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Fulltext Lessons of the month 2: A case of inappropriate drug-drug interaction in kidney transplant

Tan MH, Yee SY, Yahya R

Clin Med (Lond), 2022 Mar;22(2):169-171.
PMID: 38589183 DOI: 10.7861/clinmed.2021-0789

Carbamazepine remains a first-line antiepileptic medication for the treatment of partial seizures. Despite its widespread use, carbamazepine has significant neurotoxicity and hypersensitivity reactions. We report a case of a patient post-kidney transplant who was on regular carbamazepine for childhood epilepsy and developed nystagmus, diplopia and a broad-base gait after receiving diltiazem. Understanding of the interaction between diltiazem and carbamazepine is necessary to prevent the neurotoxic effects.
Biomarkers as diagnostic tests for delayed graft function in kidney transplantation

Lai C, Yee SY, Ying T, Chadban S

Transpl Int, 2021 12;34(12):2431-2441.
PMID: 34626503 DOI: 10.1111/tri.14132

Delayed graft function (DGF) after kidney transplantation is associated with inferior outcomes and higher healthcare costs. DGF is currently defined as the requirement for dialysis within seven days post-transplant; however, this definition is subjective and nonspecific. Novel biomarkers have potential to improve objectivity and enable earlier diagnosis of DGF. We reviewed the literature to describe the range of novel biomarkers previously studied to predict DGF. We identified marked heterogeneity and low reporting quality of published studies. Among the novel biomarkers, serum NGAL had the greatest potential as a biomarker to predict DGF, but requires further assessment and validation through larger scale studies of diagnostic test performance. Given inadequacies in the dialysis-based definition, coupled with the high incidence and impact of DGF, such studies should be pursued.
Male-specific RNA coliphages detected by plaque assay and RT-PCR in tropical river waters and animal fecal matter

Yee SY, Fong NY, Fong GT, Tak OJ, Hui GT, Su Ming Y

Int J Environ Health Res, 2006 Feb;16(1):59-68.
PMID: 16507481

Male-specific RNA coliphages (FRNA) have been recommended as indicators of fecal contamination and of the virological quality of water. In this study, 16 river water and 183 animal fecal samples were examined for the presence of FRNA coliphages by a plaque assay using Salmonella typhimurium WG49 and WG25 to differentiate between male-specific and somatic phages, a RNase spot test to differentiate between DNA and RNA phages and a reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific identification of FRNA phages. The overall recovery rate for F-specific coliphages was 8.0%. (4.4% from animal fecal matter and 50% from river water samples). Plaque counts were generally low (< 6 x 10(2) pfu per g feces or ml water), with FRNA (6.5%) and Male-specific DNA coliphages (FDNA) (7.0%) phages occurring at almost equal frequencies. The RT-PCR was positive in all FRNA plaques and was able to identify FRNA phages in mixed populations of FRNA, FDNA and somatic phages.
Value of Baseline Post-Transplant MAG3 Renal Scintigraphy in the Evaluation of Graft Function

Boey CY, Yee SY, Amir Hassan SZ, Yahya R, Hashim H

Transplant Proc, 2022 Jan 24.
PMID: 35086676 DOI: 10.1016/j.transproceed.2021.12.016

INTRODUCTION: Accurate assessment of renal graft function in the early post-transplant period is crucial, as it influences clinical management and graft prognostication. However, there are limitations in current available modalities. MAG3 scintigraphy could contribute vital information on graft function.
OBJECTIVES: This study aimed to determine the predictive value of parameters derived from MAG3 performed within 72 hours post transplant in detecting graft function. Delayed graft function (DGF), which is defined as dialysis requirement within the first week post transplant, is chosen as a surrogate measure of graft function.
METHODOLOGY: All renal transplant recipients who underwent MAG3 within 72 hours post transplant from 2017 to 2019 were enrolled. Three MAG3 parameters, renogram grade, tubular injury severity score, and R20:3, were evaluated.
RESULTS: A total of 117 patients were enrolled. The overall incidence of DGF was 16.2% with a significantly higher incidence amongst cadaveric graft recipients (53.6%) compared with living graft recipients (4.5%). Renogram grade ≥2, tubular injury severity score ≥4, and R20:3 > 1.31 significantly predicted DGF, P < .05 with high area under the curve for R20:3 of 0.97. Grafts with parameters above the cutoffs also showed significantly worse GFR at 1- and 3-months post-transplant. On multivariate analysis, prolonged cold ischemia time was associated with a higher risk of DGF, odds ratio 1.005 (95% confidence interval 1.003-1.007), P < .05.
CONCLUSION: Baseline MAG3 accurately depicts early graft function and was also predictive of GFR at 1- and 3- months post-transplant. These baseline MAG3 scans could be particularly useful amongst deceased donor graft recipients owing to the higher risk of poor graft function.
Audit on data accuracy of the Malaysian Dialysis and Transplant Registry (MDTR)

Thong KM, Jalalonmuhali M, Choo CL, Yee SY, Yahya R, Jeremiah PN, et al.

Med J Malaysia, 2024 Mar;79(2):234-236.
PMID: 38553931

Diabetes mellitus is the main aetiology of end stage kidney disease (ESKD) in Malaysia. However, there may be concerns of over-reporting of diabetes mellitus as the cause of ESKD in the Malaysian Dialysis and Transplant Registry (MDTR). The objective of this audit is to assess the accuracy of data collected in the MDTR. There were 151 centres/source data providers (SDP) with a total of 1977 patients included in this audit. The audit showed that 80.2% of doctors' records matched the MDTR data. The results were comparable with published validation studies in other countries.
Fulltext Visual inspection reveals a novel pathogenic mutation in PKD1 missed by the variant caller in whole‑exome sequencing

Koay BT, Chiow MY, Ismail J, Fahmy NK, Yee SY, Mustafa N, et al.

Mol Med Rep, 2022 Dec;26(6).
PMID: 36281931 DOI: 10.3892/mmr.2022.12882

Autosomal dominant polycystic kidney disease (ADPKD) is the most common type of inherited cystic kidney disease. The feasibility of whole‑exome sequencing (WES) to obtain molecular diagnosis of ADPKD is still in question as previous studies showed conflicting results. Utilizing WES on a patient with ADPKD, standard bioinformatics pipeline demonstrated no pathogenic variant in the genes of interest. By visualizing read alignments using the Integrative Genomics Viewer, a region with atypical alignment of numerous soft‑clipped reads at exon 45 of polycystin 1, transient receptor potential channel interacting (PKD1) gene was demonstrated. A total of four visual inspection steps were outlined to assess the origin of these soft‑clipped reads as strand bias during capture, poor mapping, sequencing error or DNA template contamination. Following assessment, the atypical alignment at PKD1 was hypothesized to be caused by an insertion/deletion mutation. Sanger sequencing confirmed the presence of a novel 20‑bp insertion in PKD1 (NM_001009944.3; c.12143_12144insTCCCCGCAGTCTTCCCCGCA; p.Val4048LeufsTer157), which introduced a premature stop codon and was predicted to be pathogenic. The present study demonstrated that WES could be utilized as a molecular diagnostic tool for ADPKD. Furthermore, visual inspection of read alignments was key in identifying the pathogenic variant. The proposed visual inspection steps may be incorporated into a typical WES data analysis workflow to improve the diagnostic yield.
First Successful Kidney Transplantation After Hematopoeitic Stem Cell Transplantation in Malaysia

Tan MH, Wan Ahmad Kamil WMR, Cheng MC, Yee SY, Abdul Wahab MZ, Yahya R, et al.

Transplant Proc, 2021 Dec 25.
PMID: 34963514 DOI: 10.1016/j.transproceed.2021.11.020

Promising outcomes of kidney transplantation following hematopoeitic stem cell transplantation has been reported. Data from some centers have demonstrated stable graft function without long term immunosuppression. We present our experience with the first successful case in Malaysia. This is a 21-year-old man who had acute myeloid leukemia, received stem cell transplant from his younger brother 8 years prior, underwent kidney transplantation from the same donor, and had an excellent 1-year graft function post-transplant. As the post-transplant genetic analysis revealed full chimerism, his immunosuppression regimen can be tapered to minimal doses safely. The concept of immunotolerance is now widely studied and could potentially be the curative strategy for patients who develop end stage kidney disease after hematopoeitic stem cell transplantation.
Comparison of Clinical Outcomes Among Deceased Donor Kidney Transplant Recipients Before and After Utilizing Estimated Posttransplant Survival Score for Kidneys Allocation in Malaysia

Ng YM, Lim YS, Ee LW, Fong VK, Low CL, Yee SY, et al.

Transplant Proc, 2022 Jan 29.
PMID: 35105465 DOI: 10.1016/j.transproceed.2022.01.002

BACKGROUND: The Malaysian Kidney Allocation System implemented in 2020 includes only kidney transplant candidates with estimated posttransplant survival (EPTS) score of ≤20%, in replacement of Malaysian Organs Sharing System, which was based solely on dialysis vintage. We aim to compare the clinical outcomes of deceased-donor kidney transplant recipients (DDKTRs) with EPTS ≤20% to those with EPTS >20%.
METHODS: All DDKTRs between January 1, 2015, and December 29, 2020, were included and categorized into 2 groups: EPTS ≤20% and EPTS >20%. Cox regression was performed to evaluate the association of EPTS score and patient survival. The rate of postoperative complications, graft failure and patient survival were compared between 2 groups. Data were analyzed with SPSS v26 and R v4.0.4. The study complies with the Helsinki Congress and the Istanbul Declaration.
RESULTS: We included 159 DDKTRs, with a median follow-up of 25 months (range, 10-60 months). The mean age of those with EPTS ≤20% was 32.2 ± 3.4 years and those with EPTS >20% was 46.0 ± 6.7 years, and the median EPTS score were 16% (range, 12%-18%) and 38% (range, 27%-56.5%), respectively. EPTS score was associated with patient survival (hazard ratio, 1.031; 95% CI 1.010-1.052; P = .003), and the cutoff points of 30% and above were associated with worse survival. It showed good discrimination (C-index, 0.729; 95% CI 0.579-0.878; P = .003) and the optimal cutoff value was 38% (65.5% sensitivity, 68.8% specificity, 17.8% positive predictive value, and 95.8% negative predictive value). Both groups had similar rate of surgical complications (P = .191), graft failure (P = .503), and patient survival (P = .654), but those with EPTS >20% had higher incidence of urinary tract infection (9.3% vs 27.6%, P = .016).
CONCLUSIONS: There was no difference in clinical outcomes using an EPTS cutoff point of 20% but worse patient survival if higher cutoff point was used.
A prospective study of incidence and outcome of acute kidney injury among hospitalised patients in Malaysia (My-AKI)

Goh CY, Visvanathan R, Leong CT, Hooi LS, Ch'ng CC, Yee SY, et al.

Med J Malaysia, 2023 Nov;78(6):733-742.
PMID: 38031214

INTRODUCTION: The incidence of acute kidney injury (AKI) among hospitalised patients has not been well studied in Malaysia.
MATERIALS AND METHODS: We conducted a prospective, multicentre study in seven hospitals in West Malaysia. All the adults admitted in March 2017 fulfilling Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI were included.
RESULTS: Of the 34,204 patients screened, 2,457 developed AKI (7.18%), 13.1% of which occurred in intensive care unit (ICU). There were 60.2% males with a mean age of 57.8 (±17.5) years. The most common comorbidities were hypertension (55.0%), diabetes (46.6%), ischaemic heart disease (15.1%) and chronic kidney disease (12.0%). The commonest causes of AKI were sepsis (41.7%), pre-renal (24.2%) and cardiorenal syndrome (10.8%). Nephrotoxin exposure was reported in 31%. At diagnosis, the proportion of AKI stages 1, 2 and 3 were 79.1%, 9.7%, 11.2%, respectively. Referral to nephrologists was reported in 16.5%. Dialysis was required in 176 (7.2%) patients and 55.6% were performed in the ICU. Acidosis (46.2%), uraemia (31.6%) and electrolyte disturbance (11.1%) were the commonest indications. Continuous renal replacement therapy (CRRT) was required in 14%. The average length of hospital stay was 9.5 days. In-hospital mortality was 16.4%. Among survivors, full and partial renal recovery was seen in 74.7% and 16.4% respectively while 8.9% failed to recover. After a mean follow-up of 13.7 months, 593 (30.2%) of survivors died and 38 (1.9%) initiated chronic dialysis. Mortality was highest among those with malignancies (Hazard Ratio, HR 2.14), chronic liver disease (HR 2.13), neurological disease (HR 1.56) and cardiovascular disease (HR 1.17).
CONCLUSION: AKI is common in hospitalised patients and is with associated high mortality during and after hospitalisation.