LABORATORIO DE URGENCIAS

Diabetic Kidney Desease 

Radica Alicic;Susanne B.Nicholas

J.Clinic Proceedings; 2022.05.003 – DOI:https://doi.org/10.1016

Chronic kidney disease (CKD) is a common microvascular complication in patients with both type 1 and type 2 diabetes. It is defined for this signs:
   1.Persistent albuminuria (urinary albumin excretion >30 mg/24 h or urinary albumin to creatinine ratio [UACR] >30 mg/g)
   2,Persistent reduction in estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m²,
   3.Both, for at least 3 months.

Current estimates suggest that approximately 40% of patients with type 2 diabetes have CKD (stages 1 to 4), more than half of whom (52.5%) have moderate to severe disease (stage 3 and stage 4).
In referring to kidney disease in patients with diabetes, the terms diabetic kidney disease (DKD) and diabetic nephropathy are frequently used interchangeably.This is incorrect, 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 tissue diagnosis that refers to the characteristic pathologic glomerular lesions specific of CKD caused by diabetes.
This distinction is important because up to 30% of patients with DKD may have other causes of CKD on kidney biopsy, and therefore their clinical presentation and management may differ. The observation that the clinical presentation and progression of CKD in patients with diabetes, and particularly type 2 diabetes, are heterogeneous. Other kidney diseases with which patients with diabetes may present include minimal change disease, primary focal and segmental glomerulosclerosis, and polycystic kidney disease alone or combined with diabetic nephropathy.
This review focuses on the management of patients with CKD due to diabetes (without other known causes), which is referred to as DKD.
As a consequence of the worldwide diabetes pandemic, recent decades have seen DKD become a global leading cause of kidney failure and the most frequent indication for kidney replacement therapy.
In contrast to the downward trends in other diabetes-related complications, including myocardial infarction, stroke, and limb amputation, the prevalence of DKD has not followed similar downward trends.
Higher albuminuria levels and lower eGFR are independently and additively associated with an increased risk for cardiovascular (CV) and all-cause mortality.For instance, the presence of kidney disease is associated with a sharp increase of 10-year cumulative all-cause mortality from 11.5% among individuals with diabetes and without kidney disease up to 31% among individuals with diabetes and kidney disease, indicating that most of the excess risk of all-cause and CV mortality for individuals with type 2 diabetes relates to the presence of DKD.
Overall, individuals with CKD have twice the risk of CV disease (CVD) compared with individuals without CKD, and death from CVD is more likely than progression to kidney failure. From the patient’s perspective, the progression of kidney disease has been associated with reduced quality of life.
Until very recently, treatments to prevent the development and progression of DKD were limited to glycemic and blood pressure control and the use of renin-angiotensin system blockers, resulting in the significant residual risk that helped establish DKD as a growing major global public health problem.
The availability of newer classes of glucose-lowering agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), and the nonsteroidal mineralocorticoid receptor antagonist finerenone, will undoubtedly change this therapeutic landscape.
Surprisingly, contemporary CV outcomes trials demonstrated reductions in not only CV events but also secondary kidney end points associated with the administration of SGLT2 inhibitors and GLP-1 RAs.
Subsequently, dedicated kidney outcomes trials have confirmed benefits associated with SGLT2 inhibitors in terms of reductions in the progression of kidney disease and CV death.Similarly, in patients with DKD, finerenone was shown to mitigate the progression of kidney disease, CV risks, and death.
As a result, there is increased recognition of the historic opportunity to reshape the care and lives of patients with DKD. The aim of this article is to provide a succinct, user-friendly update on guidelines-recommended care, including the importance of early detection, as well as tailored follow-up with a focus on treatment that reduces the risk of kidney disease progression and CV death, to improve overall clinical outcomes.

DIAGNOSIS OF DKD

Diabetic kidney disease is generally diagnosed and classified as the presence of albuminuria or a reduction in eGFR in the absence of clinical indictors of other causes of kidney disease. Typically, DKD is manifested in a patient with long-standing (>10 years) type 2 diabetes in the presence of retinopathy, albuminuria without macroscopic hematuria, and progressive eGFR decline.
Alternatively, in a subset of patients, evidence of DKD with reduced eGFR can be present at diagnosis of type 2 diabetes in the absence of retinopathy and without albuminuria.
Albuminuria is best assessed with spot urine samples (ideally, early morning samples) to calculate the UACR. Because DKD is usually asymptomatic until advanced stages, guidelines from the ADA and KDIGO recommend that all individuals with type 2 diabetes have eGFR and UACR measured at the time of diagnosis and annually thereafter.
Individuals with type 1 diabetes should be screened within 5 years of diagnosis. Evaluation of DKD, especially at the time of initial diagnosis, should include careful medical and family history to look for other possible causes of kidney disease, such as family history of polycystic kidney disease, presence of chronic infections (such as HIV infection, hepatitis C), autoimmune disorders (systemic lupus erythematosus, vasculitis), malignant neoplasms (lymphoma, myeloma, solid tumors), episodes of acute kidney injury, frequent infections, and exposure to toxins.
Kidney function is assessed by a serum creatinine or cystatin C–based eGFR calculation, preferably with the CKD Epidemiology Collaboration (CKD-EPI) equation, which is more accurate than the Modification of Diet in Renal Disease study equation.
The serum creatinine–based CKD-EPI eGFR equation includes approximately 16% higher eGFR values for individuals self-identified as Black because of the use of a correction factor for self-reported Black race.
Incorporation of the correction factor in the serum creatinine–based eGFR calculation was derived from findings of a small study that showed higher serum creatinine levels in Black vs White patients.
Although the findings were not validated by direct measurements of glomerular filtration or lean body mass, the correction factor for race has subsequently been used inappropriately as a proxy for serum creatinine, which is derived primarily from skeletal muscle, in other eGFR equations. However, serum creatinine values may reflect other conditions, such as dietary protein levels, vigorous exercise, or long-term glucocorticoid therapy, as well as changes in creatinine filtration.
On the other hand, the cystatin C–based CKD-EPI eGFR equation does not include a modifier for race and appears to have a more linear association with CV events compared with the creatinine-based CKD-EPI equation.
Given the approximately 4-fold higher prevalence of CKD in Blacks/African Americans, the National Kidney Foundation and the American Society of Nephrology created a Task Force to address the use of Black race in eGFR reporting in these vulnerable patients. As such, the Task Force has provided the following recommendations: use of the CKD-EPI creatinine-based equation without the race variable; use of cystatin C for eGFR confirmation in clinical decision-making; and research on new endogenous filtration markers that interventions may eliminate racial and ethnic disparities.
These approaches would advance unbiased assessments on informed decisions toward achieving health care equity for all individuals with CKD.
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. For instance, the ADA recommends twice-yearly monitoring for individuals with UACR of 300 mg/g or higher and CKD stage 3b and stage 4 (eGFR <45 mL/min per 1.73 m²) irrespective of therapy.
In addition, repeated testing should be performed if there is a change in clinical status (indicating rapid progression or advanced stages of DKD) or when new medications are started (such as an SGLT2 inhibitor, angiotensin-converting enzyme inhibitor [ACEI], or angiotensin receptor blocker [ARB]).Initiation of SGLT2 inhibitors or ACEI/ARBs may result in a transient reduction of up to 25% in eGFR, attributed to a change in glomerular hemodynamics rather than intrinsic renal disease, such as renal artery stenosis. Timely referral to a nephrologist may be considered for individuals with eGFR below 45 mL/min per 1.73 m² for coordinated care to slow the progression of DKD, to improve the management of complications as the disease worsens, and to prepare patients adequately for kidney replacement therapy, as indicated.
Referral to a nephrologist may also increase appropriate use of renin-angiotensin-aldosterone system blockers and optimal management of comorbidities, such as anemia, hypertension, and CKD mineral and bone disorders. Furthermore, referral to a nephrologist is strongly recommended once the eGFR drops below 30 mL/min per 1.73 m², if there is consistent finding of significant albuminuria (UACR ≥300 mg/g), if DKD progresses to a new CKD category, or if there is an abrupt, sustained decline in eGFR of more than 5 mL/min per 1.73 m² per year.

KEY POINTS FROM CURRENT CLINICAL GUIDELINES

To slow the progression of kidney disease and to reduce CV events, individuals with DKD should receive comprehensive care. The foundation of this care includes a diabetes structured self-management education program, diet, exercise, and smoking cessation counseling, as well as treatment of hyperglycemia, optimization of blood pressure control using ACEIs or ARBs, and lipid management.
The significant positive results of recent trials involving SGLT2 inhibitors, GLP-1 RAs, and finerenone on top of standard of care therapy with an ACEI or an ARB laid the foundation for new clinical guidelines recommending these agents in the treatment of DKD for their proven kidney and CV protective benefits

International Guideline Recommendations for Monitoring of Kidney Function and Risk Factor Management in Patients with Diabetes and DKD (ADA-2022)

I.- Monitorind of Kidney Function

A.Screening and Monitoring for DKD
   * At least annual UACR (preferably morning spot UACR) and eGFR in T1D ≥5 years
     and all T2D patients
    * Monitor twice annually if UACR >300 mg/g and/or eGFR 30-60 mL/min per 1.73 m²
B. Blood Pressure Management
    * <140/90 mm Hg for 10-year ASCVD risk of <15%
    * <130/80 mm Hg for 10-year ASCVD risk of >15% if appropriate and can be
       achieved safely
C. HbA_1c Targets.
    * <7.0% for most patients
    * <8.0% if high risk of hypoglycemia or multiple comorbidities

II.- Risk Factor Management

A. Lifestyle Interventions
Special emphasis in the approach to treatment of all DKD patients should be placed on adherence to a healthy diet high in vegetables, vegetable-based proteins, whole grains, unsaturated fat, fiber, and nuts. Sodium chloride intake should be limited to less than 5 g/d (equivalent to <2 g, or 90 mmol of sodium per day).
The recommended protein intake for all DKD patients, not on dialysis, is approximately 0.8 g/kg per day. Lower levels of physical activity have been associated with higher risk of atherosclerotic CVD (ASCVD) and risk of dying. Therefore, it is recommended that patients with DKD undertake 150 minutes per week of moderate-intensity activity. Similarly, to achieve the glycemic target, the level and intensity of activity should be adjusted to individual CV and physical tolerance.
B. Glycemic Targets
Achieving glycemic targets in individuals with DKD and especially advanced DKD is challenging primarily because of reduced kidney capacity for gluconeogenesis and altered metabolism and clearance of glucose-lowering therapies.Consequently, patients with DKD may be at high risk for hypoglycemia and other adverse drug events.
Within the guidelines, there is agreement on the need for individualized glycemic targets for people with type 2 diabetes. The choice of tighter or less rigorous targets should be based on individual factors, including CKD stage, presence and severity of comorbidities, and age of the patient.
Overall, the guidelines recommend a target glycated hemoglobin (HbA_1c) level of less than 6.5% for patients at low risk of hypoglycemia and no comorbidities, less than 7.0% for most patients, and less than 8.0% for elderly patients and those with multiple comorbidities or advanced DKD.
C.Glycemic Monitoting
The recommended biomarker for long-term monitoring of glycemia is HbA_1c, with several important caveats to keep in mind. The HbA_1cvalue may be decreased by factors that reduce the erythrocyte life span and are frequently present in patients with more advanced CKD, such as in the presence of anemia, after blood transfusion, and during the use of erythrocyte-stimulating agents or iron replacement therapy. These factors can decrease the precision and accuracy of HbA_1cmeasurements in advanced CKD, particularly in patients undergoing dialysiConversely, in later stages of DKD, levels of HbA_1c may be falsely increased by metabolic acidosis, carbamylation, and advanced glycation end-product formation.
In these patients and in individuals undergoing hemodialysis, for whom the reliability of the HbA_1c measurements is uncertain, self-monitoring of blood glucose concentration or continuous monitoring of glucose level is recommended to inform daily treatment decisions.
D. Antihyperglycemic Therapeutic Options
The 2022 ADA standards of care specify that in individuals with or at high risk for 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, at this point they are 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 higher independent of the need for HbA_1c lowering or individualized HbA_1c target.
The 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 are intolerant of SGLT2 inhibitors.
The 2022 KDIGO guideline recommendations differ from the 2022 ADA guidance as the 2022 KDIGO guideline recommends the use of SGLT2 inhibitors in all patients with eGFR above 20 mL/min per 1.73 m² independent of the presence of albuminuria. The GLP-1 RAs with proven CVD benefits can be used if SGLT2 inhibitors are not tolerated or are contraindicated.
The decision may be further informed by consideration of the individual preferences of the patient and balancing the risk of possible adverse effects with the risk of DKD progression.
 If additional therapy is required for glycemic management, a GLP-1 RA is generally preferred.
The GLP-1 RAs with proven CVD benefit are the preferred choice for patients with type 2 diabetes and eGFR of 2 mL/min per 1.73 m² or lower or UACR of 30 mg/g or higher (no dosage adjustments required), with existing or high risk of ASCVD, or in the presence of metabolic risk factors such as poorly controlled type 2 diabetes and obesity.
 Furthermore, semaglutide is recommended as an effective therapy for weight management in people with type 2 diabetes.
Patients should be monitored for rare but serious possible adverse effects mentioned later. In addition, patients should receive advice on symptom recognition and mitigating strategies.
E. Lipid Management
In 1998, the National Kidney Foundation Task Force on Cardiovascular Disease recommended that CKD patients be considered in the “highest risk group” for subsequent CV events.
The landmark Study of Heart and Renal Protection showed a significant decrease in atherosclerotic events with simvastatin and ezetimibe compared with placebo in dialysis-dependent and non–dialysis-dependent patients and helped shape the KDIGO clinical practice guidelines for lipid management in CKD patients.
Therefore, KDIGO recommends that at the time of CKD diagnosis, all adults with diabetes should have a lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides).
All adults aged 18 to 49 years not treated with long-term dialysis or kidney transplant should be treated with statin, and those 50 years of age and older should be treated with statin or statin/ezetimibe combination. Follow-up measurement of lipid levels after starting of a pharmacologic agent is not required for most patients. It could be considered to assess compliance with pharmacologic therapy. Because of concerns of increased toxicity, CKD-specific lipid management guidelines suggest using dose reduction of statins for individuals with eGFR below 60 mL/min per 1.73 m²
Unadjusted dosing used in the general population, including a high-intensity statin dosing, could be considered for individuals with eGFR of 45 to 59 mL/min per 1.73 m² with acute coronary syndrome. In this scenario, unadjusted dosing could be considered with even lower eGFRs unless there are significant drug interactions with concomitant medications.

CONCLUSION

The health consequences of DKD are severe.
Early identification and initiation of interventions that can prevent progression of kidney disease combined with reduction in rates of CVD and the risk of dying are crucial. Until the introduction of SGLT2 inhibitors and GLP-1 RAs into clinical practice, even state-of-the-art standard of care resulted in a significant residual risk for DKD progression. For the very first time we have at our disposal therapeutic agents that offer promise to abate and ultimately to reverse the trend of DKD-associated morbidity and mortality and associated human suffering.
Simultaneously we are increasingly becoming aware of the importance of the active role of patients in their own care, with treatment approaches tailored for their individual needs. Involving patients in shared clinical decision-making, including counseling about possible adverse effects, is key to optimizing treatment compliance with the new antihyperglycemic agents. To achieve this paradigm shift in care, we aspire to an integrated approach with a multidisciplinary focus that incorporates opportunities for primary care physicians and subspecialists, including nephrologists, cardiologists, and endocrinologists, to comanage treatments in the harmonized effort to reduce burden of disease and to improve quality of lives for patients with DKD. In parallel to medical care, there is a need for the reenergized legislative effort that will allow access to lifesaving therapies for all eligible individuals.

NOTE: this is an important part of the published work. Tables, Graphs, Text and Complete Bibliography in the work cited at the beginning.

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