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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Oct.31.2022

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 ^r3^r4
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 ^r5^r6
Leading cause of end-stage renal disease (advanced kidney failure) ^r7^r8

Classification

Albuminuria level ^r9
- 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 ^r10
- G1: normal or increased renal function
  - GFR is greater than or equal to 90 mL/minute/1.73 m²
- 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 ^r11
- 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 ^r12^c1
- 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 ^r12
- As the filtration ability of the kidneys deteriorates, the following clinical features can be recognized:
  - Symptoms caused by edema ^r6^c2
    - Swelling of feet, ankles, and periorbital area (30%-40% of patients) ^r12^c3^c4^c5
    - Weight gain ^r12^c6
  - Foamy urine (consequence of increased protein concentration) is a classic but late symptom ^r13^c7
  - Symptoms caused by electrolyte imbalance and worsening uremia ^c8^c9
    - Nausea and vomiting ^c10^c11
    - Poor appetite, resulting in weight loss ^c12^c13
    - Generalized pruritus ^c14
  - Symptoms caused by anemia from erythropoietin deficiency ^c15
    - Fatigue and generalized weakness ^c16^c17
    - Dyspnea on exertion ^c18

Physical examination

Hypertension is very common (blood pressure of 130/90 mm Hg or higher is considered elevated for diabetes) ^r14^c19
- Associated with sodium and fluid retention, causing edema (particularly evident in lower extremities) ^r13^c20^c21^c22
Diabetic retinopathy often precedes diabetic kidney disease; funduscopy may find the following: ^c23
- Microaneurysms ^c24
- Blot hemorrhages ^c25
- Exudative, ischemic, and proliferative changes ^c26^c27^c28
- 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 ^r7^c30^c31
- Hyperglycemia lowers sodium exposure at macula densa, which inhibits tubuloglomerular feedback, dilates afferent arteriole, and induces glomerular hyperfiltration ^r15
- Increased filtration pressure produces podocyte barotrauma, resulting in podocyte and nephron loss ^r15
Condition is accelerated by ongoing albuminuria and hypertension ^r16
- Excessive protein reabsorption causes further injury to tubular epithelium and interstitial cells (ie, apoptosis), 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 ^r17^c32^c33
- Onset of type 2 diabetes during youth increases risk of developing diabetic kidney disease in adulthood ^r17^c34^c35^c36
Type 1 diabetes
- Onset of type 1 diabetes significantly before puberty has protective effect ^r17

Sex

Male individuals are at higher risk than female individuals ^r7^c37^c38

Genetics

Genetic predisposition ^c39
- Inherited susceptibility to diabetic kidney disease exists for both type 1 and type 2 diabetes ^r18^r19
- Candidate gene and genome-wide association studies have identified a few genes with polymorphisms that confer increased risk, including the following: ^r20
  - ACE (angiotensin-converting enzyme) insertion/deletion polymorphism D allele
  - Single nucleotide polymorphisms within AGT (angiotensinogen) and AGTR1 (angiotensin II receptor type 1) genes
  - Single nucleotide polymorphisms within promoter of FRMD3 gene (FERM domain containing 3)

Ethnicity/race

Highest incidence in Hispanic, Native American, and African American/Black populations ^r21^c40^c41^c42^c43

Other risk factors/associations

Long duration of diabetes and poor glycemic control account for most of the risk ^c44^c45^c46
Presence of proliferative diabetic retinopathy is highly predictive of diabetic kidney disease ^r22^c47
Effects of other exposures
- Moderate alcohol consumption is associated with lower risk of chronic kidney disease in both type 1^r23 and type 2 diabetes^r24^r25
- NSAIDs cause significant drop in GFR in patients with diabetic kidney disease ^r26^c48
- Radiocontrast dye can induce acute kidney injury in patients with diabetic kidney disease ^r27^c49
Risk factors for progression include:
- Hypertension (associated with diabetes in approximately 75% of patients) ^r28^c50
  - Accelerates renal injury induced by hyperglycemia ^r16
- Dyslipidemia (associated with diabetic macrovascular complications aggravating nephropathy),^r29 characterized by: ^c51
  - Hypertriglyceridemia
  - Elevated LDL-C levels
  - Reduced HDL-C levels ^r30
  - Elevated apolipoprotein B levels
- Diet ^c52
  - High-protein diet deteriorates renal function by increasing glomerular capillary pressure, causing hyperfiltration (which exacerbates albuminuria) and reducing GFR ^r31^c53
  - Diet high in cholesterol and saturated fats worsens dyslipidemia and renal accumulation of lipids ^r32^c54
  - Vitamin D deficiency abrogates nephroprotective action of that vitamin ^r33^c55
- Smoking ^r34^r35^c56
  - 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 ^r36^c57

Diagnostic Procedures

Primary diagnostic tools

Suspect diabetic kidney disease in patients with long-duration diabetes, especially when accompanied by other microvascular complications (eg, retinopathy) ^r1^c58
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 ^c59
  - Obtain through serum creatinine levels (a proxy variable) ^r37
  - 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) ^c60
- Albuminuria level greater than or equal to 30 mg/g (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) ^r8
  - 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 ^r1
- Categories of albuminuria ^r9
  - 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 ^r8
- Test result serves as biomarker predictive of cardiovascular events and mortality ^r8
- Nondiabetic chronic kidney disease may be suspected when albuminuria is absent and estimated GFR is reduced in patients with diabetes ^r8
Serum creatinine level ^c61
- Needed to calculate estimated GFR
- Increasing trend in serum creatinine level indicates loss of kidney function ^r40
Estimated GFR (calculated from serum creatinine^r37) ^c62
- GFR categories: ^r1
  - Greater than or equal to 90 mL/minute/1.73 m² defines stage 1 chronic kidney disease
  - 60 to 89 mL/minute/1.73 m² defines 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)
- Commonly used mathematical formulas include:
  - CKD-EPI equation: preferred (named for its developers, the Chronic Kidney Disease Epidemiology Collaboration) ^r41^c63
  - MDRD equation:^r42 less accurate; presents risk of underestimating or overestimating GFR in patients who are overweight or underweight, respectively^r37 (named for its origin, the Modification of Diet in Renal Disease study) ^c64

Imaging

Renal ultrasonography ^r38^c65
- 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 ^c66

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: ^r9
- 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 ^r46^c67^d1
- 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 ^r45^c68
- Includes a group of conditions characterized by inflammation of the glomeruli, generally of autoimmune nature^r45 (eg, lupus nephritis^r47) ^d2
- 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 ^r48^c69^c70
- 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 ^r48^c71^d3
- 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

Slow progression of kidney disease (ie, reduce albuminuria and slow decline in GFR)
Prevent development of complications (eg, renal failure, cardiovascular disease)
Attain blood pressure targets
- Blood pressure levels lower than 140/90 mm Hg are recommended in all patients with diabetes to reduce cardiovascular disease mortality and slow chronic kidney disease progression ^r51
- Consider lower blood pressure targets of 130/80 mm Hg or lower for patients who are at high risk of cardiovascular events (particularly stroke) or albuminuria and can attain these levels relatively easily and without substantial adverse effects ^r51
- 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 ^r8
- Relaxed targets are also advisable for adults on numerous medications and those with multiple comorbidities ^r51
Strive to achieve recommended glycemic goals
- General glycemic goal for most patients with diabetes is hemoglobin A1C level lower than 7% ^r52
- Specific target hemoglobin A1C levels have not been formally identified, but levels between 7% and 8% are associated with the highest survival rates in retrospective analyses of patients with diabetic kidney disease ^r8
- Relaxed target hemoglobin A1C levels are also acceptable for patients with comorbidities, limited life expectancy, or unacceptable risk of hypoglycemia ^r52

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 ^r53

Lactic acidosis

Possible symptoms include malaise, respiratory distress, myalgia, abdominal discomfort, disorientation, and somnolence ^r54
Presents with elevated arterial lactate concentration (greater than 5 mmol/L) and decreased arterial blood pH (less than 7.35) ^r55

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: ^r56
- 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 include renin-angiotensin-aldosterone system blockade, blood pressure control, and strict glycemic control
Additional components include lifestyle modifications, treatment of comorbidities, and when needed, renal replacement therapy

Renin-angiotensin-aldosterone system blockade and blood pressure control

Renin-angiotensin-aldosterone system blockade is the mainstay treatment of proteinuric diabetic kidney disease ^r3^r7
- Benefits extend beyond blood pressure effects alone; blood pressure–independent renoprotective properties occur in both type 1^r57 and type 2 diabetes^r58^r59^r60
- Consider treatment in patients with diabetes and albuminuria even if they have normal blood pressure ^r3
- For nonpregnant patients with hypertension and diabetes, prescribe 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 ^r1
Optimize blood pressure control to slow progression of diabetic kidney disease
- Earlier guidelines recommend target blood pressure of lower than 140/90 mm Hg (130/80 mm Hg in patients with albuminuria) ^r51^r61^r62
- 2021 guidelines from Kidney Disease: Improving Global Outcomes (KDIGO) recommend a target systolic blood pressure below 120 mm Hg for all patients with chronic kidney disease, including those with diabetes ^r63
- 2021 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 ^r64
  - Target blood pressure of 140/90mm Hg is recommended for patients older than 65 years
- 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 ^r63
- First line option is renin-angiotensin-aldosterone system inhibitor using either of the following drug classes: ^r7
  - ACE inhibitors (eg, benazepril, captopril, lisinopril, ramipril)
  - Angiotensin receptor blockers (eg, irbesartan, losartan, telmisartan)
    - Both drug classes have the dual effect of controlling blood pressure and slowing progression of kidney damage
    - 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,^r65 but evidence for cardiovascular benefit is strongest for ACE inhibitors^r66
    - No head-to-head comparisons of an ACE inhibitor and an angiotensin receptor blocker on progression of diabetic kidney disease are available for patients with type 1 diabetes ^r67
    - Angiotensin receptor blockers alone are recommended for patients unable to tolerate ACE inhibitors (eg, those who develop a dry cough)
    - Do not combine use of an ACE inhibitor and an angiotensin receptor blocker, owing to higher risks of hyperkalemia and acute kidney injury ^r68^r69
- Second line options ^r51
  - Indicated for either of the following:
    - Add-on therapy to achieve blood pressure goals in those already treated with maximum doses of ACE inhibitors or angiotensin receptor blockers
    - Alternative therapy for those individuals unable to tolerate either ACE inhibitors or angiotensin receptor blockers and for pregnant patients include: ^r51^r70
      - Diuretics (often required to attain blood pressure goals)
      - Calcium channel blockers ^r51
- Add on therapy
  - Mineralocorticoid receptor blocker (eg, spironolactone, eplerenone, finerenone) may be added to ACE inhibitors or angiotensin receptor blockers as long as potassium levels are not elevated on an ACE inhibitor or angiotensin receptor blocker ^r1
    - 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 ^r71^r72^r73
- Not recommended (because of uncertain benefit or possible harm) ^r74
  - Renin inhibitors (eg, aliskiren) in combination with ACE inhibitors or angiotensin receptor blockers do not improve renal outcomes ^r75
  - Combined use of ACE inhibitor and angiotensin receptor blocker increases risks of hyperkalemia and acute kidney injury ^r69
  - ACE inhibitors and angiotensin receptor blockers are not recommended for patients who do not have albuminuria or hypertension to prevent development of kidney disease ^r3

Glycemic control

Intensive measures to optimize glycemic control are indicated in most patients to limit albuminuria and slow progression of nephropathy
- Glycemic goal for most patients with diabetes is hemoglobin A1C level less than 7%; in young adults with early stage kidney disease target may be as low as 6.5% ^r52^r76
- Intensive diabetes management delays onset and progression of nephropathy in both type 1 diabetes^r78 and type 2 diabetes; however, the effects on end-stage renal disease and mortality are not clear^r79^r80^r81^r77
- Maintaining glycemic control is particularly important early in the course of diabetes, but it can be challenging because patients with chronic kidney disease (of any etiology) are at greater risk for hypoglycemia than those with a normal GFR^r82
- Disadvantage of intensive glycemic control is hypoglycemia; severe hypoglycemia has been associated with a slight increase in mortality in some, but not all, studies ^r52^r83
- 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, less aggressive treatment of diabetes (eg, hemoglobin A1C target 7.58.5%)^r76 may be considered on an individual basis ^r84
Choice of antihyperglycemic drug is influenced by several factors:
- Type of diabetes
  - Insulin is always required in type 1 diabetes, whereas oral or injectable drugs can be used in early stages of type 2 diabetes
- Stage of kidney disease or risk of progression
  - Sodium-glucose cotransporter 2 inhibitors are beneficial for patients at high risk of chronic kidney disease progression ^r1
  - At higher levels of albuminuria or higher serum creatinine levels, there is greater risk of severe hypoglycemia; therefore, for patients most at risk for adverse outcomes with hypoglycemia (ie, older adults, those with several comorbidities), agents that promote hypoglycemia are less desirable ^r85
  - Greater degree of renal dysfunction can increase toxicity of some medications, owing to impaired drug clearance ^r84
  - Metformin is contraindicated when estimated GFR is less than 30 mL/minute/1.73 m² or in any situation in which there is elevated risk of lactic acidosis ^r1
- Intended intensity of diabetes treatment
  - More potent diabetes drugs (eg, insulin, sulfonylureas, glucagonlike peptide 1 receptor agonists) are more effective in achieving lower hemoglobin A1C levels
- Priorities of care
  - Desire to balance risks (ie, progression of chronic kidney disease, cardiovascular events, likelihood of inducing hypoglycemia)
    - 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 ^r86^r87
    - Consider selected sodium-glucose cotransporter 2 inhibitors (eg empagliflozin, dapagliflozin, canagliflozin, sotagliflozin) for patients with type 2 diabetes and diabetic kidney disease who require a drug added to metformin to attain glycemic goals ^r3^r88
    - Glucagonlike peptide 1 receptor agonists (liraglutide and semaglutide) are recommended for patients who fail to achieve glycemic targets with use of metformin and sodium-glucose cotransporter 2 inhibitors or who are unable to take these medications ^r3
- Special drug considerations for patients with diabetic kidney disease ^r89
  - Metformin
    - First line treatment for patients with type 2 diabetes, including those with kidney disease ^r3^r90
    - Appropriate to begin if GFR is greater than 45 mL/minute/1.73 m² ^r1
    - When GFR is between 30 and 45 mL/minute/1.73 m², monitor cautiously and reassess risks and benefits; contraindicated if estimated GFR is less than 30 mL/minute/1.73 m² ^r91
    - Discontinue when estimated GFR is less than 30 mL/minute/1.73 m² or in any situation in which there is an elevated risk of lactic acidosis, such as: ^r1
      - Hypotension
      - Hypoxia
      - High risk of acute kidney injury (eg, administration of contrast material for kidney imaging in patients with estimated GFR of 30-60 mL/minute/1.73 m²)
  - Sodium-glucose cotransporter 2 inhibitors ^r92
    - These drugs have nephroprotective properties ^r93^r94
      - Utilize in patients with type 2 diabetes and chronic kidney disease with an estimated glomerular filtration rate of 20 mL/minute/1.73 m² or less and urinary albumin less than or equal to 300 mg/g creatinine ^r1^r95
      - Empagliflozin was shown to reduce incidence of nephropathy, slow its progression, and lower rate of renal replacement therapy in patients with type 2 diabetes whose GFR was least 30 mL/minute/1.73 m² ^r96
      - Canagliflozin was shown to improve renal outcomes in patients with type 2 diabetes whose GFR was least 30 mL/minute/1.73 m² ^r97
        There is also evidence that canagliflozin slows progression of kidney disease and improves outcomes even in patients with estimated GFR less than 30 mL/minute/1.73 m² ^r98
    - These drugs have cardioprotective properties ^r92
      - Reduce blood pressure, reduce severity of heart failure, and lessen hyperkalemia ^r99
    - At category G3a chronic kidney disease or higher, sodium-glucose cotransporter 2 inhibitors require dose adjustment or are contraindicated
    - Empagliflozin and dapagliflozin are contraindicated if estimated GFR is less than 45 mL/minute/1.73 m² (category G3b chronic kidney disease and higher) ^r1
    - Canagliflozin is contraindicated if estimated GFR is less than 30 mL/minute/1.73 m² (categories G4 and G5 chronic kidney disease) ^r1
  - 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 ^r100^r101^r102
      - Liraglutide, dulaglutide, and semaglutide appear to reduce risk of new or worsening nephropathy ^r103^r104^r105
      - An exendin-based glucagonlike peptide 1 receptor agonist, efpeglenatide, also demonstrates cardiovascular and renal benefits in patients with type 2 diabetes ^r106
    - Liraglutide, albiglutide, and dulaglutide can be used without dose alterations in category G2, G3a, or G3b chronic kidney disease
    - All glucagonlike peptide 1 receptor agonists are contraindicated in categories G4 and G5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²) ^r11
  - Sulfonylureas
    - At advanced stages of nephropathy, this class carries high risk of hypoglycemia
    - If this class is used, carefully monitor blood glucose level and give conservative dosing
    - Most sulfonylureas are contraindicated in patients with category G4 or G5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²)
  - 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
    - Do not use in patients with estimated GFR less than 60 mL/minute/1.73 m² because an active metabolite of nateglinide accumulates in patients with chronic kidney disease
  - Thiazolidinediones
    - Only pioglitazone is advisable, owing to safety concerns with other agents in this class
    - Do not use pioglitazone in patients requiring dialysis
  - Dipeptidyl-peptidase IV inhibitors
    - Require dose reduction in patients with moderate or severe renal impairment, except linagliptin, for which no dose adjustment is necessary
  - α-glucosidase inhibitors
    - Unaltered renal excretion; therefore, not recommended in patients with category G4 or G5 chronic kidney disease
  - 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) ^r89
    At categories G3 through G5 of chronic kidney disease, clearance of insulin is reduced, and risk for hypoglycemia increases ^r84
    Insulin requirements may decrease by 20% or more when GFR decreases to less than 45 mL/minute/1.73 m² ^r107

Lifestyle modifications

Smoking cessation^r108 and moderate alcohol consumption^r11 (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 ^r11
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

Treatment of comorbidities and complications

Treat dyslipidemia to reduce risk of cardiovascular disease (eg, atherosclerosis) ^r30
Prescribe antiplatelet therapy with aspirin to prevent atherosclerotic cardiovascular complications ^r5
Aspirin is indicated for secondary prevention of cardiovascular disease in all patients with diabetes
Aspirin in a low dose (75-162 mg daily) 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 ^r109
Aspirin's effect on ischemic vascular events is modest, with the absolute reduction in events depending on the underlying atherosclerotic cardiovascular risk
Aspirin's main risk is gastrointestinal bleeding
Therefore, assess the constellation and summation of all cardiovascular risks when determining whether aspirin is appropriate for primary prevention
Prescribe erythropoietin (eg, epoetin alfa) to treat anemia ^r11
Treat to maintain hemoglobin level at 11 g/dL or greater ^r11

Renal replacement therapy ^r110

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 ^c72
ACE inhibitors ^r1^r5^c73
Ramipril ^c74
Ramipril Oral tablet; Adults: Usual dose range: 1.25 to 10 mg PO once daily. Begin with a low dose and titrate to response and tolerance.
Benazepril ^c75
Benazepril Hydrochloride Oral tablet; Adults: Dose range: 10 to 40 mg PO once daily. Usually begin with a low dose and titrate to response and tolerance. Common dose: 20 mg PO once daily.
Captopril ^c76
Captopril Oral tablet; Adults: The FDA-approved dosage is 25 mg PO 3 times daily.
Lisinopril ^c77
Lisinopril Oral tablet; Adults: Doses vary within the usual dose range. Usual range: 10 to 20 mg PO once daily, adjusted to response and tolerance.
Angiotensin receptor blockers ^r1^r5^c78
Irbesartan ^c79
Irbesartan Oral tablet; Adults: Initially, 75 mg PO once daily. Titrate to target dose of 300 mg PO once daily, as tolerated.
Losartan ^c80
Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. Increase dose to 100 mg PO once daily based on blood pressure response.
Telmisartan ^c81
Telmisartan Oral tablet; Adults: 40 mg PO once daily for 4 to 12 weeks, followed by titration to 80 mg PO once daily, has been effective.
Other antihypertensives
Diuretics ^r5^c82
Furosemide ^c83
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.
Calcium channel blockers ^r5^r111^c84^c85^c86
Diltiazem
Diltiazem Hydrochloride Oral capsule, sustained release 12 hour; Adults: 90 to 120 mg PO twice daily.
Verapamil
Verapamil Hydrochloride Oral tablet, extended-release; Adults: Initially, 180 mg PO once daily in the morning. May increase to 240 mg PO twice daily.
Verapamil Hydrochloride Oral tablet, extended-release; Geriatric: Use lower initial dose (e.g., 120 mg PO once daily in the morning).
β-adrenergic receptor blockers ^r5^c87
Labetalol ^c88
Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage by 100 to 200 mg twice daily every 2 to 3 days until goal blood pressure is attained. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
Antihyperglycemic agents ^c89
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
Oral agents
Metformin ^r52^c90
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 ^r52
Empagliflozin ^c91
Empagliflozin Oral tablet; Adults: 10 mg PO once daily in the morning with or without food. May increase to 25 mg PO once daily for additional glycemic control.
Canagliflozin ^c92
Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase dose to 300 mg PO once daily if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Dapagliflozin ^c93
Dapagliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 10 mg PO once daily if needed.
Ertugliflozin ^c94
Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 15 mg PO once daily if needed.
Sulfonylureas^r52^c95
Glipizide ^c96
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; Geriatric 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.
Glyburide ^c97
Glyburide Oral tablet; Adults: 2.5 to 5 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Glyburide Oral tablet; Geriatric Adults: 1.25 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed; a conservative titration scheme is recommended. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Chlorpropamide ^c98
Chlorpropamide Oral tablet; Adults: Initially, 250 mg PO once daily with breakfast or in divided doses if GI intolerance occurs. Increase by 50 to 125 mg every 3 to 5 days if needed to attain glycemic goals. Some patients may be maintained on 100 mg/day PO. Patients who fail to respond to a maintenance dose of 500 mg/day do not generally respond to higher doses. Max: 750 mg/day PO.
Chlorpropamide Oral tablet; Geriatric Adults: Avoid use in elderly patients due to the risk of prolonged hypoglycemia. If this drug is necessary, use a reduced initial dose of 100 to 125 mg PO once daily, followed by careful dosage titration to achieve clinical goals.
Meglitinides ^c99
Nateglinide ^c100
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 ^c101
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.
Dipeptidyl-peptidase IV inhibitors ^c102
Linagliptin ^c103
Linagliptin Oral tablet; Adults: 5 mg PO once daily.
Alogliptin ^c104
Alogliptin Oral tablet; Adults: 25 mg PO once daily.
Saxagliptin ^c105
Saxagliptin Oral tablet; Adults: 2.5 or 5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Sitagliptin ^c106
Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
α-glucosidase inhibitors ^c107
Acarbose ^c108
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 ^c109
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.
Thiazolidinediones ^c110
Pioglitazone ^c111
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
Rosiglitazone ^c112
Rosiglitazone Maleate Oral tablet; Adults: 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 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.
Noninsulin injectables
Glucagonlike peptide 1 mimetics ^c113
Liraglutide ^c114
Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
Semaglutide ^c115
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. Max: 2 mg/week.
Insulin ^r52^c116
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.
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 Lispro Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily with 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 ^r108^c117

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 ^r112
In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly-processed foods
Protein intake ^r1^c118
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 ^r7^c119
American Diabetes Association recommends total sodium of 2300 mg/day or less, which is the same as in general population ^r113
Earlier recommendations by KDIGO (Kidney Disease: Improving Global Outcomes) suggested less than 2000 mg/day ^r9
Individualize dietary sodium and potassium intake based on comorbid conditions, medications, blood pressure, and electrolyte levels
Reduced dietary sodium intake to less than 2300 mg/day may be useful to control hypertension and reduce cardiovascular risk ^r1

Lifestyle modifications ^c120

Medical nutrition therapy and physical activity, to reduce weight and maintain healthy weight ^r9^r11^c121^c122^c123
Regular physical activity
Combination of aerobic and muscle strengthening exercise is recommended ^r114
Encourage at least 150 min of moderate intensity aerobic activity per week ^r114
Recommend activities aimed at improving or maintaining muscle strength, balance, and flexibility on at least 2 days a week ^r114
Advise smoking cessation and avoidance of secondhand smoke exposure ^r108^c124^c125^d4
Advise moderate alcohol consumption (2 or fewer daily drinks for most males or 1 daily drink for females and lighter-weight individuals) ^r11^c126

Procedures

Renal transplant ^r115^c127

General explanation
Surgical procedure to place healthy kidney from living or deceased donor into recipient ^r116
Option for patients with diabetic kidney disease who have developed end-stage renal disease, providing: ^r110
Better quality of life ^r110
Significant survival advantage over dialysis ^r117
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) ^r118
Congestive heart failure and pulmonary disease (unless patient is stable) ^r118
Active infection ^r118
Active gastrointestinal bleeding ^r118
Active malignancy ^r118
Dementia ^r118
Nonadherence to immunosuppressive therapy or refusal of the procedure ^r118

Complications
Allograft thrombosis
Anastomotic leakage
Rejection
Infections due to immunosuppressant drugs ^r119
Posttransplant lymphoproliferative disorder and other malignancies, such as squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma ^r119

Kidney dialysis ^r120^c128

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) ^r120^r121

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 ^r118
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 ^r122

Contraindications
Specific to peritoneal dialysis:
Inadequate peritoneal membrane (eg, peritoneal sclerosis, extensive surgical resection) ^r120
Abdominal cavity incompetence (eg, peritoneal compartmentalization, peritoneal-pleural communication) ^r120
High risk of abdominal infection (eg, recurrent diverticulitis, active inflammatory bowel disease) ^r120^r123
Previous major abdominal surgery (relative contraindication) ^r124
Older adults (older than 75 years) with illness and no social support (potential nonadherence; difficult/impossible to perform procedure in home setting) ^r125
Specific to hemodialysis: ^r126^r127
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

Comorbidities

Dyslipidemia ^r128^c129^d3
Diabetic kidney disease is accompanied by abnormalities in lipid metabolism
Statin^r129or statin plus ezetimibe^r130 is recommended for all adults aged 50 years or older who have diabetes and an estimated GFR less than 60 mL/minute/1.73 m² but who are not treated with chronic dialysis or kidney transplantation
Cardiovascular events and mortality are reduced with statins and statins plus ezetimibe in patients with non–dialysis-dependent chronic kidney disease ^r131
However, statins do not slow rate of kidney disease progression in those with preexisting chronic kidney disease ^r132
Statins are not recommended to be started in patients undergoing dialysis because use of statins in these patients shows no cardiovascular or survival advantage; however, continuation of statins is appropriate in those patients who are already using them and who have progression to end-stage renal disease ^r133
Do not use measurement of LDL-C to identify patients for statin therapy, as it is appropriate for assessing coronary risk in patients with chronic kidney disease
Initial evaluation of lipid profile is intended to diagnose severe hypertriglyceridemia and/or hypercholesterolemia while ruling out any underlying secondary causes
Statin dose titration is unnecessary, and follow-up measurements of lipid levels are suggested only to help assess adherence to statin therapy ^r8

Special populations

Pregnant patients
Pregnant females with concomitant nephropathy are at risk of deteriorating maternal kidney function, leading to end-stage renal disease ^r134
Compared with the healthy population, pregnant females 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
Preconception counseling for patients with preexisting diabetes and nephropathy or microalbuminuria should address the following issues: ^r134
Use of contraception in planning stages
Evaluate and discuss the risks of pregnancy-induced kidney failure, preeclampsia, and preterm delivery
Treatment is modified accordingly: ^r70
Strict glycemic control during pregnancy is necessary (target hemoglobin A1C less than 6%) ^r70
Establish intensive antihypertensive treatment (blood pressure goal lower than 130/80 mm Hg) early in pregnancy, using pregnancy-friendly antihypertensive agents (ideally before conception) ^r70
ACE inhibitors and angiotensin receptor blockers are contraindicated during all stages of pregnancy because of teratogenic risk ^r135
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
Methyldopa, β-blockers (eg, labetalol), and calcium antagonists (eg, nifedipine, diltiazem) can be used safely ^r70
Methyldopa is drug of choice ^r136
Use diuretics as alternative or add-on therapy, but only with caution ^r70
Low-dose aspirin is recommended (75 mg/day 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 ^r134
Screen for sight-threatening diabetic retinopathy ^r134
Supplement with folic acid during the first 12 gestational weeks ^r134
Patients with more advanced stages of chronic kidney disease
Hypoglycemia ^r107
Severe hypoglycemia has been associated with a slight increase in mortality ^r137
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 ^r82

Monitoring

Monitoring is necessary to assess progression, relying on the assessments of albuminuria (indicative of kidney damage) and estimated GFR (indicative of kidney function) ^c130
Perform physical examination and measure weight and blood pressure at every clinical encounter ^r51
Measure orthostatic blood pressure periodically or when symptoms of orthostatic hypotension occur ^c131
If orthostatic hypotension develops, consider nocturnal dosing of antihypertensives and/or stopping α-blockers and diuretics ^r51
Assess for albuminuria (spot urinary albumin to creatinine ratio) and obtain serum creatinine level and estimated GFR at least annually ^r74^c132
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 ^r74
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
Patients on metformin
Metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function ^r138
GFR is the most appropriate monitoring parameter because serum creatinine measurements account for additional factors that are important (eg, patient's age, gender, race, and/or weight)
If estimated GFR is 30 to 60 mL/minute/1.73 m², monitor every 3 to 6 months ^r90
Reduce maximum dose when estimated GFR is less than 45 mL/minute/1.73 m², and discontinue when estimated GFR is less than 30 mL/minute/1.73 m²

Complications and Prognosis

Complications

Cardiovascular disease ^c133
In general, incidence increases according to severity of kidney disease ^r139
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) ^c134^d5
Left ventricular hypertrophy (affects approximately 74% of patients with chronic kidney disease) ^r140^c135
Congestive heart failure (31% of patients with chronic kidney disease) ^r140^c136^d6
Stroke (5- to 10-fold increased incidence in patients with end-stage renal disease) ^r140^c137^d7
Peripheral artery disease (eg, atherosclerosis, thrombosis, stenosis; reported in 25% of patients older than 40 years) ^r11^c138^c139^c140^c141^c142^c143^c144^c145^d8
Anemia ^r141^c146
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
Chronic kidney disease–mineral bone disorder ^r142^r143^c147
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 ^c148^c149^c150
Tertiary hyperparathyroidism and hypercalcemia develop after chronic secondary hyperparathyroidism, owing to autonomous parathyroid hormone secretion that is unregulated by calcium levels
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 ^r143
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 ^r144^r145^r146
Metabolic acidosis ^r62
May be complicated by hyperkalemia
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 ^r147
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% ^r147
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 greater than or equal to 30 mg/g) 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 have progression to end-stage renal disease within 10 years and 75% have progression 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 normal albumin levels present a hazard ratio for death—due to any cardiovascular cause—approximately 2 times higher than that of patients older than 75 years ^r148
Patients with prior cardiovascular disease, chronic kidney disease, or both have increased risk of cardiovascular events and mortality; risk increases with worsening baseline GFR ^r149
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

Patients with type 1 diabetes: screen annually beginning at 5 years after initial diagnosis ^r1^c151^c152
Patients with type 2 diabetes: screen annually starting at time of diagnosis ^r1^c153^c154
Patients with any type of diabetes and who have comorbid hypertension: screen annually ^r1^c155^c156

Screening tests

Annual assessment of albuminuria (spot urinary albumin to creatinine ratio) and estimated GFR ^r74^c157^c158
Positive test result is marked by either of the following:
Urinary albumin to creatinine ratio greater than or equal to 30 mg/g ^r74
Estimated GFR less than 60 mL/minute/1.73 m² ^r74

Prevention

Progression of diabetic kidney disease can be slowed by:
Intensive treatment of diabetes ^c159
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) ^r7^c160
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 ^r71^r72
Renin-angiotensin-aldosterone system blockade is controversial for prevention of diabetic kidney disease patients with diabetes who are normotensive and do not have albuminuria ^r7^c161
Not recommended for primary prevention of diabetic kidney disease in patients with normal blood pressure, urinary albumin to creatinine ratio (less than 30 mg/g), and estimated GFR ^r1

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Diabetic Kidney Disease

Synopsis

Key Points

Urgent Action

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Sex

Genetics

Ethnicity/race

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Procedures

Kidney biopsy c66

General explanation

Indication

Contraindications

Complications

Interpretation of results

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Admission criteria

Criteria for ICU admission

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures

Renal transplant r115c127

Kidney dialysis r120c128

Comorbidities

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations

Screening tests

Prevention

Kidney biopsy ^c66

Renal transplant ^r115^c127

Kidney dialysis ^r120^c128