The mainland is not only a major country for diabetes, but also a country for chronic kidney disease (CKD), and the management of CKD related to type 2 diabetes mellitus (T2DM) faces great challenges such as a large number of patients and limited treatment methods. In recent years, microalbuminuria has become a key indicator for screening, diagnosis, and evaluation of efficacy of T2DM-related CKD, and experts at home and abroad have unanimously called for and explored the optimal management of CKD with urine albumin-to-creatinine ratio (UACR) as the intervention target [1]. The latest data show that nearly three-quarters (72.6%) of patients with T2DM-associated CKD in mainland China are in the microalbuminuria phase (UACR 30~300 mg/g) [2]. The long-term persistence of microalbumin has become a major problem for clinicians, and many patients with diabetic nephropathy have fallen into treatment difficulties, and the difficulty of treating proteinuria also means that the progression of the disease is not effectively controlled, and the risk of adverse renal and cardiac outcomes increases.
In this paper, Yao Ting, deputy chief physician of the Second Affiliated Hospital of Chengdu Medical College, shared the diagnosis and treatment experience of a related case, and invited Ran Xingwu, chief physician of West China Hospital of Sichuan University, to comment on the case. It is hoped that this case sharing will provide inspiration for clinicians to treat similar patients.
Case authors
Yao Ting, Deputy Chief Physician
Review experts
Ran Xingwu is the chief physician
Basic patient information
The patient, a 51-year-old male, presented in April 2023 with "elevated blood glucose for 11+ years and proteinuria for 6+ years".
History and physical examination
History of present illness
The patient was diagnosed with "type 2 diabetes" 11+ years ago due to "dry mouth, polydipsia, polyuria, and weight loss", and was given hypoglycemic therapy such as metformin, acarbose, and gliclazide sustained-release tablets. 6+ years ago, he was admitted to the hospital due to "poor blood sugar control", and the examination found that HbA1c was 9.9%, fasting blood glucose was 14.5 mmol/L, and the pancreatic islet function was poor, and insulin aspart 30 combined with acarbose was given to control glucose, and microalbuminuria (UACR 86 mg/g) was found for the first time, and strict lifestyle intervention (diet and exercise therapy) and strict glucose control were ordered. After that, the patient was followed up regularly, and the overall glycemic control was acceptable.
When the patient was hospitalized again 3+ years ago due to "numbness of both lower limbs", it was found that the persistent microalbuminuria increased (UACR 101 mg/g), the renal function decreased significantly (serum creatinine 198 μmol/L, eGFR 33.7 ml/min/1.73m2), and the blood lipids increased significantly (triglycerides 2.23 mmol/L, total cholesterol 6.85 mmol/ L, the rest of the lipid-related indexes were not abnormal), fundus examination showed hard exudation of the fundus, so the treatment regimen was adjusted, acarbose was discontinued, and DPP-4 inhibitor was combined with insulin (insulin aspart 30 injection 20u ih before breakfast and 18u ih before dinner), and SGLT2 inhibitor (dapagliflozin 10 mg qd) was activated, and atorvastatin was added to regulate lipids.
After that, the patient's blood glucose was well controlled, and the original hypoglycemic treatment regimen was maintained, but the albuminuria gradually worsened, and progressed from micro-volume to massive albuminuria 2+ years ago (April 2022, 24-hour urine protein quantification was 312 mg/24 h; in April, October, and December 2022, UACR was 298 mg/g, 326 mg/g, and 297 mg/g, respectively), accompanied by an increase in serum creatinine, and the eGFR fluctuated at 30~60 ml/min/1.73m2 (April, 10, 2022, In December, the serum creatinine was 119 μmol/L, 201 μmol/L, and 122 μmol/L, and the eGFR was 61.4 ml/min/1.73 m2, 32.6 ml/min/1.73 m2, and 59.6 ml/min/1.73 m2, respectively. Symptoms of diabetic peripheral neuropathy are mild and severe, and fundus examination shows persistent effusion, and no microhemangiomas or hemorrhagic spots are seen. Traditional complications treatment drugs such as nephritis rehabilitation tablets, calcium oxybenzenesulfonate, piperazine ferulate, pancreatic kininogenase, and epastastat were added successively, and the symptoms were not significantly relieved. The patient's UACR fluctuated around 300 mg/g, and repeatedly jumped horizontally between "microalbuminuria" and "macroalbuminuria". He is now seeing a doctor to further improve proteinuria and renal function.
Anamnesis
No special.
physical examination
Blood pressure 130/78 mmHg, weight 68 kg, BMI 25.28 kg/m2, waist circumference 94 cm. The dorsalis pedis artery pulse was present, and there were no obvious abnormalities in the acupuncture, temperature, vibration, and pressure sensations of both lower limbs.
Laboratory tests
INVESTIGATIONS
Fundus examination: exudation can be seen in the fundus, and there are no microhemangiomas and hemorrhage spots.
Carotid ultrasound: the thickness of the common carotid artery intima was uneven, with the last 16.8 mm × 3.0 mm at the bifurcation of the right common carotid artery and 10.2 mm × 2.2 mm at the thickest part of the posterior wall of the left common carotid artery.
Current diagnosis
Type 2 Diabetes
糖尿病合并慢性肾脏病(Q3B2期)
Diabetic peripheral neuropathy
Diabetic retinopathy (non-proliferative phase)
Treatment ideas and medication adjustments
Combined with the individual situation of the patient, Deputy Chief Physician Yao Ting sorted out the characteristics of the case as follows:
01
Middle-aged males who have been diagnosed with diabetes for a long time (more than 10 years);
02
Multiple diabetes-related complications, including T2DM-associated CKD with proteinuria, diabetic retinopathy (non-proliferative), and diabetic peripheral neuropathy;
03
Lifestyle intervention and comprehensive management of blood glucose, blood lipids, and blood pressure (without hypertension) have been adopted, combined with drugs such as kidney protection, microcirculation improvement, and neuronutrition, but a variety of complications have not been alleviated, and renal lesions have a tendency to progress slowly.
Combined with the above characteristics, and considering that the patient has a strong willingness to treat, high compliance, and acceptable economic conditions, the UACR is still gradually increasing after comprehensive management of blood glucose, blood lipids, and blood pressure. According to the current guideline recommendations and instructions, the serum potassium level of the patient should be assessed at the beginning of finerenone, and the low-dose 10 mg once a day or the standard dose of 20 mg once a day should be selected according to the eGFR level, and the serum potassium should be measured and the dose adjusted within 4 weeks after starting treatment. At the beginning (April 2023), the patient's serum potassium level was < 4.8 mmol/L, and the eGFR was slightly less than 60 ml/min/1.73 m2 (54.8 ml/min/1.73 m2), so the starting dose of finerenone was 10 mg qd.
At the follow-up (May 2023) after 1 month of finerenone treatment, the serum potassium < 4.8 mmol/L and eGFR 32.3 ml/min/1.73m2 were rechecked, which were significantly lower than those 1 month ago, but the proteinuria was significantly relieved (UACR decreased from 216 mg/g to 168 mg/g). However, the patient was deeply anxious because he could not buy the drug, and successively stopped nephritis rehabilitation tablets, pancreatic kininogenase and epalastat. Through online follow-up, the patient repeatedly expressed concerns about his kidney function and voluntarily adjusted the dose of finerenone to 20 mg once a day. As the doctor in charge, Deputy Chief Physician Yao Ting fully understands the patient's concern and expectation for his own health on the one hand, calms the patient's anxiety, and on the other hand, educates and communicates with the patient, requiring the patient to closely monitor the renal function indicators in the local area and contact him at any time if he has any questions.
At the follow-up (July 2023) after 3 months of finerenone treatment, the patient's albuminuria was further decreased, with UACR 67 mg/g, serum creatinine 178 μmol/L, eGFR 37.5 ml/min/1.73m2, no abnormal electrolytes, and a slight recovery in renal function. The patient was satisfied with the outcome and continued maintenance therapy.
At the follow-up (September 2023) after 5 months of finerenone treatment, the UACR decreased to 43 mg/g, the serum creatinine decreased to 106 μmol/L, and the eGFR increased to 70.1 ml/min/1.73m2.
At the follow-up (November 2023) after 7 months of finerenone treatment, the patient's eGFR was maintained at 69.3 ml/min/1.73m2 and UACR 61 mg/g, and the patient was very satisfied with the treatment effect.
Changes in urine protein and renal function from the time albuminuria was first identified to the initiation of finerenone treatment are shown in Figure 1. It can be seen that albuminuria improves rapidly and remains low after finerenone therapy, and eGFR gradually recovers and improves to normal levels after a transient decline. During finerenone treatment, serum potassium levels remain normal.
Figure 1. Changes in urine protein and renal function before and after initiation of finerenone therapy
In addition, at the follow-up (September 2023) after 5 months of finerenone treatment, a re-examination of the fundus showed that the previous hard exudation of the fundus disappeared and the diabetic retinopathy (DR) was significantly relieved (Fig. 2).
Figure 2. Fundus changes before and after initiation of finerenone treatment
Expert commentary
Clinically, patients with a long course of diabetes, even if the progression of diabetes-related complications is found, they are usually limited by the lack of treatment and feel powerless. For example, this case had T2DM-associated CKD with albuminuria for more than 6 years, but it has been poorly controlled, and the disease has gradually progressed. On the basis of lifestyle intervention, the patient comprehensively managed blood glucose, blood lipids, and blood pressure (because of normal blood pressure, RAS inhibitors were not used), and were given traditional Chinese and Western drug treatments such as kidney protection and microcirculation improvement, and SGLT2 inhibitors were enabled 3+ years ago to protect the heart and kidney and assist in lowering urine protein, but diabetes-related complications are still progressing slowly, especially the treatment effect of albuminuria is very small, UACR fluctuates around 300 mg/g, and eGFR once dropped to only slightly higher than 30 ml/min/ 1.73m2。 At this time, the treatment of this patient is in a dilemma, what other "weapons" can help the clinic?
The emergence of a new non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone, has brought a new dawn to patients with T2DM-related CKD. This is the world's first novel MRA that has been shown to have clear renal and cardiovascular protective effects in patients with T2DM-associated CKD, which can not only improve renal and cardiac outcomes, reduce the risk of renal composite endpoint and cardiovascular composite endpoint, but also show a significant effect in reducing albuminuria, reducing UACR by 32% and remaining stable at 4 months [3]. In this patient, the effect of finerenone in lowering urine albumin was verified, reducing UACR by 22% after 1 month and 69% after 3 months of treatment, and then remained stable. The microalbuminuria phase is regarded as an effective "window period" to "reverse" the condition of CKD, and with the significant reduction of urine protein, the patient's renal function also improves correspondingly, which is more helpful to improve treatment compliance and treatment confidence, delay the progression of diabetic nephropathy and reduce the risk of future cardiovascular events.
We noted that this patient experienced a short-term decrease in eGFR after finenrenone. This situation is thought to be due to the rapid impact of MRA on intraglomerular pressure and hemodynamics at the initial stage of treatment, so a significant decrease in eGFR can occur in the early stages of treatment, mostly within one month of initiation of treatment [4]. In fact, current medications used for the management of diabetes-related CKD, such as RAS inhibitors and SGLT2 inhibitors, cause a decrease in eGFR early in treatment, which is mostly transient and independent of nephron loss. An early reversible decrease in eGFR does not mean that these agents need to be discontinued, and it does not affect the long-term cardiorenal benefit of these agents. In this case, the eGFR decreased in the first month of finerenone treatment, but then began to rise, and the eGFR improved to more than 60 ml/min/1.73 m2 by 4 months of treatment, and the response was maintained subsequently.
In addition, we observed fundus improvement after finerenone initiation in this case, which was both surprising and proven. In addition to diabetic nephropathy, the patient also had diabetic retinopathy (DR). In fact, CKD and DR share common risk factors and similar pathophysiology [5], and they often occur together. The patient had DR on fundus examination 3+ years ago and continued until the initiation of finerenone therapy, while re-examination after 4 months of finerenone treatment showed the disappearance of the previous hard exudate from the fundus, indicating that DR had been significantly relieved.
This corroborates the results of a previously published retrospective analysis (ReFineDR/DeFineDR study). The study found a potential benefit of combining finerenone with standard care (RAS inhibitors) in patients with T2DM-associated CKD and DR—reducing the tendency to develop vision-threatening events and reducing the proportion of patients requiring ocular intervention, which may prevent the progression of nonproliferative DR [6]. This suggests that finerenone may bring a wider range of long-term benefits to patients with T2DM-related CKD beyond the heart and kidney, and it is expected that it will be supported and verified by more research evidence in the future.
In conclusion, when the current standard treatment of T2DM-related CKD patients had been used but the microalbuminuria was still poorly controlled for a long time, and the treatment was deadlocked, the initial finerenone treatment brought a significant turnaround, and the patient's proteinuria and renal function were significantly improved in the short term, and the DR was also significantly relieved, and the safety was good, the serum potassium was normal during the treatment, and the patient satisfaction was high. It is suggested that for appropriate patients with T2DM-related CKD, early management of microalbuminuria should be carried out, and finerenone, a drug with clear renal and cardiac benefits, can be used in combination with SGLT2 inhibitors in a timely manner, so as to further strengthen the management of albuminuria, break the treatment dilemma as soon as possible, and benefit from early use.
Expert Profile
Ran Xingwu
Professor, Chief Physician, Master's Supervisor, Postdoctoral Supervisor. Director of the Diabetic Foot Diagnosis and Treatment Center of West China Hospital, Sichuan University, Director of the Wound Repair Innovation Center of West China Hospital, Sichuan University, and Director of the Department of Endocrinology, West China Hospital, Sichuan University. Member of the Standing Committee of the Diabetes Branch of the Chinese Medical Association and the leader of the Diabetic Podiatry and Peripheral Vascular Disease Group, Vice Chairman of the Tissue Infection and Injury Prevention and Control Professional Committee of the Chinese Preventive Medicine Association, Vice Chairman of the Internal Medicine Training Professional Steering Committee of the Chinese Medical Doctor Association, Vice Chairman of the Diabetic Foot Branch of the Chinese Association for the Promotion of International Exchange in Health Care, Chairman of the Endocrinology and Diabetes Professional Committee of the Western Psychiatric Association, Vice President of the Sichuan Diabetes Prevention and Control Association, Chairman of the Wound Repair Professional Committee of the Sichuan Medical Association, and Chairman of the Endocrinology and Diabetes Professional Committee of the Sichuan Medical AssociationHe is the vice president of the Endocrinology and Metabolism Specialist Branch of Sichuan Medical Doctor Association, the academic and technical leader of Sichuan Province, and the leading talent of Sichuan Provincial Health and Family Planning Commission.
Yao Ting
He is an associate professor of Chengdu Medical College, and the deputy chief physician of the Second Affiliated Hospital of Chengdu Medical College of Chengdu Nuclear Industry 416 Hospital. He is an outstanding teacher of Chengdu Medical College, a member of the Sichuan Provincial Geriatric Endocrinology and Diabetes Committee, and a member of the Council of the Sichuan Diabetes Prevention and Control Association. He has been engaged in endocrinology clinical work for a long time, and is good at the diagnosis and treatment of obesity, diabetes, thyroid disease, osteoporosis, polycystic ovary syndrome, adrenal gland, pituitary gland and other related diseases, and has published more than 10 papers in core journals.
bibliography
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3. Agarwal R, et al. Eur Hart J. 2022; 43(6):474484.
4. Expert Group on the Application of Finerenone in Patients with Diabetes Mellitus and Chronic Kidney Disease (2023 Edition). Chinese Journal of Diabetes. 2023; 15(10): 907-916.
5. Park HC, et al. PLoS One. 2019; 14(7): e0220506.
6. Rossing P, et al. ADA 2022; Poster 826-P.