Review Reports

Round 1

Reviewer 1 Report

The authors provide a sound overview of AKI post HSCT which is a valuable addition to previous overviews.

I recommend the authors to expand the last paragraph of the manuscript and provide readers with some more tools how to manage post HSCT AKI, when to start which treatment, depending on the cause of AKI and how to manage follow-up (in addition to ACE inhibitor...).

Author Response

We thank the reviewer for his comments and feedback. We expanded the last paragraph to cover the chronic management of CKD:

"

CKD in children post HCT has a reported incidence of 48%. CKD is defined by estimated GFR <90 mL/min/1.73 BSA or presence of markers of kidney damage for > 3 months (64). CKD can develop at 6 months to up to 10 years following transplant. Incidence of CKD in this population is ten-fold higher than in the healthy population. In a cohort of 1635 adult and pediatric HCT patients, CKD developed in 23% (65).

The most common etiologies and risk factors for CKD development are TMA, total body irradiation, nephrotic syndrome, AKI, acute GVHD, and drug toxicity (calcineurin inhibitors) (66).  Estimated GFR at the time of AKI is an important risk factor for the development of CKD. In a cohort of 275 children post allogeneic HCT, CKD developed in 69.5% and 69.8% at 1 and 3 years if GFR was <80 mL/min/1.73 m² at the initial AKI episode (67). Therefore, renal function in these higher-risk children who developed AKI with GFR<80 mL/min/1.73 m² must be monitored closely for early detection of CKD.  Similar to the approach to AKI noted previously, the management of CKD post-HCT requires regular monitoring for long term changes in estimated GFR to identify patients with CKD, followed by preventive strategies that minimize nephrotoxic medication exposure, ensure adequate hydration and nutrition, optimize blood pressure control, and minimize proteinuria.

Albuminuria (albumin-to-creatinine ratio over 30 mg/g) is an important parameter to monitor in children post HCT during long-term follow-up for early recognition of CKD. Albuminuria is relatively common (detected in 50% of patients one-year post-HCT) (68). Furthermore, albuminuria at day 100 was associated with CKD at 1 year (OR=4.0; 95% CI=1.1 to 14.6). Proteinuria at day 100 conveyed a 6-fold increase in the risk of non-relapse mortality by 1 year post HCT. Moreover, hypertension seen in 20-70% of patients post-HCT, can contribute to the development and progression of CKD (69). Close monitoring for the development of hypertension is warranted for children post HCT and should follow similar guidelines for the detection and management of hypertension in children in other settings, including obtaining 24-hour ambulatory blood pressure monitoring when available (70).  Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) can be used to preserve kidney function, control hypertension and to reduce proteinuria (70, 71).  Other antihypertensive medications that can be utilized for optimal control of blood pressure or if ACEi/ARB is not tolerated include long-acting calcium channel blockers and diuretics.  In addition to the initiation of antihypertensive medications, other lifestyle modifications including low sodium diet and increased physical activity should be encouraged to reduce long term risk of hypertension. Target BP goals for patients with CKD should be less than or equal to 50^th percentile for age, sex, and height unless achieving this is limited by symptomatic hypotension (70, 72).    

Additional long-term follow-up for HCT patients with CKD includes monitoring and treatment of other consequences of progressive CKD including electrolyte disturbances, such as metabolic acidosis, anemia of CKD and CKD related bone disease (66).  Consultation with nephrology is recommended for patients with any degree of CKD to coordinate CKD care, and frequency of follow up is then based on the severity of CKD.  These multiple complications of CKD highlight the need for a multidisciplinary approach to post-HCT patients with CKD as these patients may have unique risk factors and needs related to underlying oncologic diagnosis and post HCT course to consider when managing their CKD."

Reviewer 2 Report

The paper by Vinson J describes the main nephrological complications after stem cell transplantation in pediatric patients. The abstract section is concise and readable even for colleagues who are not concerned specifically with stem cell transplantation, the introduction section is enriched with a summary table aimed at renal toxicity after transplantation. The authors subsequently describe SOS, thrombotic microangiopathy along with fluid overload and renal toxicity following CAR-T therapy.  The authors subsequently describe dialysis replacement therapy and biohumoral markers of renal damage.

The overall assessment of the text is for this reviewer positive.

Problems:

1) Authors should describe at least briefly the risk factors to develop these complications such as the type of transplantation and previous renal toxicity 

2) as indicated in Figure 1, drug toxicity and haemorrhagic cystitis are among the most common causes of renal damage that authors should discuss.  

3) renal gvhd should be at least mentioned

Author Response

We thank reviewer for comments and feedback.

1.Authors should describe at least briefly the risk factors to develop these complications such as the type of transplantation and previous renal toxicity.

That was added to the manuscript:"Common risk factors for kidney injury include myeloablative conditioning, older age, acute GVHD, and SOS (Table 1). Satwani et al. observed a significant increase in the incidence of kidney injury in children who received myeloablative conditioning versus reduced intensity conditioning (45.7% and 17.1% respectively) (6). In addition to its contribution to a higher rate of mortality, previous AKI predisposes to chronic kidney disease (CKD). "

2) as indicated in Figure 1, drug toxicity and haemorrhagic cystitis are among the most common causes of renal damage that authors should discuss.

That was added:"

Drug induced nephrotoxicity is relatively common in HCT patients.  Antimicrobials that are often used to treat infections post-HCT such as aminoglycoside, vancomycin, or amphotericin can induce direct kidney injury. Nephrotoxicity is also encountered with calcineurin inhibitors such as cyclosporin or tacrolimus that can cause kidney arteriolar vasoconstriction via activation of the renin-angiotensin-aldosterone system (14). In addition, calcineurin inhibitors may trigger endothelial injury and subsequent TMA (15). Moreover, kidneys can be a target of GVHD, although less described than other organs like skin, liver, and lungs. Kidney injury related to GVHD is mediated by donor T-cells as well as proinflammatory cytokines. Kidney GVHD can present as AKI, nephrotic syndrome, glomerulonephritis, and TMA (16). However, the most common presentation is nephrotic syndrome with a high degree of proteinuria, hypoalbuminemia, and edema.

Hemorrhagic cystitis can cause obstructive kidney injury when clots in the bladder obstruct the outflow tract. The etiology of hemorrhagic cystitis is usually multifactorial, but often encountered with the use of cyclophosphamide or in the context of reactivation of virus infections such as BK virus, adenovirus, and cytomegalovirus.  Treatment include hyperhydration, diuresis, and bladder irrigation with a three-way bladder catheter."

3) renal gvhd should be at least mentioned: was added : "Moreover, kidneys can be a target of GVHD, although less described than other organs like skin, liver, and lungs. Kidney injury related to GVHD is mediated by donor T-cells as well as proinflammatory cytokines. Kidney GVHD can present as AKI, nephrotic syndrome, glomerulonephritis, and TMA (16). However, the most common presentation is nephrotic syndrome with a high degree of proteinuria, hypoalbuminemia, and edema."