English

ThisiscontentfromClinicalKey

Want even more answers?

Sign up for your free ClinicalKey trial today!  Your first step in getting the right answers when you need them. ClinicalKey is a clinical knowledge solution designed to help healthcare professionals and students find the right answers by providing in-depth, evidence-based knowledge – all from one resource.

Oct.31.2022

Diabetic Kidney Disease

Synopsis

Key Points

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

Urgent Action

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

Pitfalls

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

Terminology

Clinical Clarification

  • Chronic kidney disease among patients with diabetes is usually attributable to diabetes pathophysiology and has been described as diabetic kidney disease and diabetic nephropathy r3
    • Chronic kidney disease is defined as elevated urine albumin excretion (greater than or equal to 30 mg/g creatinine), reduced estimated GFR (less than 60 mL/minute/1.73 m²), or both, persisting for more than 3 months r3
  • Encompasses all categories of chronic kidney disease, and includes patients requiring treatment with hemodialysis, peritoneal dialysis, and kidney transplant r3r4
  • Chronic kidney disease resulting as a complication of long-standing and/or poorly controlled diabetes mellitus occurs in 20% to 40% of patients with diabetes r5r6
  • Leading cause of end-stage renal disease (advanced kidney failure) r7r8

Classification

  • Albuminuria level r9
    • Normal to mildly increased: urinary albumin to creatinine ratio is less than 30 mg/g
    • Moderately increased: urinary albumin to creatinine ratio is 30 to 300 mg/g
    • Severely increased: urinary albumin to creatinine ratio is greater than 300 mg/g
  • Classification of chronic kidney disease, according to GFR category r10
    • G1: normal or increased renal function
      • GFR is greater than or equal to 90 mL/minute/1.73 m²
    • G2: mildly decreased renal function
      • GFR is 60 to 89 mL/minute/1.73 m²
    • G3a: mildly to moderately decreased renal function
      • GFR is 45 to 59 mL/minute/1.73 m²
    • G3b: moderately to severely decreased renal function
      • GFR is 30 to 44 mL/minute/1.73 m²
    • G4: severely decreased renal function
      • GFR is 15 to 29 mL/minute/1.73 m²
    • G5: kidney failure
      • GFR is less than 15 mL/minute/1.73 m²
  • Classification of chronic kidney disease, according to albuminuria category r11
    • A1: normal to mildly increased
      • Albumin to creatinine ratio: less than 30 mg/g
      • Albumin excretion rate: less than 30 mg/24 hours
    • A2: moderately increased
      • Albumin to creatinine ratio: 30 to 300 mg/g
      • Albumin excretion rate: 30 to 300 mg/24 hours
    • A3: severely increased
      • Albumin to creatinine ratio: greater than 300 mg/g
      • Albumin excretion rate: greater than 300 mg/24 hours

Diagnosis

Clinical Presentation

History

  • Symptoms vary according to severity of disease
    • Early stages of disease are asymptomatic r12c1
    • Symptoms develop as urinary albumin to creatinine ratio progressively increases in the 30 to 299 mg/g range and/or as GFR decreases in the 60 to 15 mL/minute/1.73 m² range r12
    • As the filtration ability of the kidneys deteriorates, the following clinical features can be recognized:
      • Symptoms caused by edema r6c2
        • Swelling of feet, ankles, and periorbital area (30%-40% of patients) r12c3c4c5
        • Weight gain r12c6
      • Foamy urine (consequence of increased protein concentration) is a classic but late symptom r13c7
      • Symptoms caused by electrolyte imbalance and worsening uremia c8c9
        • Nausea and vomiting c10c11
        • Poor appetite, resulting in weight loss c12c13
        • Generalized pruritus c14
      • Symptoms caused by anemia from erythropoietin deficiency c15
        • Fatigue and generalized weakness c16c17
        • Dyspnea on exertion c18

Physical examination

  • Hypertension is very common (blood pressure of 130/90 mm Hg or higher is considered elevated for diabetes) r14c19
    • Associated with sodium and fluid retention, causing edema (particularly evident in lower extremities) r13c20c21c22
  • Diabetic retinopathy often precedes diabetic kidney disease; funduscopy may find the following: c23
    • Microaneurysms c24
    • Blot hemorrhages c25
    • Exudative, ischemic, and proliferative changes c26c27c28
    • Macular edema c29

Causes and Risk Factors

Causes

  • Prolonged exposure to hyperglycemia causes damage to kidney structure (eg, glomerulus, tubulointerstitium, vasculature), either directly or through hemodynamic changes r7c30c31
    • Hyperglycemia lowers sodium exposure at macula densa, which inhibits tubuloglomerular feedback, dilates afferent arteriole, and induces glomerular hyperfiltration r15
    • Increased filtration pressure produces podocyte barotrauma, resulting in podocyte and nephron loss r15
  • Condition is accelerated by ongoing albuminuria and hypertension r16
    • Excessive protein reabsorption causes further injury to tubular epithelium and interstitial cells (ie, apoptosis), whereas increased concentration of activated complement proteins at tubular epithelium level triggers inflammatory processes
    • Hypertension exacerbates vascular problems of diabetic kidney disease, eventually affecting whole cardiovascular system

Risk factors and/or associations

Age
  • Type 2 diabetes
    • Age older than 40 years is associated with increased risk of diabetic kidney disease r17c32c33
    • Onset of type 2 diabetes during youth increases risk of developing diabetic kidney disease in adulthood r17c34c35c36
  • Type 1 diabetes
    • Onset of type 1 diabetes significantly before puberty has protective effect r17
Sex
  • Male individuals are at higher risk than female individuals r7c37c38
Genetics
  • Genetic predisposition c39
    • Inherited susceptibility to diabetic kidney disease exists for both type 1 and type 2 diabetes r18r19
    • Candidate gene and genome-wide association studies have identified a few genes with polymorphisms that confer increased risk, including the following: r20
      • ACE (angiotensin-converting enzyme) insertion/deletion polymorphism D allele
      • Single nucleotide polymorphisms within AGT (angiotensinogen) and AGTR1 (angiotensin II receptor type 1) genes
      • Single nucleotide polymorphisms within promoter of FRMD3 gene (FERM domain containing 3)
Ethnicity/race
  • Highest incidence in Hispanic, Native American, and African American/Black populations r21c40c41c42c43
Other risk factors/associations
  • Long duration of diabetes and poor glycemic control account for most of the risk c44c45c46
  • Presence of proliferative diabetic retinopathy is highly predictive of diabetic kidney disease r22c47
  • Effects of other exposures
    • Moderate alcohol consumption is associated with lower risk of chronic kidney disease in both type 1r23 and type 2 diabetesr24r25
    • NSAIDs cause significant drop in GFR in patients with diabetic kidney disease r26c48
    • Radiocontrast dye can induce acute kidney injury in patients with diabetic kidney disease r27c49
  • Risk factors for progression include:
    • Hypertension (associated with diabetes in approximately 75% of patients) r28c50
      • Accelerates renal injury induced by hyperglycemia r16
    • Dyslipidemia (associated with diabetic macrovascular complications aggravating nephropathy),r29 characterized by: c51
      • Hypertriglyceridemia
      • Elevated LDL-C levels
      • Reduced HDL-C levels r30
      • Elevated apolipoprotein B levels
    • Diet c52
      • High-protein diet deteriorates renal function by increasing glomerular capillary pressure, causing hyperfiltration (which exacerbates albuminuria) and reducing GFR r31c53
      • Diet high in cholesterol and saturated fats worsens dyslipidemia and renal accumulation of lipids r32c54
      • Vitamin D deficiency abrogates nephroprotective action of that vitamin r33c55
    • Smoking r34r35c56
      • Independent risk factor in progression of diabetic kidney disease for both type 1 and type 2 diabetes
      • Increases rate of transition from microalbuminuria to persistent proteinuria and promotes progression to end-stage renal disease
      • Former smokers and nonsmokers carry similar risk of disease progression
      • Passive smokers and active smokers carry similar risk of disease progression
    • Recurrent acute kidney injury increases risk of disease progression r36c57

Diagnostic Procedures

Primary diagnostic tools

  • Suspect diabetic kidney disease in patients with long-duration diabetes, especially when accompanied by other microvascular complications (eg, retinopathy) r1c58
  • Base diagnosis on persistent presence of albuminuria, reduction in estimated GFR, or both in patients with diabetes r1
    • Albuminuria
      • Measure urine albumin to creatinine ratio
        • Spot collection of urine (eg, first void in morning) is generally preferred method, given that randomly timed or 24-hour collections are inconvenient and add little to accuracy r1
        • Spot collection for albumin alone (using a dipstick) without simultaneous measurement of urine creatinine is also less accurate, owing to variation in urine concentration according to hydration status
    • Estimated GFR c59
      • Obtain through serum creatinine levels (a proxy variable) r37
      • Serves as essential diagnostic parameter if urinary albumin excretion is within reference range
    • Comprehensive chronic kidney disease staging takes into account level of albuminuria at each estimated GFR stage r1
  • Consider alternative causes of renal disease in patients with urinary sediment containing red or white blood cells or casts, rapidly increasing albuminuria or decreasing GFR, or no concomitant retinopathy (type 1 diabetes) r1
    • Investigation for alternative causes may be required (eg, kidney biopsy)
  • Use renal ultrasonography to exclude obstruction and other structural causes of kidney disease r38
  • Kidney biopsy is the only method to absolutely confirm diagnosis, but it is not performed routinely r39
    • Recommended when diagnosis is inconclusive or another cause of renal disease is suspected

Laboratory

  • Albumin excretion levels (using urine albumin to creatinine ratio; preferred test) c60
    • Albuminuria level greater than or equal to 30 mg/g (urine albumin to creatinine ratio) in random spot collection is indicative of nephropathy r1
      • Measurement must be confirmed on at least 2 tests performed 3 to 6 months apart because of variability in urinary albumin excretion (to avoid false-positive results) r8
      • Transient albuminuria can be attributed to multiple causes, such as vigorous exercise in the past 24 hours, urinary tract infection, febrile illness, short-term elevated hyperglycemia, severe hypertension, menstruation, or congestive heart failure r1
    • Categories of albuminuria r9
      • Normal to mildly increased: urinary albumin to creatinine ratio is less than 30 mg/g
      • Moderately increased: urinary albumin to creatinine ratio is 30 to 300 mg/g
      • Severely increased: urinary albumin to creatinine ratio is greater than 300 mg/g
    • Test is not entirely sensitive for kidney disease because low estimated GFR (less than 60 mL/minute/1.73 m²) is present in approximately 50% of patients without increased albuminuria r8
    • Test result serves as biomarker predictive of cardiovascular events and mortality r8
    • Nondiabetic chronic kidney disease may be suspected when albuminuria is absent and estimated GFR is reduced in patients with diabetes r8
  • Serum creatinine level c61
    • Needed to calculate estimated GFR
    • Increasing trend in serum creatinine level indicates loss of kidney function r40
  • Estimated GFR (calculated from serum creatininer37) c62
    • GFR categories: r1
      • Greater than or equal to 90 mL/minute/1.73 m² defines stage 1 chronic kidney disease
      • 60 to 89 mL/minute/1.73 m² defines stage 2 chronic kidney disease
      • 45 to 59 mL/minute/1.73 m² indicates stage 3a chronic kidney disease
      • 30 to 44 mL/minute/1.73 m² indicates stage 3b chronic kidney disease
      • 15 to 29 mL/minute/1.73 m² indicates stage 4 chronic kidney disease
      • Less than 15 mL/minute/1.73 m² indicates kidney failure (stage 5 chronic kidney disease)
    • Commonly used mathematical formulas include:
      • CKD-EPI equation: preferred (named for its developers, the Chronic Kidney Disease Epidemiology Collaboration) r41c63
      • MDRD equation:r42 less accurate; presents risk of underestimating or overestimating GFR in patients who are overweight or underweight, respectivelyr37 (named for its origin, the Modification of Diet in Renal Disease study) c64

Imaging

  • Renal ultrasonography r38c65
    • Used to identify any structural abnormalities that may suggest an alternative cause of kidney disease
    • Increased renal volume marks initial phases of diabetic kidney disease
    • Decreased renal volume characterizes chronic diabetic kidney disease

Procedures

Kidney biopsy c66
General explanation
  • Percutaneous procedure involving placement of long, thin needle into the kidney through flank to obtain tissue sample; confirms diagnosis r43
Indication
  • Only necessary if diagnosis is uncertain or alternative cause of kidney disease is suspected r39
  • Cause of kidney disease is uncertain if any of the following situations apply: r9
    • Absence of diabetic retinopathy
    • Low or rapidly decreasing GFR
    • Rapidly increasing proteinuria or nephrotic syndrome
    • Refractory hypertension
    • Presence of active urinary sediment
    • Signs or symptoms of other systemic disease
    • Greater than 30% reduction in GFR 2 to 3 months after beginning therapy with ACE inhibitor or angiotensin receptor blocker
Contraindications
  • Absolute r44
    • Solitary kidney
    • Uncontrollable bleeding diathesis
  • Relative r44
    • Severe azotemia
    • Anatomic renal abnormalities
    • Anticoagulation
    • Pregnancy
    • Urinary tract infection
Complications
  • Gross hematuria
  • Hematoma r43
  • Pneumothorax
Interpretation of results
  • Typical immunohistopathologic features r45
    • Histopathologic features
      • Mesangial expansion by extracellular matrix deposition
      • Thickening of glomerular basement membrane with diffuse glomerulosclerosis
      • Characteristic nodular pattern (Kimmelstiel-Wilson lesions) with nodular glomerulosclerosis
        • Specific for diabetic kidney disease and not found in any other condition
      • Afferent and efferent hyaline arteriolosclerosis
      • Areas of mesangiolysis (presence of foam cells and loss of matrix), resulting in glomerular capillary microaneurysms
      • Accumulation of plasma proteins, causing hyalinosis between glomerular endothelium and glomerular basement membrane (fibrin caps) or between glomerular tuft and Bowman capsule (capsular drop)
      • Interstitial fibrosis and tubular atrophy
      • Interstitial mononuclear inflammatory cell infiltrate
    • Immunofluorescence features
      • Positive staining of glomerular basement membrane and tubular basement membrane for IgG and albumin
      • Nonspecific staining for IgM and complement C3 in sclerotic nodules
      • Variable staining of both κ and λ light chains

Differential Diagnosis

Most common

  • Nondiabetic chronic kidney disease r46c67d1
    • 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 r45c68
    • Includes a group of conditions characterized by inflammation of the glomeruli, generally of autoimmune naturer45 (eg, lupus nephritisr47) d2
    • Similar clinical features include proteinuria and hypertension; similar pathologic changes include glomerulosclerosis and hyalinization of renal microvasculature r45
    • Differentiated by:
      • Microscopic urinalysis showing active urine sediment with dysmorphic RBCs and casts
      • Histologic analysis of renal biopsy specimens showing less severe changes in kidney structure than that of diabetic kidney disease (eg, hyalinization can affect only the afferent arterioles, sparing the efferent arterioles) r45
      • Immunohistochemistry of renal biopsy specimens showing characteristic staining patterns (eg, IgG, IgM, complement C3) of the renal mesangium, glomerular basement membrane, or both r45
  • Hypertensive nephropathy or nephrosclerosis r48c69c70
    • Condition caused by chronic hypertension, leading to renal damage
    • Hypertension is the principal common sign r45
    • Differentiated by biopsy findings; hyalinization is limited to afferent renal arterioles and is absent from efferent arterioles r45
  • Renovascular hypertension r48c71d3
    • Condition caused by atherosclerotic narrowing or blockage of blood supply to kidney (eg, renal artery stenosis) r49
    • Uncontrolled hypertension and rapid rise in serum creatinine level are the principal findings
    • Recurrent flash pulmonary edema and a flank bruit are other suggestive clinical clues
    • Presence of anatomically evident arterial occlusive disease (ie, atherosclerosis) on renal duplex ultrasonography is a differentiating factor
    • Gold standard test is invasive renal angiography, but this is only done to differentiate from diabetic kidney disease if hypertension is severe and serum creatinine level rises rapidly (especially at an early age)
    • Angiographic imaging that demonstrates lesions in renal vasculature provides definitive evidence for this condition r50

Treatment

Goals

  • Slow progression of kidney disease (ie, reduce albuminuria and slow decline in GFR)
  • Prevent development of complications (eg, renal failure, cardiovascular disease)
  • Attain blood pressure targets
    • Blood pressure levels lower than 140/90 mm Hg are recommended in all patients with diabetes to reduce cardiovascular disease mortality and slow chronic kidney disease progression r51
    • Consider lower blood pressure targets of 130/80 mm Hg or lower for patients who are at high risk of cardiovascular events (particularly stroke) or albuminuria and can attain these levels relatively easily and without substantial adverse effects r51
    • Adverse safety signal in clinical trials of diabetic kidney disease cautions against diastolic blood pressure targets lower than 70 mm Hg, and especially below 60 mm Hg, in older adults r8
    • Relaxed targets are also advisable for adults on numerous medications and those with multiple comorbidities r51
  • Strive to achieve recommended glycemic goals
    • General glycemic goal for most patients with diabetes is hemoglobin A1C level lower than 7% r52
    • Specific target hemoglobin A1C levels have not been formally identified, but levels between 7% and 8% are associated with the highest survival rates in retrospective analyses of patients with diabetic kidney disease r8
    • Relaxed target hemoglobin A1C levels are also acceptable for patients with comorbidities, limited life expectancy, or unacceptable risk of hypoglycemia r52

Disposition

Admission criteria

Requirement for urgent dialysis, such as:

  • Acute kidney injury
  • Volume overload causing pulmonary edema

Severe (persisting) hyperkalemia

  • Identified by serum potassium level greater than 5.5 mmol/L r53

Lactic acidosis

  • Possible symptoms include malaise, respiratory distress, myalgia, abdominal discomfort, disorientation, and somnolence r54
  • Presents with elevated arterial lactate concentration (greater than 5 mmol/L) and decreased arterial blood pH (less than 7.35) r55
Criteria for ICU admission
  • Acute or chronic kidney injury accompanied by fluid overload, pulmonary edema, and impending respiratory failure

Recommendations for specialist referral

  • Refer to nephrologist for evaluation and comanagement of diabetic kidney disease if there are any of the following: r56
    • Uncertain renal diagnosis
    • Complications (eg, anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, electrolyte disturbances)
    • Rapidly progressing or advanced kidney disease (estimated GFR is less than 30 mL/minute/1.73 m²) with anticipated need for eventual renal replacement therapy
  • Refer to endocrinologist for treatment of diabetes mellitus
  • Refer to dietitian or nutritionist for specific dietary counseling

Treatment Options

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

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

Renin-angiotensin-aldosterone system blockade and blood pressure control

  • Renin-angiotensin-aldosterone system blockade is the mainstay treatment of proteinuric diabetic kidney disease r3r7
    • Benefits extend beyond blood pressure effects alone; blood pressure–independent renoprotective properties occur in both type 1r57 and type 2 diabetesr58r59r60
    • Consider treatment in patients with diabetes and albuminuria even if they have normal blood pressure r3
    • For nonpregnant patients with hypertension and diabetes, prescribe an ACE inhibitor or angiotensin receptor blocker if urinary albumin to creatinine ratio is greater than or equal to 30 mg/g or estimated GFR is less than 60 mL/minute/1.73 m² r1
  • Optimize blood pressure control to slow progression of diabetic kidney disease
    • Earlier guidelines recommend target blood pressure of lower than 140/90 mm Hg (130/80 mm Hg in patients with albuminuria) r51r61r62
    • 2021 guidelines from Kidney Disease: Improving Global Outcomes (KDIGO) recommend a target systolic blood pressure below 120 mm Hg for all patients with chronic kidney disease, including those with diabetes r63
    • 2021 Association of British Clinical Diabetologists and the Renal Association UK guideline proposes a target blood pressure of 120/80 mm Hg for younger adults with diabetes and chronic kidney disease with no significant proteinuria and less than 130/80 mm Hg for those with proteinuria r64
      • Target blood pressure of 140/90mm Hg is recommended for patients older than 65 years
    • The lower recommendation is based primarily on established cardioprotective and survival benefits and potential cognitive benefits observed at this systolic blood pressure level; evidence does not suggest lowering blood pressure below 140 mm Hg has additional renoprotective effect r63
    • First line option is renin-angiotensin-aldosterone system inhibitor using either of the following drug classes: r7
      • ACE inhibitors (eg, benazepril, captopril, lisinopril, ramipril)
      • Angiotensin receptor blockers (eg, irbesartan, losartan, telmisartan)
        • Both drug classes have the dual effect of controlling blood pressure and slowing progression of kidney damage
        • Head-to-head comparisons of an ACE inhibitor and an angiotensin receptor blocker in a patient with type 2 diabetes with elevated urine albumin excretion show clinically equivalent effects on chronic kidney disease progression,r65 but evidence for cardiovascular benefit is strongest for ACE inhibitorsr66
        • No head-to-head comparisons of an ACE inhibitor and an angiotensin receptor blocker on progression of diabetic kidney disease are available for patients with type 1 diabetes r67
        • Angiotensin receptor blockers alone are recommended for patients unable to tolerate ACE inhibitors (eg, those who develop a dry cough)
        • Do not combine use of an ACE inhibitor and an angiotensin receptor blocker, owing to higher risks of hyperkalemia and acute kidney injury r68r69
    • Second line options r51
      • Indicated for either of the following:
        • Add-on therapy to achieve blood pressure goals in those already treated with maximum doses of ACE inhibitors or angiotensin receptor blockers
        • Alternative therapy for those individuals unable to tolerate either ACE inhibitors or angiotensin receptor blockers and for pregnant patients include: r51r70
          • Diuretics (often required to attain blood pressure goals)
          • Calcium channel blockers r51
    • Add on therapy
      • Mineralocorticoid receptor blocker (eg, spironolactone, eplerenone, finerenone) may be added to ACE inhibitors or angiotensin receptor blockers as long as potassium levels are not elevated on an ACE inhibitor or angiotensin receptor blocker r1
        • 2 randomized controlled trials found that finerenone has favorable effects on cardiovascular outcomes and slows progression of loss of kidney function in patients with type 2 diabetes, diabetic kidney disease, and albuminuria r71r72r73
    • Not recommended (because of uncertain benefit or possible harm) r74
      • Renin inhibitors (eg, aliskiren) in combination with ACE inhibitors or angiotensin receptor blockers do not improve renal outcomes r75
      • Combined use of ACE inhibitor and angiotensin receptor blocker increases risks of hyperkalemia and acute kidney injury r69
      • ACE inhibitors and angiotensin receptor blockers are not recommended for patients who do not have albuminuria or hypertension to prevent development of kidney disease r3

Glycemic control

  • Intensive measures to optimize glycemic control are indicated in most patients to limit albuminuria and slow progression of nephropathy
    • Glycemic goal for most patients with diabetes is hemoglobin A1C level less than 7%; in young adults with early stage kidney disease target may be as low as 6.5% r52r76
    • Intensive diabetes management delays onset and progression of nephropathy in both type 1 diabetesr78 and type 2 diabetes; however, the effects on end-stage renal disease and mortality are not clearr79r80r81r77
    • 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 GFRr82
    • Disadvantage of intensive glycemic control is hypoglycemia; severe hypoglycemia has been associated with a slight increase in mortality in some, but not all, studies r52r83
    • As a result, patients with end-stage renal disease and/or likely reduced longevity may not derive the benefits of tight glucose control; for such patients, less aggressive treatment of diabetes (eg, hemoglobin A1C target 7.58.5%)r76 may be considered on an individual basis r84
  • Choice of antihyperglycemic drug is influenced by several factors:
    • Type of diabetes
      • Insulin is always required in type 1 diabetes, whereas oral or injectable drugs can be used in early stages of type 2 diabetes
    • Stage of kidney disease or risk of progression
      • Sodium-glucose cotransporter 2 inhibitors are beneficial for patients at high risk of chronic kidney disease progression r1
      • At higher levels of albuminuria or higher serum creatinine levels, there is greater risk of severe hypoglycemia; therefore, for patients most at risk for adverse outcomes with hypoglycemia (ie, older adults, those with several comorbidities), agents that promote hypoglycemia are less desirable r85
      • Greater degree of renal dysfunction can increase toxicity of some medications, owing to impaired drug clearance r84
      • Metformin is contraindicated when estimated GFR is less than 30 mL/minute/1.73 m² or in any situation in which there is elevated risk of lactic acidosis r1
    • Intended intensity of diabetes treatment
      • More potent diabetes drugs (eg, insulin, sulfonylureas, glucagonlike peptide 1 receptor agonists) are more effective in achieving lower hemoglobin A1C levels
    • Priorities of care
      • Desire to balance risks (ie, progression of chronic kidney disease, cardiovascular events, likelihood of inducing hypoglycemia)
        • Both sodium-glucose cotransporter 2 inhibitors and glucagonlike peptide 1 receptor agonists have been found to reduce risk of chronic kidney disease progression, hypoglycemia, and cardiovascular events; however, renal benefits of glucagonlike peptide 1 receptor agonists are less well established r86r87
        • Consider selected sodium-glucose cotransporter 2 inhibitors (eg empagliflozin, dapagliflozin, canagliflozin, sotagliflozin) for patients with type 2 diabetes and diabetic kidney disease who require a drug added to metformin to attain glycemic goals r3r88
        • Glucagonlike peptide 1 receptor agonists (liraglutide and semaglutide) are recommended for patients who fail to achieve glycemic targets with use of metformin and sodium-glucose cotransporter 2 inhibitors or who are unable to take these medications r3
    • Special drug considerations for patients with diabetic kidney disease r89
      • Metformin
        • First line treatment for patients with type 2 diabetes, including those with kidney disease r3r90
        • Appropriate to begin if GFR is greater than 45 mL/minute/1.73 m² r1
        • When GFR is between 30 and 45 mL/minute/1.73 m², monitor cautiously and reassess risks and benefits; contraindicated if estimated GFR is less than 30 mL/minute/1.73 m² r91
        • Discontinue when estimated GFR is less than 30 mL/minute/1.73 m² or in any situation in which there is an elevated risk of lactic acidosis, such as: r1
          • Hypotension
          • Hypoxia
          • High risk of acute kidney injury (eg, administration of contrast material for kidney imaging in patients with estimated GFR of 30-60 mL/minute/1.73 m²)
      • Sodium-glucose cotransporter 2 inhibitors r92
        • These drugs have nephroprotective properties r93r94
          • Utilize in patients with type 2 diabetes and chronic kidney disease with an estimated glomerular filtration rate of 20 mL/minute/1.73 m² or less and urinary albumin less than or equal to 300 mg/g creatinine r1r95
          • Empagliflozin was shown to reduce incidence of nephropathy, slow its progression, and lower rate of renal replacement therapy in patients with type 2 diabetes whose GFR was least 30 mL/minute/1.73 m² r96
          • Canagliflozin was shown to improve renal outcomes in patients with type 2 diabetes whose GFR was least 30 mL/minute/1.73 m² r97
            • There is also evidence that canagliflozin slows progression of kidney disease and improves outcomes even in patients with estimated GFR less than 30 mL/minute/1.73 m² r98
        • These drugs have cardioprotective properties r92
          • Reduce blood pressure, reduce severity of heart failure, and lessen hyperkalemia r99
        • At category G3a chronic kidney disease or higher, sodium-glucose cotransporter 2 inhibitors require dose adjustment or are contraindicated
        • Empagliflozin and dapagliflozin are contraindicated if estimated GFR is less than 45 mL/minute/1.73 m² (category G3b chronic kidney disease and higher) r1
        • Canagliflozin is contraindicated if estimated GFR is less than 30 mL/minute/1.73 m² (categories G4 and G5 chronic kidney disease) r1
      • Glucagonlike peptide 1 receptor agonists
        • These drugs have cardioprotective and nephroprotective properties; however, the renal benefits are less well established than sodium-glucose cotransporter 2 inhibitors r100r101r102
          • Liraglutide, dulaglutide, and semaglutide appear to reduce risk of new or worsening nephropathy r103r104r105
          • An exendin-based glucagonlike peptide 1 receptor agonist, efpeglenatide, also demonstrates cardiovascular and renal benefits in patients with type 2 diabetes r106
        • Liraglutide, albiglutide, and dulaglutide can be used without dose alterations in category G2, G3a, or G3b chronic kidney disease
        • All glucagonlike peptide 1 receptor agonists are contraindicated in categories G4 and G5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²) r11
      • Sulfonylureas
        • At advanced stages of nephropathy, this class carries high risk of hypoglycemia
        • If this class is used, carefully monitor blood glucose level and give conservative dosing
        • Most sulfonylureas are contraindicated in patients with category G4 or G5 chronic kidney disease (estimated GFR less than 30 mL/minute/1.73 m²)
      • Meglitinides
        • Meglitinides are short acting and are taken at meals, mitigating some of the risk of hypoglycemia
        • Repaglinide is mostly metabolized by the liver and may be used with dose adjustments
        • Do not use in patients with estimated GFR less than 60 mL/minute/1.73 m² because an active metabolite of nateglinide accumulates in patients with chronic kidney disease
      • Thiazolidinediones
        • Only pioglitazone is advisable, owing to safety concerns with other agents in this class
        • Do not use pioglitazone in patients requiring dialysis
      • Dipeptidyl-peptidase IV inhibitors
        • Require dose reduction in patients with moderate or severe renal impairment, except linagliptin, for which no dose adjustment is necessary
      • α-glucosidase inhibitors
        • Unaltered renal excretion; therefore, not recommended in patients with category G4 or G5 chronic kidney disease
      • Insulin
        • For type 2 diabetes, insulin can be added to the other antihyperglycemic agents or replace them entirely in later stages of chronic kidney disease (categories G3-G5) r89
        • At categories G3 through G5 of chronic kidney disease, clearance of insulin is reduced, and risk for hypoglycemia increases r84
        • Insulin requirements may decrease by 20% or more when GFR decreases to less than 45 mL/minute/1.73 m² r107

Lifestyle modifications

  • Smoking cessationr108 and moderate alcohol consumptionr11 (2 or fewer daily drinks for most males or 1 daily drink for females and lighter-weight individuals) are recommended to help reduce blood pressure and prevent cardiovascular complications r11
  • Adherence to recommended dietary protein intake r1
    • For non–dialysis-dependent diabetic kidney disease, dietary protein intake should be 0.8 g/kg body weight per day (recommended daily allowance for the general population)
      • Avoid exceeding protein intake recommendations because higher levels (more than 20% of daily calories from protein or more than 1.3 g/kg body weight per day) are associated with increased albuminuria, more rapid kidney function loss, and cardiovascular mortality
      • Reducing dietary protein below the recommended daily allowance of 0.8 g/kg/day is also not recommended because it does not alter glycemic measures, cardiovascular risk measures, or course of GFR decline
    • Patients on dialysis may require higher levels of dietary protein intake

Treatment of comorbidities and complications

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

Renal replacement therapy r110

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

Drug therapy

  • Renin-angiotensin-aldosterone system inhibitors c72
    • ACE inhibitors r1r5c73
      • Ramipril c74
        • Ramipril Oral tablet; Adults: Usual dose range: 1.25 to 10 mg PO once daily. Begin with a low dose and titrate to response and tolerance.
      • Benazepril c75
        • Benazepril Hydrochloride Oral tablet; Adults: Dose range: 10 to 40 mg PO once daily. Usually begin with a low dose and titrate to response and tolerance. Common dose: 20 mg PO once daily.
      • Captopril c76
        • Captopril Oral tablet; Adults: The FDA-approved dosage is 25 mg PO 3 times daily.
      • Lisinopril c77
        • Lisinopril Oral tablet; Adults: Doses vary within the usual dose range. Usual range: 10 to 20 mg PO once daily, adjusted to response and tolerance.
    • Angiotensin receptor blockers r1r5c78
      • Irbesartan c79
        • Irbesartan Oral tablet; Adults: Initially, 75 mg PO once daily. Titrate to target dose of 300 mg PO once daily, as tolerated.
      • Losartan c80
        • Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. Increase dose to 100 mg PO once daily based on blood pressure response.
      • Telmisartan c81
        • Telmisartan Oral tablet; Adults: 40 mg PO once daily for 4 to 12 weeks, followed by titration to 80 mg PO once daily, has been effective.
  • Other antihypertensives
    • Diuretics r5c82
      • Furosemide c83
        • Furosemide Oral tablet; Adults: 40 mg PO twice daily, initially. May increase dose if further control is needed. Usual dose range: 20 to 80 mg/day. Max: 600 mg/day.
    • Calcium channel blockers r5r111c84c85c86
      • Diltiazem
        • Diltiazem Hydrochloride Oral capsule, sustained release 12 hour; Adults: 90 to 120 mg PO twice daily.
      • Verapamil
        • Verapamil Hydrochloride Oral tablet, extended-release; Adults: Initially, 180 mg PO once daily in the morning. May increase to 240 mg PO twice daily.
        • Verapamil Hydrochloride Oral tablet, extended-release; Geriatric: Use lower initial dose (e.g., 120 mg PO once daily in the morning).
    • β-adrenergic receptor blockers r5c87
      • Labetalol c88
        • Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage by 100 to 200 mg twice daily every 2 to 3 days until goal blood pressure is attained. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
  • Antihyperglycemic agents c89
    • Oral agents and insulin and noninsulin injectables are used in type 2 diabetes
    • Insulin is always required in type 1 diabetes; in long-standing type 2 diabetes, it is used in certain circumstances as monotherapy or in combination with other drugs
    • Oral agents
      • Metformin r52c90
        • Immediate release
          • Metformin Hydrochloride Oral tablet; Adults: 500 mg PO twice daily or 850 mg PO once daily, initially. May increase dose by 500 mg/week or 850 mg every 2 weeks if needed. Doses more than 2,000 mg/day may be better tolerated in 3 divided doses. Max: 2,550 mg/day. Use doses more than 1,000 mg/day with caution in older adults.
        • Extended-release
          • Metformin Hydrochloride Oral tablet, extended-release; Adults: 500 mg PO once daily, initially. May increase dose by 500 mg/week if needed. Max: 2,000 mg/day; may consider 1,000 mg PO twice daily if glycemic control is not achieved with 2,000 mg PO once daily. Use doses more than 1,000 mg/day with caution in older adults.
      • SGLT2 (sodium-glucose cotransporter 2) inhibitor r52
        • Empagliflozin c91
          • Empagliflozin Oral tablet; Adults: 10 mg PO once daily in the morning with or without food. May increase to 25 mg PO once daily for additional glycemic control.
        • Canagliflozin c92
          • Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase dose to 300 mg PO once daily if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Dapagliflozin c93
          • Dapagliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 10 mg PO once daily if needed.
        • Ertugliflozin c94
          • Ertugliflozin Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose to 15 mg PO once daily if needed.
      • Sulfonylureasr52c95
        • Glipizide c96
          • Glipizide Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Glipizide Oral tablet; Geriatric Adults: 2.5 mg PO once daily, initially. May increase dose by 2.5 to 5 mg/day after several days if needed; a conservative titration scheme is recommended. Divide doses more than 15 mg/day into 2 doses. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Glyburide c97
          • Glyburide Oral tablet; Adults: 2.5 to 5 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Glyburide Oral tablet; Geriatric Adults: 1.25 mg PO once daily, initially. May increase dose by 2.5 mg/day every week if needed; a conservative titration scheme is recommended. Consider dividing dose more than 10 mg/day into 2 doses. Usual dose range: 1.25 to 20 mg/day. Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Chlorpropamide c98
          • Chlorpropamide Oral tablet; Adults: Initially, 250 mg PO once daily with breakfast or in divided doses if GI intolerance occurs. Increase by 50 to 125 mg every 3 to 5 days if needed to attain glycemic goals. Some patients may be maintained on 100 mg/day PO. Patients who fail to respond to a maintenance dose of 500 mg/day do not generally respond to higher doses. Max: 750 mg/day PO.
          • Chlorpropamide Oral tablet; Geriatric Adults: Avoid use in elderly patients due to the risk of prolonged hypoglycemia. If this drug is necessary, use a reduced initial dose of 100 to 125 mg PO once daily, followed by careful dosage titration to achieve clinical goals.
      • Meglitinides c99
        • Nateglinide c100
          • Nateglinide Oral tablet; Adults: 120 mg PO 3 times daily, or 60 mg PO 3 times daily for patients who are near glycemic goal when treatment is initiated.
        • Repaglinide c101
          • Repaglinide Oral tablet; Adults: 0.5 mg PO before each meal for patients whose HbA1c is less than 8% and 1 or 2 mg PO before each meal for patients whose HbA1c is 8% or more. May double the dose after at least 1 week if needed. Usual dose range: 0.5 to 4 mg PO before each meal. Max: 4 mg/dose and 16 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Dipeptidyl-peptidase IV inhibitors c102
        • Linagliptin c103
          • Linagliptin Oral tablet; Adults: 5 mg PO once daily.
        • Alogliptin c104
          • Alogliptin Oral tablet; Adults: 25 mg PO once daily.
        • Saxagliptin c105
          • Saxagliptin Oral tablet; Adults: 2.5 or 5 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Sitagliptin c106
          • Sitagliptin Phosphate Oral tablet; Adults: 100 mg PO once daily.
      • α-glucosidase inhibitors c107
        • Acarbose c108
          • Acarbose Oral tablet; Adults weighing 60 kg or less: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 50 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Acarbose Oral tablet; Adults weighing more than 60 kg: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose to 50 mg PO 3 times daily and then 100 mg PO 3 times daily every 4 to 8 weeks based on 1-hour post-prandial glucose or HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Miglitol c109
          • Miglitol Oral tablet; Adults: 25 mg PO 3 times daily, initially, or alternately, 25 mg PO once daily to minimize gastrointestinal side effects. May increase dose after 4 to 8 weeks to 50 mg PO 3 times daily for 3 months and then 100 mg PO 3 times daily based on HbA1c if needed. Max: 100 mg PO 3 times daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Thiazolidinediones c110
        • Pioglitazone c111
          • Pioglitazone Hydrochloride Oral tablet; Adults: 15 or 30 mg PO once daily, initially. May increase dose by 15 mg/day based on HbA1c if needed. Max: 45 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions
        • Rosiglitazone c112
          • Rosiglitazone Maleate Oral tablet; Adults: 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. 4 mg PO once daily or 2 mg PO twice daily, initially. May increase dose to 8 mg/day after 12 weeks if needed. Max: 8 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Noninsulin injectables
      • Glucagonlike peptide 1 mimetics c113
        • Liraglutide c114
          • Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
        • Semaglutide c115
          • Semaglutide Solution for injection; Adults: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly, initially. May increase the dose to 1 mg subcutaneously once weekly after 4 weeks on 0.5 mg/week and 2 mg subcutaneously once weekly after 4 weeks on 1 mg/week if additional glycemic control is needed. Max: 2 mg/week.
    • Insulin r52c116
      • Insulin Glargine Solution for injection; Adults: 10 units subcutaneously once daily, or alternately, 0.1 to 0.2 units/kg/dose subcutaneously once daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
      • Insulin Detemir (Recombinant) Solution for injection; Adults: 10 units subcutaneously once daily or divided twice daily, or alternately, 0.1 to 0.2 units/kg/day subcutaneously once daily or divided twice daily, initially. Increase dose by 2 units every 3 days to achieve target fasting plasma glucose without hypoglycemia; reduce dose by 10% to 20% if hypoglycemia of undetermined cause occurs.
      • Insulin Lispro Solution for injection; Adults: 4 units or 10% of basal insulin dose subcutaneously once daily with the largest meal or meal with the greatest postprandial glucose excursion, initially. Consider lowering the basal insulin dose by 4 units or 10% of basal dose if HbA1c is less than 8%. Increase dose by 1 to 2 units or 10% to 15% twice weekly and proceed to full basal-bolus regimen based on blood glucose or HbA1c if further glycemic control is needed; reduce corresponding dose by 10% to 20% if hypoglycemia of undetermined cause occurs.

Nondrug and supportive care

Diet r108c117

  • Dietary recommendations are individualized according to weight loss goals, caloric needs, and distribution of macronutrients, taking into account lifestyle, preferences, eating patterns, culture, and comorbidities of patient
  • Various eating patterns, including DASH diet (Dietary Approaches to Stop Hypertension) and Mediterranean diet are effective for controlling glycemia and lowering cardiovascular risk factors r112
    • In general, diets should emphasize nonstarchy vegetables, minimize added sugars and refined grains, and avoid highly-processed foods
  • Protein intake r1c118
    • Usual protein intake: 15% to 20% of total energy
    • Dietary protein restriction is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline
      • For patients with non–dialysis-dependent diabetic kidney disease, the recommended daily dietary protein intake is the same as that of the general population (0.8 g/kg body weight)
      • For patients receiving dialysis, consider higher levels of dietary protein intake
  • Sodium intake r7c119
    • American Diabetes Association recommends total sodium of 2300 mg/day or less, which is the same as in general population r113
      • Earlier recommendations by KDIGO (Kidney Disease: Improving Global Outcomes) suggested less than 2000 mg/day r9
    • Individualize dietary sodium and potassium intake based on comorbid conditions, medications, blood pressure, and electrolyte levels
    • Reduced dietary sodium intake to less than 2300 mg/day may be useful to control hypertension and reduce cardiovascular risk r1

Lifestyle modifications c120

  • Medical nutrition therapy and physical activity, to reduce weight and maintain healthy weight r9r11c121c122c123
  • Regular physical activity
    • Combination of aerobic and muscle strengthening exercise is recommended r114
    • Encourage at least 150 min of moderate intensity aerobic activity per week r114
    • Recommend activities aimed at improving or maintaining muscle strength, balance, and flexibility on at least 2 days a week r114
  • Advise smoking cessation and avoidance of secondhand smoke exposure r108c124c125d4
  • Advise moderate alcohol consumption (2 or fewer daily drinks for most males or 1 daily drink for females and lighter-weight individuals) r11c126
Procedures
Renal transplant r115c127
General explanation
  • Surgical procedure to place healthy kidney from living or deceased donor into recipient r116
  • Option for patients with diabetic kidney disease who have developed end-stage renal disease, providing: r110
    • Better quality of life r110
    • Significant survival advantage over dialysis r117
  • Procedures for patients with type 1 diabetes and chronic kidney failure
    • Isolated kidney transplant from living donor
    • Isolated kidney transplant from deceased donor
    • Pancreas transplant after kidney transplant
    • Simultaneous pancreas-kidney transplant
  • Procedure for patients with type 2 diabetes and chronic kidney failure
    • Kidney transplant from deceased or living donor
Indication
  • Deteriorating renal function, nearing end stage
Contraindications
  • Unstable cardiovascular disease (eg, coronary and peripheral artery disease, peripheral arterial occlusive disease, carotid arterial stenosis, stroke) r118
  • Congestive heart failure and pulmonary disease (unless patient is stable) r118
  • Active infection r118
  • Active gastrointestinal bleeding r118
  • Active malignancy r118
  • Dementia r118
  • Nonadherence to immunosuppressive therapy or refusal of the procedure r118
Complications
  • Allograft thrombosis
  • Anastomotic leakage
  • Rejection
  • Infections due to immunosuppressant drugs r119
  • Posttransplant lymphoproliferative disorder and other malignancies, such as squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma r119
Kidney dialysis r120c128
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) r120r121
Indication
  • Option for patients with diabetic kidney disease and end-stage renal disease who are on waiting list for transplant and do not have potential living donor r118
  • Paucity of data from randomized controlled trials that establish optimal timing for renal replacement therapy
    • Timing of dialysis is often affected by multiple factors, including age, diabetes mellitus, individual desire, personal beliefs, and cultural and educational backgrounds r122
Contraindications
  • Specific to peritoneal dialysis:
    • Inadequate peritoneal membrane (eg, peritoneal sclerosis, extensive surgical resection) r120
    • Abdominal cavity incompetence (eg, peritoneal compartmentalization, peritoneal-pleural communication) r120
    • High risk of abdominal infection (eg, recurrent diverticulitis, active inflammatory bowel disease) r120r123
    • Previous major abdominal surgery (relative contraindication) r124
    • Older adults (older than 75 years) with illness and no social support (potential nonadherence; difficult/impossible to perform procedure in home setting) r125
  • Specific to hemodialysis: r126r127
    • 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 r128c129d3
    • Diabetic kidney disease is accompanied by abnormalities in lipid metabolism
    • Statinr129or statin plus ezetimiber130 is recommended for all adults aged 50 years or older who have diabetes and an estimated GFR less than 60 mL/minute/1.73 m² but who are not treated with chronic dialysis or kidney transplantation
      • Cardiovascular events and mortality are reduced with statins and statins plus ezetimibe in patients with non–dialysis-dependent chronic kidney disease r131
      • However, statins do not slow rate of kidney disease progression in those with preexisting chronic kidney disease r132
    • Statins are not recommended to be started in patients undergoing dialysis because use of statins in these patients shows no cardiovascular or survival advantage; however, continuation of statins is appropriate in those patients who are already using them and who have progression to end-stage renal disease r133
    • Do not use measurement of LDL-C to identify patients for statin therapy, as it is appropriate for assessing coronary risk in patients with chronic kidney disease
    • Initial evaluation of lipid profile is intended to diagnose severe hypertriglyceridemia and/or hypercholesterolemia while ruling out any underlying secondary causes
    • Statin dose titration is unnecessary, and follow-up measurements of lipid levels are suggested only to help assess adherence to statin therapy r8

Special populations

  • Pregnant patients
    • Pregnant females with concomitant nephropathy are at risk of deteriorating maternal kidney function, leading to end-stage renal disease r134
    • Compared with the healthy population, pregnant females with either type 1 or type 2 diabetes present a 2- to 4-fold increased risk of preeclampsia, preterm delivery, and perinatal mortality; in the presence of concomitant nephropathy, the risk is even higher r70
    • Preconception counseling for patients with preexisting diabetes and nephropathy or microalbuminuria should address the following issues: r134
      • Use of contraception in planning stages
      • Evaluate and discuss the risks of pregnancy-induced kidney failure, preeclampsia, and preterm delivery
    • Treatment is modified accordingly: r70
      • Strict glycemic control during pregnancy is necessary (target hemoglobin A1C less than 6%) r70
      • Establish intensive antihypertensive treatment (blood pressure goal lower than 130/80 mm Hg) early in pregnancy, using pregnancy-friendly antihypertensive agents (ideally before conception) r70
        • ACE inhibitors and angiotensin receptor blockers are contraindicated during all stages of pregnancy because of teratogenic risk r135
          • Female patients who are taking an ACE inhibitor or an angiotensin receptor blocker should discontinue the medication if pregnancy is being planned/considered, or immediately upon learning of a positive pregnancy test result
        • Methyldopa, β-blockers (eg, labetalol), and calcium antagonists (eg, nifedipine, diltiazem) can be used safely r70
          • Methyldopa is drug of choice r136
        • Use diuretics as alternative or add-on therapy, but only with caution r70
      • Low-dose aspirin is recommended (75 mg/day beginning at 10-12 gestational weeks until approximately 1 week before delivery) for all pregnant patients with diabetic kidney disease or microalbuminuria to prevent cardiovascular events and to reduce the risk of preeclampsia r134
      • Screen for sight-threatening diabetic retinopathy r134
      • Supplement with folic acid during the first 12 gestational weeks r134
  • Patients with more advanced stages of chronic kidney disease
    • Hypoglycemia r107
      • Severe hypoglycemia has been associated with a slight increase in mortality r137
      • Becomes a greater concern with worsening kidney dysfunction (chronic kidney disease categories G3-G5)
      • Can occur readily in patients who have GFR levels less than 30 mL/minute/1.73 m² and who are receiving treatment with oral antidiabetic drugs that are primarily eliminated by the kidneys (eg, sulfonylureas)
      • Especially likely in patients with impaired renal function who are treated with insulin, owing to reduced renal clearance of insulin and decreased insulin degradation in peripheral tissues
      • To reduce risk of hypoglycemia in patients on insulin or insulin secretagogues, greater frequency of self-monitoring of blood glucose and modification of antihyperglycemic drug dosing is advisable r82

Monitoring

  • Monitoring is necessary to assess progression, relying on the assessments of albuminuria (indicative of kidney damage) and estimated GFR (indicative of kidney function) c130
  • Perform physical examination and measure weight and blood pressure at every clinical encounter r51
    • Measure orthostatic blood pressure periodically or when symptoms of orthostatic hypotension occur c131
      • If orthostatic hypotension develops, consider nocturnal dosing of antihypertensives and/or stopping α-blockers and diuretics r51
  • Assess for albuminuria (spot urinary albumin to creatinine ratio) and obtain serum creatinine level and estimated GFR at least annually r74c132
    • In patients with urinary albumin to creatinine ratio greater than 30 mg/g or estimated GFR less than 60 mL/minute/1.73 m², assess every 3 to 6 months (according to severity) to guide management r1
    • Patients on ACE inhibitors, angiotensin receptor blockers, or diuretics
      • Periodically monitor serum creatinine and potassium levels for development of increased creatinine level or changes in potassium concentration r74
      • Debate continues regarding the need for annual quantitative assessment of albumin excretion after evidence of albuminuria has been established or after starting an ACE inhibitor or angiotensin receptor blocker
        • Ongoing monitoring of urinary albumin to creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment, monitor progression of diabetic kidney disease, and facilitate adherence to pharmacotherapy r1
    • Patients on metformin
      • Metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function r138
      • GFR is the most appropriate monitoring parameter because serum creatinine measurements account for additional factors that are important (eg, patient's age, gender, race, and/or weight)
      • If estimated GFR is 30 to 60 mL/minute/1.73 m², monitor every 3 to 6 months r90
      • Reduce maximum dose when estimated GFR is less than 45 mL/minute/1.73 m², and discontinue when estimated GFR is less than 30 mL/minute/1.73 m²

Complications and Prognosis

Complications

  • Cardiovascular disease c133
    • In general, incidence increases according to severity of kidney disease r139
      • Approximately 3.5-fold increased risk of cardiovascular disease and 6-fold increased risk of death has been shown for patients with GFR of less than 15 mL/minute/1.73 m²
    • Most frequent specific complications include the following:
      • Coronary artery disease (increased risk of death and nonfatal cardiovascular outcomes after myocardial infarction) c134d5
      • Left ventricular hypertrophy (affects approximately 74% of patients with chronic kidney disease) r140c135
      • Congestive heart failure (31% of patients with chronic kidney disease) r140c136d6
      • Stroke (5- to 10-fold increased incidence in patients with end-stage renal disease) r140c137d7
      • Peripheral artery disease (eg, atherosclerosis, thrombosis, stenosis; reported in 25% of patients older than 40 years) r11c138c139c140c141c142c143c144c145d8
  • Anemia r141c146
    • Estimated incidence is 20% of patients with diabetes and category G3 chronic kidney disease
    • Multiple contributing causes, including iron deficiency, erythropoietin deficiency and hyporesponsiveness, folate deficiency, and vitamin B₁₂ deficiency
  • Chronic kidney disease–mineral bone disorder r142r143c147
    • 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 c148c149c150
    • Tertiary hyperparathyroidism and hypercalcemia develop after chronic secondary hyperparathyroidism, owing to autonomous parathyroid hormone secretion that is unregulated by calcium levels
    • Patients should have serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase measured regularly, and those with evidence of chronic kidney disease–mineral bone disorder and/or risk factors for osteoporosis should undergo bone marrow density screening and be considered for bone biopsy r143
    • Initial management consists of lowering elevated serum phosphate with dietary phosphate restriction and phosphate binders, maintaining serum calcium level within reference range, and antiresorptive therapy if at high risk of fracture
    • Treatment of secondary hyperparathyroidism consists of calcitriol and vitamin D analogues, dietary phosphate restriction, and phosphate binders; total or 3.5 gland parathyroidectomy is indicated for tertiary hyperparathyroidism r144r145r146
  • Metabolic acidosis r62
    • May be complicated by hyperkalemia
    • Management includes low-potassium diet, diuretics, and sodium bicarbonate supplementation

Prognosis

  • Diabetic kidney disease and type 1 diabetes
    • If condition is left untreated, average survival is 5 to 7 years from diagnosis for patients with diabetic kidney disease associated with type 1 diabetes r147
      • Along with current therapies (eg, strict control of blood pressure, lipids, and glycemia; improved lifestyle), prognosis has improved such that mortality is reduced by 30% r147
    • Disease progression is well characterized in patients with type 1 diabetes
      • Without therapeutic intervention, approximately 80% of patients with type 1 diabetes and moderately increased albuminuria (albumin to creatinine ratio greater than or equal to 30 mg/g) progress to develop severe albuminuria (albumin to creatinine ratio of 300 mg/g or greater) in 10 to 15 years on average r39
      • Approximately 50% of patients with severe albuminuria have progression to end-stage renal disease within 10 years and 75% have progression to end-stage renal disease within 20 years r39
  • Diabetic kidney disease and type 2 diabetes
    • In patients with type 2 diabetes, mortality associated with cardiovascular complications increases in relation to poor glycemic control, severity of renal complications, and patient's age
      • Patients younger than 55 years with optimal glycemic control (hemoglobin A1C level of 6.9% or lower) and normal albumin levels present a hazard ratio for death—due to any cardiovascular cause—approximately 2 times higher than that of patients older than 75 years r148
      • Patients with prior cardiovascular disease, chronic kidney disease, or both have increased risk of cardiovascular events and mortality; risk increases with worsening baseline GFR r149
    • Disease progression is generally more indolent in patients with type 2 diabetes than in patients with type 1 diabetes r39
      • Without therapeutic intervention, 20% to 40% of patients with type 2 diabetes and moderately increased albuminuria (albumin to creatinine ratio of 30-300 mg/g) develop severe albuminuria (albumin to creatinine ratio of 300 mg/g or greater), and only 20% of these patients progress to end-stage renal disease after 20 years r39
  • 5-year survival rate of patients with diabetes and end-stage renal disease is poor (30% after initiation of dialysis) r2
    • Renal replacement therapy (eg, renal transplant, dialysis) increases 5-year survival rate by 30% in these patients r2

Screening and Prevention

Screening

At-risk populations

  • Patients with type 1 diabetes: screen annually beginning at 5 years after initial diagnosis r1c151c152
  • Patients with type 2 diabetes: screen annually starting at time of diagnosis r1c153c154
  • Patients with any type of diabetes and who have comorbid hypertension: screen annually r1c155c156

Screening tests

  • Annual assessment of albuminuria (spot urinary albumin to creatinine ratio) and estimated GFR r74c157c158
    • Positive test result is marked by either of the following:
      • Urinary albumin to creatinine ratio greater than or equal to 30 mg/g r74
      • Estimated GFR less than 60 mL/minute/1.73 m² r74

Prevention

  • Progression of diabetic kidney disease can be slowed by:
    • Intensive treatment of diabetes c159
    • Maintaining control of blood pressure (ideally to a level lower than 140/90 mm Hg or 130/80 mm Hg in patients with diabetes who already have albuminuria) r7c160
    • Use of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes r1
    • Use of mineralocorticoid receptor antagonists (eg, finerenone) in patients with hypertension and diabetic kidney disease r71r72
  • Renin-angiotensin-aldosterone system blockade is controversial for prevention of diabetic kidney disease patients with diabetes who are normotensive and do not have albuminuria r7c161
    • Not recommended for primary prevention of diabetic kidney disease in patients with normal blood pressure, urinary albumin to creatinine ratio (less than 30 mg/g), and estimated GFR r1
American Diabetes Association Professional Practice Committee, et al: 11. Chronic kidney disease and risk management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 45(Suppl 1):S175-84, 202234964873Ghaderian SB et al: Diabetes and end-stage renal disease; a review article on new concepts. J Renal Inj Prev. 4(2):28-33, 201526060834Kidney disease: improving global outcomes (KDIGO) diabetes work group: KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 98(4S):S1-S115, 202032998798National Kidney Foundation: KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 60(5):850-86, 201223067652American Diabetes Association Professional Practice Committee, et al: 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 45(Suppl 1):S144-74, 202234964815Persson F et al: Diagnosis of diabetic kidney disease: state of the art and future perspective. Kidney Int Suppl (2011). 8(1):2-7, 201830675433Gallagher H et al: Diabetic nephropathy--where are we on the journey from pathophysiology to treatment? Diabetes Obes Metab. 18(7):641-7, 201626743887Tuttle KR et al: Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 37(10):2864-83, 201425249672Kidney Disease: Improving Global Outcomes: KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 3(1):1-150, 2013https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdfStevens PE et al: Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 158(11):825-30, 201323732715Bakris GL: Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc. 86(5):444-56, 201121531886Woredekal Y et al: Clinical aspects of diabetic neuropathy. In: Schrier RW, ed: Diseases of the Kidney and Urinary Tract: Volume III. 8th ed. Lippincott Williams and Wilkins; 2007:1894-908Yee J: Diabetic kidney disease: chronic kidney disease and diabetes. Diabetes Spectrum. 21(1):8-10, 2008https://doi.org/10.2337/diaspect.21.1.8Van Buren PN et al: Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management. Adv Chronic Kidney Dis. 18(1):28-41, 201121224028Anders HJ et al: Nephron protection in diabetic kidney disease. N Engl J Med. 375(21):2096-8, 201627959742Kanwar YS et al: A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 6:395-423, 201121261520Radcliffe NJ et al: Clinical predictive factors in diabetic kidney disease progression. J Diabetes Investig. 8(1):6-18, 201727181363McKnight AJ et al: Genetics of diabetic nephropathy: a long road of discovery. Curr Diab Rep. 15(7):41, 201525971618Davoudi S et al: Novel genetic actors of diabetes-associated microvascular complications: retinopathy, kidney disease and neuropathy. Rev Diabet Stud. 12(3-4):243-59, 201526859656Brennan E et al: The genetics of diabetic nephropathy. Genes (Basel). 4(4):596-619, 201324705265Komorowsky CV et al: Perspectives on systems biology applications in diabetic kidney disease. J Cardiovasc Transl Res. 5(4):491-508, 201222733404He F et al: Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia. 56(3):457-66, 201323232641Beulens JW et al: Alcohol consumption and risk of microvascular complications in type 1 diabetes patients: the EURODIAB Prospective Complications Study. Diabetologia. 51(9):1631-8, 200818626626Blomster JI et al: The relationship between alcohol consumption and vascular complications and mortality in individuals with type 2 diabetes. Diabetes Care. 37(5):1353-9, 201424578358Dunkler D et al: Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus. Kidney Int. 87(4):784-91, 201525493953Hörl WH: Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals (Basel). 3(7):2291-321, 2010https://doi.org/10.3390%2Fph3072291Brown JR et al: Contrast-induced acute kidney injury: the at-risk patient and protective measures. Curr Cardiol Rep. 12(5):440-5, 201020640537Long AN et al: Comorbidities of diabetes and hypertension: mechanisms and approach to target organ protection. J Clin Hypertens (Greenwich). 13(4):244-51, 201121466619Chen SC et al: Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud. 10(2-3):88-100, 201324380085Morton J et al: Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy: results of the ADVANCE study. Diabetes Care. 35(11):2201-6, 201222891258Workeneh B et al: High-protein diet in diabetic nephropathy: what is really safe? Am J Clin Nutr. 98(2):266-8, 201323824718Sun H et al: Cholesterol contributes to diabetic nephropathy through SCAP-SREBP-2 pathway. Int J Endocrinol. 2013:592576, 201324369464Klaus G: Renoprotection with vitamin D: specific for diabetic nephropathy? Kidney Int. 73(2):141-3, 200818165810Bentata Y et al: Does smoking increase the risk of progression of nephropathy and/or cardiovascular disease in type 2 diabetic patients with albuminuria and those without albuminuria? Am J Cardiovasc Dis. 6(2):66-9, 201627335692Feodoroff M et al: Smoking and progression of diabetic nephropathy in patients with type 1 diabetes. Acta Diabetol. 53(4):525-33, 201626668013Thakar CV et al: Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol. 6(11):2567-72, 201121903988Siddiqui MM et al: Urologic assessment of decreasing renal function. Med Clin North Am. 95(1):161-8, 201121095419Fiorini F et al: The role of ultrasonography in the study of medical nephropathy. J Ultrasound. 10(4):161-7, 200723396246Espinel E et al: Renal biopsy in type 2 diabetic patients. J Clin Med. 4(5):998-1009, 201526239461Onuigbo MA et al: Diabetic nephropathy and CKD-analysis of individual patient serum creatinine trajectories: a forgotten diagnostic methodology for diabetic CKD prognostication and prediction. J Clin Med. 4(7):1348-68, 201526239680National Institute of Diabetes and Digestive and Kidney Diseases: CKD-EPI Adults (Conventional Units). NIDDK website. Accessed April 19, 2022. https://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/adults-conventional-unit-ckd-epi/Pages/default.aspxhttps://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/adults-conventional-unit-ckd-epi/Pages/default.aspxNational Institute of Diabetes and Digestive and Kidney Diseases: MDRD for Adults (Conventional Units). NIDDK website. Accessed April 19, 2022. https://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/adults-conventional-unit/Pages/adults-conventional-unit.aspxhttps://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/adults-conventional-unit/Pages/adults-conventional-unit.aspxVisconti L et al: Renal biopsy: still a landmark for the nephrologist. World J Nephrol. 5(4):321-7, 201627458561Bandari J et al: Renal biopsy for medical renal disease: indications and contraindications. Can J Urol. 23(1):8121-6, 201626892051Alsaad KO et al: Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. J Clin Pathol. 60(1):18-26, 200717213346KDOQI: KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 49(2 suppl 2):S12-154, 200717276798Mok CC: Towards new avenues in the management of lupus glomerulonephritis. Nat Rev Rheumatol. 12(4):221-34, 201626729459Victor RG: Arterial hypertension. In: Goldman L et al, eds: Goldman-Cecil Medicine. 25th ed. Saunders; 2016:381-97Textor SC et al: Paradigm shifts in atherosclerotic renovascular disease: where are we now? J Am Soc Nephrol. 26(9):2074-80, 201525868641Mark PB et al: Renovascular hypertension: to stent or not to stent? Hypertension. 64(6):1165-8, 201425245390de Boer IH et al: Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care. 40(9):1273-84, 201728830958American Diabetes Association Professional Practice Committee, et al: 6. Glycemic targets: Standards of Medical Care in Diabetes-2022. Diabetes Care. 45(Suppl 1):S83-96, 202234964868Lehnhardt A et al: Pathogenesis, diagnosis and management of hyperkalemia. Pediatr Nephrol. 26(3):377-84, 201121181208Alivanis P et al: Metformin-associated lactic acidosis treated with continuous renal replacement therapy. Clin Ther. 28(3):396-400, 200616750454DeFronzo R et al: Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism. 65(2):20-9, 201626773926Smart NA et al: Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease. Cochrane Database Syst Rev. 6:CD007333, 201424938824Lewis EJ et al: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 329(20):1456-62, 19938413456Parving HH et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 345(12):870-8, 200111565519Brenner BM et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 345(12):861-9, 200111565518Lewis EJ et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 345(12):851-60, 200111565517Selby NM et al: An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab. 22 Suppl 1:3-15, 202032267079Stephens JW et al: Chronic kidney disease in type 2 diabetes: implications for managing glycaemic control, cardiovascular and renal risk. Diabetes Obes Metab. 22 Suppl 1:32-45, 202032267078Kidney Disease Improving Global Outcomes: KDIGO 2021 Clinical Practice Guideline on the Management of Blood Pressure in Chronic Kidney Disease. KDIGO website. Published March 2021. Accessed August 23, 2022. https://kdigo.org/guidelines/blood-pressure-in-ckd/ https://kdigo.org/guidelines/blood-pressure-in-ckd/Banerjee D et al: Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021. BMC Nephrol. 23(1):9, 202234979961Barnett AH et al: Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 351(19):1952-61, 200415516696Cheng J et al: Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 174(5):773-85, 201424687000Lozano-Maneiro L et al: Renin-angiotensin-aldosterone system blockade in diabetic nephropathy. Present evidences. J Clin Med. 4(11):1908-37, 201526569322ONTARGET Investigators et al: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 358(15):1547-59, 200818378520Fried LF et al: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 369(20):1892-903, 201324206457Mathiesen ER et al: Obstetric nephrology: pregnancy in women with diabetic nephropathy--the role of antihypertensive treatment. Clin J Am Soc Nephrol. 7(12):2081-8, 201222917698Bakris GL et al: Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 383(23):2219-29, 202033264825Pitt B et al: Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 385(24):2252-63, 202134449181Agarwal R et al: Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 43(6):474-484, 202235023547American Diabetes Association Professional Practice Committee, et al: 12. Retinopathy, neuropathy, and foot care: Standards of Medical Care in Diabetes-2022. Diabetes Care. 45(Suppl 1):S185-94, 202234964887Parving HH et al: Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 367(23):2204-13, 201223121378Karalliedde J et al: Clinical practice guidelines for management of hyperglycaemia in adults with diabetic kidney disease. Diabet Med. 39(4):e14769, 202235080257Lo C et al: Intensive glucose control in patients with diabetes prevents onset and progression of microalbuminuria, but effects on end-stage kidney disease are still uncertain. Evid Based Med. 22(6):219-20, 201729097446Diabetes Control and Complications (DCCT) Research Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 47(6):1703-20, 19957643540Ruospo M et al: Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev. 6:CD010137, 201728594069Holman RR et al: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 359(15):1577-89, 200818784090ADVANCE Collaborative Group et al: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 358(24):2560-72, 200818539916Molitch ME: Diabetic kidney disease: much progress, but still more to do. Diabetes Spectr. 28(3):154-6, 201526300605Papademetriou V et al: Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int. 87(3):649-59, 201525229335Lovre D et al: Managing diabetes and cardiovascular risk in chronic kidney disease patients. Endocrinol Metab Clin North Am. 47(1):237-57, 201829407054Miller ME et al: The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 340:b5444, 201020061360Neuen BL et al: SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 7(11):845-54, 201931495651Salah HM et al: Effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular and kidney outcomes-systematic review and meta-analysis of randomized placebo-controlled trials. Am Heart J. 232:10-22, 202133214130Bhatt DL et al: Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 384(2):129-39, 202133200891Davies M et al: The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol. 8:61-81, 201627382338Ioannidis I: Diabetes treatment in patients with renal disease: is the landscape clear enough? World J Diabetes. 5(5):651-8, 201425317242FDA: FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Updated April 2017. Accessed January 24, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certainhttps://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certainWeir MR et al: Renal and cardiovascular effects of sodium glucose co-transporter 2 inhibitors in patients with type 2 diabetes and chronic kidney disease: perspectives on the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial results. Am J Nephrol. 51(4):276-88, 202032172239Sridhar VS et al: What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors? Diabetes Obes Metab. 22 Suppl 1:55-68, 202032267075Vallianou NG et al: Sodium glucose co-transporter 2 inhibitors and their nephroprotective potential. Clin Nephrol. ePub, 201728177279Addendum. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes-2022: Diabetes Care 2022;45(Suppl. 1):S175-S184. Diabetes Care. ePub, 202235639487Wanner C et al: Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 375(18):1800-1, 201627299675Perkovic V et al: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 380(24):2295-306, 201930990260Bakris G et al: Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m2: subgroup analysis of the randomized CREDENCE trial. Clin J Am Soc Nephrol. 15(12):1705-14, 202033214158Lo C et al: Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. Cochrane Database Syst Rev. 9:CD011798, 201830246878Yin WL et al: The effect of glucagon-like peptide-1 receptor agonists on renal outcomes in type 2 diabetes. Diabetes Ther. 11(4):835-44, 202032185624Kristensen SL et al: Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 7(10):776-85, 201931422062Scheen AJ: Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes. Diabetes Metab. 45(2):110-21, 201930477733Marso SP et al: Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 375(19):1834-44, 201627633186Gerstein HC et al: Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 394(10193):131-138, 201931189509Marso SP et al: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. ePub, 201627295427Gerstein HC et al: Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med. 385(10):896-907, 202134215025Alsahli M et al: Hypoglycemia in patients with diabetes and renal disease. J Clin Med. 4(5):948-64, 201526239457Quiroga B et al: Present and future in the treatment of diabetic kidney disease. J Diabetes Res. 2015:801348, 201525945357Pignone M et al: Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 33(6):1395-402, 201020508233Fourtounas C: Transplant options for patients with type 2 diabetes and chronic kidney disease. World J Transplant. 4(2):102-10, 201425032099Bakris GL et al: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int. 50(5):1641-50, 19968914031Evert AB et al: Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 42(5):731-54, 201931000505American Diabetes Association Professional Practice Committee, et al: 5. Facilitating behavior change and well-being to improve health outcomes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 45(Suppl 1):S60-82, 202234964866Baker LA et al: Clinical practice guideline exercise and lifestyle in chronic kidney disease. BMC Nephrol. 23(1):75, 202235193515Rangel EB et al: Kidney transplant in diabetic patients: modalities, indications and results. Diabetol Metab Syndr. 1(1):2, 200919825194Redfield RR et al: Graft and patient survival outcomes of a third kidney transplant. Transplantation. 99(2):416-23, 201525121473Wolfe RA et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 341(23):1725-30, 199910580071Kiberd BA et al: Contraindications to kidney transplantation: uneven grounds? Transplant Res. 4:2, 201526203355Wong CJ et al: Primary care of the solid organ transplant recipient. Med Clin North Am. 99(5):1075-103, 201526320047Franco MR et al: Dialysis in the elderly patient: a challenge of the XXI century--narrative review. J Bras Nefrol. 35(2):132-41, 201323812571Suzuki H et al: New modality of dialysis therapy: peritoneal dialysis first and transition to home hemodialysis. Adv Perit Dial. 28:106-11, 201223311225Lin ZH et al: When to initiate renal replacement therapy: the trend of dialysis initiation. World J Nephrol. 4(5):521-7, 201526558189Jager KJ et al: The effect of contraindications and patient preference on dialysis modality selection in ESRD patients in The Netherlands. Am J Kidney Dis. 43(5):891-9, 200415112180Crabtree JH: Previous abdominal surgery is not necessarily a contraindication for peritoneal dialysis. Nat Clin Pract Nephrol. 4(1):16-7, 200817984988Taveras AE et al: Peritoneal dialysis in patients 75 years of age and older--a 22-year experience. Adv Perit Dial. 28:84-8, 201223311220Cohen LS: Nurse to nurse: nursing role in diabetic nephropathy management. In: Friedman EA et al, eds: Diabetic Nephropathy: Strategy for Therapy. Springer; 1986:195-212Pendse S et al: Initiation of dialysis. In: Daugirdas JT et al, eds: Handbook of Dialysis. 4th ed. Lippincott Williams and Wilkins; 2007:14-24Wanner C et al: KDIGO clinical practice guideline for lipid management in CKD: summary of recommendation statements and clinical approach to the patient. Kidney Int. 85(6):1303-9, 201424552851Palmer SC et al: HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 5:CD007784, 201424880031Baigent C et al: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 377(9784):2181-92, 201121663949Palmer SC et al: Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 157(4):263-75, 201222910937Haynes R et al: Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol. 25(8):1825-33, 201424790178Palmer SC et al: HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst Rev. CD004289, 201324022428Ringholm L et al: Diabetic nephropathy in women with preexisting diabetes: from pregnancy planning to breastfeeding. Curr Diab Rep. 16(2):12, 201626803648Young EC et al: Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes. Diabetes Metab Syndr. 5(3):137-42, 201122813566Podymow T et al: Update on the use of antihypertensive drugs in pregnancy. Hypertension. 51(4):960-9, 200818259046Joseph JJ et al: Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation.145(9):e722-59, 202235000404Ekström N et al: Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2(4):e001076, 201222798258Magri CJ et al: Diabetic nephropathy: a cardiovascular risk factor. In: Sahay M, ed: Diseases of Renal Parenchyma. InTech; 2012:271-304https://www.intechopen.com/books/diseases-of-renal-parenchyma/diabetic-nephropathy-a-cardiovascular-risk-factorPálsson R et al: Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis. 21(3):273-80, 201424780455Mehdi U et al: Anemia, diabetes, and chronic kidney disease. Diabetes Care. 32(7):1320-6, 200919564475Kochanek M et al: Mineral metabolism in chronic kidney disease. Dis Mon. 61(10):425-33, 201526518114Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group: KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 7(1):1-59, 2017https://www.kisupplements.org/article/S2157-1716(17)30001-1/fulltextMadorin C et al: The surgical management of renal hyperparathyroidism. Eur Arch Otorhinolaryngol. 269(6):1565-76, 201222101574Isakova T et al: KDOQI US commentary on the 2017 KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Am J Kidney Dis. 70(6):737-51, 201728941764Ketteler M et al: Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what's changed and why it matters. Kidney Int. 92(1):26-36, 201728646995Andrésdóttir G et al: Improved prognosis of diabetic nephropathy in type 1 diabetes. Kidney Int. 87(2):417-26, 201524918158Tancredi M et al: Excess mortality among persons with type 2 diabetes. N Engl J Med. 373(18):1720-32, 201526510021Amod A et al: Glomerular filtration rate and associated risks of cardiovascular events, mortality, and severe hypoglycemia in patients with type 2 diabetes: secondary analysis (DEVOTE 11). Diabetes Ther. 11(1):53-70, 202031667706
;