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    Diabetic nephropathy

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    Jul.28.2023

    Diabetic Kidney Disease

    Synopsis

    Key Points

    • Diabetic kidney disease is kidney disease characterized by persistent albuminuria due to kidney injury that is caused by prolonged exposure to hyperglycemia and exacerbated by hypertension
    • Diagnosis is based on urinary albumin to creatinine ratio of 30 mg/g or greater, GFR less than 60 mL/minute/1.73 m² (which can occur with normal urinary albumin excretion), or both r1
    • Treatment consists of intensive blood glucose and blood pressure control aimed at limiting albuminuria and progression of nephropathy, as well as reducing hypertension to protect the renal and cardiovascular systems
      • Insulin and other antihyperglycemic agents, together with antihypertensives such as ACE inhibitors or angiotensin receptor blockers, are the preferred drugs
      • Supportive care (eg, smoking cessation, reducing alcohol consumption, healthy diet) is also important to achieve successful treatment results
    • Complications are life threatening and include end-stage renal disease, cardiovascular morbidity, and anemia
    • Progression of nephropathy can be slowed with therapies such as strict control of blood pressure, glycemia, and lipids, as well as certain lifestyle modifications
    • Patients with end-stage renal disease present the worst outcome; however, renal replacement therapy (eg, renal transplant, dialysis) increases 5-year survival rate by 30% in these patients r2

    Urgent Action

    • Life-threatening hyperkalemia or fluid overload (pulmonary edema) in the setting of an event causing acute or chronic kidney injury requires immediate treatment

    Pitfalls

    • Absence of albuminuria in patients with diabetes and reduced estimated GFR raises the possibility of nondiabetic chronic kidney disease

    Terminology

    Clinical Clarification

    • Chronic kidney disease among patients with diabetes is usually attributable to diabetes pathophysiology and has been described as diabetic kidney disease and diabetic nephropathy r3
      • Chronic kidney disease is defined as elevated urine albumin excretion (greater than or equal to 30 mg/g creatinine), reduced estimated GFR (less than 60 mL/minute/1.73 m²), or both, persisting for more than 3 months r3
    • Encompasses all categories of chronic kidney disease and includes patients requiring treatment with hemodialysis, peritoneal dialysis, and kidney transplant r3r4
    • Chronic kidney disease resulting as a complication of long-standing and/or poorly controlled diabetes mellitus occurs in 20% to 40% of patients with diabetes r1r5
    • Leading cause of end-stage renal disease (advanced kidney failure) r6r7

    Classification

    • Albuminuria level r8
      • Normal to mildly increased: urinary albumin to creatinine ratio is less than 30 mg/g
      • Moderately increased: urinary albumin to creatinine ratio is 30 to 300 mg/g
      • Severely increased: urinary albumin to creatinine ratio is greater than 300 mg/g
    • Classification of chronic kidney disease, according to GFR category r9
      • G1: normal or increased renal function
        • GFR is 90 mL/minute/1.73 m² or higher
      • G2: mildly decreased renal function
        • GFR is 60 to 89 mL/minute/1.73 m²
      • G3a: mildly to moderately decreased renal function
        • GFR is 45 to 59 mL/minute/1.73 m²
      • G3b: moderately to severely decreased renal function
        • GFR is 30 to 44 mL/minute/1.73 m²
      • G4: severely decreased renal function
        • GFR is 15 to 29 mL/minute/1.73 m²
      • G5: kidney failure
        • GFR is less than 15 mL/minute/1.73 m²
    • Classification of chronic kidney disease, according to albuminuria category r10
      • A1: normal to mildly increased
        • Albumin to creatinine ratio: less than 30 mg/g
        • Albumin excretion rate: less than 30 mg/24 hours
      • A2: moderately increased
        • Albumin to creatinine ratio: 30 to 300 mg/g
        • Albumin excretion rate: 30 to 300 mg/24 hours
      • A3: severely increased
        • Albumin to creatinine ratio: greater than 300 mg/g
        • Albumin excretion rate: greater than 300 mg/24 hours

    Diagnosis

    Clinical Presentation

    History

    • Symptoms vary according to severity of disease
      • Early stages of disease are asymptomatic r11c1
      • Symptoms develop as urinary albumin to creatinine ratio progressively increases in the 30 to 299 mg/g range and/or as GFR decreases in the 60 to 15 mL/minute/1.73 m² range r11
      • As the filtration ability of the kidneys deteriorates, the following clinical features can be recognized:
        • Symptoms caused by edema r5c2
          • Swelling of feet, ankles, and periorbital area (30%-40% of patients) r11c3c4c5
          • Weight gain r11c6
        • Foamy urine (consequence of increased protein concentration) is a classic but late symptom r12c7
        • Symptoms caused by electrolyte imbalance and worsening uremia c8c9
          • Nausea and vomiting c10c11
          • Poor appetite, resulting in weight loss c12c13
          • Generalized pruritus c14
        • Symptoms caused by anemia from erythropoietin deficiency c15
          • Fatigue and generalized weakness c16c17
          • Dyspnea on exertion c18

    Physical examination

    • Hypertension is very common (blood pressure of 130/80 mm Hg or higher is considered elevated for diabetes) r13c19
      • Associated with sodium and fluid retention, causing edema (particularly evident in lower extremities) r12c20c21c22
    • Diabetic retinopathy often precedes diabetic kidney disease; funduscopy may find the following: c23
      • Microaneurysms c24
      • Blot hemorrhages c25
      • Exudative, ischemic, and proliferative changes c26c27c28
      • Macular edema c29

    Causes and Risk Factors

    Causes

    • Prolonged exposure to hyperglycemia causes damage to kidney structure (eg, glomerulus, tubulointerstitium, vasculature), either directly or through hemodynamic changes r7c30c31
      • Hyperglycemia lowers sodium exposure at macula densa, which inhibits tubuloglomerular feedback, dilates afferent arteriole, and induces glomerular hyperfiltration r14c32
      • Increased filtration pressure produces podocyte barotrauma, resulting in podocyte and nephron loss r14c33
    • Condition is accelerated by ongoing albuminuria and hypertension r15c34c35
      • Excessive protein reabsorption causes further injury (ie, apoptosis) to tubular epithelium and interstitial cells, whereas increased concentration of activated complement proteins at tubular epithelium level triggers inflammatory processes
      • Hypertension exacerbates vascular problems of diabetic kidney disease, eventually affecting whole cardiovascular system

    Risk factors and/or associations

    Age
    • Type 2 diabetes
      • Age older than 40 years is associated with increased risk of diabetic kidney disease r16c36c37
      • Onset of type 2 diabetes during youth increases risk of developing diabetic kidney disease in adulthood r16c38c39c40
    • Type 1 diabetes
      • Onset of type 1 diabetes significantly before puberty has protective effect r16
    Sex
    • Male individuals are at higher risk than female individuals r7c41c42
    Genetics
    • Genetic predisposition c43
      • Inherited susceptibility to diabetic kidney disease exists for both type 1 and type 2 diabetes r17r18
      • Candidate gene and genome-wide association studies have identified a few genes with polymorphisms that confer increased risk, including the following: r19
        • ACE (angiotensin-converting enzyme) insertion/deletion polymorphism D allele c44
        • Single nucleotide polymorphisms within AGT (angiotensinogen) and AGTR1 (angiotensin II receptor type 1) genes c45c46
        • Single nucleotide polymorphisms within promoter of FRMD3 gene (FERM domain containing 3) c47
    Ethnicity/race
    • Highest incidence in Hispanic, Native American, and African American/Black populations r20c48c49c50c51
    Other risk factors/associations
    • Long duration of diabetes and poor glycemic control account for most of the risk c52c53c54
    • Presence of proliferative diabetic retinopathy is highly predictive of diabetic kidney disease r21c55
    • Effects of other exposures
      • Moderate alcohol consumption is associated with lower risk of chronic kidney disease in both type 1r22 and type 2 diabetesr23r24c56
      • NSAIDs cause significant drop in GFR in patients with diabetic kidney disease r25c57
      • Radiocontrast dye can induce acute kidney injury in patients with diabetic kidney disease r26c58
    • Risk factors for progression include:
      • Hypertension (associated with diabetes in approximately 75% of patients) r27c59
        • Accelerates renal injury induced by hyperglycemia r15
      • Dyslipidemia (associated with diabetic macrovascular complications aggravating nephropathy),r28 characterized by: c60
        • Hypertriglyceridemia c61
        • Elevated LDL-C levels c62
        • Reduced HDL-C levels r29c63
        • Elevated apolipoprotein B levels
      • Diet c64
        • High-protein diet deteriorates renal function by increasing glomerular capillary pressure, causing hyperfiltration (which exacerbates albuminuria) and reducing GFR r30c65
        • Diet high in cholesterol and saturated fats worsens dyslipidemia and renal accumulation of lipids r31c66
        • Vitamin D deficiency abrogates nephroprotective action of that vitamin r32c67
      • Smoking r33r34c68
        • Independent risk factor in progression of diabetic kidney disease for both type 1 and type 2 diabetes
        • Increases rate of transition from microalbuminuria to persistent proteinuria and promotes progression to end-stage renal disease
        • Former smokers and nonsmokers carry similar risk of disease progression
        • Passive smokers and active smokers carry similar risk of disease progression
      • Recurrent acute kidney injury increases risk of disease progression r35c69

    Diagnostic Procedures

    Primary diagnostic tools

    • Suspect diabetic kidney disease in patients with long-duration diabetes, especially when accompanied by other microvascular complications (eg, retinopathy) r1c70
    • Base diagnosis on persistent presence of albuminuria, reduction in estimated GFR, or both in patients with diabetes r1
      • Albuminuria
        • Measure urine albumin to creatinine ratio
          • Spot collection of urine (eg, first void in morning) is generally preferred method, given that randomly timed or 24-hour collections are inconvenient and add little to accuracy r1
          • Spot collection for albumin alone (using a dipstick) without simultaneous measurement of urine creatinine is also less accurate, owing to variation in urine concentration according to hydration status
      • Estimated GFR c71
        • Calculated on the basis of serum creatinine level and other variables, which may include serum cystatin C level r36r37
        • Serves as essential diagnostic parameter if urinary albumin excretion is within reference range
      • Comprehensive chronic kidney disease staging takes into account level of albuminuria at each estimated GFR stage r1
    • Consider alternative causes of renal disease in patients with urinary sediment containing red or white blood cells or casts, rapidly increasing albuminuria or decreasing GFR, or no concomitant retinopathy (type 1 diabetes) r1
      • Investigation for alternative causes may be required (eg, kidney biopsy)
    • Use renal ultrasonography to exclude obstruction and other structural causes of kidney disease r38
    • Kidney biopsy is the only method to absolutely confirm diagnosis, but it is not performed routinely r39
      • Recommended when diagnosis is inconclusive or another cause of renal disease is suspected

    Laboratory

    • Albumin excretion levels (using urine albumin to creatinine ratio; preferred test) c72
      • Albuminuria level 30 mg/g or higher (urine albumin to creatinine ratio) in random spot collection is indicative of nephropathy r1
        • Measurement must be confirmed on at least 2 tests performed 3 to 6 months apart because of variability in urinary albumin excretion (to avoid false-positive results) r6
        • Transient albuminuria can be attributed to multiple causes, such as vigorous exercise in the past 24 hours, urinary tract infection, febrile illness, short-term elevated hyperglycemia, severe hypertension, menstruation, or congestive heart failure
      • Categories of albuminuria r8
        • Normal to mildly increased: urinary albumin to creatinine ratio is less than 30 mg/g
        • Moderately increased: urinary albumin to creatinine ratio is 30 to 300 mg/g
        • Severely increased: urinary albumin to creatinine ratio is greater than 300 mg/g
      • Test is not entirely sensitive for kidney disease because low estimated GFR (less than 60 mL/minute/1.73 m²) is present in approximately 50% of patients without increased albuminuria r6
      • Test result serves as biomarker predictive of cardiovascular events and mortality r6
      • Suspect nondiabetic chronic kidney disease when albuminuria is absent and estimated GFR is reduced in patients with diabetes r6
    • Serum creatinine level c73
      • Needed to calculate estimated GFR
      • Increasing trend in serum creatinine level indicates loss of kidney function r40
    • Estimated GFR c74
      • GFR categories: r1
        • 90 mL/minute/1.73 m² or higher indicates stage 1 chronic kidney disease
        • 60 to 89 mL/minute/1.73 m² indicates stage 2 chronic kidney disease
        • 45 to 59 mL/minute/1.73 m² indicates stage 3a chronic kidney disease
        • 30 to 44 mL/minute/1.73 m² indicates stage 3b chronic kidney disease
        • 15 to 29 mL/minute/1.73 m² indicates stage 4 chronic kidney disease
        • Less than 15 mL/minute/1.73 m² indicates kidney failure (stage 5 chronic kidney disease)
      • The National Kidney Foundation recommends using the 2021 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) Creatinine Equation to estimate GFR r36
        • This equation does not include a race coefficient
        • When serum cystatin C level is available, use the combined serum creatinine-cystatin C equation as this is more accurate than using serum creatinine alone and reduces racial and ethnic bias r1r41
      • Historically, CKD-EPI equation used serum creatinine, age, race, and gender to estimate GFR r42c75

    Imaging

    • Renal ultrasonography r38c76
      • Used to identify any structural abnormalities that may suggest an alternative cause of kidney disease
      • Increased renal volume marks initial phases of diabetic kidney disease
      • Decreased renal volume characterizes chronic diabetic kidney disease

    Procedures

    Kidney biopsy c77
    General explanation
    • Percutaneous procedure involving placement of long, thin needle into the kidney through flank to obtain tissue sample; confirms diagnosis r43
    Indication
    • Only necessary if diagnosis is uncertain or alternative cause of kidney disease is suspected r39
    • Cause of kidney disease is uncertain if any of the following situations apply: r8
      • Absence of diabetic retinopathy
      • Low or rapidly decreasing GFR
      • Rapidly increasing proteinuria or nephrotic syndrome
      • Refractory hypertension
      • Presence of active urinary sediment
      • Signs or symptoms of other systemic disease
      • Greater than 30% reduction in GFR 2 to 3 months after beginning therapy with ACE inhibitor or angiotensin receptor blocker
    Contraindications
    • Absolute r44
      • Solitary kidney
      • Uncontrollable bleeding diathesis
    • Relative r44
      • Severe azotemia
      • Anatomic renal abnormalities
      • Anticoagulation
      • Pregnancy
      • Urinary tract infection
    Complications
    • Gross hematuria
    • Hematoma r43
    • Pneumothorax
    Interpretation of results
    • Typical immunohistopathologic features r45
      • Histopathologic features
        • Mesangial expansion by extracellular matrix deposition
        • Thickening of glomerular basement membrane with diffuse glomerulosclerosis
        • Characteristic nodular pattern (Kimmelstiel-Wilson lesions) with nodular glomerulosclerosis
          • Specific for diabetic kidney disease and not found in any other condition
        • Afferent and efferent hyaline arteriolosclerosis
        • Areas of mesangiolysis (presence of foam cells and loss of matrix), resulting in glomerular capillary microaneurysms
        • Accumulation of plasma proteins, causing hyalinosis between glomerular endothelium and glomerular basement membrane (fibrin caps) or between glomerular tuft and Bowman capsule (capsular drop)
        • Interstitial fibrosis and tubular atrophy
        • Interstitial mononuclear inflammatory cell infiltrate
      • Immunofluorescence features
        • Positive staining of glomerular basement membrane and tubular basement membrane for IgG and albumin
        • Nonspecific staining for IgM and complement C3 in sclerotic nodules
        • Variable staining of both κ and λ light chains

    Differential Diagnosis

    Most common

    • Nondiabetic chronic kidney disease r46c78d1
      • Consider alternative causes of chronic kidney disease in the following situations:
        • Absence of diabetic retinopathy
        • Low or rapidly decreasing GFR
        • Rapidly increasing proteinuria or nephrotic syndrome
        • Refractory hypertension
        • Presence of active urinary sediment
        • Signs or symptoms of other systemic disease
        • Greater than 30% reduction in GFR 2 to 3 months after beginning therapy with ACE inhibitor or angiotensin receptor blocker
        • May have absence of albuminuria
    • Glomerulonephritis r45c79
      • Includes a group of conditions characterized by inflammation of the glomeruli, generally of autoimmune nature (eg, lupus nephritisr47) r45c80d2
      • Similar clinical features include proteinuria and hypertension; similar pathologic changes include glomerulosclerosis and hyalinization of renal microvasculature r45
      • Differentiated by:
        • Microscopic urinalysis showing active urine sediment with dysmorphic RBCs and casts
        • Histologic analysis of renal biopsy specimens showing less severe changes in kidney structure than that of diabetic kidney disease (eg, hyalinization can affect only the afferent arterioles, sparing the efferent arterioles) r45
        • Immunohistochemistry of renal biopsy specimens showing characteristic staining patterns (eg, IgG, IgM, complement C3) of the renal mesangium, glomerular basement membrane, or both r45
    • Hypertensive nephropathy or nephrosclerosis r48c81c82
      • Condition caused by chronic hypertension leading to renal damage
      • Hypertension is the principal common sign r45
      • Differentiated by biopsy findings; hyalinization is limited to afferent renal arterioles and is absent from efferent arterioles r45
    • Renovascular hypertension r48c83d3
      • Condition caused by atherosclerotic narrowing or blockage of blood supply to kidney (eg, renal artery stenosis) r49
      • Uncontrolled hypertension and rapid rise in serum creatinine level are the principal findings
      • Recurrent flash pulmonary edema and a flank bruit are other suggestive clinical clues
      • Presence of anatomically evident arterial occlusive disease (ie, atherosclerosis) on renal duplex ultrasonography is a differentiating factor
      • Gold standard test is invasive renal angiography, but this is only done to differentiate from diabetic kidney disease if hypertension is severe and serum creatinine level rises rapidly (especially at an early age)
      • Angiographic imaging that demonstrates lesions in renal vasculature provides definitive evidence for this condition r50

    Treatment

    Goals

    • Goals of treatment
      • Slow progression of kidney disease via intensive blood glucose and blood pressure control
      • Prevent development of complications (eg, end-stage renal failure, cardiovascular disease)
    • Glycemic goals
      • General goals nonspecific to diabetic kidney disease
        • American Diabetes Association recommends a hemoglobin A1C level lower than 7% as an appropriate target in most nonpregnant adult patients with diabetes; in patients with low hypoglycemia risk and a long life expectancy, the goal may be 6% to 7% r51
        • American Association of Clinical Endocrinologists recommends hemoglobin A1C level of 6.5% or lower for most nonpregnant adults with diabetes, if it can be achieved safely r52
        • Relaxed target hemoglobin A1C levels (eg, 7%-8%) are acceptable for patients with comorbidities, limited life expectancy, or unacceptable risk of hypoglycemia r1r52
      • Recommended goals for patients with diabetic kidney disease
        • Kidney Disease: Improving Global Outcomes guidelines recommend an individualized hemoglobin A1C target of lower than 6.5% to lower than 8.0% for patients with diabetes and chronic kidney disease r41
          • Targets in this range are associated with improved survival, cardiovascular outcomes, and microvascular end points, and lower rate of kidney disease progression
        • Association of British Clinical Diabetologists and the Renal Association UK guidelines recommend a hemoglobin A1C level of 6.5% to 7.5% for younger patients with diabetes and stage 1 to stage 2 kidney disease and hemoglobin A1C target of 6.9% to 8.5% for patients of any age with stage 3 to stage 5 kidney disease r53
        • In some patients with diabetic kidney disease the risks of lower glycemic targets may outweigh the potential benefit with regard to microvascular complications
          • Patients with kidney disease at baseline have an increased risk of adverse effects (hypoglycemia and mortality) associated with intensive diabetes control r1r54r55
          • Renal benefits of intensive glucose control lag by at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes r1
            • As a result, patients with end-stage renal disease and/or likely reduced longevity may not derive the benefits of tight glucose control; for such patients, consider less aggressive treatment of diabetes on an individual basis r56
    • Blood pressure targets
      • American Diabetes Association, American Association of Clinical Endocrinologists, and American College of Cardiology/American Heart Association guidelines recommend blood pressure target of lower than 130/80 mm Hg for most patients with diabetes r52r57r58
        • Individualization of blood pressure targets is emphasized in all guidelines, with consideration of other factors such as age and presence of kidney disease and/or coronary artery disease r59
        • Lower blood pressure targets may be suitable for patients with chronic kidney disease, particularly those with severely elevated albuminuria (300 mg/g creatinine or greater) r1r59
        • Adverse safety signal in clinical trials of diabetic kidney disease cautions against diastolic blood pressure targets lower than 70 mm Hg, and especially below 60 mm Hg, in older adults r6
      • Association of British Clinical Diabetologists and the Renal Association UK guideline proposes a target blood pressure of 120/80 mm Hg for younger adults with diabetes and chronic kidney disease with no significant proteinuria and less than 130/80 mm Hg for those with proteinuria r60
        • Target blood pressure of 140/90 mm Hg is recommended for patients older than 65 years
      • Kidney Disease: Improving Global Outcomes guidelines recommend a target systolic blood pressure lower than 120 mm Hg for all patients with chronic kidney disease, including those with diabetes r61
        • The lower recommendation is based primarily on established cardioprotective and survival benefits and potential cognitive benefits observed at this systolic blood pressure level; evidence does not suggest lowering blood pressure below 140 mm Hg has additional renoprotective effect r61
        • There is limited evidence for this threshold in patients with diabetes and there may be safety considerations r41

    Disposition

    Admission criteria

    Requirement for urgent dialysis, such as:

    • Acute kidney injury
    • Volume overload causing pulmonary edema

    Severe (persisting) hyperkalemia

    • Identified by serum potassium level greater than 5.5 mmol/L r62

    Lactic acidosis

    • Possible symptoms include malaise, respiratory distress, myalgia, abdominal discomfort, disorientation, and somnolence r63
    • Presents with elevated arterial lactate concentration (greater than 5 mmol/L) and decreased arterial blood pH (less than 7.35) r64
    Criteria for ICU admission
    • Acute or chronic kidney injury accompanied by fluid overload, pulmonary edema, and impending respiratory failure

    Recommendations for specialist referral

    • Refer to nephrologist for evaluation and comanagement of diabetic kidney disease if there are any of the following: r65
      • Uncertain renal diagnosis
      • Complications (eg, anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, electrolyte disturbances)
      • Rapidly progressing or advanced kidney disease (estimated GFR is less than 30 mL/minute/1.73 m²) with anticipated need for eventual renal replacement therapy
    • Refer to endocrinologist for treatment of diabetes mellitus
    • Refer to dietitian or nutritionist for specific dietary counseling

    Treatment Options

    Multifactorial approach to treatment focuses on interventions proven to slow progression of nephropathy as well as preventing associated complications

    • Main components for all patients with diabetic kidney disease include blood pressure control, strict glycemic control, lifestyle modifications (eg, healthy diet, regular exercise, weight loss if needed) and statin therapy
    • Additional components may include:
      • Renin-angiotensin-aldosterone system blockade for patients with severe albuminuria (in practice most patients with hypertension are treated with these agents)
      • Kidney-protective therapies (eg, sodium-glucose cotransporter 2 inhibitor, nonsteroidal selective mineralocorticoid receptor antagonist) in patients with type 2 diabetes
      • Treatment of any comorbidities
      • Renal replacement therapy when needed

    Blood pressure control

    • ACE inhibitors (eg, benazepril, captopril, lisinopril, ramipril) or angiotensin receptor blockers (eg, irbesartan, losartan, telmisartan) are preferred first line agents for blood pressure treatment among people with diabetes, hypertension, and diabetic kidney disease r7
      • For nonpregnant patients with hypertension and diabetes, prescribe either an ACE inhibitor or angiotensin receptor blocker if urinary albumin to creatinine ratio is greater than or equal to 30 mg/g or estimated GFR is less than 60 mL/minute/1.73 m² r1r61
        • Do not combine use of an ACE inhibitor and an angiotensin receptor blocker owing to higher risks of hyperkalemia and acute kidney injury r66r67
      • Both drug classes control blood pressure and reduce the risk of progression to end stage renal disease in patients with type 1 and type 2 diabetes with diabetic kidney disease (eGFR less than 60 mL/min/1.73 m² and urinary albumin to creatinine ratio of 300 mg/g or higher)
      • In patients with lower levels of albuminuria (30-299 mg/g creatinine), both drug classes may reduce progression to more advanced albuminuria and cardiovascular events, and slow chronic kidney disease progression but do not reduce progression to end stage renal disease r1
      • Head-to-head comparisons of an ACE inhibitor and an angiotensin receptor blocker in a patient with type 2 diabetes with elevated urine albumin excretion show clinically equivalent effects on chronic kidney disease progression,r68 but evidence for cardiovascular benefit is strongest for ACE inhibitorsr69
    • Alternative agents for patients with hypertension who do not have albuminuria, patients unable to tolerate either ACE inhibitors or angiotensin receptor blockers, and for pregnant patients (these may also be added to renin-angiotensin system blockers if blood pressure targets are not achieved with monotherapy) r41r59r70
      • Dihydropyridine calcium channel blockers
      • Thiazide-like diuretics

    Statin therapy r29r71

    • Recommended for all patients with diabetes and chronic kidney disease
    • Prescribe moderate intensity statin therapy for primary prevention of atherosclerotic cardiovascular disease and high intensity treatment for patients with known atherosclerotic cardiovascular disease or multiple risk factors r41

    Kidney-protective agents for patients with type 2 diabetes

    • A sodium-glucose cotransporter 2 inhibitor (eg, empagliflozin, dapagliflozin, canagliflozin, sotagliflozin) is recommended in addition to the angiotensin receptor blocker or ACE inhibitor to reduce chronic kidney disease progression, all cause mortality and cardiovascular mortality, and hospitalization for heart failure, in patients with type 2 diabetes and diabetic kidney disease r3r41r72
      • In patients with type 2 diabetes, both sodium-glucose cotransporter 2 inhibitors and glucagonlike peptide-1 receptor agonists have been found to reduce risk of chronic kidney disease progression, hypoglycemia, and cardiovascular events; however, renal benefits of glucagonlike peptide-1 receptor agonists are less well established r73r74
      • Glucagonlike peptide-1 receptor agonists (liraglutide and semaglutide) are recommended for patients who fail to achieve glycemic targets with use of metformin and a sodium-glucose cotransporter 2 inhibitor or who are unable to take these medications r3
    • A non-steroidal mineralocorticoid receptor antagonist (finerenone) with proven kidney and cardiovascular benefit is recommended for patients with type 2 diabetes and albuminuria despite a maximum tolerated dose of a renin-angiotensin system inhibitor provided they have an estimated GFR of 25 mL/min/1.73 m² or more and serum potassium concentration within reference range r1r41r75
      • 2 randomized controlled trials found that finerenone has favorable effects on cardiovascular outcomes and slows progression of loss of kidney function in patients with type 2 diabetes, diabetic kidney disease, and albuminuria r76r77r78

    Glycemic control

    • Intensive measures to optimize glycemic control are indicated in most patients to limit albuminuria and slow progression of nephropathy
      • Intensive diabetes management delays onset and progression of nephropathy in both type 1 diabetesr80 and type 2 diabetes; however, the effects on end-stage renal disease and mortality are not clearr81r82r83r79
      • This need to be balanced against greater risk of severe hypoglycemia and impaired drug clearance associated with more severe kidney disease r56r84
    • Insulin is always required in type 1 diabetes, whereas a variety of oral and injectable drugs, including insulin, can be used in type 2 diabetes
    • Glycemic control is based on a combination of metformin and sodium-glucose cotransporter-2 inhibitors in most patients with type 2 diabetes r75
    • Special drug considerations for patients with diabetic kidney disease r85
      • Insulin
        • For type 2 diabetes, insulin can be added to the other antihyperglycemic agents or replace them entirely in later stages of chronic kidney disease (categories G3-G5) r85
        • At categories G3 through G5 of chronic kidney disease, clearance of insulin is reduced and risk for hypoglycemia increases r56
        • Insulin requirements may decrease by 20% or more when GFR decreases to less than 45 mL/minute/1.73 m² r86
      • Metformin
        • First line treatment for patients with type 2 diabetes, including those with kidney disease r3r87
        • Appropriate to begin if GFR is 30 mL/minute/1.73 m² or higher r41r75
        • Increase frequency of GFR monitoring when GFR is less than 60 mL/min/1.73 m² r41
        • Dosage adjustment is required when the eGFR is less than 45 mL/min/1.73 m² (adjust dosage for patients with conditions that predispose to hypoperfusion and hypoxemia when the eGFR is 45-59 mL/min/1.73 m²) r41
        • Temporarily discontinue for iodinated contrast imaging procedures in patients with eGFR 30 to 60 mL/min/1.73 m² r41
        • Discontinue when estimated GFR is less than 30 mL/minute/1.73 m² r1
      • Sodium-glucose cotransporter 2 inhibitors r88
        • These drugs have nephroprotective and cardioprotective properties r88r89r90r91
        • Recommended in addition to the angiotensin receptor blocker or ACE inhibitor to reduce chronic kidney disease progression, all cause mortality and cardiovascular mortality, and hospitalization for heart failure in patients with with an estimated GFR of 20 mL/min/1.73 m² or higher and urinary albumin-creatinine ratio of 200 mg/g or higher r1r92
          • May also be beneficial in patients with urinary albumin-creatinine ratio ranging from within reference range to 200 mg/g
          • Can be continued even if the estimate GFR is less than 20 ml/min per 1.73 m², unless it is not tolerated or kidney replacement therapy is initiated r41
        • Shown to reduce risk of kidney disease progression in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function r93r94
      • Glucagonlike peptide-1 receptor agonists
        • These drugs have cardioprotective and nephroprotective properties; however, the renal benefits are less well established than sodium-glucose cotransporter 2 inhibitors r95r96r97
        • Recommended for patients who have not achieved glycemic targets despite use of metformin and a sodium-glucose cotransporter-2 inhibitor (or who are unable to use those medications) r41
          • Dulagutide, liraglutide, and semaglutide may be used in all stages of renal impairment
          • Exenatide immediate release is not recommended when estimated GFR is less than 30 mL/minute/1.73m²; exenatide extended release is not recommended when estimated GFR is less than 45 mL/minute/1.73 m²
          • Lixisenatide is not recommended when estimated GFR less than 15 mL/minute/1.73 m²
        • An exendin-based glucagonlike peptide-1 receptor agonist, efpeglenatide, also demonstrates cardiovascular and renal benefits in patients with type 2 diabetes r98
      • Dual glucose-dependent insulinotropic polypeptide and glucagonlike peptide-1 agonists (tirzepatide)
        • Can be used in all stages of renal impairment
        • Use of tirzepatide is associated with nausea, vomiting, and diarrhea, which may lead to dehydration. This dehydration has resulted in acute kidney injury
      • Dipeptidyl-peptidase IV inhibitors
        • Can be used in all stages of renal impairment
        • Require dose reduction in patients with moderate or severe renal impairment, except linagliptin, for which no dose adjustment is necessary
      • Meglitinides
        • Meglitinides are short acting and are taken at meals, mitigating some of the risk of hypoglycemia
        • Repaglinide is mostly metabolized by the liver and may be used with dose adjustments
        • May be used in stage 3 to 5 chronic kidney disease but requires careful dose adjustments
      • Sulfonylureas r75
        • Undesirable to use this class in general, particularly glipizide, owing to the risk of hypoglycemia
        • If this class is used, carefully monitor blood glucose level and give conservative dosing
        • Most sulfonylureas are contraindicated in patients with stage 4 or 5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²)
      • Thiazolidinediones
        • Only pioglitazone is advisable, owing to safety concerns with other agents in this class r85
        • Do not use pioglitazone in patients with end stage renal disease requiring hemodialysis
      • α-glucosidase inhibitors
        • Unaltered renal excretion; therefore, not recommended in patients with category G4 or G5 chronic kidney disease

    Renin-angiotensin-aldosterone system inhibition

    • Most patients with proteinuric diabetic kidney disease require blood pressure control, and angiotensin-aldosterone system blockade is the mainstay treatment for this r3r7
    • In rare patients with albuminuria who are normotensive, the evidence for treatment with renin-angiotensin-aldosterone system inhibition is less strong r41
      • Consider treatment with renin-angiotensin-aldosterone system inhibitors in patients with diabetes and albuminuria even if they have blood pressure within reference range r3
      • However, trials have not shown ACE inhibitors or angiotensin receptor blockers improve renal outcomes in patients with moderately increased albuminuria without hypertension
    • ACE inhibitors and angiotensin receptor blockers are not recommended for the primary prevention of chronic kidney disease in patients with diabetes who have blood pressure, urinary albumin-to-creatinine ratio (less than 30 mg/g creatinine), and estimated GFR within reference ranges r1r3
      • No renoprotective effect has been demonstrated in patients with type 1 and type 2 diabetes with or without high albuminuria who were normotensive

    Lifestyle modifications

    • Smoking cessationr99 and moderate alcohol consumptionr10 (2 or fewer daily drinks for most males or 1 daily drink for females and lighter-weight individuals) are recommended to help reduce blood pressure and prevent cardiovascular complications r10
    • Adherence to recommended dietary protein intake r1
      • For non–dialysis-dependent diabetic kidney disease, dietary protein intake should be 0.8 g/kg body weight per day (recommended daily allowance for the general population)
        • Avoid exceeding protein intake recommendations because higher levels (more than 20% of daily calories from protein or more than 1.3 g/kg body weight per day) are associated with increased albuminuria, more rapid kidney function loss, and cardiovascular mortality
        • Reducing dietary protein below the recommended daily allowance of 0.8 g/kg/day is also not recommended because it does not alter glycemic measures, cardiovascular risk measures, or course of GFR decline
      • Patients on dialysis may require higher levels of dietary protein intake

    Renal replacement therapy r100

    • Dialysis or kidney transplant is necessary to treat category G5 chronic kidney disease (renal failure)
    • Barring major contraindications, kidney transplant is first line treatment of renal failure associated with diabetic kidney disease (provides better quality of life and significant survival advantage over dialysis)
    • Refer for evaluation for renal replacement therapy when estimated GFR is less than 30 mL/minute/1.73 m²

    Drug therapy

    • Renin-angiotensin-aldosterone system inhibitors c84
      • ACE inhibitors r57c85
        • Benazepril c86
          • Benazepril Hydrochloride Oral tablet; Adults: 10 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 80 mg/day in 1 or 2 divided doses.
        • Captopril c87
          • Captopril Oral tablet; Adults: 12.5 to 25 mg PO 2 to 3 times daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Usual dose: 50 mg PO 3 times daily. Max: 450 mg/day in 2 or 3 divided doses.
        • Lisinopril c88
          • Lisinopril Oral tablet; Adults: 10 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 40 mg/day.
        • Ramipril c89
          • Ramipril Oral tablet; Adults: 2.5 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 20 mg/day in 1 or 2 divided doses.
      • Angiotensin receptor blockers r57c90
        • Irbesartan c91
          • Irbesartan Oral tablet; Adults: 150 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 300 mg/day.
        • Losartan c92
          • Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 100 mg/day in 1 or 2 divided doses.
        • Telmisartan c93
          • Telmisartan Oral tablet; Adults: 40 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 80 mg/day.
    • Calcium channel blockers r101c94c95c96
      • Diltiazem
        • Diltiazem Hydrochloride Oral capsule, extended release 24 hour; Adults: 180 to 240 mg PO once daily, initially. May increase dose after 14 days if further control is needed. Usual dose range: 120 to 360 mg/day. Max: 540 mg/day.
      • Verapamil
        • Verapamil Hydrochloride Oral tablet, extended-release; Adults: 180 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if additional control is needed. Usual dose: 120 to 360 mg/day in 1 or 2 divided doses. Max: 240 mg PO twice daily.
        • Verapamil Hydrochloride Oral tablet, extended-release; Older or Small Stature Adults: 120 mg PO once daily, initially. May increase the dose by 120 mg/day weekly if additional control is needed. Usual dose: 120 to 360 mg/day in 1 or 2 divided doses. Max: 240 mg PO twice daily.
    • Diuretics c97
      • Furosemide c98
        • Furosemide Oral tablet; Adults: 40 mg PO twice daily, initially. May increase dose if further control is needed. Usual dose range: 20 to 80 mg/day. Max: 600 mg/day.
    • Non-steroidal mineralocorticoid receptor antagonist
      • Finerenone
        • Finerenone Oral tablet; Adults: 20 mg PO once daily. Adjust dose based on serum potassium concentrations every 4 weeks as needed. Dose range: 10 to 20 mg PO once daily.
    • Antihyperglycemic agents c99
      • Oral agents and insulin and noninsulin injectables are used in type 2 diabetes
      • Insulin is always required in type 1 diabetes; in long-standing type 2 diabetes, it is used in certain circumstances as monotherapy or in combination with other drugs
      • Biguanides
        • Metformin c100
          • Immediate release
            • Metformin Hydrochloride Oral tablet; Adults: 500 mg PO twice daily or 850 mg PO once daily, initially. May increase dose by 500 mg/week or 850 mg every 2 weeks if needed. Doses more than 2,000 mg/day may be better tolerated in 3 divided doses. Max: 2,550 mg/day. Use doses more than 1,000 mg/day with caution in older adults.
          • Extended-release
            • Metformin Hydrochloride Oral tablet, extended-release; Adults: 500 mg PO once daily, initially. May increase dose by 500 mg/week if needed. Max: 2,000 mg/day; may consider 1,000 mg PO twice daily if glycemic control is not achieved with 2,000 mg PO once daily. Use doses more than 1,000 mg/day with caution in older adults.
      • SGLT2 (sodium-glucose cotransporter 2) inhibitor
        • Canagliflozin c101
          • Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase the dose to 300 mg PO once daily if additional glycemic control is needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Dapagliflozin c102
          • Dapagliflozin Oral tablet; Adults: 10 mg PO once daily.
        • Empagliflozin c103
          • Empagliflozin Oral tablet; Adults: 10 mg PO once daily, initially. May increase dose to 25 mg PO once daily if additional glycemic control is needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Glucagonlike peptide-1 mimetics c104
        • Liraglutide c105
          • Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase the dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
        • Semaglutide c106
          • Oral
            • Semaglutide Oral tablet; Adults: 3 mg PO once daily for 30 days, then 7 mg PO once daily, initially. May increase the dose to 14 mg PO once daily after at least 30 days on 7 mg/day if additional glycemic control is needed.
          • Subcutaneous
            • Semaglutide Solution for injection; Adults: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly, initially. May increase the dose to 1 mg subcutaneously once weekly after 4 weeks on 0.5 mg/week and 2 mg subcutaneously once weekly after 4 weeks on 1 mg/week if additional glycemic control is needed.
      • Dipeptidyl-peptidase IV inhibitors c107
        • Linagliptin c108
          • Linagliptin Oral tablet; Adults: 5 mg PO once daily.
        • Sitagliptin c109
          • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
      • Meglitinides c110
        • Nateglinide c111
          • Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily, or 60 mg PO 3 times daily for patients who are near glycemic goal when treatment is initiated.
        • Repaglinide c112
          • Repaglinide Oral tablet; Adults: 0.5 mg PO before each meal for patients whose HbA1c is less than 8% and 1 or 2 mg PO before each meal for patients whose HbA1c is 8% or more. May double the dose after at least 1 week if needed. Usual dose range: 0.5 to 4 mg PO before each meal. Max: 4 mg/dose and 16 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Sulfonylureas c113
        • Glimepiride
          • Glimepiride Oral tablet; Adults: 1 or 2 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Glimepiride Oral tablet; Older Adults: 1 mg PO once daily, initially. May increase dose by 1 or 2 mg/day every 1 to 2 weeks if needed; a conservative titration scheme is recommended.  Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Glipizide c114
          • Glipizide Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Glipizide Oral tablet; Older Adults: 2.5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed; a conservative titration scheme is recommended. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Thiazolidinediones c115
        • Pioglitazone c116
          • Pioglitazone Hydrochloride Oral tablet; Adults: 15 or 30 mg PO once daily, initially. May increase dose by 15 mg/day based on HbA1c if needed. Max: 45 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions
      • α-glucosidase inhibitors c117
        • Acarbose c118
          • Acarbose Oral tablet; Adults weighing 60 kg or less: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 50 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Acarbose Oral tablet; Adults weighing more than 60 kg: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily and then 100 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Miglitol c119
          • Miglitol Oral tablet; Adults: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose after 4 to 8 weeks to 50 mg PO 3 times daily for 3 months and then 100 mg PO 3 times daily based on HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Insulin c120
        • Basal insulin
          • Insulin detemir
            • Insulin Detemir (Recombinant) Solution for injection; Adults: 10 units subcutaneously once daily or divided twice daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily or divided twice daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
          • Insulin glargine
            • Insulin Glargine Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/dose subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
        • Prandial insulin
          • Insulin lispro
            • Insulin Lispro Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily 15 minutes before or immediately after the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
          • Regular insulin
            • Insulin Regular (Recombinant) Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily approximately 30 minutes before the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.

    Nondrug and supportive care

    Diet r99c121

    • Dietary recommendations are individualized according to weight loss goals, caloric needs, and distribution of macronutrients, taking into account lifestyle, preferences, eating patterns, culture, and comorbidities of patient
    • Various eating patterns, including DASH diet (Dietary Approaches to Stop Hypertension) and Mediterranean diet are effective for controlling glycemia and lowering cardiovascular risk factors r102c122
      • In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly-processed foods
    • Protein intake r1c123
      • Usual protein intake: 15% to 20% of total energy
      • Dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline
        • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that of the general population (0.8 g/kg body weight)
        • For patients receiving dialysis, consider higher levels of dietary protein intake
    • Sodium intake r7c124
      • American Diabetes Association recommends total sodium of 2300 mg/day or less, which is the same as in general population r1
        • Earlier recommendations by KDIGO (Kidney Disease: Improving Global Outcomes) suggested less than 2000 mg/day r8
      • Individualize dietary sodium and potassium intake based on comorbid conditions, medications, blood pressure, and electrolyte levels

    Lifestyle modifications c125

    • Medical nutrition therapy and physical activity, to reduce weight and maintain healthy weight r8r10c126c127c128
    • Regular physical activity
      • Combination of aerobic and muscle strengthening exercise is recommended r103
      • Encourage at least 150 min of moderate intensity aerobic activity per week r103
      • Recommend activities aimed at improving or maintaining muscle strength, balance, and flexibility at least 2 days a week r103
    • Advise smoking cessation and avoidance of secondhand smoke exposure r99c129c130d4
    • Alcohol should be consumed in moderation, if at all (1 or fewer drinks per day for women, 2 or fewer drinks per day for men) r10c131
    Procedures
    Renal transplant r104c132
    General explanation
    • Surgical procedure to place healthy kidney from living or deceased donor into recipient r105
    • Option for patients with diabetic kidney disease who have developed end-stage renal disease, providing: r100
      • Better quality of life r100
      • Significant survival advantage over dialysis r106
    • Procedures for patients with type 1 diabetes and chronic kidney failure
      • Isolated kidney transplant from living donor
      • Isolated kidney transplant from deceased donor
      • Pancreas transplant after kidney transplant
      • Simultaneous pancreas-kidney transplant
    • Procedure for patients with type 2 diabetes and chronic kidney failure
      • Kidney transplant from deceased or living donor
    Indication
    • Deteriorating renal function, nearing end stage
    Contraindications
    • Unstable cardiovascular disease (eg, coronary and peripheral artery disease, peripheral arterial occlusive disease, carotid arterial stenosis, stroke) r107
    • Congestive heart failure and pulmonary disease (unless patient is stable) r107
    • Active infection r107
    • Active gastrointestinal bleeding r107
    • Active malignancy r107
    • Dementia r107
    • Nonadherence to immunosuppressive therapy or refusal of the procedure r107
    Complications
    • Allograft thrombosis
    • Anastomotic leakage
    • Rejection
    • Infections due to immunosuppressant drugs r108
    • Posttransplant lymphoproliferative disorder and other malignancies, such as squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma r108
    Renal replacement therapy r109c133
    General explanation
    • Form of artificial kidney replacement therapy that uses cycling machines to bypass failing kidneys and remove waste from blood
    • Performed either as hemodialysis or peritoneal dialysis (patient's choice in absence of contraindications) r109r110
    Indication
    • Option for patients with diabetic kidney disease and end-stage renal disease who are on waiting list for transplant and do not have potential living donor r107
    • Paucity of data from randomized controlled trials that establish optimal timing for renal replacement therapy
      • Timing of dialysis is often affected by multiple factors, including age, diabetes mellitus, individual desire, personal beliefs, and cultural and educational backgrounds r111
    Contraindications
    • Specific to peritoneal dialysis:
      • Inadequate peritoneal membrane (eg, peritoneal sclerosis, extensive surgical resection) r109
      • Abdominal cavity incompetence (eg, peritoneal compartmentalization, peritoneal-pleural communication) r109
      • High risk of abdominal infection (eg, recurrent diverticulitis, active inflammatory bowel disease) r109r112
      • Previous major abdominal surgery (relative contraindication) r113
      • Older adults (older than 75 years) with illness and no social support (potential nonadherence; difficult/impossible to perform procedure in home setting) r114
    • Specific to hemodialysis: r115r116
      • Symptomatic cardiovascular disease
      • Difficult vascular access, especially in patients with diabetes
    Interpretation of results
    • Long-term survival is improved among patients with diabetes who received a kidney transplant compared with patients on dialysis; risk of death is reduced by 73% at 18 months after transplant r2

    Special populations

    • Pregnant patients r117
      • Pregnant patients with concomitant nephropathy are at risk of deteriorating maternal kidney function, leading to end-stage renal disease r117
      • Compared with the healthy population, pregnant patients with either type 1 or type 2 diabetes present a 2- to 4-fold increased risk of preeclampsia, preterm delivery, and perinatal mortality; in the presence of concomitant nephropathy, the risk is even higher r70
      • Female patients who are taking an ACE inhibitor or an angiotensin receptor blocker should discontinue the medication if pregnancy is being planned/considered, or immediately upon learning of a positive pregnancy test result
        • ACE inhibitors and angiotensin receptor blockers are contraindicated during all stages of pregnancy because of teratogenic risk r118
        • Methyldopa, β-blockers (eg, labetalol), and calcium antagonists (eg, nifedipine, diltiazem) can be used safely r70
          • Methyldopa is drug of choice r119
      • Low-dose aspirin is recommended beginning at 10-12 gestational weeks until approximately 1 week before delivery for all pregnant patients with diabetic kidney disease or microalbuminuria to prevent cardiovascular events and to reduce the risk of preeclampsia r117

    Monitoring

    • Monitoring is necessary to assess progression, relying on the assessments of albuminuria (indicative of kidney damage) and estimated GFR (indicative of kidney function) c134
    • Perform physical examination and measure weight and blood pressure at every clinical encounter r59c135
      • Measure orthostatic blood pressure periodically or when symptoms of orthostatic hypotension occur c136
        • If orthostatic hypotension develops, consider nocturnal dosing of antihypertensives and/or stopping α-blockers and diuretics r59
    • Assess for albuminuria (spot urinary albumin to creatinine ratio) and obtain serum creatinine level and estimated GFR at least annually r120c137
      • In patients with urinary albumin to creatinine ratio greater than 30 mg/g or estimated GFR less than 60 mL/minute/1.73 m², assess every 3 to 6 months (according to severity) to guide management r1
      • Patients on ACE inhibitors, angiotensin receptor blockers, or diuretics
        • Periodically monitor serum creatinine and potassium levels for development of increased creatinine level or changes in potassium concentration c138c139
        • Debate continues regarding the need for annual quantitative assessment of albumin excretion after evidence of albuminuria has been established or after starting an ACE inhibitor or angiotensin receptor blocker
          • Ongoing monitoring of urinary albumin to creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment, monitor progression of diabetic kidney disease, and facilitate adherence to pharmacotherapy r1

    Complications and Prognosis

    Complications

    • Hypoglycemia r86
      • Severe hypoglycemia has been associated with a slight increase in mortality r121
      • Becomes a greater concern with worsening kidney dysfunction (chronic kidney disease categories G3-G5)
      • Can occur readily in patients who have GFR levels less than 30 mL/minute/1.73 m² and who are receiving treatment with oral antidiabetic drugs that are primarily eliminated by the kidneys (eg, sulfonylureas)
      • Especially likely in patients with impaired renal function who are treated with insulin, owing to reduced renal clearance of insulin and decreased insulin degradation in peripheral tissues
      • To reduce risk of hypoglycemia in patients on insulin or insulin secretagogues, greater frequency of self-monitoring of blood glucose and modification of antihyperglycemic drug dosing is advisable r54
    • Cardiovascular disease c140
      • In general, incidence increases according to severity of kidney disease r122
        • Approximately 3.5-fold increased risk of cardiovascular disease and 6-fold increased risk of death has been shown for patients with GFR of less than 15 mL/minute/1.73 m²
      • Most frequent specific complications include the following:
        • Coronary artery disease (increased risk of death and nonfatal cardiovascular outcomes after myocardial infarction) c141d5
        • Left ventricular hypertrophy (affects approximately 74% of patients with chronic kidney disease) r123c142
        • Congestive heart failure (31% of patients with chronic kidney disease) r123c143d6
        • Stroke (5- to 10-fold increased incidence in patients with end-stage renal disease) r123c144d7
        • Peripheral artery disease (eg, atherosclerosis, thrombosis, stenosis; reported in 25% of patients older than 40 years) r10c145c146c147c148c149c150c151c152d8
    • Antiplatelet therapy with low dose aspirin is indicated for secondary prevention of cardiovascular disease in all patients with diabetes r57
      • Can be considered for primary prevention among patients with diabetes and diabetic kidney disease, after discussion with the patient on the benefits versus increased risk of bleeding r57r124
    • Anemia r125c153
      • Estimated incidence is 20% of patients with diabetes and category G3 chronic kidney disease
      • Multiple contributing causes, including iron deficiency, erythropoietin deficiency and hyporesponsiveness, folate deficiency, and vitamin B₁₂ deficiency
      • Treat anemia with erythropoietin (eg, epoetin alfa) to maintain hemoglobin level at 11 g/dL or higher r10
    • Chronic kidney disease–mineral bone disorder r126r127c154
      • Syndrome characterized by:
        • Abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, and vitamin D metabolism
        • Abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy)
        • Vascular and other soft tissue calcification
      • Results in bone pain, fractures, hyperparathyroidism, cardiovascular disease, and elevated mortality
      • At the earliest stages, when biochemical parameters are altered (mildly elevated parathyroid hormone levels), patients are asymptomatic
      • Later in the course of disease, the most common symptoms are nonspecific myalgias and arthralgias at the lower back, hips, and legs
        • Hip fractures are a particular concern in chronic kidney disease category G5
      • Secondary hyperparathyroidism, abnormalities of vitamin D, and extraskeletal calcifications can develop in advanced chronic kidney disease c155c156c157
      • Tertiary hyperparathyroidism and hypercalcemia develop after chronic secondary hyperparathyroidism, owing to autonomous parathyroid hormone secretion that is unregulated by calcium levels c158c159
      • Patients should have serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase measured regularly, and those with evidence of chronic kidney disease–mineral bone disorder and/or risk factors for osteoporosis should undergo bone marrow density screening and be considered for bone biopsy r126
      • Initial management consists of lowering elevated serum phosphate with dietary phosphate restriction and phosphate binders, maintaining serum calcium level within reference range, and antiresorptive therapy if at high risk of fracture
      • Treatment of secondary hyperparathyroidism consists of calcitriol and vitamin D analogues, dietary phosphate restriction, and phosphate binders; total or 3.5 gland parathyroidectomy is indicated for tertiary hyperparathyroidism r128r129r130
    • Metabolic acidosis r131
      • May be complicated by hyperkalemia c160
      • Management includes low-potassium diet, diuretics, and sodium bicarbonate supplementation

    Prognosis

    • Diabetic kidney disease and type 1 diabetes
      • If condition is left untreated, average survival is 5 to 7 years from diagnosis for patients with diabetic kidney disease associated with type 1 diabetes r132
        • Along with current therapies (eg, strict control of blood pressure, lipids, and glycemia; improved lifestyle), prognosis has improved such that mortality is reduced by 30% r132
      • Disease progression is well characterized in patients with type 1 diabetes
        • Without therapeutic intervention, approximately 80% of patients with type 1 diabetes and moderately increased albuminuria (albumin to creatinine ratio 30 mg/g or greater) progress to develop severe albuminuria (albumin to creatinine ratio of 300 mg/g or greater) in 10 to 15 years on average r39
        • Approximately 50% of patients with severe albuminuria progress to end-stage renal disease within 10 years and 75% progress to end-stage renal disease within 20 years r39
    • Diabetic kidney disease and type 2 diabetes
      • In patients with type 2 diabetes, mortality associated with cardiovascular complications increases in relation to poor glycemic control, severity of renal complications, and patient's age
        • Patients younger than 55 years with optimal glycemic control (hemoglobin A1C level of 6.9% or lower) and albumin levels within reference range present a hazard ratio for death—due to any cardiovascular cause—approximately 2 times higher than that of patients older than 75 years r133
        • Patients with prior cardiovascular disease, chronic kidney disease, or both have increased risk of cardiovascular events and mortality; risk increases with worsening baseline GFR r134
      • Disease progression is generally more indolent in patients with type 2 diabetes than in patients with type 1 diabetes r39
        • Without therapeutic intervention, 20% to 40% of patients with type 2 diabetes and moderately increased albuminuria (albumin to creatinine ratio of 30-300 mg/g) develop severe albuminuria (albumin to creatinine ratio of 300 mg/g or greater), and only 20% of these patients progress to end-stage renal disease after 20 years r39
    • 5-year survival rate of patients with diabetes and end-stage renal disease is poor (30% after initiation of dialysis) r2
      • Renal replacement therapy (eg, renal transplant, dialysis) increases 5-year survival rate by 30% in these patients r2

    Screening and Prevention

    Screening

    At-risk populations r1

    • Patients with type 1 diabetes: screen annually beginning at 5 years after initial diagnosis c161c162
    • Patients with type 2 diabetes: screen annually starting at time of diagnosis c163c164
    • Patients with any type of diabetes and who have comorbid hypertension: screen annually c165c166

    Screening tests

    • Annual assessment of albuminuria (spot urinary albumin to creatinine ratio) and estimated GFR c167c168

    Prevention

    • Progression of diabetic kidney disease can be slowed by:
      • Intensive blood glucose control c169
      • Maintaining control of blood pressure (ideally to a level lower than 140/90 mm Hg or 130/80 mm Hg in patients with diabetes who already have albuminuria) with renin-angiotensin-aldosterone system inhibitors r7c170
      • Use of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes r1
      • Use of mineralocorticoid receptor antagonists (eg, finerenone) in patients with hypertension and diabetic kidney disease r76r78
    • Renin-angiotensin-aldosterone system inhibitors are not recommended for primary prevention of diabetic kidney disease in patients with blood pressure, urinary albumin to creatinine ratio (less than 30 mg/g), and estimated GFR within reference ranges r1r7c171
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