Diabetes & Metabolism Journal

Review

Others
Risk Prediction and Management of Chronic Kidney Disease in People Living with Type 2 Diabetes Mellitus: Ying-Guat Ooi, Tharsini Sarvanandan, Nicholas Ken Yoong Hee, Quan-Hziung Lim, Sharmila S. Paramasivam, Jeyakantha Ratnasingam, Shireene R. Vethakkan, Soo-Kun Lim, Lee-Ling Lim; Diabetes Metab J. 2024;48(2):196-207. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0244

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Abstract PDF Supplementary Material PubReader ePub: People with type 2 diabetes mellitus have increased risk of chronic kidney disease and atherosclerotic cardiovascular disease. Improved care delivery and implementation of guideline-directed medical therapy have contributed to the declining incidence of atherosclerotic cardiovascular disease in high-income countries. By contrast, the global incidence of chronic kidney disease and associated mortality is either plateaued or increased, leading to escalating direct and indirect medical costs. Given limited resources, better risk stratification approaches to identify people at risk of rapid progression to end-stage kidney disease can reduce therapeutic inertia, facilitate timely interventions and identify the need for early nephrologist referral. Among people with chronic kidney disease G3a and beyond, the kidney failure risk equations (KFRE) have been externally validated and outperformed other risk prediction models. The KFRE can also guide the timing of preparation for kidney replacement therapy with improved healthcare resources planning and may prevent multiple complications and premature mortality among people with chronic kidney disease with and without type 2 diabetes mellitus. The present review summarizes the evidence of KFRE to date and call for future research to validate and evaluate its impact on cardiovascular and mortality outcomes, as well as healthcare resource utilization in multiethnic populations and different healthcare settings.

Original Articles

Drug/Regimen
Abrupt Decline in Estimated Glomerular Filtration Rate after Initiating Sodium-Glucose Cotransporter 2 Inhibitors Predicts Clinical Outcomes: A Systematic Review and Meta-Analysis: Min-Hsiang Chuang, Yu-Shuo Tang, Jui-Yi Chen, Heng-Chih Pan, Hung-Wei Liao, Wen-Kai Chu, Chung-Yi Cheng, Vin-Cent Wu, Michael Heung; Diabetes Metab J. 2024;48(2):242-252. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0201

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Abstract PDF Supplementary Material PubReader ePub: Background
The initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) typically leads to a reversible initial dip in estimated glomerular filtration rate (eGFR). The implications of this phenomenon on clinical outcomes are not well-defined.
Methods
We searched MEDLINE, Embase, and Cochrane Library from inception to March 23, 2023 to identify randomized controlled trials and cohort studies comparing kidney and cardiovascular outcomes in patients with and without initial eGFR dip after initiating SGLT2i. Pooled estimates were calculated using random-effect meta-analysis.
Results
We included seven studies in our analysis, which revealed that an initial eGFR dip following the initiation of SGLT2i was associated with less annual eGFR decline (mean difference, 0.64; 95% confidence interval [CI], 0.437 to 0.843) regardless of baseline eGFR. The risk of major adverse kidney events was similar between the non-dipping and dipping groups but reduced in patients with a ≤10% eGFR dip (hazard ratio [HR], 0.915; 95% CI, 0.865 to 0.967). No significant differences were observed in the composite of hospitalized heart failure and cardiovascular death (HR, 0.824; 95% CI, 0.633 to 1.074), hospitalized heart failure (HR, 1.059; 95% CI, 0.574 to 1.952), or all-cause mortality (HR, 0.83; 95% CI, 0.589 to 1.170). The risk of serious adverse events (AEs), discontinuation of SGLT2i due to AEs, kidney-related AEs, and volume depletion were similar between the two groups. Patients with >10% eGFR dip had increased risk of hyperkalemia compared to the non-dipping group.
Conclusion
Initial eGFR dip after initiating SGLT2i might be associated with less annual eGFR decline. There were no significant disparities in the risks of adverse cardiovascular outcomes between the dipping and non-dipping groups.

Cardiovascular Risk/Epidemiology
The Ratio of Estimated Glomerular Filtration Rate Based on Cystatin C and Creatinine Reflecting Cardiovascular Risk in Diabetic Patients: Ah Reum Khang, Min Jin Lee, Dongwon Yi, Yang Ho Kang; Diabetes Metab J. 2023;47(3):415-425. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0177

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Background
The ratio of estimated glomerular filtration rate (eGFR) based on cystatin C and creatinine (eGFR_{cystatin C}/eGF_Rcreatinine ratio) is related to accumulating atherosclerosis-promoting proteins and increased mortality in several cohorts.
Methods
We assessed whether the eGFR_{cystatin C}/eGFR_creatinine ratio is a predictor of arterial stiffness and sub-clinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, who were followed up during 2008 to 2016. GFR was estimated using an equation based on cystatin C and creatinine.
Results
A total of 860 patients were stratified according to their eGFR_{cystatin C}/eGF_Rcreatinine ratio (i.e., <0.9, 0.9–1.1 [a reference group], and >1.1). Intima-media thickness was comparable among the groups; however, presence of carotid plaque was frequent in the <0.9 group (<0.9 group, 38.3%; 0.9–1.1 group, 21.6% vs. >1.1 group, 17.2%, P<0.001). Brachial-ankle pulse wave velocity (baPWV) was faster in the <0.9 group (<0.9 group, 1,656.3±333.0 cm/sec; 0.9–1.1 group, 1,550.5±294.8 cm/sec vs. >1.1 group, 1,494.0±252.2 cm/sec, P<0.001). On comparing the <0.9 group with the 0.9–1.1 group, the multivariate-adjusted odds ratios of prevalence of high baPWV and carotid plaque were 2.54 (P=0.007) and 1.95 (P=0.042), respectively. Cox regression analysis demonstrated near or over 3-fold higher risks of the prevalence of high baPWV and carotid plaque in the <0.9 group without chronic kidney disease (CKD).
Conclusion
We concluded that eGFR_{cystatin C}/eGFR_creatinine ratio <0.9 was related to an increased risk of high baPWV and carotid plaque in T2DM patients, especially, those without CKD. Careful monitoring of cardiovascular disease is needed for T2DM patients with low eGFR_{cystatin C}/eGFR_creatinine ratio.

Citations

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Research Progress of Creatinine, Cystatin C, and Their Ratio in Renal Diseases
广智杨
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Muscle mass, creatinine, cystatin C and selective glomerular hypofiltration syndromes
Linnea Malmgren, Anders Grubb
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Complications
High Incidence of Chronic Kidney Disease among Iranian Diabetic Adults: Using CKD-EPI and MDRD Equations for Estimated Glomerular Filtration Rate: Seyyed Saeed Moazzeni, Reyhane Hizomi Arani, Mitra Hasheminia, Maryam Tohidi, Fereidoun Azizi, Farzad Hadaegh; Diabetes Metab J. 2021;45(5):684-697. Published online March 16, 2021; DOI: https://doi.org/10.4093/dmj.2020.0109

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Background
To investigate the population based incidence rate of chronic kidney disease (CKD) and its potential risk factors among Iranian diabetic adults during over 14 years of follow-up.
Methods
Two different equations (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease [MDRD]) were applied for the calculating the estimated glomerular filtration rate (eGFR). Among a total of 1,374 diabetic Tehranian adults, 797 and 680 individuals were eligible for CKD-EPI and MDRD analyses, respectively. CKD was defined as eGFR lower than 60 mL/min/1.73 m². Multivariable Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CI) for all potential risk factors.
Results
The incidence rates (95% CI) of CKD per 1,000 person-years were 43.84 (39.49 to 48.66) and 55.80 (50.29 to 61.91) based on CKD-EPI and MDRD equations, respectively. Being older, a history of cardiovascular disease, and having lower levels of eGFR were significant risk factors in both equations. Moreover, in CKD-EPI, using glucose-lowering medications and hypertension, and in MDRD, female sex and fasting plasma glucose ≥10 mmol/L were also independent risk factors. Regarding the discrimination index, CKD-EPI equation showed a higher range of C-index for the predicted probability of incident CKD in the full-adjusted model, compared to MDRD equation (0.75 [0.72 to 0.77] vs. 0.69 [0.66 to 0.72]).
Conclusion
We found an incidence rate of more than 4%/year for CKD development among our Iranian diabetic population. Compared to MDRD, it can be suggested that CKD-EPI equation can be a better choice to use for prediction models of incident CKD among the Iranian diabetic populations.

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Review

Guideline/Fact Sheet
Sodium-Glucose Cotransporter-2 Inhibitor for Renal Function Preservation in Patients with Type 2 Diabetes Mellitus: A Korean Diabetes Association and Korean Society of Nephrology Consensus Statement: Tae Jung Oh, Ju-Young Moon, Kyu Yeon Hur, Seung Hyun Ko, Hyun Jung Kim, Taehee Kim, Dong Won Lee, Min Kyong Moon, The Committee of Clinical Practice Guideline, Korean Diabetes Association and Committee of the Cooperative Studies, Korean Society of Nephrology; Diabetes Metab J. 2020;44(4):489-497. Published online August 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0172

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Abstract PDF Supplementary Material PubReader ePub

Diabetes is a leading cause of end-stage renal disease. Therefore, prevention of renal dysfunction is an important treatment goal in the management of diabetes. The data of landmark cardiovascular outcome trials of sodium-glucose cotransporter-2 (SGLT2) inhibitor showed profound reno-protective effects. The Korean Diabetes Association and the Korean Society of Nephrology reviewed clinical trials and performed meta-analysis to assess the effects of SGLT2 inhibitors on the preservation of estimated glomerular filtration rate (eGFR). We limited the data of SGLT2 inhibitors which can be prescribed in Korea. Both eGFR value and its change from the baseline were significantly more preserved in the SGLT2 inhibitor treatment group compared to the control group after 156 weeks. However, some known adverse events were increased in SGLT2 inhibitor treatment, such as genital infection, diabetic ketoacidosis, and volume depletion. We recommend the long-term use SGLT2 inhibitor in patients with type 2 diabetes mellitus (T2DM) for attenuation of renal function decline. However, we cannot generalize our recommendation due to lack of long-term clinical trials testing reno-protective effects of every SGLT2 inhibitor in a broad range of patients with T2DM. This recommendation can be revised and updated after publication of several large-scale renal outcome trials.

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Real-World Treatment Patterns according to Clinical Practice Guidelines in Patients with Type 2 Diabetes Mellitus and Established Cardiovascular Disease in Korea: Multicenter, Retrospective, Observational Study
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Renoprotective Mechanism of Sodium-Glucose Cotransporter 2 Inhibitors: Focusing on Renal Hemodynamics
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Original Articles

Complication
Soluble Dipeptidyl Peptidase-4 Levels Are Associated with Decreased Renal Function in Patients with Type 2 Diabetes Mellitus: Eun-Hee Cho, Sang-Wook Kim; Diabetes Metab J. 2019;43(1):97-104. Published online October 8, 2018; DOI: https://doi.org/10.4093/dmj.2018.0030

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Abstract PDF PubReader

Background

Dipeptidyl peptidase-4 (DPP-4) is strongly expressed in the kidney, and soluble levels of this protein are used as a marker in various chronic inflammatory diseases, including diabetes, coronary artery disease, and cancer. This study examined the association between the serum soluble DPP-4 levels and renal function or cardiovascular risk in patients with type 2 diabetes mellitus.

Methods

In this retrospective analysis, soluble DPP-4 levels were measured in preserved sera from 140 patients with type 2 diabetes mellitus who had participated in our previous coronary artery calcium (CAC) score study.

Results

The mean±standard deviation soluble DPP-4 levels in our study sample were 645±152 ng/mL. Univariate analyses revealed significant correlations of soluble DPP-4 levels with the total cholesterol (r=0.214, P=0.019) and serum creatinine levels (r=−0.315, P<0.001) and the estimated glomerular filtration rate (eGFR; estimated using the modification of diet in renal disease equation) (r=0.303, P=0.001). The associations of soluble DPP-4 levels with serum creatinine and GFR remained significant after adjusting for age, body mass index, and duration of diabetes. However, no associations were observed between soluble DPP-4 levels and the body mass index, waist circumference, or CAC score.

Conclusion

These data suggest the potential use of serum soluble DPP-4 levels as a future biomarker of deteriorated renal function in patients with type 2 diabetes mellitus.

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Renoprotective Effects of DPP-4 Inhibitors
Daiji Kawanami, Yuichi Takashi, Hiroyuki Takahashi, Ryoko Motonaga, Makito Tanabe
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Urinary Neutrophil Gelatinase-Associated Lipocalin Levels in Comparison with Glomerular Filtration Rate for Evaluation of Renal Function in Patients with Diabetic Chronic Kidney Disease: Kwang-Sook Woo, Jae-Lim Choi, Bo-Ram Kim, Ji-Eun Kim, Won-Suk An, Jin-Yeong Han; Diabetes Metab J. 2012;36(4):307-313. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.307

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Abstract PDF PubReader

Background

Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker of acute kidney injury. There is a growing body of evidence suggesting that NGAL is also a marker of kidney disease and severity in chronic kidney disease (CKD). We studied the utility of urinary NGAL in more accurately predicting renal function in patients with diabetic CKD.

Methods

We studied possible relationships between urinary NGAL, estimated glomerular filtration rate (eGFR), and proteinuria in diabetic CKD patients and in healthy populations.

Results

Urinary NGAL levels were significantly higher in CKD patients than in healthy controls (96.0 [2.7 to 975.2] ng/mL vs. 18.8 [1.3 to 81.9] ng/mL, P=0.02), and the GFR was lower among CKD patients (49.3 [13.1 to 78.3] mL/min/1.73 m² vs. 85.6 [72 to 106.7] mL/min/1.73 m², P<0.0001). The urinary NGAL level showed a significant inverse correlation with GFR (r=-0.5634, P<0.0001). The correlation analyses between urinary protein level and urinary NGAL levels and GFR were as follows: urine protein and urinary NGAL (r=0.3009, P=0.0256), urine protein and GFR (r=-0.6245, P<0.0001), urine microalbumin and urinary NGAL (r=0.1794, P=0.2275), and urine microalbumin and GFR (r=-0.5190, P=0.0002).

Conclusion

From these results, we concluded that urinary NGAL is a reliable marker of renal function in diabetic CKD patients. However, urinary NGAL did not provide more accurate information regarding renal function than GFR.

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Clinical Significance of Decreased Glomerular Filtration Rate (GFR) without Albuminuria among Type 2 Diabetics.: Ji Eun Lee, Kyu Chang Won, Hyoung Woo Lee, Ji Sung Yoon; Korean Diabetes J. 2008;32(3):252-258. Published online June 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.3.252

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Abstract PDF

BACKGROUND
Microalbuminuria in type 2 diabetes is a predictor of development of clinical nephropathy and cardiovascular disease. But, it has been reported that reduced glomerular filtration rate (GFR) may occur in some normoalbuminuric diabetic patients. The aim of this study was to identify whether decreased GFR without microalbuminuria is to predict diabetic vascular complications. METHODS: Between January 1998 and February 2001, 73 patients with type 2 diabetes who visited Yeungnam university medical center were divided into 5 groups according to initial GFR ranges: group 1 (GFR < 30 mL/min), group 2 (30 < or = GFR < 60 mL/min), group 3 (60 < or = GFR < 90 mL/min), group 4 (90 < or = GFR < 125 mL/min), group 5 (125 mL/min < or = GFR). They were examined for microvascular and macrovascular complications initially and after 4 years. RESULTS: Decreased GFR had a negative correlation with age (r = -0.472, P = 0.001). Decreased GFR without microalbuminuria had a significant correlation with development of diabetic nephropathy (P = 0.016) after 4 years. There were no significant correlation with the prevalence of diabetic retinopathy, peripheral neuropathy, and macrovacular disease. But, our study showed that coronary artery disease had an increasing tendency with decreased GFR without statistical significance (P = 0.085). CONCLUSIONS: Our data suggest that reduced GFR, independent of albuminuria, may be an important predictor of diabetic nephropathy and coronary artery disease to some extent. So we recommend that not only the microalbuminuria, but also the decrease in GFR should be evaluated at the follow-up of patients with type 2 diabetes.

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Screening and Management of Diabetic Nephropathy
Ji Sung Yoon
The Journal of Korean Diabetes.2013; 14(1): 19. CrossRef

Changes of Glomerular Filtration Rate and Urinary Albumin Excretion Rate in NIDDM patients with Microalbuminuria.: Hyo Jung Kim, Jung Min Koh, Eun Sug Shin, Yun Ey Chung, Young Il Kim, Chul Hee Kim, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee; Korean Diabetes J. 1997;21(4):414-424. Published online January 1, 2001

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Abstract PDF: BACKGROUND
We previously suggested that micro-albuminuria in the presence of retinopathy may represent a state of real incipient diabetic nephropathy with declining glomerular filtration rate(GFR), while the meaning of microalbuminuria in the absence of retinopathy may be more heterogeneous. This study was performed to further test this hypothesis. METHODS: We prospectively followed up the changes in GFR and urinary albumin excretinn rate (UAE) in microalbuminuric NIDDM patients with or without diabetic retinopathy for 3.1 years. RESULTS: 1) Among 45 patients who completed the followup, 27 had retinopathy from the baseline(group A), while 18 patients did not have retinopathy throughout the study(group B). 2) UAE at baseline was not statistically different between the group A and group B. During follow-up, VAE remained stable in the group B patients(40.0 [20.5 ~ 158.0) to 60.0[20.2 ~ 231.0] ug/min, NS). On the other hand, UAE significantly increased in the group A patients(47.9[20.0~186.0] to 140.0[24.5~2862.0] ug/min, P <0.001). 3) Thirty percent of the group A patients(8/27) progressed to overt proteinuria, while 11%(2/18) of the group B patients developed overt proteinuria(NS). 4) GFR significantly decreased both in the group A (113.0+21.2 to 89.1+24.0 mL/min/1.73 m, P < 0,001) and in the group B patients(134.1+27.2 to 121.5+27.3 mL/min/1.73 m, P<0.01). However, the magnitude of change in GFR was significantly higher in the group A than in the group B patients(7.7+7.6 vs 3.9+4.2 mL/min/1.73 m /year, P <0.05), 5) Multiple logistic regression analysis revealed that the presence of retinopathy was a independent risk factor for faster decline in GFR. CONCLUSION: It appears that clinical course is different in NIDDM patients with microalbuminuria, according to the presence or absence of diabetic retinopathy. Microalbuminuria in the presence of retinopathy predicts aggravation of albuminuria and decline in GFR. In contrast, the renal function in microalbuminuric NIDDM patients in the absence of retinopathy may remain stable for years.

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