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Jan.30.2020

Diabetic nephropathy

Synopsis

Key Points

  • Diabetic nephropathy is kidney disease characterized by persistent albuminuria due to kidney injury that is caused by prolonged exposure to hyperglycemia and exacerbated by hypertension
  • Diagnosis relies on a urinary albumin to creatinine ratio of 30 mg/g or higher and GFR of less than 60 mL/minute/1.73 m² (which can occur with normal urinary albumin excretion) 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, maintaining a low-protein/low-fat diet, getting physical exercise, reducing alcohol consumption, quitting smoking) 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

  • Albuminuria can progress despite achieving good glycemic control
  • Absence of albuminuria in patients with diabetes and a reduced estimated GFR raises the possibility of nondiabetic chronic kidney disease
  • Hemoglobin A1C level that is low or trending lower may not signify improved glycemic control but instead indicate reduced kidney function and a sign of progressive diabetic kidney disease r3

Terminology

Clinical Clarification

  • Diabetic nephropathy is chronic diabetic kidney disease resulting as a complication of long-standing and/or poorly controlled diabetes mellitus r4
    • Occurs in 20% to 40% of patients with diabetes r4
    • American Diabetes Associationr1 and National Kidney Foundationr5 define diabetic nephropathy based on the following criteria:
      • Persistent albuminuria such that urinary albumin to creatinine ratio is 30 mg/g or higher in a random spot urine collection, and result is confirmed on 2 or more tests obtained 3 to 6 months apart r1r5
      • Decreased estimated GFR (less than 60 mL/minute/1.73 m²), which can occur with normal urinary albumin excretion r5
    • National Kidney Foundation also defines diabetic nephropathy as the combination of diabetes and chronic kidney disease of any category, including non–dialysis dependent, dialysis dependent, and with or without kidney transplant r6
  • Leading cause of end-stage renal disease (renal failure) r3r7

Classification

  • Albuminuria level r5
    • 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 r8
    • G1: normal or increased renal function
      • GFR is greater than 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 r9
    • 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 r10c1c2
    • 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 r10
    • As the filtration ability of the kidneys deteriorates, the following clinical features can be recognized:
      • Symptoms caused by edema: r4c3
        • Swelling of feet, ankles, and periorbital area (30%-40% of patients) r10c4c5c6
        • Weight gain r10c7c8
      • Foamy urine (consequence of increased protein concentration) is a classic but late symptom r11c9
      • Symptoms caused by electrolyte imbalance and worsening uremia c10c11
      • Symptoms caused by anemia from erythropoietin deficiency c22

Physical examination

  • Hypertension is very commonr12 (blood pressure of 140/90 mm Hg or higherr1) c29
    • Associated with sodium and fluid retention, causing edema (particularly evident in lower extremities) r11c30c31c32c33c34
  • Diabetic retinopathy often precedes diabetic nephropathy; funduscopy may find the following: c35

Causes and Risk Factors

Causes

  • Prolonged exposure to hyperglycemia causes damage to kidney structure (eg, glomerulus, tubulointerstitium, vasculature), either directly or through hemodynamic changes r7c48c49
    • Hyperglycemia lowers sodium exposure at the macula densa, which inhibits tubuloglomerular feedback, dilates the afferent arteriole, and induces glomerular hyperfiltration r13
    • Increased filtration pressure produces podocyte barotrauma resulting in podocyte and nephron loss r13
  • Condition is accelerated by ongoing albuminuria and hypertension r14
    • Excessive protein reabsorption causes further injury to the tubular epithelium and interstitial cells (ie, apoptosis), whereas increased concentration of activated complement proteins at the tubular epithelium level triggers inflammatory processes
    • Hypertension exacerbates the vascular problems of diabetic nephropathy, eventually affecting the whole cardiovascular system

Risk factors and/or associations

Age
  • Type 2 diabetes
    • Age older than 40 years is associated with an increased risk of diabetic nephropathy r15c50
    • Onset of type 2 diabetes during youth increases risk of developing diabetic nephropathy in adulthood r15c51
  • Type 1 diabetes
    • Onset of type 1 diabetes significantly before puberty has a protective effect against developing diabetic nephropathy r15
Sex
  • Men are at higher risk than women r7c52c53
Genetics
  • Genetic predisposition c54
    • Inherited susceptibility to diabetic nephropathy exists for both type 1 and type 2 diabetes r16r17
    • Candidate gene and genome-wide association studies have identified a few genes with polymorphisms that confer increased risk, including the following: r18
      • ACE (angiotensin-converting enzyme) insertion/deletion polymorphism D allele
      • Single nucleotide polymorphisms within the AGT (angiotensinogen) and AGTR1(angiotensin II receptor type 1) genes
      • Single nucleotide polymorphisms within the promoter of the FRMD3 gene (FERM domain containing 3)
Ethnicity/race
  • Highest incidence in Hispanic, Native American, and African American populations r19c55c56c57c58
Other risk factors/associations
  • Long duration of diabetes and poor glycemic control account for most of the risk c59c60c61
  • Presence of proliferative diabetic retinopathy is highly predictive of diabetic nephropathy r20c62
  • Effects of other exposures
    • Moderate alcohol consumption is associated with lower risk of chronic kidney disease in both type 1r21 and type 2 diabetesr22r23
    • NSAIDs cause a significant drop in GFR in patients with diabetic nephropathy r24c63
    • Radiocontrast dye can induce acute kidney injury in patients with diabetic nephropathy r25c64
  • Risk factors for progression of diabetic nephropathy include:
    • Hypertension (associated with diabetes in approximately 75% of patients) r26c65
      • Accelerates renal injury induced by hyperglycemia r14
    • Dyslipidemia (associated with diabetic macrovascular complications aggravating nephropathy),r27 characterized by: c66
      • Hypertriglyceridemia
      • Elevated LDL-C levels
      • Reduced HDL-C levels r28
      • Elevated apolipoprotein B levels
    • Diet c67
      • High-protein diet deteriorates renal function by increasing glomerular capillary pressure, causing hyperfiltration (which exacerbates albuminuria) and reducing GFR r29c68
      • Diet high in cholesterol and saturated fats worsens dyslipidemia and renal accumulation of lipids r30c69
      • Vitamin D deficiency abrogates the nephroprotective action of that vitamin r31c70
    • Smoking r32r33c71
      • Independent risk factor in the progression of diabetic nephropathy for both type 1 and type 2 diabetes
      • Increases the rate of transition from microalbuminuria to persistent proteinuria and promotes progression to end-stage renal disease
      • Former smokers and nonsmokers carry similar risks of disease progression
      • Passive smokers and active smokers carry similar risk of disease progression
    • Recurrent acute kidney injury increases the risk of disease progression r34c72

Diagnostic Procedures

Primary diagnostic tools

  • History of diabetes is required for diagnosis; renal abnormalities in a patient with diabetes, especially when accompanied by other microvascular complications (eg, retinopathy), are suggestive of diabetic nephropathy r35c73
  • Diagnosis is suggested by demonstration of albuminuria and/or reduction in GFR, then formally confirmed (as needed) by renal biopsy; obtain both estimated GFR and albuminuria measurements
    • Albuminuria r1
      • Measure urine albumin to creatinine ratio
        • Spot collection of urine (eg, first void in the morning) is generally the 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 r35
      • Obtain through serum creatinine levels (a proxy variable) r36
      • Serves as an essential diagnostic parameter if urinary albumin excretion is within reference range
  • Renal ultrasonography is used to exclude obstruction and other structural causes of kidney disease
  • Kidney biopsy is the only method to absolutely confirm the diagnosis, but it is not performed routinely r37
    • 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) c74
    • Albuminuria level of 30 mg/g or more (urine albumin to creatinine ratio) in a 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 the variability in urinary albumin excretion (to avoid false-positive results) r3
      • 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 r5
      • 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 r3
    • Test result serves as a biomarker predictive of cardiovascular events and mortality r3
    • Nondiabetic chronic kidney disease may be suspected when albuminuria is absent and estimated GFR is reduced in a patient with diabetes
  • Serum creatinine level c75
    • Needed to calculate estimated GFR
    • Increasing trend in serum creatinine level indicates loss of kidney function r38
  • Estimated GFR (calculated from serum creatininer36) c76
    • GFR categories: r1
      • More than 90 mL/minute/1.73 m²: with evidence of kidney damage (albuminuria) defines stages 1 chronic kidney disease
      • 60-89 mL/minute/1.73 m²: with evidence of kidney damage (albuminuria) defines stages 2 and 3 chronic kidney disease
      • 30-59 mL/minute/1.73 m²: regardless of degree of albuminuria, indicates stage 3 chronic kidney disease
      • 15-29 mL/minute/1.73 m²: regardless of degree of albuminuria, indicates stage 4 chronic kidney disease
      • Less than 15 mL/minute/1.73 m²: regardless of degree of albuminuria, indicates kidney failure (stage 5 chronic kidney disease)
    • Commonly used mathematical formulas include the following:
      • CKD-EPI equation (preferred) (named for its developers, the Chronic Kidney Disease Epidemiology Collaboration) r39
      • MDRD equationr40 (less accurate; presents the risk of underestimating or overestimating GFR in patients who are overweight or underweight, respectivelyr36) (named for its origin, the Modification of Diet in Renal Disease study)

Imaging

  • Renal ultrasonography r41c77
    • Used to identify any structural abnormalities that may suggest an alternative cause of kidney disease
    • Increased renal volume marks the initial phases of diabetic nephropathy
    • Decreased renal volume characterizes chronic diabetic nephropathy

Procedures

Kidney biopsy c78
General explanation
  • Percutaneous procedure involving placement of a long, thin needle into the kidney through a flank to obtain a tissue sample; confirms nephropathy diagnosis
Indication
  • Only necessary if diagnosis is uncertain or alternative cause of kidney disease is suspected r37
  • Cause of kidney disease is uncertain if any of the following situations apply: r5
    • 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
    • More than 30% reduction in GFR 2 to 3 months after beginning therapy with an ACE inhibitor or angiotensin receptor blocker
Contraindications r42
  • Absolute
    • Solitary kidney
    • Uncontrollable bleeding diathesis
  • Relative
    • Severe azotemia
    • Anatomic renal abnormalities
    • Anticoagulation
    • Pregnancy
    • Urinary tract infection
Complications r43
  • Gross hematuria
  • Hematoma
  • Pneumothorax
Interpretation of results
  • Immunohistopathologic features typical of diabetic nephropathy r44
    • Histopathologic features
      • Mesangial expansion by extracellular matrix deposition
      • Thickening of the glomerular basement membrane, in diffuse glomerulosclerosis
      • Presence of characteristic nodular pattern (Kimmelstiel-Wilson lesions), in nodular glomerulosclerosis
        • Specific for diabetic nephropathy 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 the glomerular endothelium and glomerular basement membrane (fibrin caps) or between the 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 r45c79
    • 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
      • More than 30% reduction in GFR 2 to 3 months after beginning therapy with an ACE inhibitor or angiotensin receptor blocker
  • Glomerulonephritis r44c80
    • Includes a group of conditions characterized by inflammation of the glomeruli, generally of autoimmune naturer44 (eg, lupus nephritisr46) d1
    • Similar clinical features include proteinuria and hypertension; similar pathologic changes include glomerulosclerosis and hyalinization of the renal microvasculature r44
    • Differentiated by:
      • Microscopic urinalysis showing an active urine sediment with dysmorphic RBCs and casts
      • Histologic analysis of renal biopsy specimens showing less severe changes in the kidney structure than that of diabetic nephropathy (eg, hyalinization can affect only the afferent arterioles, sparing the efferent arterioles) r44
      • Immunohistochemistry of renal biopsy specimens showing characteristic staining patterns (eg, IgG, IgM, complement C3) of the renal mesangium and/or glomerular basement membrane r44
  • Hypertensive nephropathy or nephrosclerosis r47c81c82
    • Condition caused by chronic hypertension, leading to renal damage
    • Hypertension is the principal common sign r44
    • Differentiated by biopsy findings; hyalinization is limited to the afferent renal arterioles and is absent from the efferent arterioles r44
  • Renovascular hypertension r47c83
    • Condition caused by atherosclerotic narrowing or blockage of blood supply to kidney (eg, renal artery stenosis) r48
    • 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 nephropathy if hypertension is severe and serum creatinine level rises rapidly (especially at an early age)
    • Angiographic imaging that demonstrates lesions in the renal vasculature provides the definitive evidence for this condition r49

Treatment

Goals

  • Slow the progression of kidney disease (ie, reduce albuminuria and slow the decline in GFR)
  • Prevent the development of complications (eg, renal failure, cardiovascular disease)
  • Attain blood pressure targets
    • Blood pressure levels below 140/90 mm Hg are recommended in all patients with diabetes to reduce cardiovascular disease mortality and slow chronic kidney disease progression r50
    • Consider lower blood pressure targets of 130/80 mm Hg or below 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 r50
    • Adverse safety signal in clinical trials of diabetic kidney disease cautions against diastolic blood pressure targets below 70 mm Hg, and especially below 60 mm Hg, in older adults r3
    • Relaxed targets are also advisable for adults on numerous medications and those with multiple comorbidities r50
  • Strive to achieve recommended glycemic goals
    • General glycemic goal for most patients with diabetes is hemoglobin A1C level less than 7% r51
    • 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 nephropathy r3
    • Relaxed target hemoglobin A1C levels are also acceptable for patients with comorbidities, limited life expectancy, or unacceptable risk of hypoglycemia r51

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 more than 5.5 mmol/L r52

Lactic acidosis

  • Possible symptoms include malaise, respiratory distress, myalgia, abdominal discomfort, disorientation, and somnolence r53
  • Presents with elevated arterial lactate concentration (more than 5 mmol/L) and decreased arterial blood pH (less than 7.35) r54
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 a nephrologist for evaluation and comanagement of diabetic kidney disease, especially for rapidly progressing or advanced kidney disease r55
    • Refer to evaluate for anticipated eventual renal replacement therapy, once the estimated GFR is less than 30 mL/minute/1.73 m² r1
    • Refer for anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, or electrolyte disturbances
  • Refer to an endocrinologist for treatment of diabetes mellitus
  • Refer to a dietitian or nutritionist for specific dietary counseling

Treatment Options

Multifactorial approach to treatment focuses on interventions proven to slow the progression of nephropathy as well as preventing the 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 nephropathy r7
    • Benefits extend beyond blood pressure effects alone; blood pressure–independent renoprotective properties occur in both type 1r56 and type 2 diabetesr57r58r59
    • For nonpregnant hypertensive patients with diabetes, prescribe an ACE inhibitor or an angiotensin receptor blocker if urinary albumin to creatinine ratio is 30 mg/g and/or estimated GFR is less than 60 mL/minute/1.73 m² r1
  • Optimize blood pressure control (less than 140/90 mm Hg, or less than 130/80 mm Hg in patients with albuminuria) to slow the progression of diabetic nephropathy r50
    • First line option is renin-angiotensin-aldosterone system inhibitor using either of the following drug classes: r1r7
      • 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 the progression of kidney damage r1
        • Head to head comparisons of an ACE inhibitor and an angiotensin receptor blocker in type 2 diabetes with elevated urine albumin excretion show clinically equivalent effects on chronic kidney disease progression,r60 but evidence for cardiovascular benefit is strongest for ACE inhibitorsr61
        • No head to head comparisons of an ACE inhibitor versus an angiotensin receptor blocker on progression of diabetic nephropathy are available for patients with type 1 diabetes r62
        • 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 r63r64
    • Second line options r50
      • 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 blockersr65 and for pregnant womenr66
      • Agents include: r50
        • Diuretics (often required to attain blood pressure goals)
        • Calcium channel blockers r50
    • Not recommended (because of uncertain benefit or possible harm) r65
      • Renin inhibitors (eg, aliskiren) in combination with ACE inhibitors or angiotensin receptor blockers do not improve renal outcomes r67
      • Combined use of ACE inhibitor and angiotensin receptor blocker increase risks of hyperkalemia and acute kidney injury r63
      • Mineralocorticoid receptor blocker (eg, spironolactone, eplerenone) in combination with ACE inhibitors or angiotensin receptor blockers is still considered an investigational strategy, as there are no long-term data to demonstrate slowing the rate of GFR loss, preventing end-stage renal disease, or reducing mortality r1
      • ACE inhibitors and angiotensin receptor blockers are not recommended for patients without hypertension to prevent the development of kidney disease r1

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% r51
    • Intensive diabetes management delays the onset and progression of nephropathy in both type 1 diabetesr69 and type 2 diabetes; however the effects on end-stage renal disease and mortality are not clearr70r71r72r68
    • 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 GFRr73
    • Disadvantage of intensive glycemic control is hypoglycemia; severe hypoglycemia has been associated with a slight increase in mortality in some, but not all, studies r1r74
    • 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 may be considered on an individual basis r75
  • In diabetic nephropathy, choice of antihyperglycemic drug is influenced by several factors: r1r75
    • 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 (gliflozins) may be more useful for patients at high risk of chronic kidney disease progression (ie, documented loss of estimated GFR)
      • At higher levels of albuminuria or higher serum creatinine level, there is greater risk of severe hypoglycemia; therefore, for patients most at risk for adverse outcomes with hypoglycemia (ie, elderly patients, those with several comorbidities), agents that promote hypoglycemia are less desirable r76
      • Greater degree of renal dysfunction can increase the toxicity of some medications, owing to impaired drug clearance r75
    • Intended intensity of diabetes treatment
      • More potent diabetes drugs (eg, insulin, sulfonylureas, glucagon-like 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) r1
        • The 2 classes of drugs that have been found to reduce risk of chronic kidney disease progression and cardiovascular events are the sodium-glucose cotransporter 2 inhibitors and the glucagon-like peptide 1 receptor agonists
        • Selected sodium-glucose cotransporter 2 inhibitors (empagliflozin and canagliflozin) and/or glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide) should be considered for patients with type 2 diabetes and diabetic nephropathy who require a drug added to metformin to attain glycemic goals r1
    • Special drug considerations for patients with diabetic kidney disease r77
      • Metformin
        • Drug of choice for patients with type 2 diabetes and early-stage kidney disease r78
        • 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 r79
        • 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: r65
          • 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) r35
      • Sodium-glucose cotransporter 2 inhibitors
        • These drugs have nephroprotective properties r80
          • 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 r81
          • Canagliflozin was shown to improve renal outcomes in patients with type 2 diabetes whose GFR was least 30 mL/minute/1.73 m²
        • These drugs have cardioprotective properties
          • Reduce blood pressure, reduce severity of heart failure, and lessen hyperkalemia r82
        • At category G3a chronic kidney disease or higher, sodium-glucose cotransporter 2 inhibitors require dose adjustment or are contraindicated
        • Empagliflozin and canagliflozin are contraindicated if estimated GFR falls below 45 mL/minute/1.73 m² (category G3b and higher chronic kidney disease)
        • Dapagliflozin is contraindicated if estimated GFR falls below 60 mL/minute/1.73 m² (category G3a and higher chronic kidney disease)
      • Glucagon-like peptide 1 receptor agonists
        • These drugs have cardioprotective and nephroprotective properties
          • Both liraglutide and semaglutide reduce the risk of new or worsening nephropathy r83r84
        • Liraglutide, albiglutide, and dulaglutide can be used without dose alterations in category G2, G3a, or G3b chronic kidney disease
        • All glucagon-like peptide 1 receptor agonists are contraindicated in categories G4 and G5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²) r9
      • 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
        • Active metabolite of nateglinide accumulates in patients with chronic kidney disease and therefore should not be used with an estimated GFR less than 60 mL/minute/1.73 m²
      • 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 the later stages of chronic kidney disease (categories G3-G5) r77
        • At categories G3 to G5 of chronic kidney disease, clearance of insulin is reduced, and the risk for hypoglycemia increases r75
        • Insulin requirements may decrease by 20% or more when GFR decreases below 45 mL/minute/1.73 m² r85

Lifestyle modifications

  • Smoking cessationr86 and moderate alcohol consumptionr9 (2 or fewer daily drinks for most men or 1 daily drink for women and lighter-weight individuals) are recommended to help reduce blood pressure and prevent cardiovascular complications r9
  • 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 r65

Treatment of comorbidities and complications

  • Treat dyslipidemia to reduce the risk of cardiovascular disease (eg, atherosclerosis) r28
  • Prescribe antiplatelet therapy with aspirin to prevent atherosclerotic cardiovascular complications r87
    • 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 nephropathy, after a discussion with the patient on the benefits versus increased risk of bleeding r88
      • 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, the constellation and summation of all cardiovascular risks should be assessed in determining whether aspirin is appropriate for primary prevention
  • Prescribe erythropoietin (eg, epoetin alfa) to treat anemia r9
    • Treat to maintain hemoglobin level at 11 g/dL or higher r9

Renal replacement therapy r89

  • Dialysis or kidney transplant is necessary to treat category G5 chronic kidney disease (renal failure)
  • Barring major contraindications, kidney transplant is the first line treatment of renal failure associated with diabetic nephropathy (provides a better quality of life and a significant survival advantage over dialysis)
  • Refer for evaluation for renal replacement therapy when estimated GFR is less than 30 mL/minute/1.73 m² r1

Drug therapy

  • Renin-angiotensin-aldosterone system inhibitors c84
    • ACE inhibitors c85
      • Ramipril c86
        • Ramipril Oral tablet; Adults: Studies in diabetic patients have utilized doses of 1.25 mg, 2.5 mg, 5 mg, and 10 mg PO once daily. Usually begin with a low dose and titrate to response and tolerance. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in at-risk patients with hypertension and in diabetic patients regardless of the presence of hypertension.
      • Benazepril c87
        • 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. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.
      • Captopril c88
        • Captopril Oral tablet; Adults: The FDA-approved dosage is 25 mg PO 3 times daily.
      • Lisinopril c89
        • Lisinopril Oral tablet; Adults: Up to 10 mg PO once daily has been studied in normotensive diabetic patients with microalbuminuria and up to 20 mg PO once daily has been studied in nondiabetic hypertensive patients with microalbuminuria; the drug slows the rate of albumin excretion in diabetic patients with or without microalbuminuria. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.Lisinopril Oral tablet; Adults: Up to 10 mg PO once daily has been studied in normotensive diabetic patients with microalbuminuria and up to 20 mg PO once daily has been studied in nondiabetic hypertensive patients with microalbuminuria; the drug slows the rate of albumin excretion in diabetic patients with or without microalbuminuria. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.
    • Angiotensin receptor blockers c90
      • Irbesartan c91
        • Irbesartan Oral tablet; Adults: Initially, 75 mg PO once daily. Titrate as tolerated to target dose of 300 mg/day PO.
      • Losartan c92
        • Losartan Potassium Oral tablet; Adults: Initially, 50 mg PO once daily; titrate to 100 mg PO once daily based on blood pressure response.
      • Telmisartan c93
        • Telmisartan Oral tablet; Adults: 40 mg PO once daily for 4 to 12 weeks, followed by titration to 80 mg PO once daily in hypertensive patients with nephropathy or proteinuria due to type 2 diabetes mellitus or chronic kidney disease. The DETAIL study reported that telmisartan delays the progression of renal dysfunction in patients with diabetic nephropathy.
  • Other antihypertensives
    • Diuretics c94
      • Furosemide c95
        • Furosemide Oral tablet; Adults: Initially, 40 mg PO twice daily. Max: 600 mg/day.Furosemide Oral tablet; Adults: Initially, 40 mg PO twice daily. Max: 600 mg/day.
    • Calcium channel blockers r90c96c97c98
      • Diltiazem
        • Diltiazem Hydrochloride Oral tablet; Adults: 90 to 120 mg PO twice daily.Diltiazem Hydrochloride Oral tablet; Adults: 90 to 120 mg PO twice daily.
        • Diltiazem Hydrochloride Oral tablet; Geriatric: Initiate at lower end of adult dosage range.Diltiazem Hydrochloride Oral tablet; Geriatric: Initiate at lower end of adult dosage range.
      • 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 c99
      • Labetalol c100
        • Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage in increments of 100 to 200 mg PO twice daily at 2- to 3-day intervals. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
  • Antihyperglycemic agents c101
    • 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 c102
        • Metformin Hydrochloride Oral tablet; Adults: Initially, 500 mg PO twice daily or 850 mg PO once daily, given with meals. In the geriatric adult 80 years or older, do not initiate unless normal renal function is documented. Increase by 500 mg per week or 850 mg every 2 weeks, given in divided doses. May also titrate from 500 mg PO twice daily to 850 mg PO twice daily after 2 weeks. Doses above 2,000 mg/day may be better tolerated if divided and given 3 times per day with meals. Max: 2,550 mg/day PO. In the geriatric adult, do not titrate to the maximum dosage.
        • Metformin Hydrochloride Oral tablet, extended-release; Adults: USUAL DOSE: 500 mg PO once daily with the evening meal. May increase by 500 mg every week as needed. Max; 2,000 mg PO once daily, or if glycemic control not achieved, consider 1,000 mg PO twice daily.
      • Sodium-glucose cotransporter 2 inhibitors
        • Empagliflozin
          • 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
          • Canagliflozin Oral tablet; Adults: 100 mg PO once daily in the morning before the first meal of the day. May increase to 300 mg PO once daily for additional glycemic control as long as eGFR is 60 mL/minute/1.73 m2 or more.
      • Sulfonylureas c103
        • Glipizide c104
          • Glipizide Oral tablet; Adults: Initially, 5 mg PO once daily given 30 minutes before breakfast. Geriatric patients or those at risk for hypoglycemia may be started on 2.5 mg/day. Adjust in increments of 2.5 to 5 mg. Several days should elapse between dosage adjustments. Usual maintenance dose: 10 to 15 mg PO once daily. Max once daily dose: 15 mg PO once daily. Some patients may have better response with twice daily dosing. Daily doses more than 30 mg/day should be divided into 2 doses. Max: 40 mg/day, given in divided doses.
        • Glyburide c105
          • Glyburide Oral tablet; Adults: Initially, 2.5 to 5 mg PO once daily with breakfast or the first main meal of the day. In the geriatric adult or those predisposed to hypoglycemia, consider an initial dose of 1.25 mg PO once daily. Titrate the daily dose by no more than 2.5 mg per week based on the blood glucose response. Usual range: 1.25 to 20 mg/day PO, given in single or divided doses. For some patients, particularly those taking more than 10 mg/day, better glucose control may be achieved with twice daily dosing. Max: 20 mg/day PO, in single or divided doses. If converting from insulin or another antidiabetic agent, consult the manufacturer's recommendations.
        • Chlorpropamide c106
          • 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 c107
        • Nateglinide c108
          • Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily given within 30 minutes before each meal. If patients are near their goal A1C at treatment initiation, 60 mg PO 3 times daily before meals may be used.Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily given within 30 minutes before each meal. If patients are near their goal A1C at treatment initiation, 60 mg PO 3 times daily before meals may be used.
        • Repaglinide c109
          • Repaglinide Oral tablet; Adults: If A1C less than 8%, start with 0.5 mg PO given within 30 minutes prior to each meal, 2, 3, or 4 times a day. If A1C is greater than 8%, start with 1 or 2 mg PO within 30 minutes prior to each meal, 2, 3, or 4 times a day. May titrate by doubling the dose until satisfactory blood glucose levels are achieved; do not exceed 4 mg/dose. Allow at least 1 week to elapse between dose adjustments. Max: 16 mg/day PO, not to exceed 4 mg/dose.
      • Dipeptidyl-peptidase IV inhibitors c110
        • Linagliptin c111
          • Linagliptin Oral tablet; Adults: 5 mg PO once daily. Used as monotherapy or in combination with other drugs used to treat type 2 diabetes mellitus, with the exception of GLP-1 agonists. When used with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be necessary to minimize the risk of hypoglycemia.
        • Alogliptin c112
          • Alogliptin Oral tablet; Adults: 25 mg PO once daily is the usual daily dose. If used with sulfonylurea or insulin, a lower sulfonylurea or insulin dose may be needed to decrease risk for hypoglycemia.
        • Saxagliptin c113
          • Saxagliptin Oral tablet; Adults: 2.5 to 5 mg PO once daily; limit to 2.5 mg/day if used with a strong CYP 3A4/5 inhibitor. May use as monotherapy or in combination with other antidiabetic agents, with the exception of GLP-1 agonists. If used with sulfonylurea or insulin, lower doses of these agents may be needed to decrease risk for hypoglycemia.
        • Sitagliptin c114
          • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily. May use as monotherapy or in combination with other hypoglycemic agents including insulin, but not GLP-1 agonists. If used with sulfonylurea or insulin, a lower sulfonylurea or insulin dose may be needed to decrease hypoglycemia.
      • α-glucosidase inhibitors c115
        • Acarbose c116
          • Acarbose Oral tablet; Adults weighing 60 kg or less: Initially, 25 mg PO 3 times daily with first bite of each main meal; may increase to 50 mg 3 times daily after 4 to 8 weeks. Max: 50 mg PO 3 times daily.
          • Acarbose Oral tablet; Adults weighing more than 60 kg: Initially, 25 mg PO 3 times daily with first bite of each main meal; may increase to 50 mg 3 times daily after 4 to 8 weeks. Usual maintenance dose: 50 to 100 mg 3 times daily. Max: 100 mg PO 3 times daily.
        • Miglitol c117
          • Miglitol Oral tablet; Adults: Initially, 25 mg PO 3 times daily given with the first bite of each main meal. After 4 to 8 weeks, the dose may be increased to 50 mg PO 3 times daily and maintained for 3 months; this is the usual maintenance dose for most patients. If at 3 months the A1C level is not satisfactory, the dose may be further titrated to 100 mg PO 3 times daily. Max: 300 mg/day PO.Miglitol Oral tablet; Adults: Initially, 25 mg PO 3 times daily given with the first bite of each main meal. After 4 to 8 weeks, the dose may be increased to 50 mg PO 3 times daily and maintained for 3 months; this is the usual maintenance dose for most patients. If at 3 months the A1C level is not satisfactory, the dose may be further titrated to 100 mg PO 3 times daily. Max: 300 mg/day PO.
      • Thiazolidinediones c118
        • Pioglitazone c119
          • Pioglitazone Hydrochloride Oral tablet; Adults: Initially, 15 mg or 30 mg PO once daily. For an inadequate response, increase by 15 mg increments as needed. Max: 45 mg/day PO. Consider combination therapy for inadequate response to monotherapy. PATIENTS RECEIVING POTENT INHIBITORS OF CYP2C8 (e.g., gemfibrozil): Max pioglitazone dose is 15 mg/day PO. ADDING TO METFORMIN: The current metformin dose can be continued. ADDING TO A SULFONYLUREA: The current sulfonylurea dose can be continued. Decrease sulfonylurea dose if the patient reports hypoglycemia.
          • Pioglitazone Hydrochloride Oral tablet; Adults without symptomatic heart disease but one or more risk factors for congestive heart failure or those with NYHA Class I or II heart failure: Initially, 15 mg PO once daily. Dose titration should be slow, allowing more time than normal to achieve target A1C. Carefully monitor; if cardiac symptoms occur, manage medically, and consider whether to discontinue the drug or reduce the dosage. Pioglitazone is not recommended in patients with ANY level of symptomatic heart failure. Contraindicated in patients with NYHA III or IV heart failure.
        • Rosiglitazone c120
          • Rosiglitazone Maleate Oral tablet; Adults: 4 mg/day PO once daily or divided bid. After 12 weeks, may titrate up to 8 mg/day.
    • Noninsulin injectables
      • Glucagon-like peptide 1 mimetics c121
        • Liraglutide
          • Liraglutide Solution for injection; Adults: Initially, 0.6 mg subcutaneously once daily for 1 week to reduce GI symptoms; must titrate to a higher dose for glycemic control. Then, increase to 1.2 mg subcutaneously once daily. If inadequate response, increase to 1.8 mg subcutaneously once daily. For a missed dose, resume with the next scheduled dose; do not take double or extra doses. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg once daily and retitrate.
        • Semaglutide
          • Semaglutide Solution for injection; Adults: Initially, 0.25 mg subcutaneously once every 7 days (weekly) at any time of day, with or without meals. Must titrate for effective glycemic control. After 4 weeks, increase to 0.5 mg subcutaneously once weekly. If needed, may increase again after 4 weeks. Max: 1 mg/week subcutaneously.
    • Insulin c122
      • Insulin Glargine Solution for injection; Adults: In insulin-naive patients on PO hypoglycemics, 10 units subcutaneously once daily (or 0.2 units/kg). Titrate to achieve blood glucose control and A1C goals in conjunction with a short-acting insulin. Give the dose at the same time every day, at any time. No dose change is necessary for conversion from once daily NPH insulin. For conversion from twice-daily NPH, reduce the total daily dose of NPH insulin (or other twice daily basal insulin) by 20% and give once daily. When transferring from once-daily Toujeo to once-daily Lantus or Basaglar, the recommended initial Lantus or Basaglar dose is 80% of the Toujeo dose that is being discontinued. Thereafter, adjust to patient response.Insulin Glargine Solution for injection; Adults: In insulin-naive patients on PO hypoglycemics, 10 units subcutaneously once daily (or 0.2 units/kg). Titrate to achieve blood glucose control and A1C goals in conjunction with a short-acting insulin. Give the dose at the same time every day, at any time. No dose change is necessary for conversion from once daily NPH insulin. For conversion from twice-daily NPH, reduce the total daily dose of NPH insulin (or other twice daily basal insulin) by 20% and give once daily. When transferring from once-daily Toujeo to once-daily Lantus or Basaglar, the recommended initial Lantus or Basaglar dose is 80% of the Toujeo dose that is being discontinued. Thereafter, adjust to patient response.
      • Insulin Detemir (Recombinant) Solution for injection; Adults: Insulin requirements range from 0.1 to 2.5 units/kg/day. Most patients require 0.5 to 1.2 units/kg/day. For Type 2 DM, the average initial dose is 0.2 to 0.6 units/kg/day. In insulin-naive patients on oral hypoglycemics: initially, insulin detemir 0.1 to 0.2 units/kg subcutaneously once daily or 10 units subcutaneously once or twice daily; adjust to response. In patients inadequately controlled on a GLP-1 receptor agonist, initiate insulin detemir 10 units subcutaneously once daily. In patients established on basal insulin, the same total daily dose of basal insulin is not changed; adjust to response. For once-daily dosing, give at dinnertime or bedtime; for twice-daily dosing, administer q12h or in the morning and dinner/at bedtime. Adjust concurrent rapid- or short-acting insulins or oral hypoglycemics as needed.
      • Insulin Lispro Solution for injection; Adults: Insulin lispro is equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given via intermittent subcutaneous injection. The total daily dose is given as 2 to 4 subcutaneous injections, within 15 minutes before or immediately after a meal to avoid hypoglycemia. Total daily insulin requirements vary between patients and depend on the patient's clinical condition and diet; however, a common dosage range is 0.5 to 1 unit/kg/day. In general, 50 to 70% of total daily insulin requirements may be provided by insulin lispro; the remainder should be provided by an intermediate- or long-acting insulin. A common regimen is to administer insulin lispro just prior to the beginning of each meal with a dose of basal insulin (i.e., insulin glargine or insulin detemir) once daily. Insulin lispro can be given in combination with NPH or Lente insulin as 2 daily injections; about two-thirds of the daily insulin dose is given before breakfast and about one-third is given before the evening meal. An intermediate-to-insulin lispro ratio of 2:1 can be given within 5 to 10 minutes of breakfast and an intermediate-to-insulin lispro ratio of 1:1 can be given 5 to 10 minutes before dinner. Alternatively, the evening dose of intermediate insulin can be given at bedtime rather than at dinner.

Nondrug and supportive care

Dietary modifications r86c123

  • Low-protein diet c124
    • Limit protein intake to 0.8 g/kg body weight per day in patients with non–dialysis-dependent diabetic nephropathy r1
    • Patients on dialysis may require higher levels of dietary protein intake r65
  • Low-fat diet c125
    • Increase consumption of fruits, vegetables, and low-fat dairy products r9c126
    • Reduce intake of saturated fat, trans fat, and cholesterol, and increase ω-3 fatty acids, viscous fiber, and plant stanols/sterols intake r9
  • Low-sodium diet r7c127
    • Reduce dietary sodium intake to no more than 2 g sodium or less than 5 g sodium chloride r5

Lifestyle modifications c128

  • Medical nutrition therapy and physical activity, to reduce weight and maintain a normal BMI (18.5-24.9 kg/m²) r9c129c130c131
  • Advise smoking cessation and avoidance of secondhand smoke exposure r86c132c133
  • Advise moderate alcohol consumption (2 or fewer daily drinks for most men or 1 daily drink for women and lighter-weight individuals) r9c134

Vaccinations

  • Early vaccination against hepatitis B virus is indicated in patients likely to have progression to end-stage renal disease (when GFR falls below 60 mL/minute/1.73 m²) r1c135c136
Procedures
Renal transplant r91c137
General explanation
  • Surgical procedure to place a healthy kidney from a living or deceased donor into a recipient r92
  • Option for patients with diabetic nephropathy who have developed end-stage renal disease, providing: r89
    • Better quality of life r89
    • Significant survival advantage over dialysis r93
  • Procedures for patients with type 1 diabetes and chronic kidney failure
    • Isolated kidney transplant from a living donor
    • Isolated kidney transplant from a 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 a deceased or living donor
Indication
  • Estimated GFR less than 15 mL/minute/1.73 m² r65
Contraindications r94
  • Unstable cardiovascular disease (eg, coronary and peripheral artery disease, peripheral arterial occlusive disease, carotid arterial stenosis, stroke)
  • Congestive heart failure and pulmonary disease (unless patient is stable)
  • Active infection
  • Active gastrointestinal bleeding
  • Active malignancy
  • Dementia
  • Nonadherence to immunosuppressive therapy or refusal of the procedure
Complications
  • Allograft thrombosis
  • Anastomotic leakage
  • Rejection
  • Infections due to immunosuppressant drugs r95
  • Posttransplant lymphoproliferative disorder and other malignancies such as squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma r95
Kidney dialysis r96c138
General explanation
  • Form of artificial kidney replacement therapy that uses cycling machines to bypass the failing kidneys and remove waste from the blood
  • Performed either as hemodialysis or peritoneal dialysis (patient's choice in absence of contraindications) r96r97
Indication
  • Option for patients with diabetic nephropathy and end-stage renal disease who are on waiting list for transplant and do not have potential living donor r94
    • When estimated GFR is approximately 5 to 9 mL/minute/1.73 m²r98
  • 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 background r99
Contraindications
  • Specific to peritoneal dialysis:
    • Inadequate peritoneal membrane (eg, peritoneal sclerosis, extensive surgical resection) r96
    • Abdominal cavity incompetence (eg, peritoneal compartmentalization, peritoneal-pleural communication) r96
    • High risk of abdominal infection (eg, recurrent diverticulitis, active inflammatory bowel disease) r96r100
    • Previous major abdominal surgery (relative contraindication) r101
    • Elderly patient (older than 75 years) with illness and no social support (potential nonadherence; difficult/impossible to perform the procedure in a home setting) r102
  • Specific to hemodialysis: r103r104
    • 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 r105c139
    • Diabetic nephropathy is accompanied by abnormalities in lipid metabolism
    • Statinr106or statin plus ezetimiber107 is recommended for all adults aged 50 years or older who have diabetes and an estimated GFR less than 60 mL/minute/1.73m² 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 r108
      • However, statins do not slow the rate of kidney disease progression in those with preexisting chronic kidney disease r109
    • 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 r110
    • Measurement of LDL-C is not appropriate for assessing coronary risk in chronic kidney disease and should not be used to identify patients for statin therapy
    • Initial evaluation of the 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 r3

Special populations

  • Pregnant women
    • Pregnant women with concomitant nephropathy are at risk of deteriorating maternal kidney function, leading to end-stage renal disease r111
    • Compared with the healthy population, pregnant women 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 r66
    • Preconception counseling for women with preexisting diabetes and nephropathy or microalbuminuria should address the following issues: r111
      • Use of contraception in planning stages
      • Evaluate and discuss the risks of pregnancy-induced maternal kidney failure, preeclampsia, and preterm delivery
    • Treatment is modified accordingly: r66
      • Strict glycemic control during pregnancy is necessary (target hemoglobin A1C less than 6%) r66
      • Intensive antihypertensive treatment (blood pressure goal lower than 130/80 mm Hg) should be established early in pregnancy, using pregnancy-friendly antihypertensive agents (ideally before conception) r66
        • ACE inhibitors and angiotensin receptor blockers are contraindicated during all stages of pregnancy because of teratogenic risk r112
          • Women 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 r66
          • Methyldopa is the drug of choice r113
        • Use diuretics as alternative or add-on therapy, but only with caution r66
      • Low-dose aspirin is recommended (75 mg/day beginning at 10-12 gestational weeks until approximately 1 week before delivery) for all pregnant women with diabetic nephropathy or microalbuminuria to prevent cardiovascular events and to reduce the risk of preeclampsia r111
      • Screen for sight-threatening diabetic retinopathy r111
      • Supplement with folic acid during the first 12 gestational weeks r111
  • Patients with more advanced stages of chronic kidney disease
    • Hypoglycemia r85
      • Severe hypoglycemia has been associated with a slight increase in mortality in some, but not all, studies r114
      • Becomes a greater concern with worsening kidney dysfunction (chronic kidney disease categories G3-G5)
      • Can occur readily in patients who have GFR levels below 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 r73

Monitoring

  • Monitoring is necessary to assess the progression of diabetic nephropathy, relying on the assessments of albuminuria (indicative of kidney damage) and estimated GFR (indicative of kidney function) r65
  • Perform physical examination and measure weight and blood pressure at every clinical encounter r1r50
    • Measure orthostatic blood pressure periodically or when symptoms of orthostatic hypotension occur
      • If orthostatic hypotension develops, consider nocturnal dosing of antihypertensives and/or stopping α-blockers and diuretics r50
  • Periodically monitor the response to treatment and consider the need for medication dose adjustments
    • Patients on ACE inhibitors, angiotensin receptor blockers, and/or diuretics r65
      • Periodically monitor serum creatinine and potassium levels for the development of increased creatinine level or changes in potassium concentration r1
      • 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, progression of diabetic kidney disease, and facilitate adherence to pharmacotherapy r65
    • 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 r115
      • Obtain estimated GFR at least annually in all patients taking metformin
        • 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 r78
        • Reduce maximum dose of metformin to 1000 mg/day 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 r65

Complications and Prognosis

Complications

  • Cardiovascular disease c140
    • In general, incidence increases according to severity of kidney disease r116
      • 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) c141d2
      • Left ventricular hypertrophy (affects approximately 74% of patients with chronic kidney disease) r117c142c143
      • Congestive heart failure (31% of patients with chronic kidney disease) r117c144c145d3
      • Stroke (5- to 10-fold increased incidence in patients with end-stage renal disease) r117c146c147d4
      • Peripheral artery disease (eg, atherosclerosis, thrombosis, stenosis; reported in 25% of patients older than 40 years) r9c148c149c150c151c152c153c154c155d5
  • Anemia r118c156c157
    • Estimated incidence is 20% of patients with diabetes and category G3 chronic kidney disease
    • Multiple contributing causes, including iron deficiency, erythropoietin deficiency/hyporesponsiveness, folate deficiency, and vitamin B₁₂ deficiency
  • Chronic kidney disease–mineral bone disorder r119r120c158
    • 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 c159c160c161
    • 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 r119
    • 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 r121r122r123

Prognosis

  • Diabetic nephropathy and type 1 diabetes
    • If the condition is left untreated, the average survival is 5 to 7 years from diagnosis for patients with diabetic nephropathy associated with type 1 diabetes r124
      • 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% r124
    • 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 of 30 mg/g or higher) progress to develop severe albuminuria (albumin to creatinine ratio of 300 mg/g or higher) in 10 to 15 years on average r37
      • 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 r37
  • Diabetic nephropathy 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 r125
    • Disease progression is generally more indolent in patients with type 2 diabetes than in patients with type 1 diabetes r37
      • 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 higher), and only 20% of these patients progress to end-stage renal disease after 20 years r37
  • 5-year survival rate of patients with diabetes and end-stage renal disease is poor (30% after initiation of dialysis) r2

Screening and Prevention

Screening

At-risk populations r87

  • Patients with type 1 diabetes: screen annually beginning at 5 years after initial diagnosis c162c163
  • Patients with type 2 diabetes: screen annually starting at time of diagnosis c164c165
  • Patients with any type of diabetes and who have comorbid hypertension: screen annually c166c167

Screening tests

  • Annual assessment of albuminuria (spot urinary albumin to creatinine ratio) and estimated GFR r87c168c169
    • Positive test result is marked by either of the following:
      • Urinary albumin to creatinine ratio of 30 mg/g or higher r1
      • Estimated GFR less than 60 mL/minute/1.73 m² r1

Prevention

  • Progression of diabetic nephropathy can be slowed by:
    • Intensive treatment of diabetes c170
    • Maintaining control of blood pressure (ideally to a level below 140/90 mm Hg or 130/80 mm Hg in patients with diabetes who already have albuminuria) r1r7c171
  • Renin-angiotensin-aldosterone system blockade is controversial for prevention of diabetic nephropathy in normotensive patients with diabetes who do not have albuminuria r7c172
    • Not recommended for the 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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