Immunosuppressant withdrawal,
• Therapeutic plasma exchange,
• Treatment with rituximab (Rituxan) or eculizumab (Soliris),
• Defibrotide,
• OMS721,
• Supportive care.

Hingorani proposed that TA-TMA should be managed by first considering a biopsy of the affected organ to confirm diagnosis, and rule out disease relapse or disseminated intravascular coagulation. Then, aggressive treatment of the underlying GVHD should be initiated. Over the course of treatment, nephrotoxic drug exposure should be reduced and hypertension should be managed. Dose adjustment must be made of immunosupressants to achieve target levels to preserve kidney function while maintaining a therapeutic index.

For optimal management of TMA-associated AKI, she advised using fluids judiciously to avoid volume overload >10%, not stopping CNI reflexively, and considering early initiation of RRT and confirming the TA-TMA diagnosis by biopsy.

“When in doubt, call [the] nephrology [department],” she concluded, while stressing the need for co-operation between compartments and colleagues being an active component of TA-TMA management.

References

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