| Highlights |
|
Chronic kidney disease (CKD) is a common microvascular complication in patients with type 1 and type 2 diabetes. It is defined as persistent albuminuria (urinary albumin excretion [UACR] > 30 mg/24 hours or urinary albumin/creatinine ratio > 30 mg/g), persistent reduction in estimated glomerular filtration rate (eGFR) below 60 ml/min per 1.73 m2, or both, for at least 3 months.
When referring to kidney disease in patients with diabetes, the terms diabetic kidney disease (DKD) and diabetic nephropathy are frequently used interchangeably. However, there are important differences between these terms.
- Diabetic kidney disease is a clinical diagnosis that describes the development of CKD in diabetes based on signs, symptoms, and laboratory values.
- Diabetic nephropathy is a morphological diagnosis that refers to the pathological glomerular lesions characteristic of CKD caused by diabetes.
This distinction is important because up to 30% of patients with ERD may have other causes of CKD on renal biopsy and therefore their clinical presentation and management may differ. This review focuses on the treatment of patients with CKD due to diabetes, with no other known causes, known as ERD.
Higher levels of albuminuria and lower eGFR are independently and cumulatively associated with increased risk of cardiovascular (CV) and all-cause mortality. In general, people with CKD have twice the risk of cardiovascular disease (CVD) compared to people without CKD.
Until very recently, treatments to prevent the development and progression of ERD were limited to control of blood glucose, blood pressure, and the use of renin-angiotensin system blockers, resulting in a significant residual risk that helped establish ERD as an increasingly important global public health problem.
The availability of newer classes of hypoglycemic agents, including sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and nonsteroidal mineralocorticoid receptor antagonist , finerenone, will undoubtedly change this therapeutic landscape.
The goal of this article is to provide a concise, easy-to-use update on guideline-recommended care, including the importance of early detection as well as personalized follow-up with a focus on treatment that reduces the risk of disease progression. kidney and cardiovascular death.
| Methods |
Recent guidelines for the management of type 2 diabetes from the American Diabetes Association (ADA) were analyzed, as well as joint guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology and joint guidelines from the European Society of Cardiology and the European Association for the Study of Diabetes. Additionally, different clinical trials were surveyed.
| Diagnosis of ERD |
Diabetic kidney disease is usually diagnosed and classified by the presence of albuminuria or a reduction in eGFR in the absence of clinical indicators of other causes of kidney disease. ERD typically manifests in a patient with long-standing type 2 diabetes (>10 years) in the presence of retinopathy, albuminuria without macroscopic hematuria, and progressive decline in eGFR.
Alternatively in a subset of patients, evidence of ERD with reduced eGFR may be present at the time of diagnosis of type 2 diabetes in the absence of retinopathy and albuminuria.
Because ERD is generally asymptomatic until advanced stages, international guidelines recommend that all people with type 2 diabetes have eGFR and UACR measured at diagnosis and annually thereafter. People with type 1 diabetes should be screened within 5 years of diagnosis.
When used together, eGFR and UACR improve risk stratification and diagnostic accuracy. More frequent testing is recommended for elevated UACR above 300 mg/g or eGFR of 30 to 60 ml/min per 1.73 m2.
> Review of the key points of current clinical guidelines
To slow the progression of kidney disease and reduce CV events, people with ERD should receive comprehensive care.
The foundation of this care includes a structured educational program of diabetes self-management, diet, exercise, and smoking cessation counseling, as well as treatment of hyperglycemia, optimization of blood pressure control with ACEIs (converting enzyme inhibitors). of angiotensin) or ARA 2 (angiotensin 2 receptor antagonists) and lipid control.
> Lifestyle interventions
Special emphasis should be placed on adhering to a healthy diet rich in vegetables, plant-based proteins, whole grains, unsaturated fats, fiber and nuts. Sodium chloride intake should be limited to less than 5 g/d. Lower levels of physical activity have been associated with an increased risk of atherosclerotic CVD and risk of death.
> Glycemic goals
The guidelines recommend a target glycosylated hemoglobin (HbA1c) of less than 6.5% for patients at low risk of hypoglycemia and without comorbidities, less than 7.0% for most patients, and less than 8.0% for elderly and those with multiple comorbidities or advanced ERD.
> Glycemic Monitoring
The recommended biomarker for long-term monitoring of blood glucose is HbA1c . It should be considered that the value may decrease due to factors that reduce the useful life of erythrocytes and are frequently present in patients with more advanced CKD, such as in the presence of anemia, after a blood transfusion and during the use of erythrocyte-stimulating agents. erythrocytes or iron replacement therapy.
In contrast, in later stages of ERD, HbA1c levels may falsely increase due to metabolic acidosis and formation of advanced glycation end products. In these patients and in individuals on hemodialysis, for whom the reliability of HbA1c is uncertain, self-monitoring of blood glucose concentration or continuous glucose level monitoring is recommended to inform daily treatment decisions.
> Antihyperglycemic therapeutic options
Current international standards specify that in people with or at high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure, or kidney disease, SGLT2 inhibitors or GLP-1 RAs can be used as first-line therapy with and without metformin. .
Although SGLT2 inhibitors were initially developed as antihyperglycemic agents, they are now recommended for most patients with type 2 diabetes and eGFR below 60 ml/min per 1.73 m2 without albuminuria and for those with albuminuria of 200 mg/g or more, regardless of the need for decreasing HbA1c or individualized HbA1c.
GLP-1 RAs with proven CV benefits (long-acting GLP-1 RAs) can be used interchangeably with SGLT2 inhibitors in patients with eGFR below 60 ml/min per 1.73 m2 or in those with albuminuria who They do not tolerate SGLT2 inhibitors. GLP-1 RAs with proven CV benefits can be used if SGLT2 inhibitors are not tolerated or are contraindicated.
These drugs are also the preferred option for patients with type 2 diabetes and eGFR of 2 ml/min per 1.73 m2 or less or UACR of 30 mg/g or more (no dose adjustments required), with high or existing risk of atherosclerotic cardiovascular disease or in the presence of metabolic risk factors such as poorly controlled type 2 diabetes and obesity.
Additionally, semaglutide is recommended as an effective weight management therapy in people with type 2 diabetes.
> Blood pressure control
A target blood pressure below 140/90 mm Hg is recommended for patients with a 10-year ASCVD risk of less than 15%. For patients at increased risk, including existing ASCVD, 10-year ASCVD risk of 15% or greater, and mild to moderate albuminuria (UACR >30 to 300 mg/d), a blood pressure goal below 130/80 mm Hg if it can be achieved safely.
To achieve reductions in the development of albuminuria, progression of ERD, and risk of renal failure in patients with hypertension and mild to moderate (UACR 30 to 300 mg/d) or severe albuminuria (UACR >300 mg/d), the initiation and subsequent dose increase to the maximum tolerated doses of ACEI and ARA 2.
Combination therapy of ACEI plus ARB 2 is not recommended due to lack of additional benefit and increased risks of hyperkalemia and acute kidney injury.
The recently approved nonsteroidal mineralocorticoid receptor antagonist, finerenone, has lower rates of hyperkalemia. It is recommended to reduce the progression of CKD and the risk of cardiovascular events.
> Lipid management
At the time of CKD diagnosis, every adult with diabetes should have a lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides).
All adults 18 to 49 years of age who have not been treated with long-term dialysis or kidney transplant should be treated with statins , and those over 50 years of age should be treated with statins or a statin/ezetimibe combination.
Due to concerns about increased toxicity, CKD-specific lipid management guidelines suggest the use of a statin dose reduction for people with an eGFR less than 60 mL/min per 1.73 m2.
> Strategies to overcome key clinical concerns
In view of the benefits of treatment with SGLT2 inhibitors and GLP-1 RAs, their incorporation into clinical care is strongly recommended for patients with type 2 diabetes and ERD.
Concerns about the use of SGLT2 inhibitors, particularly with respect to potential adverse effects such as euglycemic diabetic ketoacidosis and the risk of gangrene and genital fungal infections, may explain the restricted adoption of SGLT2 inhibitors in clinical practice.
Similarly, primary care providers’ limited experience with GLP-1 RAs and concerns about tolerability, particularly gastrointestinal adverse effects, have contributed to delayed acceptance of these agents.
> SGLT2 inhibitors
Clinical studies with SGLT2 inhibitors have indicated that these agents are associated with an initial decrease in eGFR of 3 to 5 ml/min per 1.73 m2 in patients with type 2 diabetes and baseline eGFR greater than 30 ml/min per 1 .73 m2. However, clinicians should note that after the initial "eGFR drop," kidney function will typically return to baseline in the following weeks and remain stable during SGLT2 inhibitor therapy or until SGLT2 inhibitor therapy is discontinued. medicine.
One of the most common adverse effects of SGLT2 inhibitor therapy is the development of genital fungal infections, which occur more frequently in women than in men. The risk of this event can be reduced by counseling patients to practice hygiene measures, including daily rinsing of the genital area after urination and at bedtime.
Another common concern with the use of SGLT2 inhibitors is the development of volume depletion and hypovolemia due to their diuretic action, particularly among patients receiving concurrent diuretic therapy. However, it is not usually necessary to discontinue or modify diuretic therapy with the initiation of SGLT2 inhibitors, although monitoring electrolyte levels is recommended when adjusting the dosage of diuretic or antihypertensive agents.
Diabetic ketoacidosis is a rare but potentially serious adverse effect associated with SGLT2 inhibitor therapy. It is thought to be due to increased oxidation of fatty acids combined with reduced insulin secretion and usually occurs in patients with long-standing type 2 diabetes who are receiving insulin therapy.
Another rare but serious adverse effect is Fournier’s gangrene, a type of necrotizing fasciitis that affects the external genitalia and perineum. This occurs more frequently in men than women and has been reported in post-marketing safety reports with a frequency of about 1 in 10,000 patients. Clinicians should maintain a high index of suspicion for this rare adverse event and advise patients to seek urgent medical attention in the presence of a serious or worsening genital infection.
> AR LPG-1
Delayed gastric emptying , due to the same mechanism that results in the strong postprandial antihyperglycemic effect of this class of medications, underlies the most common adverse effects of GLP-1 RAs of nausea, vomiting, and diarrhea. The risk of these effects can be reduced by starting treatment with the lowest possible dose and increasing the dose over several weeks.
These drugs can cause stimulation of the sympathetic nervous system, leading to an increase in heart rate, although no harmful effects of this have been reported to date.
They should be used with caution in patients with a history of cholelithiasis and in addition, concerns have been raised about the risk of pancreatitis with GLP-1 RA therapy, although the risk of this event appears to be very low.
| Conclusions |
The health consequences of ERD are serious. Early identification and initiation of interventions that can prevent the progression of kidney disease along with reducing CVD rates and risk of death are crucial.
Until the introduction of SGLT2 inhibitors and GLP-1 RAs into clinical practice, even the most advanced standard of care resulted in a significant residual risk of ERD progression.
For the first time we have at our disposal therapeutic agents that promise to reduce and ultimately reverse the trend of morbidity and mortality associated with ERD. At the same time, we are increasingly aware of the importance of patients’ active role in their own care, with treatment approaches tailored to their individual needs.
To achieve this paradigm shift in care, we aspire to an integrated multidisciplinary approach that incorporates opportunities for the primary care physician, along with nephrologists, cardiologists, and endocrinologists, to co-manage treatments in the harmonized effort to reduce the burden of disease and improve the quality of life of patients with ERD. In parallel with healthcare, there is a need for a revitalized legislative effort that allows access to life-saving therapies.
