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Canadian Pharmacists Association
Canadian Pharmacists Association
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Chapter 29: Chronic Kidney Disease in Diabetes

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Introduction
  • Diseases of the kidney are a common finding in people with diabetes, with up to half demonstrating signs of kidney damage in their lifetime. Diabetes is the leading cause of kidney disease in Canada.
  • Kidney disease can be a particularly devastating complication, as it is associated with significant reductions in both length and quality of life.
  • A variety of forms of kidney disease can be seen in people with diabetes, including diabetic nephropathy, ischemic damage related to vascular disease and hypertension, as well as other renal diseases that are unrelated to diabetes.

FIGURE 1

Diabetic Nephropathy
  • The classic description of diabetic nephropathy is of a progressive increase in proteinuria in people with longstanding diabetes followed by declining function that can eventually lead to end stage renal disease (ESRD)
  • Key risk factors for diabetic nephropathy include long duration of diabetes, poor glycemic control, hypertension, male gender, obesity and cigarette smoking
  • Persistent albuminuria is considered the earliest clinical sign of diabetic nephropathy. Initially, in the “microalbuminuria” stage, small amounts of albumin are leaked, below the detection threshold of a urine dipstick. This can worsen so that the urinary albumin excretion is sufficient to be detectable by a urine dipstick, a stage known as “overt nephropathy.”
  • Progression from normoalbuminuria to microalbuminuria then to overt nephropathy may vary among individuals but usually is slow, typically taking 5 years or longer to progress through each stage. Significant renal dysfunction is not usually seen until late in the course of diabetic nephropathy.
    • Rate of progression varies among individuals and clinical markers such as estimated glomerular filtration rate (eGFR) do not always correlate with severity of renal disease

FIGURE 2

TABLE 1

Other Kidney Diseases in People with Diabetes
  • Kidney biopsy series in type 2 diabetes have found that nondiabetic glomerular disease, particularly hypertensive or ischemic nephropathy, is as common as diabetic nephropathy in people with diabetes. Some disease states may overlap.
  • Some studies have suggested that half of everyone with diabetes and significant kidney function impairment do not have albuminuria. These studies suggest that testing for albuminuria may be insufficient in identifying all patients with diabetes who have renal disease.
  • In addition to measurements of urinary albumin excretion, estimations of the level of kidney function and urinalyses are required to identify patients with kidney disease other than diabetic nephropathy.

TABLE 2

Screening for Kidney Disease in People with Diabetes
  • In adults, screening for CKD in diabetes should be conducted using random urine albumin-to-creatinine ratio (ACR) and a serum creatinine converted into an eGFR [Grade D, Consensus].
  • Screening should start at diagnosis of diabetes in individuals with type 2 diabetes, 5 years after diagnosis in adults with type 1 diabetes and repeated yearly thereafter. A diagnosis of CKD should be made in patients with a random urine ACR ≥2.0 mg/mmol and/or an eGFR<60 mL/min on at least 2 of 3 samples over a 3-month period [Grade D, Consensus].
Screening for Albuminuria
  • When screening for albuminuria, the test of choice is the random urine albumin-to-creatinine ratio (urinary ACR).
  • The 24-hour urine collection for protein/albumin is the gold standard, however it is difficult to implement on a large scale and is often performed incorrectly.
  • There is substantial day-to-day variability in albuminuria.
    • Transient increases in albuminuria can be caused by a number of factors. When such conditions are present, screening for kidney disease should be delayed to avoid false positives.

TABLE 3

Estimation of GFR
  • The serum creatinine is the most common measurement of kidney function; however it can inaccurately reflect renal function in many scenarios, particularly in extremes of patient age or size.
  • The most common method of estimating renal function in Canada currently is the eGFR, using the 4-variable MDRD (“Modification of Diet in Renal Disease”) equation.
    • The equation requires knowledge of the patient's age, sex, serum creatinine and race and is automatically computed and reported by many labs whenever a serum creatinine is ordered.
  • The MDRD eGFR performs well when the GFR is <60 mL/min and is generally a better estimate of glomerular filtration than the serum creatinine value.
  • The eGFR is useful for assessing chronic changes in renal function but should not be used in situations where kidney function is changing rapidly. Dehydration and other conditions that lead to intravascular volume contraction can lead to a transient decline in renal function. When such conditions are present, assessment of the level of kidney function may be clinically necessary but should not be used to assess the stage of CKD.
  • Because renal function can be transiently depressed, a persistent reduction in eGFR is required before it is considered to be abnormal.
Other Clinical Features and Urinary Abnormalities: When to Consider Additional Testing or Referral
  • Urinalysis findings of red blood cell casts are uncommon in renal disease due to diabetes, and white blood cell casts or heme-granular casts are not compatible with a diagnosis of kidney disease due to diabetes.
  • Although persistent microscopic hematuria can occur in about 20% of people with diabetic nephropathy, its presence should lead to the consideration of other urological or nephrological conditions.
Screening Recommendations
  • People with diabetes should undergo annual screening for the presence of kidney disease when they are clinically stable and not suspected of having acute kidney injury or nondiabetic renal disease. Screening should be delayed in the presence of conditions that can cause transient albuminuria or a transient fall in eGFR.
Prevention, Treatment and Follow Up
  • Optimal glycemic and BP control established as soon as possible after diagnosis can help reduce the risk of development of diabetic nephropathy.
  • Blockade of the renin-angiotensin-aldosterone system (RAAS) with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can reduce the risk of diabetic nephropathy independent of their effect on BP. This protective effect has been demonstrated in people with diabetes and hypertension but not in normotensive people with diabetes.
  • All patients with diabetes and CKD should receive a comprehensive, multifaceted approach to reduce cardiovascular risk [Grade A, Level 1A].
  • Adults with diabetes and CKD with either hypertension or albuminuria should receive an ACE inhibitor or an ARB to delay progression of CKD [Grade A, Level 1A for ACE inhibitor use in type 1 and type 2 diabetes, and for ARB use in type 2 diabetes; Grade D, Consensus, for ARB use in type 1 diabetes].
  • Combination of agents that block the renin-angiotensin-aldosterone system (ACE inhibitor, ARB, DRI) should not be routinely used in the management of diabetes and CKD [Grade A, Level 1].

TABLE 4

Treating Kidney Disease Safely
  • Adults with diabetes and CKD should be given a “sick day” medication list that outlines which medications should be held during times of acute illness [Grade D, Consensus].
  • Diuretics can exacerbate intravascular volume contraction during periods of intercurrent illness.
  • Blockers of the RAAS interfere with the kidney's response to intravascular volume contraction, namely, the ability of angiotensin II to contract the efferent arteriole to support glomerular filtration during these periods.
  • Nonsteroidal anti-inflammatory drugs cause constriction of the afferent arterioles, which can further reduce blood flow into the glomerulus in patients who are volume contracted.
  • For these reasons, all of these drugs can reduce kidney function during times of intercurrent illness.
  • A number of additional medications need to be dose adjusted in patients with renal dysfunction, so their usage and dosage should be reevaluated during periods where kidney function changes.
The safe use of RAAS blockers (ACE inhibitors, ARBs, and direct renin inhibitors [DRIs])
  • Drugs that block the RAAS reduce intraglomerular pressure, which, in turn, leads to a rise in serum creatinine of up to 30%, which then stabilizes. Although these drugs can be used safely in patients with renovascular disease, these patients may have an even larger rise in serum creatinine when these drugs are used.
  • In the case of severe renovascular disease that is bilateral (or unilateral in a person with a single functioning kidney), RAAS blockade can precipitate renal failure or hyperkalemia.
  • People with diabetes on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked at baseline and within 1 to 2 weeks of initiation or titration of therapy and during times of acute illness [Grade D, Consensus].
  • If hyperkalemia is severe, RAAS blockade would need to be held or discontinued.
  • Mild-to-moderate hyperkalemia can be managed through dietary counseling.
  • As the use of RAAS blockers during pregnancy has been associated with congenital malformations, women with diabetes of childbearing age should avoid pregnancy if drugs from these classes are required.
  • If a woman with diabetes receiving such medications wishes to become pregnant, consideration should be given to their discontinuation prior to conception.
Medication selection and dosing in CKD
  • For patients with low kidney function, many of their medications need dose adjustments. Furthermore, some medications are contraindicated for patients with significant disease.
Referral to a specialized renal clinic
  • People with diabetes should be referred to a nephrologist or internist with an expertise in CKD in the following situations:
    • Chronic, progressive loss of kidney function
    • ACR persistently >60 mg/mmol
    • eGFR<30 mL/min
    • Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or >30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB
    • Unable to achieve target BP (could be referred to any specialist in hypertension) [Grade D, Consensus].

FIGURE 3

FIGURE 4

For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on this topic, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 29.

For information regarding therapeutic considerations for renal impairment, see Appendix 6. For a list of “sick day” medications, see Appendix 7.