Clinical Predictors and Long-term Impact of Acute Kidney Injury on Progression of Diabetic Kidney Disease in Chinese Patients With Type 2 Diabetes

Jiang, Guozhi; Luk, Andrea O. Y.; Tam, Claudia H.T.; Ozaki, Risa; Lim, CL; Chow, Elaine; Lau, Eric S.H.; Kong, Alice Pik Shan; Fan, Baoqi; Lee, Ka Fai; Siu, Shing Chung; Hui, Grace; Tsang, Chiu Chi; Lau, Kam Piu; Leung, Jason C. S.; Tsang, Man-Wo; Kam, Grace; Lau, Ip Tim; Li, June K.; Yeung, Ming Wai; Lau, Emmy; Lo, Stanley; Fung, Samuel; Cheng, Yuk Lun; Chow, Chun Chung; Tang, Nelson L. S.; Huang, Yü; Lan, Hui‐Yao; Oram, Richard A.; Szeto, Cheuk Chun; So, Wing Yee; Chan, Ting‐Fung; Ma, Rong

doi:10.2337/db21-0694

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Third, diabetes is a common patient-based risk factor in those undergoing CPB surgery, [15] and diabetic patients who have an AKI episode have a greater risk of developing CKD. [16] Other patient-based risk factors have been investigated in IRI models, such as aging. For example, 12-month old mice show enhanced AKI in response to renal IRI compared to younger mice, despite a baseline of normal renal function.…”

Section: Discussionmentioning

confidence: 99%

A Model of Ischaemia-Induced Renal Interstitial Fibrosis in Mice with Established Diabetes

Frank

Tesch

Grynberg

et al. 2023

Integr Med Nephrol Androl

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Background: Diabetes is a well-established clinical risk factor for the development of acute kidney injury (AKI) following an episode of renal ischaemia. However, we lack a robust animal model to investigate the pathological mechanisms underpinning the increased susceptibility of the diabetic kidney to ischaemia-induced AKI and the transition to chronic kidney disease. The aim of this study was to develop a mouse model in which renal ischaemia induces renal interstitial fibrosis in diabetic mice, but not in control mice.Methods: C57BL6/J mice were made diabetic via 5 low dose streptozotocin injections. 8 weeks later, diabetic mice underwent 12 min of bilateral renal ischaemia and were killed on days 1, 7 or 28 after reperfusion. For comparison, groups of age-matched non-diabetic mice underwent the same renal ischaemia/reperfusion injury (IRI) protocol.Results: Non-diabetic mice developed AKI on day 1 which showed a virtually complete recovery of structure and function by day 7. By contrast, diabetic mice exhibited a state of chronic renal inflammation and developed a much more severe AKI on day 1 after IRI. Diabetic mice showed a marked delay in the repair response on day 7, and exhibited chronic tubular damage, inflammation and robust interstitial fibrosis on day 28. Conclusion:We have developed a mouse model suitable for the dissection of the mechanisms by which diabetes makes the kidney highly susceptible to an ischaemic insult and the transition to chronic kidney disease.

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Section: Discussionmentioning

confidence: 99%

A Model of Ischaemia-Induced Renal Interstitial Fibrosis in Mice with Established Diabetes

Frank

Tesch

Grynberg

et al. 2023

Integr Med Nephrol Androl

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“…Furthermore, we have shown that a senolytic HSP90 inhibitor and a senostatic ASK1 inhibitor can be effective in suppressing the progression of DKD associated with an episode of AKI. The clinical relevance of this finding is supported by the knowledge that the incidence of end stage renal disease (ESRD) increases in diabetic patients in proportion to the number of episodes of AKI and their severity [ 10 ]. Applying senotherapies to patients with DKD, particularly those who experience AKI, may significantly reduce the progression to ESRD.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, it is proposed that progression of DKD, and particularly TIF, occurs after episodes of ischemia [ 8 , 9 ]. The clinical relevance of this concept is supported by a study of >9000 patients showing that the incidence and frequency of episodes of AKI in diabetes patients correlates with progression to CKD and end-stage renal disease [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury

Tesch,

Ma,

Ozols

et al. 2024

Clinical Science

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Senescence of kidney tubules leads to tubulointerstitial fibrosis (TIF). Proximal tubular epithelial cells undergo stress-induced senescence during diabetes and episodes of acute kidney injury (AKI), and combining these injuries promotes the progression of diabetic kidney disease (DKD). Since TIF is crucial to progression of DKD, we examined the therapeutic potential of targeting senescence with a senolytic drug (HSP90 inhibitor) and/or a senostatic drug (ASK1 inhibitor) in a model of TIF in which AKI is superimposed on diabetes. After 8 weeks of streptozotocin-induced diabetes, mice underwent bilateral clamping of renal pedicles to induce mild AKI, followed by 28 days of reperfusion. Groups of mice (n=10-12) received either vehicle, HSP90 inhibitor (alvespimycin), ASK1 inhibitor (GS-444217), or both treatments. Vehicle-treated mice displayed tubular injury at day 3 and extensive tubular cell senescence at day 10, which remained unresolved at day 28. Markers of senescence (Cdkn1a, Cdkn2a), inflammation (Cd68, Tnf, Ccl2) and TIF (Col1a1, Col4a3, α-Sma/Acta2, Tgfb1) were elevated at day 28, coinciding with renal function impairment. Treatment with alvespimycin alone reduced kidney senescence and levels of Col1a1, Acta2, Tgfb1, and Cd68; however, further treatment with GS-444217 also reduced Col4a3, Tnf, Ccl2 and renal function impairment. Senolytic therapy can inhibit TIF during DKD, but its effectiveness can be improved by follow-up treatment with a senostatic inhibitor, which has important implications for treating progressive DKD.

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“…In a 10-year study of 3679 patients, AKI episode was an important risk factor for the progression of renal function to stage 4 CKD (HR = 3.56, 95% CI 2.76–4.71), and each episode of AKI doubled that risk (HR = 2.02, 95% CI 1.78–2.30) [ 35 ]. Our study showed that the 90-day renal function failure rate was 66.8%, while a retrospective cohort study showed that the 7-day failure rate of renal function recovery in diabetes patients with AKI was about 46.9% [ 36 ]. It can be seen that the short-term renal prognosis of diabetic patients with AKI is poor.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of short-term renal prognosis prediction model in diabetic patients with acute kidney injury

Huang

Gao

et al. 2022

Diabetol Metab Syndr

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Objective Diabetes is a major cause of the progression of acute kidney injury (AKI). Few prediction models have been developed to predict the renal prognosis in diabetic patients with AKI so far. The aim of this study was to develop and validate a predictive model to identify high-risk individuals with non-recovery of renal function at 90 days in diabetic patients with AKI. Methods Demographic data and related laboratory indicators of diabetic patients with AKI in the First Affiliated Hospital of Guangxi Medical University from January 31, 2012 to January 31, 2022 were retrospectively analysed, and patients were followed up to 90 days after AKI diagnosis. Based on the results of Logistic regression, a model predicting the risk of non-recovery of renal function at 90 days in diabetic patients with AKI was developed and internal validated. Consistency index (C-index), calibration curve, and decision curve analysis were used to evaluate the differentiation, accuracy, and clinical utility of the prediction model, respectively. Results A total of 916 diabetic patients with AKI were enrolled, with a male to female ratio of 2.14:1. The rate of non-recovery of renal function at 90 days was 66.8% (612/916). There were 641 in development cohort and 275 in validation cohort (ration of 7:3). In the development cohort, a prediction model was developed based on the results of Logistic regression analysis. The variables included in the model were: diabetes duration (OR = 1.022, 95% CI 1.012–1.032), hypertension (OR = 1.574, 95% CI 1.043–2.377), chronic kidney disease (OR = 2.241, 95% CI 1.399–3.591), platelet (OR = 0.997, 95% CI 0.995–1.000), 25-hydroxyvitamin D3 (OR = 0.966, 95% CI 0.956–0.976), postprandial blood glucose (OR = 1.104, 95% CI 1.032–1.181), discharged serum creatinine (OR = 1.003, 95% CI 1.001–1.005). The C-indices of the prediction model were 0.807 (95% CI 0.738–0.875) and 0.803 (95% CI 0.713–0.893) in the development and validation cohorts, respectively. The calibration curves were all close to the straight line with slope 1. The decision curve analysis showed that in a wide range of threshold probabilities. Conclusion A prediction model was developed to help predict short-term renal prognosis of diabetic patients with AKI, which has been verified to have good differentiation, calibration degree and clinical practicability.

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Clinical Predictors and Long-term Impact of Acute Kidney Injury on Progression of Diabetic Kidney Disease in Chinese Patients With Type 2 Diabetes

Cited by 10 publications

References 44 publications

A Model of Ischaemia-Induced Renal Interstitial Fibrosis in Mice with Established Diabetes

A Model of Ischaemia-Induced Renal Interstitial Fibrosis in Mice with Established Diabetes

Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury

Development and validation of short-term renal prognosis prediction model in diabetic patients with acute kidney injury

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