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Diabetic nephropathy

Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

May.14.2024

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
- Sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide 1 receptor agonists, 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 kidney 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 kidney disease present the worst outcome; however, kidney replacement therapy (eg, kidney 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

Urine with red or white blood cells or cellular casts, nephrotic syndrome, rapidly increasing albuminuria or rapidly decreasing eGFR, or the absence of retinopathy in patients with type 1 diabetes raises the possibility of nondiabetic chronic kidney disease ^r1

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 (30 mg/g or greater creatinine), reduced eGFR (estimated GFR; less than 60 mL/minute/1.73 m²), or both, persisting for more than 3 months
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 diabetes mellitus occurs in 20% to 40% of patients with diabetes ^r1^r5
Leading cause of end-stage kidney disease (advanced kidney failure) ^r6^r7

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 299 mg/g
- Severely increased: urinary albumin to creatinine ratio is 300 mg/g or greater
Classification of chronic kidney disease, according to GFR category ^r8
- G1: normal or high GFR
  - GFR is 90 mL/minute/1.73 m² or higher
- G2: mildly decreased GFR
  - GFR is 60 to 89 mL/minute/1.73 m²
- G3a: mildly to moderately decreased GFR
  - GFR is 45 to 59 mL/minute/1.73 m²
- G3b: moderately to severely decreased GFR
  - GFR is 30 to 44 mL/minute/1.73 m²
- G4: severely decreased GFR
  - 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 ^r8
- A1: normal to mildly increased
  - Albumin to creatinine ratio: less than 30 mg/g
- A2: moderately increased
  - Albumin to creatinine ratio: 30 to 299 mg/g
- A3: severely increased
  - Albumin to creatinine ratio: 300 mg/g or greater

Diagnosis

Clinical Presentation

History

Symptoms vary according to severity of disease ^r9
- Early stages of disease are asymptomatic ^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
- As the filtration ability of the kidneys deteriorates, the following clinical features can be recognized: ^r9
  - Symptoms caused by edema (swelling of lower extremities, weight gain) ^r5^c2
  - Foamy urine (consequence of increased protein concentration) is a classic but late symptom ^r10^c3
  - Symptoms caused by electrolyte imbalance and worsening uremia ^c4^c5
    - Nausea and vomiting ^c6^c7
    - Poor appetite resulting in weight loss ^c8^c9
    - Generalized pruritus ^c10
  - Symptoms caused by anemia from erythropoietin deficiency ^c11
    - Fatigue and generalized weakness ^c12^c13
    - Dyspnea on exertion ^c14

Physical examination

Hypertension is very common (blood pressure of 130/80 mm Hg or higher is considered elevated for diabetes) ^r11^c15
- Associated with sodium and fluid retention, causing edema (particularly evident in lower extremities) ^r10^c16^c17^c18
Diabetic retinopathy often precedes diabetic kidney disease; funduscopy may find the following: ^c19
- Microaneurysms ^c20
- Blot hemorrhages ^c21
- Exudative, ischemic, and proliferative changes ^c22^c23^c24
- Macular edema ^c25

Causes and Risk Factors

Causes

Prolonged exposure to hyperglycemia causes damage to kidney structure (eg, glomerulus, tubulointerstitium, vasculature), either directly or through hemodynamic changes ^r6^c26^c27
- Hyperglycemia lowers sodium exposure at macula densa, which inhibits tubuloglomerular feedback, dilates afferent arteriole, and induces glomerular hyperfiltration ^r12^c28
- Increased filtration pressure produces podocyte barotrauma, resulting in podocyte and nephron loss ^r12^c29
Condition is accelerated by ongoing albuminuria and hypertension ^r13^c30^c31
- 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 ^r14^c32^c33
- Onset of type 2 diabetes during youth increases risk of developing diabetic kidney disease in adulthood ^r14^c34^c35^c36
Type 1 diabetes
- Onset of type 1 diabetes significantly before puberty has protective effect ^r14

Sex

Male individuals are at higher risk than female individuals ^r6^c37^c38

Genetics

Genetic predisposition ^c39
- Inherited susceptibility to diabetic kidney disease exists for both type 1 and type 2 diabetes ^r15^r16
- Candidate gene and genome-wide association studies have identified a few genes with polymorphisms that confer increased risk, including the following: ^r17
  - ACE (angiotensin-converting enzyme) insertion/deletion polymorphism D allele ^c40
  - Single nucleotide polymorphisms within AGT (angiotensinogen) and AGTR1 (angiotensin II receptor type 1) genes ^c41^c42
  - Single nucleotide polymorphisms within promoter of FRMD3 gene (FERM domain containing 3) ^c43

Ethnicity/race

Highest incidence in Hispanic, Native American, and African American/Black populations ^r18^c44^c45^c46^c47

Other risk factors/associations

Duration of diabetes and poor glycemic control account for most of the risk ^c48^c49^c50
Presence of proliferative diabetic retinopathy is highly predictive of diabetic kidney disease ^r19^c51
Effects of other exposures
- NSAIDs cause significant drop in GFR in patients with diabetic kidney disease ^r20^c52
- Radiocontrast dye can induce acute kidney injury in patients with diabetic kidney disease ^r21^c53
- Obesity is a predictor of chronic kidney disease in patients with diabetes and is an independent predictor of chronic kidney disease in general ^r22^r23
- Conflicting evidence suggests moderate alcohol consumption is associated with lower risk of chronic kidney disease in both type 1 and type 2 diabetes compared to no alcohol use ^r24^r25^r26^c54
  - However, people who stopped use of alcohol due to adverse health effects may be reported in the nondrinker category in studies, and no randomized controlled trials confirm any health benefits of alcohol ^r27
Risk factors for progression include:
- Hypertension (associated with diabetes in approximately 75% of patients) ^r28^c55
  - Accelerates kidney injury induced by hyperglycemia ^r13
- Dyslipidemia (associated with diabetic macrovascular complications aggravating nephropathy),^r29 characterized by the following: ^c56
  - Hypertriglyceridemia ^c57
  - Elevated LDL-C levels ^c58
  - Reduced HDL-C levels ^r30^c59
  - Elevated apolipoprotein B levels
- Diet ^c60
  - High-protein diet deteriorates kidney function by increasing glomerular capillary pressure, causing hyperfiltration (which exacerbates albuminuria) and reducing GFR ^r31^c61
  - Diet high in cholesterol and saturated fats worsens dyslipidemia and kidney accumulation of lipids ^r32^c62
  - Vitamin D deficiency abrogates nephroprotective action of that vitamin; vitamin D supplementation may decrease albuminuria and serum creatinine ^r33^r34^c63
- Smoking ^r35^r36^c64
  - 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 kidney disease
  - Former smokers and nonsmokers carry similar risk of disease progression
    - Up to 20 years of abstinence may be needed to decrease the risk of new-onset smoking-associated kidney disease to that of nonsmokers ^r22
  - Passive smokers and active smokers carry similar risk of disease progression
- Recurrent acute kidney injury increases risk of disease progression ^r37^c65

Diagnostic Procedures

Primary diagnostic tools

Suspect diabetic kidney disease in patients with type 1 diabetes duration greater than 5 to 10 years, type 2 diabetes of any duration, or in the presence of other microvascular complications (eg, retinopathy) ^r1^c66
Base diagnosis on persistent presence of albuminuria, reduction in eGFR, or both in patients with diabetes ^r1
- Albuminuria
  - Measure urine albumin to creatinine ratio ^r1
    - 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
    - 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
    - At least 2 out of 3 measurements in a 3- to 6-month period should be abnormal for diagnosis, due to high biologic variability
- eGFR ^r1^c67
  - Calculate eGFR based on CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation without race with creatinine and cystatin C, if available ^r38^r39
    - Combining measurements of creatinine and cystatin C improves accuracy over either alone
    - Older formulas that use race in calculation for eGFR are no longer recommended due to inaccuracy
- Comprehensive chronic kidney disease staging takes into account level of albuminuria at each eGFR stage ^r1
Consider alternative causes of kidney disease in patients with urinary sediment containing red or white blood cells or casts, nephrotic syndrome, rapidly increasing albuminuria or decreasing GFR, or no concomitant retinopathy in patients with type 1 diabetes ^r1
- Investigation for alternative causes may be required (eg, kidney biopsy)
Use kidney ultrasonography to exclude obstruction and other structural causes of kidney disease ^r40
Kidney biopsy is the only method to absolutely confirm diagnosis, but it is not performed routinely ^r41
- Recommended when diagnosis is inconclusive or another cause of kidney disease is suspected

Laboratory

Albumin excretion levels (using urine albumin to creatinine ratio; preferred test) ^c68
- 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) ^r1
  - 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 299 mg/g
  - Severely increased: urinary albumin to creatinine ratio is 300 mg/g or greater
- Test is not entirely sensitive for kidney disease; using both albuminuria and eGFR is recommended because normal albumin excretion may be present at any eGFR ^r1
  - Reduced eGFR without albuminuria is becoming more common in patients with both type 1 and type 2 diabetes ^r1
- Test result serves as biomarker predictive of cardiovascular events and mortality ^r1
Serum creatinine level ^c69
- Needed to calculate eGFR
- Increasing trend in serum creatinine level indicates loss of kidney function ^r42
eGFR ^c70
- GFR categories ^r8
  - Stage 1: normal or high GFR, 90 mL/minute/1.73 m² or higher
  - Stage 2: mildly decreased GFR, 60 to 89 mL/minute/1.73 m²
  - Stage 3a: mildly to moderately decreased GFR, 45 to 59 mL/minute/1.73 m²
  - Stage 3b: moderately to severely decreased GFR, 30 to 44 mL/minute/1.73 m²
  - Stage 4: severely decreased GFR, 15 to 29 mL/minute/1.73 m²
  - Stage 5: kidney failure, less than 15 mL/minute/1.73 m²
- National Kidney Foundation recommends using the 2021 CKD-EPI creatinine equation to estimate GFR ^r8^r39
  - This equation does not include a race coefficient
  - When serum cystatin C level is available, use the combined serum creatinine-cystatin C equation because this is more accurate than using serum creatinine alone and reduces racial and ethnic bias ^r8^r38
- Historically, CKD-EPI equation used serum creatinine, age, race, and gender to estimate GFR ^r43^c71

Imaging

Kidney ultrasonography ^r40^c72
- Used to identify any structural abnormalities that may suggest an alternative cause of kidney disease
- Increased kidney volume marks initial phases of diabetic kidney disease
- Decreased kidney volume characterizes chronic diabetic kidney disease

Procedures

Kidney biopsy ^c73

General explanation

Percutaneous procedure involving placement of long, thin needle into the kidney through flank to obtain tissue sample; confirms diagnosis ^r44

Indication

Only necessary if diagnosis is uncertain or alternative cause of kidney disease is suspected ^r41
- Consider alternative causes of kidney disease in patients with urinary sediment containing red or white blood cells or casts, nephrotic syndrome, rapidly increasing albuminuria or decreasing GFR, or no concomitant retinopathy in patients with type 1 diabetes ^r1

Contraindications

Absolute ^r45
- Solitary kidney
- Uncontrollable bleeding diathesis
Relative ^r45
- Severe azotemia
- Anatomic kidney abnormalities
- Anticoagulation
- Pregnancy
- Urinary tract infection

Complications

Gross hematuria
Hematoma ^r44
Pneumothorax

Interpretation of results

Typical immunohistopathologic features ^r46
- 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 ^r47^c74^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 ^r46^c75
- Includes a group of conditions characterized by inflammation of the glomeruli, generally of autoimmune nature (eg, lupus nephritis^r48) ^r46^c76^d2
- Similar clinical features include proteinuria and hypertension; similar pathologic changes include glomerulosclerosis and hyalinization of kidney microvasculature ^r46
- Differentiated by the following:
  - Microscopic urinalysis showing active urine sediment with dysmorphic RBCs and casts
  - Histologic analysis of kidney 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) ^r46
  - Immunohistochemistry of kidney biopsy specimens showing characteristic staining patterns (eg, IgG, IgM, complement C3) of kidney mesangium, glomerular basement membrane, or both ^r46
Hypertensive nephropathy or nephrosclerosis ^r49^c77^c78
- Condition caused by chronic hypertension leading to kidney damage
- Hypertension is the principal common sign ^r46
- Differentiated by biopsy findings; hyalinization is limited to afferent renal arterioles and is absent from efferent arterioles ^r46
Renovascular hypertension ^r49^c79
- Condition caused by atherosclerotic narrowing or blockage of blood supply to kidney (eg, renal artery stenosis) ^r50
- 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 kidney duplex ultrasonography is a differentiating factor
- Gold standard test is invasive kidney 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 kidney vasculature provides definitive evidence for this condition ^r51

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 kidney 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 ^r52
    - Lower hemoglobin A1C goal than 7% may be appropriate and beneficial if it can be achieved without significant hypoglycemia or adverse effects of medications
    - Higher hemoglobin A1C goal than 7% may be appropriate for patients with limited life expectancy or when harms of treatment outweigh the benefits
  - 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 ^r53
    - Target hemoglobin A1C levels of 7% to 8% without hyperglycemia symptoms are recommended for patients with extensive comorbidities or advanced kidney disease, limited life expectancy, history of severe hypoglycemia or hypoglycemia unawareness, or long-standing diabetes in which the A1C goal has been difficult to attain despite intensive efforts
- 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 ^r8
    - Targets in this range are associated with improved survival, cardiovascular outcomes, and microvascular end points, as well as 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
  - 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 ^r1^r54^r55
    - Kidney benefits of intensive glucose control lag by at least 2 years in type 2 diabetes to more than 10 years in type 1 diabetes ^r1
      - As a result, patients with end-stage kidney 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 ^r53^r57^r58
  - 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) ^r1^r59
  - Low diastolic blood pressure is not a contraindication to intensive blood pressure management, with awareness that chronic kidney disease, older age, and frailty are at higher risk of adverse effects of intensive treatment ^r57
- 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 ^r8

Disposition

Admission criteria

Requirement for urgent dialysis, such as the following:

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 kidney diagnosis
- Complications (eg, anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, electrolyte disturbances)
- Rapidly progressing or advanced kidney disease (eGFR less than 30 mL/minute/1.73 m²) with anticipated need for eventual kidney 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
- Kidney 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 ^r6
- 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 eGFR is less than 60 mL/minute/1.73 m² ^r61
  - Do not combine use of an ACE inhibitor and an angiotensin receptor blocker owing to higher risks of hyperkalemia and acute kidney injury ^r66^r67
- Both drug classes control blood pressure and reduce the risk of progression to end-stage kidney disease in patients with type 1 or type 2 diabetes with diabetic kidney disease (eGFR less than 60 mL/minute/1.73 m² and urinary albumin to creatinine ratio of 300 mg/g or higher) ^r1
- In patients with lower levels of albuminuria (30-299 mg/g creatinine), both drug classes reduce progression to more advanced albuminuria and cardiovascular events and slow chronic kidney disease progression but do not reduce progression to end-stage kidney disease ^r1
- Head-to-head comparisons of an ACE inhibitor and an angiotensin receptor blocker show clinical equivalence, but angiotensin receptor blockers have a better safety profile ^r8
- Ace inhibitor or angiotensin receptor blocker therapy should be increased to maximal tolerated dosage to achieve benefits ^r1
  - Continue treatment if serum creatinine increases up to 30%, unless volume depletion or hyperkalemia develop
- ACE inhibitors and angiotensin receptor blockers have not been shown to have benefit for patients with increased albumin excretion (albumin to creatinine ratio of 30 mg/g or greater) without hypertension ^r1
- ACE inhibitors and angiotensin receptor blockers have not been shown to be superior to dihydropyridine calcium channel blockers or thiazide-like diuretics for treatment of hypertension in patients without kidney disease ^r1
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) ^r8^r59^r68
- Dihydropyridine calcium channel blockers
- Thiazide-like diuretics

Statin therapy ^r30^r69

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 ^r8

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 ^r1^r3^r8^r70
- 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, kidney benefits of glucagonlike peptide 1 receptor agonists are less well established ^r71^r72
- 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 ^r1^r3
A nonsteroidal 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 eGFR of 25 mL/minute/1.73 m² or more and serum potassium concentration within reference range ^r1^r8^r73
- Randomized controlled trials and pooled analysis 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 ^r74^r75^r76^r77

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 diabetes and type 2 diabetes; intensive glycemic control has also been shown to decrease long-term cardiovascular outcomes (eg, myocardial infarction, cardiovascular death) and all-cause mortality ^r52
  - These trials were conducted before the availability of sodium-glucose cotransporter-2 inhibitors and glucagonlike peptide 1 receptor agonists, which have demonstrated protective effects and do not cause hypoglycemia, which is linked to adverse effects ^r78^r79^r80^r81^r82^r83
- This need to be balanced against greater risk of severe hypoglycemia and impaired drug clearance associated with more severe kidney disease ^r1^r56^r84
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, with glucagonlike peptide 1 receptor agonists added in patients who have not achieved target hemoglobin A1C ^r1^r73
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 ^r8
  Appropriate to begin if GFR is 30 mL/minute/1.73 m² or higher ^r8^r73
  Increase frequency of GFR monitoring when GFR is less than 60 mL/minute/1.73 m² ^r8
  Dosage adjustment is required when eGFR is less than 45 mL/minute/1.73 m² (adjust dosage for patients with conditions that predispose to hypoperfusion and hypoxemia when eGFR is 45-59 mL/minute/1.73 m²) ^r8
  Temporarily discontinue for iodinated contrast imaging procedures in patients with eGFR 30 to 60 mL/minute/1.73 m² ^r8
  Discontinue when eGFR is less than 30 mL/minute/1.73 m² ^r1
- Sodium-glucose cotransporter 2 inhibitors ^r87
  These drugs have nephroprotective and cardioprotective properties ^r87^r88^r89^r90
  Recommended in addition to 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 an eGFR of 20 mL/minute/1.73 m² or higher and urinary albumin to creatinine ratio of 200 mg/g or higher ^r1^r91
  May also be beneficial in patients with urinary albumin to creatinine ratio ranging from within reference range to 200 mg/g
  Can be continued even if eGFR is less than 20 mL/minute/1.73 m², unless it is not tolerated or kidney replacement therapy is initiated ^r8
  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 ^r92^r93
- Glucagonlike peptide 1 receptor agonists
  These drugs have cardioprotective and nephroprotective properties; however, the kidney benefits are less well established than sodium-glucose cotransporter 2 inhibitors ^r94^r95^r96
  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) ^r8
  Dulaglutide, liraglutide, and semaglutide may be used in all stages of kidney impairment
  Exenatide immediate release is not recommended when eGFR is less than 30 mL/minute/1.73m²; exenatide extended release is not recommended when eGFR is less than 45 mL/minute/1.73 m²
  Lixisenatide is not recommended when eGFR is less than 15 mL/minute/1.73 m²
  An exendin-based glucagonlike peptide 1 receptor agonist, efpeglenatide, also demonstrates cardiovascular and kidney benefits in patients with type 2 diabetes ^r97
- Dual glucose-dependent insulinotropic polypeptide and glucagonlike peptide 1 agonists (tirzepatide)
  Can be used in all stages of kidney impairment
  Use of tirzepatide is associated with nausea, vomiting, and diarrhea, which may lead to dehydration. This dehydration has resulted in acute kidney injury

Lifestyle modifications

Smoking cessation is recommended to reduce blood pressure, prevent cardiovascular complications, and prevent progression of kidney disease ^r8^r22^r98^r99
Avoid excessive alcohol consumption (not more than 1 drink per day in women and lighter-weight individuals, or 2 drinks per day in men) ^r98
Adhere to recommended dietary protein intake ^r1
For non–dialysis-dependent diabetic kidney disease, dietary protein intake should be 0.8 g/kg/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/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 is also not recommended because it does not alter glycemic measures, cardiovascular risk measures, or course of GFR decline
A Cochrane review of low-protein diet (0.6-0.8 g/kg/day) did not show an effect on kidney failure or death and uncertain effect on kidney function ^r100
Patients on dialysis may require higher levels of dietary protein intake
Limit sodium consumption (2-2.3 g/day) to reduce blood pressure and possibly reduce cardiovascular risk ^r1^r101

Kidney replacement therapy ^r102

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

Drug therapy

Renin-angiotensin-aldosterone system inhibitors ^c80
ACE inhibitors ^r1^c81
Benazepril ^c82
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 ^c83
Captopril Oral tablet; Adults: 12.5 to 25 mg PO 2 to 3 times daily, initially. Titrate dose based on blood pressure, serum creatinine, and potassium concentrations every 2 to 4 weeks (Usual dose: 50 mg PO 3 times daily [Max: 450 mg/day]).
Lisinopril ^c84
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 ^c85
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 ^r1^c86
Irbesartan ^c87
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 ^c88
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 ^c89
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.
Dihydropyridine calcium channel blockers ^r1^r57^c90^c91^c92
Amlodipine
Amlodipine Besylate Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose after 7 to 14 days if further control is needed. Max: 10 mg/day.
Nifedipine
Nifedipine Oral tablet, extended-release; Adults: 30 or 60 mg PO once daily, initially. May increase dose over 7 to 14 days if further control is needed. Usual dose range: 30 to 90 mg/day. Max: 120 mg/day.
Thiazide-like diuretics ^r1^r57^c93
Chlorthalidone
Chlorthalidone Oral tablet; Adults: 12.5 to 25 mg PO once daily, initially. May increase dose to 50 mg PO once daily if response is insufficient and to 100 mg PO once daily if further control is needed.
Indapamide
Indapamide Oral tablet; Adults: 1.25 mg PO once daily, initially. May double dose every 4 weeks if further control is needed. Max: 5 mg/day.
Nonsteroidal mineralocorticoid receptor antagonist ^r1
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 ^r103^c94
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 ^r1^c95
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.
Sodium-glucose cotransporter 2 inhibitor ^r1
Canagliflozin ^c96
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 ^c97
Dapagliflozin Oral tablet; Adults: 10 mg PO once daily.
Empagliflozin ^c98
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.
Glucagonlike peptide 1 mimetics ^r1^c99
Liraglutide ^c100
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 ^c101
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.
Insulin ^r103^c102
Basal insulin
Insulin degludec
Insulin Degludec Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/day 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 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 ^r99^c103

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 Dietary Approaches to Stop Hypertension diet and Mediterranean diet, are effective for controlling glycemia and lowering cardiovascular risk factors ^r104^c104
In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly processed foods
Protein intake ^c105
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 ^r1^r100
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 ^r6^r101^c106
American Diabetes Association recommends total sodium of 2300 mg/day or less, which is the same as in general population ^r1
Recommendations by Kidney Disease: Improving Global Outcomes suggest less than 2000 mg/day ^r61
Individualize dietary sodium and potassium intake based on comorbid conditions, medications, blood pressure, and electrolyte levels

Lifestyle modifications ^c107

Medical nutrition therapy and physical activity to reduce weight and maintain healthy weight ^c108^c109^c110
Regular physical activity
Combination of aerobic and muscle strengthening exercise is recommended ^r105
Encourage at least 150 minutes of moderate intensity aerobic activity per week ^r105
Recommend activities aimed at improving or maintaining muscle strength, balance, and flexibility at least 2 days a week ^r105
Advise smoking cessation and avoidance of secondhand smoke exposure ^r99^c111^c112^d3
Alcohol should be consumed in moderation, if at all (1 or fewer drinks per day for women or lighter-weight individuals, 2 or fewer drinks per day for men) ^r98^c113

Procedures

Kidney transplant ^r106^c114

General explanation
Surgical procedure to place healthy kidney from living or deceased donor into recipient ^r107
Option for patients with diabetic kidney disease who have developed end-stage kidney disease, providing the following: ^r102
Better quality of life ^r102
Significant survival advantage over dialysis ^r108
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 kidney function, nearing end stage

Contraindications
Unstable cardiovascular disease (eg, coronary and peripheral artery disease, peripheral arterial occlusive disease, carotid arterial stenosis, stroke) ^r109
Congestive heart failure and pulmonary disease (unless patient is stable) ^r109
Active infection ^r109
Active gastrointestinal bleeding ^r109
Active malignancy ^r109
Dementia ^r109
Nonadherence to immunosuppressive therapy or refusal of the procedure ^r109

Complications
Allograft thrombosis
Anastomotic leakage
Rejection
Infections due to immunosuppressant drugs ^r110
Posttransplant lymphoproliferative disorder and other malignancies, such as squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma ^r110

Kidney replacement therapy ^r111^c115

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) ^r111^r112

Indication
Option for patients with diabetic kidney disease and end-stage kidney disease who are on waiting list for transplant and do not have potential living donor ^r109
Paucity of data from randomized controlled trials that establish optimal timing for kidney replacement therapy
Timing of dialysis is often affected by multiple factors, including age, diabetes mellitus, individual desire, personal beliefs, and cultural and educational backgrounds ^r113

Contraindications
Specific to peritoneal dialysis ^r114
Inadequate peritoneal membrane (eg, peritoneal sclerosis, extensive surgical resection) ^r111
Abdominal cavity incompetence (eg, peritoneal compartmentalization, peritoneal-pleural communication) ^r111
High risk of abdominal infection (eg, recurrent diverticulitis, active inflammatory bowel disease) ^r111^r115
Previous major abdominal surgery (relative contraindication) ^r116
Older adults (older than 75 years) with illness and no social support (potential nonadherence; difficult or impossible to perform procedure in home setting) ^r117
Specific to hemodialysis ^r114
Unable to maintain adequate blood pressure during dialysis
Lack of vascular access

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 ^r118
Pregnant patients with concomitant nephropathy are at risk of deteriorating maternal kidney function, leading to end-stage kidney disease ^r118
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 ^r68
Female patients taking an ACE inhibitor or an angiotensin receptor blocker should discontinue the medication if pregnancy is being planned or 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 ^r119
Methyldopa, β-blockers (eg, labetalol), and calcium channel blockers (eg, nifedipine) can be used safely ^r68
Methyldopa is drug of choice ^r120
Low-dose aspirin is recommended beginning at 10 to 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 ^r118

Monitoring

Monitoring is necessary to assess progression, relying on the assessments of albuminuria (indicative of kidney damage) and eGFR (indicative of kidney function) ^c116
Perform physical examination and measure weight and blood pressure at every clinical encounter ^r59^c117
Measure orthostatic blood pressure periodically or when symptoms of orthostatic hypotension occur ^c118
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 calculate eGFR (using serum creatinine level, and cystatin C level if available) at least annually ^r1^c119
In patients with urinary albumin to creatinine ratio 30 mg/g or greater, or eGFR less than 90 mL/minute/1.73 m², assess 1 to 4 or more times per year, according to severity
Annual surveillance should continue for patients on ACE inhibitors and angiotensin receptor blockers, even in patients whose albuminuria has resolved with therapy, to detect disease progression and ongoing response to therapy
Monitor potassium levels periodically for patients on ACE inhibitors, angiotensin receptor blockers, diuretics, or finerenone ^r1
For patients with decreasing eGFR (less than 60 mL/minute/1.73 m²), periodically evaluate dose of medications for needed adjustments and counsel avoidance of nephrotoxic agents (eg, NSAIDs) ^r1
Do not discontinue renin angiotensin system blockade for increases in serum creatinine of 30% or less, unless signs of extracellular fluid volume depletion are present

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, metformin)
Especially likely in patients with impaired kidney function who are treated with insulin, owing to reduced kidney clearance of insulin and decreased insulin degradation in peripheral tissues
To reduce risk of hypoglycemia in patients taking insulin or insulin secretagogues, greater frequency of self-monitoring of blood glucose and modification of antihyperglycemic drug dosing is advisable ^r54
Cardiovascular disease ^c120
In general, incidence increases according to severity of kidney disease ^r122
Risk of cardiovascular death progressively increases with declining eGFR (independent of albuminuria) and progressively increases with increasing albuminuria (independent of eGFR)
Most frequent specific complications include the following:
Coronary artery disease (increased risk of death and nonfatal cardiovascular outcomes after myocardial infarction) ^c121^d4
Left ventricular hypertrophy (affects approximately 74% of patients with chronic kidney disease) ^r122^c122
Congestive heart failure (31% of patients with chronic kidney disease) ^r122^c123^d5
Stroke (5- to 10-fold increased incidence in patients with end-stage kidney disease) ^r122^c124^d6
Peripheral artery disease (eg, atherosclerosis, thrombosis, stenosis; reported in 25% of patients older than 40 years) ^r98^c125^c126^c127^c128^c129^c130^c131^c132^d7
Antiplatelet therapy with low-dose aspirin is indicated for secondary prevention of cardiovascular disease in all patients with diabetes and atherosclerotic cardiovascular disease ^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 ^r57^r123
Anemia ^r124^c133
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 ^r98
Chronic kidney disease–mineral bone disorder ^r125^r126^r127^c134
Syndrome characterized by the following:
Abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, and vitamin D metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength (kidney 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 ^c135^c136^c137
Tertiary hyperparathyroidism and hypercalcemia develop after chronic secondary hyperparathyroidism, owing to autonomous parathyroid hormone secretion that is unregulated by calcium levels ^c138^c139
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 ^r125^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 ^r128^r129^r130
Metabolic acidosis ^r131
May be complicated by hyperkalemia ^c140
Management includes low-potassium diet, diuretics, and sodium bicarbonate supplementation
Depression is more common in patients who have diabetes and kidney disease than in patients who have diabetes without kidney disease ^r132

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 ^r133
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% ^r133
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 ^r41
Approximately 50% of patients with severe albuminuria progress to end-stage kidney disease within 10 years and 75% progress to end-stage kidney disease within 20 years ^r41
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 kidney 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 ^r134
Patients with prior cardiovascular disease, chronic kidney disease, or both have increased risk of cardiovascular events and mortality; risk increases with worsening baseline GFR ^r135
Disease progression is generally more indolent in patients with type 2 diabetes than in patients with type 1 diabetes ^r41
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 kidney disease after 20 years ^r41
5-year survival rate of patients with diabetes and end-stage kidney disease is poor (30% after initiation of dialysis) ^r2
Kidney replacement therapy (eg, kidney transplant, dialysis) increases 5-year survival rate by 30% in these patients ^r2

Screening and Prevention

Screening

At-risk populations ^r136

Patients with type 1 diabetes: screen annually beginning at 5 years after initial diagnosis ^c141^c142
Patients with type 2 diabetes: screen annually starting at time of diagnosis ^c143^c144

Screening tests

Annual assessment of albuminuria (spot urinary albumin to creatinine ratio) and eGFR ^c145^c146

Prevention

Primary prevention of kidney disease in patients with diabetes ^r1^r22
Excellent glycemic control
Excellent blood pressure control
Healthy diet (eg, plant-based diets, Mediterranean diet) is associated with lower risk of developing kidney disease
Avoiding smoking or quitting smoking
Avoid use of ACE inhibitors and angiotensin receptor blockers for primary prevention because renin-angiotensin system blockade has not been shown to prevent development of kidney disease ^r1^r6^c147
Progression of diabetic kidney disease can be slowed by the following:
Intensive blood glucose control ^c148
Maintaining control of blood pressure to a target lower than 130/80 mm Hg, particularly with renin-angiotensin system blockade ^r1^c149
Use of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes ^r1
Use of nonsteroidal mineralocorticoid receptor antagonists (eg, finerenone) in patients with hypertension and diabetic kidney disease ^r75^r76

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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 c73

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

Kidney transplant r106c114

Kidney replacement therapy r111c115

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations r136

Screening tests

Prevention

Kidney biopsy ^c73

Kidney transplant ^r106^c114

Kidney replacement therapy ^r111^c115

At-risk populations ^r136