Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function

Sindhura Lakshmi Koulmane Laxminarayana; Shreya Jayaram; Shilna Muttickal Swaminathan; Ravindra Prabhu Attur; Dharshan Rangaswamy; Indu Ramachandra Rao; Mohan V Bhojaraja; Srinivas Vinayak Shenoy; Shankar Prasad Nagaraju

doi:10.12688/f1000research.144124.2

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Research Article

Revised

Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function

[version 2; peer review: 2 approved]

Sindhura Lakshmi Koulmane Laxminarayana¹, Shreya Jayaram², Shilna Muttickal Swaminathan², [...] Ravindra Prabhu Attur², Dharshan Rangaswamy², Indu Ramachandra Rao², Mohan V Bhojaraja², Srinivas Vinayak Shenoy², Shankar Prasad Nagaraju ²

Sindhura Lakshmi Koulmane Laxminarayana¹, Shreya Jayaram², [...] Shilna Muttickal Swaminathan², Ravindra Prabhu Attur², Dharshan Rangaswamy², Indu Ramachandra Rao², Mohan V Bhojaraja², Srinivas Vinayak Shenoy², Shankar Prasad Nagaraju ²

PUBLISHED 26 Sep 2024

Author details Author details

¹ Department of Pathology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education,, Manipal, Karnataka, 576104, India
² Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

Sindhura Lakshmi Koulmane Laxminarayana
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Shreya Jayaram
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Shilna Muttickal Swaminathan
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Ravindra Prabhu Attur
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Validation, Visualization, Writing – Review & Editing

Dharshan Rangaswamy
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Review & Editing

Indu Ramachandra Rao
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation

Mohan V Bhojaraja
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Review & Editing

Srinivas Vinayak Shenoy
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation

Shankar Prasad Nagaraju
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Manipal Academy of Higher Education gateway.

Abstract

Background

Haematological abnormalities following renal transplantation are frequently observed and have a significant effect on survival and graft outcomes. The pattern of haematological abnormalities varies globally. Few studies have been conducted in Asian countries. We aimed to evaluate the patterns of haematological abnormalities in post-transplant recipients in our center during the first year after post-renal transplant and the association of post-transplant anemia with graft function.

Methods

This single-center retrospective study was conducted on renal transplantation recipients between 2014 and 2019. The study included all patients who received kidney transplants from live/cadaveric donors and had follow-up data collected up to 12 months after the transplant. The outcome studied was the prevalence of haematological abnormalities and the association between post-transplant anemia (PTA) and graft function in post-transplant recipients.

Results

A total of 106 renal transplant recipients were included in the study. The prevalence of PTA was 98% in the first week, 75% at one month, 35% at three months, 32% at six months, and 27% at 12 months. The other cytopenia cases were leukopenia (43.4%), thrombocytopenia (33.2%), and pancytopenia (15.1%). Post-transplant erythrocytosis was observed in 17.9% of patients. 18 patients with severe PTA in the first week of transplant had significant allograft dysfunction (p=0.04). Patients with and without PTA had similar graft functions at six and 12 months (p=0.50).

Conclusions

Haematological abnormalities are common in renal transplant recipients. PTA is highly prevalent during the first week and improves over time. Other haematological abnormalities observed were leukopenia, thrombocytopenia, pancytopenia, and post-transplant erythrocytosis. Leucopenia was primarily drug-induced, and thrombocytopenia and pancytopenia were frequently caused by infections in our cohort. Additionally, severe PTA was significantly associated with graft dysfunction in the first week post-transplant, whereas similar graft function was observed at 6 and 12 months post-transplant, irrespective of the presence or absence of PTA.

Keywords

chronic kidney disease, renal transplantation, post-transplant anemia, renal allograft rejection, post-transplant infections

Corresponding author: Shankar Prasad Nagaraju

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Laxminarayana SLK et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Laxminarayana SLK, Jayaram S, Swaminathan SM et al. Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function [version 2; peer review: 2 approved]. F1000Research 2024, 13:241 (https://doi.org/10.12688/f1000research.144124.2) First published: 02 Apr 2024, 13:241 (https://doi.org/10.12688/f1000research.144124.1) Latest published: 26 Sep 2024, 13:241 (https://doi.org/10.12688/f1000research.144124.2)

Revised Amendments from Version 1

In response to the reviewer’s suggestion, we have revised the manuscript by stratifying the severity of PTA in Table 3, and included details on the requirement for G-CSF treatment for neutropenia, as well as the presence or absence of leukopenia and thrombocytopenia at specific time points. We have also provided treatment details for Valganciclovir, trimethoprim/sulfamethoxazole, and the initial dose of mycophenolate. Figure 3 has also been modified to include the proportion of cases.

See the authors' detailed response to the review by Abraham Cohen-Bucay
See the authors' detailed response to the review by Dr Sonia Sharma

Introduction

Chronic kidney disease (CKD) is recognized as a significant cause of morbidity and mortality and globally around 843.6 million individuals are affected by this condition¹ End-stage kidney disease (ESKD) is a growing global health concern and has a substantial impact on the quality of life²; renal transplantation represents the ultimate treatment modality for patients with stage 5 CKD or ESKD³; however, renal transplantation improves the quality of life and is susceptible to various post-transplant complications such as metabolic disturbances, life-threatening infections, malignancy, and haematological disturbances. Haematological abnormalities are frequently observed in renal transplant recipients and can lead to severe complications in transplant recipients if not recognized early. Common post-transplant blood disorders include post-transplant anemia (PTA), post-transplant cytopenia (PTC), including leukopenia, thrombocytopenia, pancytopenia, post-transplant lymphoproliferative disorder (PTLD), and post-transplant erythrocytosis (PTE).⁴^,⁵ A better understanding of the prevalence and etiology of haematological abnormalities may help effectively address and mitigate these complications in our day-to-day practice.

Anemia is a frequently observed complication in CKD patients, and its prevalence is higher in renal transplant patients and varies with time after transplantation.⁶ Earlier studies have shown that in post-renal transplantation, there is a biphasic pattern of anemia, and the incidence rate is higher, about 76% at the time of transplantation, 21% in 1^st year, and 36% in the 4^th year of transplantation.⁷ Several factors are linked to PTA, such as infection, iron deficiency, declining renal function, recurrent transplantation, and administration of immunosuppressive medications. Furthermore, long-term follow-up studies (nearly 4 years) have demonstrated that baseline anemia serves as an effective predictor of mortality and graft failure in kidney transplant recipients, and anemia can be considered as an important risk factor for graft rejection/dysfunction in these patients.⁶^,⁸

Other common haematological abnormalities, such as leukopenia, thrombocytopenia, and pancytopenia, change with the type of induction agent, maintenance immunosuppressive drug, and dose used, which varies across centers. Over the past few decades, the implementation of CMV prophylaxis has led to a reduction in both its prevalence and associated haematological abnormalities. The estimated incidence of leukopenia in kidney transplant patients ranges from 10–55%.⁹ There is also a high rate of thrombocytopenia following renal transplantation in the first year, with the majority of recipients experiencing the lowest platelet counts within the first three months after the transplant¹⁰ which causes an oxygen deficit and immune system dysfunction that have a broad impact on the body.¹¹ Post-transplant erythrocytosis is usually observed in 10–15% of patients¹² and is typically evident within the first year of transplant. These haematological abnormalities can indicate various underlying causes, leading to a therapeutic dilemma in determining the most appropriate course of treatment. Against this backdrop, the present study aimed to evaluate haematological abnormalities in post-renal transplant patients. Additionally, we studied the association between the first week post-transplant severe anemia and graft dysfunction, and compared graft function at both early (6 months) and late (12 months) post-transplant anemia.

Methods

Study design

This retrospective single-center observational study included 106 renal transplant recipients who underwent kidney transplantation at Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Inclusion criteria

The study included all patients who underwent kidney transplants from live/cadaveric donors between January 2014 and December 2019 (Figure 1).

Figure 1. Flow diagram of the study population.

Exclusion criteria

Renal recipients below the age of 18 years and those without available follow-up data for a minimum of one year were excluded (Figure 1).

Study procedure

This was a retrospective case-record-based study. Medical records were reviewed and clinical and laboratory parameters were tabulated. The research conducted in this study adhered to the principles outlined in the Declaration of Helsinki and was approved by the Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee (IEC 542/2019) on 6^th September 2019. A waiver of consent was granted as per our institutional ethics committee due to the retrospective nature of the study. Baseline demographic data and laboratory data, including complete blood counts (CBC) and serum creatinine levels, were collected from the pre-transplant period (<1 week). The follow-up details of CBC and serum creatinine were collected at the post-transplant first week, one month, three months, six months, and 12 months and tabulated, and the prevalence of PTA was studied. The time taken for normalization of the hemoglobin level was also documented.

Other haematological abnormalities including leukopenia, thrombocytopenia, and pancytopenia were also collected, and the type of immunosuppression was noted. The donor details were also collected. The association between the first week post-transplant severe anemia and graft dysfunction was analyzed, and graft function was compared at both early (six months) and late (12 months) post-transplant anemia.

Definitions

Anemia: “Hemoglobin level less than 12 g/dL in women and less than 13 g/dL in men according to the World Health Organization (WHO) criteria and KDIGO”.¹³

Leukopenia: WBC count less than 4000/μL.¹⁴

Thrombocytopenia: platelet count less than 150,000/μL.¹⁴

The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months.

Acute and chronic rejections were confirmed by biopsy. Delayed graft function was characterized by the need for at least one dialysis treatment during the first week following transplantation. Slow graft function was characterized by a 30% creatinine reduction ratio on day two and 70% creatinine reduction ratio on day 7.¹⁵

Outcome measures

The primary outcome studied was the prevalence of the most common haematological abnormalities in post-renal transplant patients.

The secondary outcomes studied were the association between the first week post-transplant severe anemia and graft dysfunction and the comparison of graft function between patients with and without PTA at six months and 12 months post-transplant.

Statistical methods

Discrete variables are represented as frequencies and percentages. Continuous data are shown as mean±SD. An unpaired T-test or Wilcoxon signed-rank test was performed to compare parameters between different time points. Normality was assessed using the Kolmogorov-Smirnov test. A chi-squared test was performed to assess the association between the parameters. Statistical significance was set at P<0.05. The data were analyzed using SPSS version 29.

Results

The demographics and clinical characteristics of the renal transplant recipients are shown in Table 1 and in the underlying data.¹⁶^,¹⁷ The dose of basiliximab used was 20 mg intravenously on 0 and 4^th-day post-operation. The ATG dose used varied from to 1-3 mg/kg at the nephrologist’s discretion. All patients received 500 mg methylprednisolone along with induction therapy. All patients were treated with triple immunosuppression (Tacrolimus, Mycophenolate, and steroids) as per KDIGO guidelines. The Tacrolimus dose used was 0.08 mg/kg/day in two divided doses to aim for 10-12 mcg/mL trough level in first month, 6-10 mcg/mL up to 3 months and then onwards 3-6 mcg/mL. The Mycophenolate mofetil dose used varied from 1.5 gram to 2 gram per day based on the nephrologist’s decision and body weight of the patient.

Table 1. Demographics and clinical characteristics of the study participants.

Variables	Renal transplant recipients (n=106)
Donor age, In years	46.6±10.3^a
Recipient age, In years	36.9±10.8^a
Donor gender (n, %)
Male	24(22.5)
Female	82(77.2)
Recipient gender (n, %)
Male	91(85.8)
Female	15(14.2)
BMI	21.0±4.2^a
Donor type (n, %)
Live	91(85.8)
Cadaveric	15(14.2)
Pre transplant Hb(g/dl)	9.4±1.7^a
Pre-transplant WBC count -*10/microL	7.2±3.1^a
Pre-transplant platelet count -*10/microL	205.8±32.4^a
Induction therapy (n (%))
Basiliximab	84(79.2)
Antithymoglobulin	22(20.7)

a Mean±SD; BMI, Body mass index.

The haematological abnormalities of patients post-transplantation are shown in Table 2.

Table 2. Post-transplant haematological abnormalities and allograft rejection status.

Clinical variables	Renal transplant recipients (n=106)
Post-transplant anemia
1 week	104(98%)
1 month	80(75%)
3 months	38(35%)
6 months	34(32%)
12 months	29(27%)
Post transplant leukopenia	46(43.4%)
Post transplant thrombocytopenia	33(31.2%)
Post transplant pancytopenia	16(15.1%)
Post transplant lympho-proliferative disorder	0
Post transplant erythrocytosis	19(17.9%)
Graft dysfunction
Slow and delayed graft function	11(10.3%)
Acute rejection	19(17.9%)
Chronic rejection	6(5.6%)

Post-transplant anemia

PTA is highly prevalent in our study population and has improved over time. Incidence of pre-transplant anemia was also high and reported in 101 patients (95%). As shown in Figure 2, the prevalence of post-transplant anemia showed a trend of 98% during the first week, 75% at one month, 35% at three months, 32% at six months, and 27% at 12 months post-transplantation. Further on stratification of severity of anemia, mild anemia was found to be common among PTA (Table 3). Additionally, 41.7% of severe anemia cases were reported within the first week after transplantation. None of the patients had features of microangiopathic hemolytic anemia.

Figure 2. Trend of post-transplant anemia.

Table 3. Stratification of post-transplant anemia.

Time of events	Severity of anemia
Time of events	Severe (Hb <10 g/dl)	Mild (Hb 10-12/13 g/dl)	No anemia (Hb >12/13 g/dl)
Post 1 week	45(41.7)	59(54.6)	2(1.9)
Post 1 month	39(36.2)	41(42.7)	26(24.5)
Post 3 month	18(16.7)	20(18.8)	68(64.1)
Post 6 month	12(11.3)	22(20.7)	72(67.9)
Post 12 month	8(7.5)	21(19.1)	77(72.6)

The pre-transplant Hb level was 9.4±1.7, and post-transplant there was a significant improvement in the Hb levels at one month (10.6±2.2), six months (11.8±2.9), and 12 months (12.5±3.1), which was significant when compared to pre-transplant levels (p<0.001) (Figure 3).

Figure 3. Comparison of pre-transplant and post-transplant hemoglobin levels.

Leukopenia

Leukopenia was observed in 35(76%) patients in first 6 months and 11(23.9%) after 6 months accounting for overall prevalence of 43%. The mean leucocyte count was 3.2 ± 1.2 ×10³/μL. Neutropenia was reported in 16 patients (34.7%) and 10 patients of them required G-CSF for recovery. The primary cause for leukopenia was drug induced (93%) and CMV was the second most common cause (7%).

Isolated thrombocytopenia

Thrombocytopenia occurred in 31.2% of the patients in the overall study group, which was observed in 20(60.2%) patients in first 6 months and 13(39.3%) developed after 6 months. The mean platelet count was 70 ± 12 × 10³/μL. The majority of cases were attributed to bacterial infections (84.5%), followed by fungal infections (9.2%), and CMV infections (6.3%).

Pancytopenia

We observed that 16(15.1%) patients had pancytopenia. The major cause was drug-induced 12(75.6%) followed by CMV in 3 patients (18.6%) and bacterial infections were found in one patient (6%). G-CSF was required in 10 patients (62%) for pancytopenia recovery.

During the cytopenia episodes, all patients underwent testing for CMV infection (CMV PCR). All patients were on mycophenolate mofetil (1.5-2.00 g/day). All transplant recipients received sulfamethoxazole and trimethoprim (400 mg + 80 mg) as bacterial infection prophylaxis for first year and Valgancyclovir 450 mg once daily as CMV prophylaxis for first 6 months. During leukopenia/pancytopenia episodes all the three drugs were withheld until count recovery. The mycophenolate mofetil was restarted after the count recovery at lower dose. The Valgancyclovir and trimethoprim sulfamethoxazole were restarted.

Erythrocytosis

Nineteen patients (17.9%) had erythrocytosis. The incidence was higher in males (72%), and the mean hematocrit count was 56±13%.

Graft dysfunction and severe anemia at first-week post-transplant

In the first week post-transplant, slow or delayed graft function was observed in 11 recipients (22.3%), 19 patients (39.5%) had acute rejection. Specifically, 15 cases were diagnosed as cell-mediated rejection, while four cases were identified as antibody-mediated rejection on biopsy. Severe post-transplant anemia in the first week was significantly associated with allograft dysfunction (SGF, DGF, and acute rejection) (p=0.04) (Table 4).

Table 4. Association between graft dysfunction (SGF+DGF/acute rejection) and severe anemia.

SGF: Slow graft function; DGF, Delayed graft function.

Variables	Severe anemia		P value
Kidney allograft dysfunction	No	Yes	P value
Yes	12	18	0.04*
No	14	05	0.04*

* Statistically significant.

Graft function in patients with and without PTA at early (six months) and late (12 months) post-transplant

At six and 12 months, mean serum creatinine levels for patients with PTA were 1.6±0.6 mg/dl with eGFR 68.0±19.3 mL/min/1.73 m² and 1.7+0.5 mg/dl with mean eGFR 74.2±22 mL/min/1.73 m². While for patients without PTA, the mean serum creatinine levels were 1.4±0.5 mg/dl with eGFR 64.3±22 mL/min/1.73 m² and 1.3±0.4 mg/dl with mean eGFR 64.8±21 mL/min/1.73 m² at six and 12 months respectively. Although the serum creatinine level was slightly higher in patients who had PTA, it was not statistically significant and was comparable between the groups (p=0.50), implying that PTA did not have any effect on graft function in our cohort at six and 12 months after renal transplant.

Discussion

Following renal transplantation, in addition to common metabolic and infectious complications, patients also encounter haematological abnormalities.¹⁸ In our study population, the most prevalent blood-related complication was PTA. Renal transplant patients experience anemia at various periods after transplantation, and the cause of anemia differs with time. post-transplant anemia is usually classified as early anemia, which occurs at or less than six months post-transplantation, with a prevalence rate of 50%, and late anemia, which occurs six months post-transplantation, with a prevalence rate of 23–35%.¹⁹ Few studies have defined PTA occurring in the first week of transplant as immediate post-transplant anemia.²⁰

In our study, the prevalence of anemia was 98% in the first week, 75% at one month, 35% at three months, 32% at six months, and 27% at 12 months after transplantation, and there was a noticeable downward trend in prevalence over the study period. Similarly, Poesen et al.²¹ observed a 98% prevalence during the immediate post-transplant period, and Talwar et al.²⁰ found that 100% of recipients had PTA in the first week and 76.7% in the third month post-transplantation. Additionally in a retrospective study by Gafter-Gvili et al.²² the prevalence of PTA at six months was 51.3% and at two years it was 36%. The notable differences in anemia prevalence may be due to various diagnostic criteria, varied causes, and different clinical practices across different healthcare centers worldwide,²³ such as iron deficiency as a result of iron store depletion during pre-transplantation, perioperative blood loss, and malnutrition.²⁴ Late PTA is usually associated with decreased graft function and occurrence of renal insufficiency.²⁵

In the present study, there was a significant improvement in the hemoglobin level at post-transplant one, six and 12 months as compared to the pre-transplant and it was significant (p<0.001), which was consistent with Radoui et al.²⁶ who reported the pre-transplant Hb improvement from 10.2 g/dl at one month to 12.8 g/dl at sixth month and then to 13.2 g/dl at one year.

The broad causes of cytopenia may be drug toxicity/interactions, immune reactions, or viral infections. In the present study, the prevalence of post-transplant leukopenia (PTL) is 43.4%, which was consistent with the findings of Smith et al.²⁷ were reported 47.5%. In our study population, drug induced was identified as the primary agent associated with leukopenia, which is consistent with Zafrani et al.⁹ In contrast, Max et al. reported a 34% incidence of CMV infection, whereas our population exhibited a lower rate of 6.3%.¹⁶ This may be due to our patients being on CMV prophylaxis for six months post-transplant.

In our study, the prevalence of post-transplant thrombocytopenia (PTT) is 31.2%, which is in line with Xie et al.²⁸ and Heaf et al.²⁹ where the prevalence was found to be 33.9% and 30%, respectively within the first year of transplantation. Previous studies have implicated immunosuppression regimens, including Grafalon and ATG, as causative agents.²⁰^,³⁰ In contrast, our observations indicated that infection was the primary trigger. ATG/Grafalon use was significantly lower in our patients. In addition, most of our patients with lower socioeconomic status were prone to infections.

We observed post-transplant pancytopenia (PTP) in 15.1% of the patients, and the major cause was drug-induced, which is consistent with previous studies.³¹ Erythrocytosis was reported in 17.9% and it had male predominance, which was consistent with reports from Friman et al. and Kessler.³²^,³³

In the present study, 30 patients were identified with allograft dysfunction, including SGF/DGF and acute rejection. Among these, 19 graft rejections were observed, which aligns with the findings of previous studies.³⁴^,³⁵ Compared with our report, Talwar et al. reported a lower incidence of DGF (only 6%). Furthermore, in our cohort, graft dysfunction was higher in patients with severe anemia in the first week after transplantation. Consistent with this, Chhabra et al. reported a significant association between graft loss and PTA at three months. PTA-mediated allograft rejection/dysfunction is caused by limited oxygen delivery to the tubular interstitium. Hypoxia generates reactive oxygen species that cause oxidative insult to the renal tissues and mediate the release of pro-inflammatory cytokines, leading to the recruitment of inflammatory cells to the interstitium.³⁶

To assess graft function, we compared the early and late serum creatinine and eGFR levels in patients with post-transplant anemia at six and 12 months. Although patients with PTA had higher serum creatinine levels than the non-anemic group, the difference was not statistically significant and was similar in patients with and without PTA in our study. This was most likely due to the small sample size. In contrast, Molnar et al. studied 938 renal transplant recipients and showed a statistically significant reduction in renal function in patients with PTA.³⁷

Limitations

The major limitation of our study was the small sample size, and the post-transplantation follow-up was limited to one year. This was a retrospective single-center study. Furthermore, we did not analyze the association between PTA and mortality or the severity of anemia and graft failure. Additionally, the young recipient age in our study may limit the genelizability to other populations. We did not perform iron studies or measure erythropoietin levels in our population.

Conclusions

Haematological abnormalities are common in post-RT patients. PTA is the most frequent abnormality, and it improves over time. There was a significant improvement in hemoglobin levels at one, six, and 12 months post-transplant compared to pre-transplant. Leukopenia, thrombocytopenia, pancytopenia, and post-transplant erythrocytosis are other common haematological abnormalities. Leucopenia and pancytopenia was primarily drug-induced, and thrombocytopenia was frequently caused by infections in our cohort. Additionally, severe post-transplant anemia was significantly associated with graft dysfunction in the first week post-transplant. However, PTA did not show any association with graft function at six and twelve months post-transplantation.

Data availability

Underlying data

Figshare: This study contains the underlying data for ‘Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function’ https://doi.org/10.6084/m9.figshare.25211441.v2.¹⁶

Extended data

Figshare: Extended data for ‘Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function’, https://doi.org/10.6084/m9.figshare.24441268.v1.¹⁷

This project contains the following extended data:

• Strobe checklist
• Proforma
• Protocol

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)

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20. Talwar S, Nair R, Sreedharan S, et al.: Prevalence of posttransplant anemia in patients undergoing renal transplantation at a tertiary care center in Kerala - A prospective observational study. Indian J. Transplant. 2021 Apr 1; 15(2): 93–98.
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Laxminarayana SLK, Jayaram S, Swaminathan SM et al. Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function [version 2; peer review: 2 approved]. F1000Research 2024, 13:241 (https://doi.org/10.12688/f1000research.144124.2)

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Reviewer Report 24 Oct 2024

Dr Sonia Sharma, Monash University, Clayton, Victoria, Australia

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https://doi.org/10.5256/f1000research.169665.r327104

The authors have incorporated the suggested points in the revised manuscript. .All necessary changes have been made in accordance ... Continue reading

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Reviewer Report 16 Oct 2024

Abraham Cohen-Bucay, Massachusetts General Hospital Global Health, Boston, Massachusetts, USA

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The authors successfully addressed all my concerns and recommendations. Therefore, I think the article is ... Continue reading

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Reviewer Report 15 Jul 2024

Dr Sonia Sharma, Monash University, Clayton, Victoria, Australia

Approved with Reservations

https://doi.org/10.5256/f1000research.157873.r281382

Good work done by the author. The research topic is important, and data from Asian countries are surely lacking.

The study design is appropriate, and sufficient details are given in the method section.
However, in the result section, some details are required to make it more informative for indexing:

1. High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part).
2. What was the severity of anemia at three months, six months, and one year?
3. About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time.
4. Were there any differences in parameters between cadaveric and live donors?

Minor:
1. The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required.
2. Figure 3. Clarity of message is required related to the proportion of patients.
3. Correction is required for the last line of the conclusion.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Clinical Nephrology, Paediatric Nephrology, Kidney Transplantation MMF AUC work, Nephrotic syndrome, Tubular disorders

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

26 Sep 2024

Author Response

We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their ... Continue reading We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript incorporating the changes suggested by reviewers

Comment 1: High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part)
Response: Dear Madam, Thank you for your valuable input on improving our manuscript.
Since most PTA are due to surgical blood loss, we didn’t evaluate in detail for PTA in all patients. As suggested we have included and discussed the causes for post-transplant anaemia in discussion section.

Comment 2: What was the severity of anemia at three months, six months, and one year?
Response: Thank you for the suggestion, which helped us refine our manuscript. We have stratified PTA severity at each time points into three categories (severe, mild, no anemia) in Table 3 (Page No.10, Line No.127)

Comment 3: About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section. (Page No.8, Line No.105-109).
During the pancytopenia episodes Valgancyclovir and/or trimethoprim/sulphamethoxozole were also stopped in addition to mycophenolate mofetil. ATG was given to 20.7% of patients as induction. Hence, as suggested by both the reviewers we have revised the manuscript. Instead of implying that the cytopenia was due to mycophenolate mofetil alone, we have mentioned that it is drug induced cytopenia. We sincerely thank both the reviewers for bringing this to our notice and helping us improving the manuscript.

Comments 4: Were there any differences in parameters between cadaveric and live donors?
Response: Dear Madam, Thank you for this query. As 85.8% of the recipients received the kidney from live donors, the difference in the parameters between the cadaveric and live donors was not analysed.
Minor
Comment 5: The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required
Response: Dear Madam, Thank you for the suggestion. The text has been suitably modified.
Comment 6: Figure 3. Clarity of message is required related to the proportion of patients.
Response: Sincere thanks for the suggestion. We have revised the graph incorporating the proportion of patients (Page No.11, Figure 3).
Comment 7: Correction is required for the last line of the conclusion
Response: Thank you for bringing this to our notice. This part has been modified (Page No.14, Line No.285-286).
We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript incorporating the changes suggested by reviewers

Comment 1: High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part)
Response: Dear Madam, Thank you for your valuable input on improving our manuscript.
Since most PTA are due to surgical blood loss, we didn’t evaluate in detail for PTA in all patients. As suggested we have included and discussed the causes for post-transplant anaemia in discussion section.

Comment 2: What was the severity of anemia at three months, six months, and one year?
Response: Thank you for the suggestion, which helped us refine our manuscript. We have stratified PTA severity at each time points into three categories (severe, mild, no anemia) in Table 3 (Page No.10, Line No.127)

Comment 3: About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section. (Page No.8, Line No.105-109).
During the pancytopenia episodes Valgancyclovir and/or trimethoprim/sulphamethoxozole were also stopped in addition to mycophenolate mofetil. ATG was given to 20.7% of patients as induction. Hence, as suggested by both the reviewers we have revised the manuscript. Instead of implying that the cytopenia was due to mycophenolate mofetil alone, we have mentioned that it is drug induced cytopenia. We sincerely thank both the reviewers for bringing this to our notice and helping us improving the manuscript.

Comments 4: Were there any differences in parameters between cadaveric and live donors?
Response: Dear Madam, Thank you for this query. As 85.8% of the recipients received the kidney from live donors, the difference in the parameters between the cadaveric and live donors was not analysed.
Minor
Comment 5: The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required
Response: Dear Madam, Thank you for the suggestion. The text has been suitably modified.
Comment 6: Figure 3. Clarity of message is required related to the proportion of patients.
Response: Sincere thanks for the suggestion. We have revised the graph incorporating the proportion of patients (Page No.11, Figure 3).
Comment 7: Correction is required for the last line of the conclusion
Response: Thank you for bringing this to our notice. This part has been modified (Page No.14, Line No.285-286).
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

26 Sep 2024

Author Response

We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their ... Continue reading We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript incorporating the changes suggested by reviewers

Comment 1: High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part)
Response: Dear Madam, Thank you for your valuable input on improving our manuscript.
Since most PTA are due to surgical blood loss, we didn’t evaluate in detail for PTA in all patients. As suggested we have included and discussed the causes for post-transplant anaemia in discussion section.

Comment 2: What was the severity of anemia at three months, six months, and one year?
Response: Thank you for the suggestion, which helped us refine our manuscript. We have stratified PTA severity at each time points into three categories (severe, mild, no anemia) in Table 3 (Page No.10, Line No.127)

Comment 3: About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section. (Page No.8, Line No.105-109).
During the pancytopenia episodes Valgancyclovir and/or trimethoprim/sulphamethoxozole were also stopped in addition to mycophenolate mofetil. ATG was given to 20.7% of patients as induction. Hence, as suggested by both the reviewers we have revised the manuscript. Instead of implying that the cytopenia was due to mycophenolate mofetil alone, we have mentioned that it is drug induced cytopenia. We sincerely thank both the reviewers for bringing this to our notice and helping us improving the manuscript.

Comments 4: Were there any differences in parameters between cadaveric and live donors?
Response: Dear Madam, Thank you for this query. As 85.8% of the recipients received the kidney from live donors, the difference in the parameters between the cadaveric and live donors was not analysed.
Minor
Comment 5: The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required
Response: Dear Madam, Thank you for the suggestion. The text has been suitably modified.
Comment 6: Figure 3. Clarity of message is required related to the proportion of patients.
Response: Sincere thanks for the suggestion. We have revised the graph incorporating the proportion of patients (Page No.11, Figure 3).
Comment 7: Correction is required for the last line of the conclusion
Response: Thank you for bringing this to our notice. This part has been modified (Page No.14, Line No.285-286).
We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript incorporating the changes suggested by reviewers

Comment 1: High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part)
Response: Dear Madam, Thank you for your valuable input on improving our manuscript.
Since most PTA are due to surgical blood loss, we didn’t evaluate in detail for PTA in all patients. As suggested we have included and discussed the causes for post-transplant anaemia in discussion section.

Comment 2: What was the severity of anemia at three months, six months, and one year?
Response: Thank you for the suggestion, which helped us refine our manuscript. We have stratified PTA severity at each time points into three categories (severe, mild, no anemia) in Table 3 (Page No.10, Line No.127)

Comment 3: About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section. (Page No.8, Line No.105-109).
During the pancytopenia episodes Valgancyclovir and/or trimethoprim/sulphamethoxozole were also stopped in addition to mycophenolate mofetil. ATG was given to 20.7% of patients as induction. Hence, as suggested by both the reviewers we have revised the manuscript. Instead of implying that the cytopenia was due to mycophenolate mofetil alone, we have mentioned that it is drug induced cytopenia. We sincerely thank both the reviewers for bringing this to our notice and helping us improving the manuscript.

Comments 4: Were there any differences in parameters between cadaveric and live donors?
Response: Dear Madam, Thank you for this query. As 85.8% of the recipients received the kidney from live donors, the difference in the parameters between the cadaveric and live donors was not analysed.
Minor
Comment 5: The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required
Response: Dear Madam, Thank you for the suggestion. The text has been suitably modified.
Comment 6: Figure 3. Clarity of message is required related to the proportion of patients.
Response: Sincere thanks for the suggestion. We have revised the graph incorporating the proportion of patients (Page No.11, Figure 3).
Comment 7: Correction is required for the last line of the conclusion
Response: Thank you for bringing this to our notice. This part has been modified (Page No.14, Line No.285-286).
Competing Interests: No competing interests were disclosed. Close
Report a concern

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Reviewer Report 11 Jun 2024

Abraham Cohen-Bucay, Massachusetts General Hospital Global Health, Boston, Massachusetts, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.157873.r281377

This single-center retrospective study examines the incidence of hematologic abnormalities in the first year post-transplant. Although not entirely novel, as some of the results are well-known (e.g., the high incidence of anemia, leukopenia, and thrombocytopenia), this report still contributes valuable ... Continue reading

Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anemia severity: <10 g/dL, 10-12/13 g/dL, and no anemia (>12/13 g/dL)
Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions.
Valganciclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenias?
Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Limitations: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Causes of cytopenias: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: kidney transplantation

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Author Response 26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

26 Sep 2024

Author Response

We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We ... Continue reading We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript to incorporate the changes suggested by reviewers.

Comment 1: Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Response: Dear Sir, Many thanks for your suggestion to improve our manuscript. We have incorporated the percentage of pre-transplant anaemia as suggested in the
result section. (Page No.9, Line No.119)

Comment 2: Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anaemia severity: <10 g/dL, 10-12/13 g/dL, and no anaemia (>12/13 g/dL)
Response: Thank you for bringing this to our attention. Based on your feedback, we have revised manuscript to more accurately reflect the clinical context of PTA. Specifically, we have categorized the severity of PTA in Table 3 as suggested into three distinct groups as no anaemia (>12/13 g/dL)
<10 g/dL, mild anaemia 10-12/13 g/dL, and severe (<10 g/dL). (Page No.10, Line No.127)

Comment 3: Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Response: Many thanks for the suggestion. We have added information regarding neutropenia and number of patients who required G-CSF treatment for neutropenia in the result section (Page No.11, Line No.164-168)

Comment 4: Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section (Page No.8, Line No.79-80). The same has been added in the results section too (Page No.11, Line No.164).

Comment 5: Valgancyclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenia?
Response: Dear Sir, Thank you for the valuable input. Our patients were on Valgancyclovir prophylaxis until first 6 months and the trimethoprim sulfamethoxazole up to 12 months after kidney transplantation. They were also stopped during leukopenia. So we have revised the section on leukopenia in the manuscript with the details and as suggested instead of implying that mycophenolate mofetil as cause of leukopenia we have mentioned it as drug induced leukopenia (Page No.12, Line No.180-186).

Comment 6: Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Response: Dear Sir, Many thanks for the suggestion. None of our patients had TMA As indicated, we have incorporated the same in the result section in the manuscript (Page No.9, Line No.124-125).

Comment 7: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Response: Dear Sir, Thank you for the input. The same has been added in the limitation section as suggested (Page No.14, Line No.274-275)

Comment 8: Causes of cytopenia: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Response: Dear Sir, Thank you for the valuable suggestions and insights to improve the manuscript. ATG may have a superimposed impact in patients where it has been administered. Additionally, when pancytopenia was present, other medications like Valgancyclovir and trimethoprim sulfamethoxazole were also stopped. All patients were tested for CMV RNA PCR during the pancytopenia episodes. The manuscript has been revised and mentioned as drug induced cytopenia as suggested instead of mycophenolate induced cytopenia. We thank the reviewer for bringing this into our notice and guiding us in revising the manuscript. The decision was made by Nephrologist and clinical hematology consultation was not sought due to non-availability of haematologist at our institute during the study period. (Page No.12, Line No.180 and 187).

Comment 9: Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions
Response: The mycophenolate dose used varied from 1.5-2.00 gm as induction based on the body weight and nephrologist clinical decision. The dose was reduced to 0.5-1.0 g per day after the cytopenia episodes and was adjusted further on follow-up on case to case basis as per etiology. The same has been incorporated in the manuscript (Page No.8, Line No.105-109)
We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript to incorporate the changes suggested by reviewers.

Comment 1: Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Response: Dear Sir, Many thanks for your suggestion to improve our manuscript. We have incorporated the percentage of pre-transplant anaemia as suggested in the
result section. (Page No.9, Line No.119)

Comment 2: Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anaemia severity: <10 g/dL, 10-12/13 g/dL, and no anaemia (>12/13 g/dL)
Response: Thank you for bringing this to our attention. Based on your feedback, we have revised manuscript to more accurately reflect the clinical context of PTA. Specifically, we have categorized the severity of PTA in Table 3 as suggested into three distinct groups as no anaemia (>12/13 g/dL)
<10 g/dL, mild anaemia 10-12/13 g/dL, and severe (<10 g/dL). (Page No.10, Line No.127)

Comment 3: Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Response: Many thanks for the suggestion. We have added information regarding neutropenia and number of patients who required G-CSF treatment for neutropenia in the result section (Page No.11, Line No.164-168)

Comment 4: Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section (Page No.8, Line No.79-80). The same has been added in the results section too (Page No.11, Line No.164).

Comment 5: Valgancyclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenia?
Response: Dear Sir, Thank you for the valuable input. Our patients were on Valgancyclovir prophylaxis until first 6 months and the trimethoprim sulfamethoxazole up to 12 months after kidney transplantation. They were also stopped during leukopenia. So we have revised the section on leukopenia in the manuscript with the details and as suggested instead of implying that mycophenolate mofetil as cause of leukopenia we have mentioned it as drug induced leukopenia (Page No.12, Line No.180-186).

Comment 6: Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Response: Dear Sir, Many thanks for the suggestion. None of our patients had TMA As indicated, we have incorporated the same in the result section in the manuscript (Page No.9, Line No.124-125).

Comment 7: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Response: Dear Sir, Thank you for the input. The same has been added in the limitation section as suggested (Page No.14, Line No.274-275)

Comment 8: Causes of cytopenia: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Response: Dear Sir, Thank you for the valuable suggestions and insights to improve the manuscript. ATG may have a superimposed impact in patients where it has been administered. Additionally, when pancytopenia was present, other medications like Valgancyclovir and trimethoprim sulfamethoxazole were also stopped. All patients were tested for CMV RNA PCR during the pancytopenia episodes. The manuscript has been revised and mentioned as drug induced cytopenia as suggested instead of mycophenolate induced cytopenia. We thank the reviewer for bringing this into our notice and guiding us in revising the manuscript. The decision was made by Nephrologist and clinical hematology consultation was not sought due to non-availability of haematologist at our institute during the study period. (Page No.12, Line No.180 and 187).

Comment 9: Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions
Response: The mycophenolate dose used varied from 1.5-2.00 gm as induction based on the body weight and nephrologist clinical decision. The dose was reduced to 0.5-1.0 g per day after the cytopenia episodes and was adjusted further on follow-up on case to case basis as per etiology. The same has been incorporated in the manuscript (Page No.8, Line No.105-109)
Competing Interests: No competing interests were disclosed. Close
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Author Response 26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

26 Sep 2024

Author Response

We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We ... Continue reading We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript to incorporate the changes suggested by reviewers.

Comment 1: Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Response: Dear Sir, Many thanks for your suggestion to improve our manuscript. We have incorporated the percentage of pre-transplant anaemia as suggested in the
result section. (Page No.9, Line No.119)

Comment 2: Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anaemia severity: <10 g/dL, 10-12/13 g/dL, and no anaemia (>12/13 g/dL)
Response: Thank you for bringing this to our attention. Based on your feedback, we have revised manuscript to more accurately reflect the clinical context of PTA. Specifically, we have categorized the severity of PTA in Table 3 as suggested into three distinct groups as no anaemia (>12/13 g/dL)
<10 g/dL, mild anaemia 10-12/13 g/dL, and severe (<10 g/dL). (Page No.10, Line No.127)

Comment 3: Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Response: Many thanks for the suggestion. We have added information regarding neutropenia and number of patients who required G-CSF treatment for neutropenia in the result section (Page No.11, Line No.164-168)

Comment 4: Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section (Page No.8, Line No.79-80). The same has been added in the results section too (Page No.11, Line No.164).

Comment 5: Valgancyclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenia?
Response: Dear Sir, Thank you for the valuable input. Our patients were on Valgancyclovir prophylaxis until first 6 months and the trimethoprim sulfamethoxazole up to 12 months after kidney transplantation. They were also stopped during leukopenia. So we have revised the section on leukopenia in the manuscript with the details and as suggested instead of implying that mycophenolate mofetil as cause of leukopenia we have mentioned it as drug induced leukopenia (Page No.12, Line No.180-186).

Comment 6: Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Response: Dear Sir, Many thanks for the suggestion. None of our patients had TMA As indicated, we have incorporated the same in the result section in the manuscript (Page No.9, Line No.124-125).

Comment 7: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Response: Dear Sir, Thank you for the input. The same has been added in the limitation section as suggested (Page No.14, Line No.274-275)

Comment 8: Causes of cytopenia: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Response: Dear Sir, Thank you for the valuable suggestions and insights to improve the manuscript. ATG may have a superimposed impact in patients where it has been administered. Additionally, when pancytopenia was present, other medications like Valgancyclovir and trimethoprim sulfamethoxazole were also stopped. All patients were tested for CMV RNA PCR during the pancytopenia episodes. The manuscript has been revised and mentioned as drug induced cytopenia as suggested instead of mycophenolate induced cytopenia. We thank the reviewer for bringing this into our notice and guiding us in revising the manuscript. The decision was made by Nephrologist and clinical hematology consultation was not sought due to non-availability of haematologist at our institute during the study period. (Page No.12, Line No.180 and 187).

Comment 9: Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions
Response: The mycophenolate dose used varied from 1.5-2.00 gm as induction based on the body weight and nephrologist clinical decision. The dose was reduced to 0.5-1.0 g per day after the cytopenia episodes and was adjusted further on follow-up on case to case basis as per etiology. The same has been incorporated in the manuscript (Page No.8, Line No.105-109)
We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript to incorporate the changes suggested by reviewers.

Comment 1: Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Response: Dear Sir, Many thanks for your suggestion to improve our manuscript. We have incorporated the percentage of pre-transplant anaemia as suggested in the
result section. (Page No.9, Line No.119)

Comment 2: Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anaemia severity: <10 g/dL, 10-12/13 g/dL, and no anaemia (>12/13 g/dL)
Response: Thank you for bringing this to our attention. Based on your feedback, we have revised manuscript to more accurately reflect the clinical context of PTA. Specifically, we have categorized the severity of PTA in Table 3 as suggested into three distinct groups as no anaemia (>12/13 g/dL)
<10 g/dL, mild anaemia 10-12/13 g/dL, and severe (<10 g/dL). (Page No.10, Line No.127)

Comment 3: Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Response: Many thanks for the suggestion. We have added information regarding neutropenia and number of patients who required G-CSF treatment for neutropenia in the result section (Page No.11, Line No.164-168)

Comment 4: Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section (Page No.8, Line No.79-80). The same has been added in the results section too (Page No.11, Line No.164).

Comment 5: Valgancyclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenia?
Response: Dear Sir, Thank you for the valuable input. Our patients were on Valgancyclovir prophylaxis until first 6 months and the trimethoprim sulfamethoxazole up to 12 months after kidney transplantation. They were also stopped during leukopenia. So we have revised the section on leukopenia in the manuscript with the details and as suggested instead of implying that mycophenolate mofetil as cause of leukopenia we have mentioned it as drug induced leukopenia (Page No.12, Line No.180-186).

Comment 6: Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Response: Dear Sir, Many thanks for the suggestion. None of our patients had TMA As indicated, we have incorporated the same in the result section in the manuscript (Page No.9, Line No.124-125).

Comment 7: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Response: Dear Sir, Thank you for the input. The same has been added in the limitation section as suggested (Page No.14, Line No.274-275)

Comment 8: Causes of cytopenia: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Response: Dear Sir, Thank you for the valuable suggestions and insights to improve the manuscript. ATG may have a superimposed impact in patients where it has been administered. Additionally, when pancytopenia was present, other medications like Valgancyclovir and trimethoprim sulfamethoxazole were also stopped. All patients were tested for CMV RNA PCR during the pancytopenia episodes. The manuscript has been revised and mentioned as drug induced cytopenia as suggested instead of mycophenolate induced cytopenia. We thank the reviewer for bringing this into our notice and guiding us in revising the manuscript. The decision was made by Nephrologist and clinical hematology consultation was not sought due to non-availability of haematologist at our institute during the study period. (Page No.12, Line No.180 and 187).

Comment 9: Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions
Response: The mycophenolate dose used varied from 1.5-2.00 gm as induction based on the body weight and nephrologist clinical decision. The dose was reduced to 0.5-1.0 g per day after the cytopenia episodes and was adjusted further on follow-up on case to case basis as per etiology. The same has been incorporated in the manuscript (Page No.8, Line No.105-109)
Competing Interests: No competing interests were disclosed. Close
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Abraham Cohen-Bucay, Massachusetts General Hospital Global Health, Boston, USA
Dr Sonia Sharma, Monash University, Clayton, Australia

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24 Oct 2024 | for Version 2

Dr Sonia Sharma, Monash University, Clayton, Victoria, Australia

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Approved

The authors have incorporated the suggested points in the revised manuscript. .All necessary changes have been made in accordance with the comments provided and there are no remaining concerns. Therefore, manuscript is ready to be indexed with no reservations.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Clinical Nephrology, Paediatric Nephrology, Kidney Transplantation, MMF AUC work, Nephrotic syndrome, Tubular disorders

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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16 Oct 2024 | for Version 2

Abraham Cohen-Bucay, Massachusetts General Hospital Global Health, Boston, Massachusetts, USA

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Approved

The authors successfully addressed all my concerns and recommendations. Therefore, I think the article is ready to be accepted without reservations from the scientific standpoint. However, there are some grammatical errors.

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I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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6 Views

15 Jul 2024 | for Version 1

Dr Sonia Sharma, Monash University, Clayton, Victoria, Australia

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Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Clinical Nephrology, Paediatric Nephrology, Kidney Transplantation MMF AUC work, Nephrotic syndrome, Tubular disorders

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Author Response

26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

We would like to thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript incorporating the changes suggested by reviewers

Comment 1: High prevalence shown at one month and in the subsequent time period. It is required, therefore, if there were any associated ongoing etiologies. Related discussions and comments on previous data are also required later in the relevant section (discussion part)
Response: Dear Madam, Thank you for your valuable input on improving our manuscript.
Since most PTA are due to surgical blood loss, we didn’t evaluate in detail for PTA in all patients. As suggested we have included and discussed the causes for post-transplant anaemia in discussion section.

Comment 2: What was the severity of anemia at three months, six months, and one year?
Response: Thank you for the suggestion, which helped us refine our manuscript. We have stratified PTA severity at each time points into three categories (severe, mild, no anemia) in Table 3 (Page No.10, Line No.127)

Comment 3: About Leukopenia and thrombocytopenia: At what stage of transplant were both noted? For Leukopenia, 90% of study patients were shown to have mycophenolate mofetil association. What dose of mycophenolate was given if there were other side effects of the drug at the same time
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section. (Page No.8, Line No.105-109).
During the pancytopenia episodes Valgancyclovir and/or trimethoprim/sulphamethoxozole were also stopped in addition to mycophenolate mofetil. ATG was given to 20.7% of patients as induction. Hence, as suggested by both the reviewers we have revised the manuscript. Instead of implying that the cytopenia was due to mycophenolate mofetil alone, we have mentioned that it is drug induced cytopenia. We sincerely thank both the reviewers for bringing this to our notice and helping us improving the manuscript.

Comments 4: Were there any differences in parameters between cadaveric and live donors?
Response: Dear Madam, Thank you for this query. As 85.8% of the recipients received the kidney from live donors, the difference in the parameters between the cadaveric and live donors was not analysed.
Minor
Comment 5: The text and tables provide almost similar information. Either must be modified to avoid repetition, and better informative tables are required
Response: Dear Madam, Thank you for the suggestion. The text has been suitably modified.
Comment 6: Figure 3. Clarity of message is required related to the proportion of patients.
Response: Sincere thanks for the suggestion. We have revised the graph incorporating the proportion of patients (Page No.11, Figure 3).
Comment 7: Correction is required for the last line of the conclusion
Response: Thank you for bringing this to our notice. This part has been modified (Page No.14, Line No.285-286).

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No competing interests were disclosed.

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11 Jun 2024 | for Version 1

Abraham Cohen-Bucay, Massachusetts General Hospital Global Health, Boston, Massachusetts, USA

8 Views Cite this report Responses(1)

Approved With Reservations

Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anemia severity: <10 g/dL, 10-12/13 g/dL, and no anemia (>12/13 g/dL)
Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions.
Valganciclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenias?
Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Limitations: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Causes of cytopenias: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

kidney transplantation

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Author Response

26 Sep 2024

Shankar Prasad Nagaraju, Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India

We thank the editorial team of F1000 research for bringing in expert reviewers to provide valuable feedback. We are also extremely grateful to the reviewers for their valuable comments. We have revised our manuscript to incorporate the changes suggested by reviewers.

Comment 1: Baseline Anemia Data: It would be beneficial to provide baseline anemia data pre-transplant. Although the mean hemoglobin level is provided, the percentage of patients with anemia is not. Given the post-transplant anemia incidence of 98% at one week, it is likely that the pre-transplant anemia incidence is similarly high
Response: Dear Sir, Many thanks for your suggestion to improve our manuscript. We have incorporated the percentage of pre-transplant anaemia as suggested in the
result section. (Page No.9, Line No.119)

Comment 2: Anemia Definition and stratification: The study defines anemia as hemoglobin levels <12 g/dL in women and <13 g/dL in men. However, this definition is unrealistic for early post-transplant patients, given the target on dialysis is only >10 g/dL with erythropoietin treatment. Therefore, It would be informative to stratify the incidence of anaemia severity: <10 g/dL, 10-12/13 g/dL, and no anaemia (>12/13 g/dL)
Response: Thank you for bringing this to our attention. Based on your feedback, we have revised manuscript to more accurately reflect the clinical context of PTA. Specifically, we have categorized the severity of PTA in Table 3 as suggested into three distinct groups as no anaemia (>12/13 g/dL)
<10 g/dL, mild anaemia 10-12/13 g/dL, and severe (<10 g/dL). (Page No.10, Line No.127)

Comment 3: Details on leukopenia: Further details regarding leukopenia would be informative. Specifically, distinguishing between lymphopenia and neutropenia, the number of patients with neutropenia, and whether any required G-CSF treatment for neutropenia
Response: Many thanks for the suggestion. We have added information regarding neutropenia and number of patients who required G-CSF treatment for neutropenia in the result section (Page No.11, Line No.164-168)

Comment 4: Timing of cytopenia definition: Please clarify if leukopenia and thrombocytopenia were defined at specific time points during follow-up or if any cytopenia (even transient) qualified a patient as having these conditions
Response: Sincere thanks for your suggestion. The presence or absence of leukopenia and thrombocytopenia were defined at post-transplant time points of <6 months and >6 months. The same has been defined in the methods section (Page No.8, Line No.79-80). The same has been added in the results section too (Page No.11, Line No.164).

Comment 5: Valgancyclovir and trimethoprim/sulfamethoxazole are known to cause leukopenia and bone marrow suppression. How many patients were on these medications, and were any of these medications needed to be discontinued due to leukopenia or other cytopenia?
Response: Dear Sir, Thank you for the valuable input. Our patients were on Valgancyclovir prophylaxis until first 6 months and the trimethoprim sulfamethoxazole up to 12 months after kidney transplantation. They were also stopped during leukopenia. So we have revised the section on leukopenia in the manuscript with the details and as suggested instead of implying that mycophenolate mofetil as cause of leukopenia we have mentioned it as drug induced leukopenia (Page No.12, Line No.180-186).

Comment 6: Did any patients have thrombotic microangiopathy, which could explain the observed thrombocytopenia and anemia (hemolysis)?
Response: Dear Sir, Many thanks for the suggestion. None of our patients had TMA As indicated, we have incorporated the same in the result section in the manuscript (Page No.9, Line No.124-125).

Comment 7: I concur with the limitations noted by the authors. Additionally, the young recipient age in your study may limit the generalizability to other populations.
Response: Dear Sir, Thank you for the input. The same has been added in the limitation section as suggested (Page No.14, Line No.274-275)

Comment 8: Causes of cytopenia: The manuscript notes that most cytopenias were attributed to mycophenolate use rather than ATG, due to the low ATG dose. How did you reach the diagnosis of mycophenolate-induced cytopenia? How were other potential causes ruled out? Was the diagnosis of mycophenolate-induced cytopenia made by the treating clinician, or were hematology consultations sought?
Response: Dear Sir, Thank you for the valuable suggestions and insights to improve the manuscript. ATG may have a superimposed impact in patients where it has been administered. Additionally, when pancytopenia was present, other medications like Valgancyclovir and trimethoprim sulfamethoxazole were also stopped. All patients were tested for CMV RNA PCR during the pancytopenia episodes. The manuscript has been revised and mentioned as drug induced cytopenia as suggested instead of mycophenolate induced cytopenia. We thank the reviewer for bringing this into our notice and guiding us in revising the manuscript. The decision was made by Nephrologist and clinical hematology consultation was not sought due to non-availability of haematologist at our institute during the study period. (Page No.12, Line No.180 and 187).

Comment 9: Mycophenolate dosing: Please provide the initial dose of mycophenolate used at the study's outset, and detail any dose adjustments made due to cytopenias/anemia, including the extent of such reductions
Response: The mycophenolate dose used varied from 1.5-2.00 gm as induction based on the body weight and nephrologist clinical decision. The dose was reduced to 0.5-1.0 g per day after the cytopenia episodes and was adjusted further on follow-up on case to case basis as per etiology. The same has been incorporated in the manuscript (Page No.8, Line No.105-109)

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Post kidney transplant hematologic abnormalities and association of post-transplant anemia with graft function

Abstract

Background

Methods

Results

Conclusions

Keywords

Revised Amendments from Version 1

Introduction

Methods

Study design

Inclusion criteria

Figure 1. Flow diagram of the study population.

Exclusion criteria

Study procedure

Definitions

Outcome measures

Statistical methods

Results

Table 1. Demographics and clinical characteristics of the study participants.

Table 2. Post-transplant haematological abnormalities and allograft rejection status.

Post-transplant anemia

Figure 2. Trend of post-transplant anemia.

Table 3. Stratification of post-transplant anemia.

Figure 3. Comparison of pre-transplant and post-transplant hemoglobin levels.

Leukopenia

Isolated thrombocytopenia

Pancytopenia

Erythrocytosis

Graft dysfunction and severe anemia at first-week post-transplant

Table 4. Association between graft dysfunction (SGF+DGF/acute rejection) and severe anemia.

Graft function in patients with and without PTA at early (six months) and late (12 months) post-transplant

Discussion

Limitations

Conclusions

Data availability

Underlying data

Extended data

References

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