Chronic kidney disease in diabetes

Contents lists available at Canadian Journal of Diabetes Clinical Practice Guidelines Chronic Kidney Disease in Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Philip McFarlane MD, FRCPC,Richard E. Gilbert MBBS, PhD, FACP, FRACP, FRCPC, Lori MacCallum BScPhm, PharmD,Peter Senior MBBS, PhD, MRCP length and quality of life A variety of forms of kidney disease can be seen in people with diabetes, including diabetic nephrop-athy, ischemic damage related to vascular disease and hyperten-  Identification of chronic kidney disease (CKD) in diabetes requires screening for proteinuria, as well as an assessment of renal function.
sion, as well as other renal diseases that are unrelated to diabetes  All individuals with CKD should be considered at high risk for cardiovas- (In this chapter, we will discuss how to screen for cular events and should be treated to reduce these risks.
and diagnose chronic kidney disease (CKD) in people with diabetes,  The progression of renal damage in diabetes can be slowed through how to treat them with an aim to slow progression of CKD and intensive glycemic control and optimization of blood pressure. Progression discuss the impact of CKD on other aspects of diabetes of diabetic nephropathy can be slowed through the use of medications thatdisrupt the renin-angiotensin-aldosterone system.
Diabetic Nephropathy The classic description of diabetic nephropathy is of a progres- Management of Potassium and Creatinine During the Use sive increase in proteinuria in people with longstanding diabetes of Angiotensin-Converting Enzyme (ACE) Inhibitor or followed by declining function that eventually can lead to end stage Angiotensin II Receptor Blocker (ARB) or Direct Renin renal disease (ESRD) ) . Key risk factors for diabetic nephropathy include long duration of diabetes, poor glycemiccontrol, hypertension, male gender, obesity and cigarette smoking.
 Check serum potassium and creatinine at baseline and within 1 to 2 Many of these factors are modifiable.
weeks of initiation or titration of therapy AND during times of acute illness.
The earliest stage of diabetic nephropathy is hyperfiltration,  If potassium becomes elevated or creatinine increases by more than 30% where the glomerular filtration rate (GFR) is significantly higher from baseline, therapy should be reviewed and serum creatinine andpotassium levels should be rechecked.
than normal. Identification of hyperfiltration is not clinically useful,  Mild-to-moderate stable hyperkalemia: as it is difficult to determine from routine testing. Persistent Counsel on a low-potassium diet.
albuminuria is considered the earliest clinical sign of diabetic If persistent, nonepotassium-sparing diuretics and/or oral sodium nephropathy Initially, small amounts of albumin are bicarbonate (in those with a metabolic acidosis) should beconsidered.
leaked, below the detection threshold of a urine dipstick. This stage Consider temporarily holding renin-angiotensin-aldosterone system is referred to as "microalbuminuria." This can worsen so that the (RAAS) blockade (i.e. ACE inhibitor, ARB or DRI).
urinary albumin excretion is sufficiently high to be detectable by  Severe hyperkalemia: a urine dipstick, a stage known as "overt nephropathy." The rate of In addition to emergency management strategies, RAAS blockade progression from normoalbuminuria to microalbuminuria then to should be held or discontinued.
overt nephropathy usually is slow, typically taking 5 years or longerto progress through each stage . During the early stages ofdiabetic nephropathy, the rate of loss of renal function is relativelyslow (1 to 2 mL/min/1.73 m2 per year) and not impressively higherthan what is seen in the general population (0.5 to 1 mL/min/ 1.73 m2 per year). However, late in the overt nephropathy phase,the rate of decline of renal function can accelerate (5 to 10 mL/min/ Diseases of the kidney are a common finding in people with 1.73 m2 per year). Thus, significant renal dysfunction is not usually diabetes, with up to half demonstrating signs of kidney damage in seen until late in the course of diabetic nephropathy .
their lifetime eDiabetes is the leading cause of kidney disease It is important to note that the rate of progression can vary in Canada . Kidney disease can be a particularly devastating between individuals, and that the clinical markers of the disease complication, as it is associated with significant reductions in both (i.e. estimated glomerular filtration rate [eGFR], urinary albumin 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Screening for Kidney Disease in People with Diabetes Screening for kidney disease in people with diabetes involves an assessment of urinary albumin excretion and a measurement ofthe overall level of kidney function through an estimation of theGFR. Persistent abnormalities of either urinary albumin excretionor GFR, or significant urinalysis abnormalities, lead to the diag-nosis of kidney disease in people with diabetes. People with type 1diabetes are not expected to have kidney disease at the time ofonset of diabetes, so screening can be delayed until the duration ofdiabetes exceeds 5 years. As the delay between onset and diag-nosis of type 2 diabetes can be many years and as nondiabetickidney disease is common, significant renal disease can be presentat the time of diagnosis of type 2 diabetes , so screeningshould be initiated immediately at the time of diagnosis in thisgroup.
Screening for Albuminuria When screening for albuminuria, the test of choice is the random urine albumin-to-creatinine ratio (urinary ACR). The24-hour urine collection for protein/albumin remains the goldstandard; however, it is cumbersome to implement on a large scale Figure 1. Causes of chronic kidney disease (CKD) in people with and without diabetes.
and is often performed incorrectly The random urine foralbumin is insufficient, as the urinary albumin concentration can levels) do not always correlate well with the severity of renal vary due to urine concentration A random urine ACR predicts disease seen on biopsy . Additionally, aggressive control of 24-hour urinary albumin excretion sufficiently well and is the test blood pressure (BP) and glycemia, and the use of renal protective of choice for screening for albuminuria drugs can slow or stop progression of diabetic nephropathy.
There is substantial day-to-day variability in albuminuria. In addition, transient increases in albuminuria can be provoked bya number of factors () When such conditions arepresent, screening for kidney disease should be delayed to avoid Other Kidney Diseases in People with Diabetes false positives. Furthermore, diagnosing a person as havingalbuminuria requires the elevated urinary albumin level to be People with diabetes (particularly type 2 diabetes) often persistent. At least 2 of 3 urine samples over time exhibiting develop kidney diseases other than diabetic nephropathy. Kidney elevations in urinary albumin levels are required before it is biopsy series in type 2 diabetes have found that nondiabetic considered to be abnormal.
nephropathy, is as common as diabetic nephropathy in people with Estimation of GFR diabetes In addition, there can be significant overlap While these biopsy series are biased (biopsies are usually done in The serum creatinine is the most common measurement of people with diabetes when nondiabetic renal disease is suspected), kidney function; however, it can inaccurately reflect renal function other studies have suggested that half of everyone with diabetes in many scenarios, particularly in extremes of patient age or size and significant kidney function impairment do not have albumin- . Indeed, in people with diabetes, the GFR usually will be less uria . These studies suggest that testing for albuminuria may be than half of normal before the serum creatinine exceeds the lab insufficient in identifying all patients with diabetes who have renal normal range .
disease. In addition to measurements of urinary albumin excretion, As mentioned, the 24-hour urine collection can be difficult to estimations of the level of kidney function and urinalyses are perform accurately. For this reason, a variety of methods have been required to identify patients with kidney disease other than dia- developed to better estimate the level of glomerular filtration by betic nephropathy. In most cases, the risk of ESRD in diabetes does combining the patient's serum creatinine with factors such as age, not appear to matter whether the renal diagnosis is one of diabetic weight, and gender. The most common method of estimating renal nephropathy or an alternative diagnosis as management is the function in Canada currently is the eGFR, using the 4-variable same . However, lists some concerning clinical and MDRD ("Modification of Diet in Renal Disease") equation laboratory features that would lead to suspicion of a kidney disease This equation requires knowledge of the patient's age, sex, serum unrelated to diabetes, requiring such a person to undergo addi- creatinine and race and is automatically computed and reported by tional testing or referral many labs whenever a serum creatinine is ordered. The MDRDeGFR performs well when the GFR is <60 mL/min and despiteits flaws is generally a better estimate of glomerular filtration thanthe serum creatinine value. Kidney diseases of all forms can bestaged based on the degree of impairment of eGFR ().
The eGFR is useful for assessing chronic changes in renal func- tion but should not be used in situations where kidney function ischanging rapidly. Dehydration and other conditions that lead tointravascular volume contraction can lead to a transient decline inrenal function. When such conditions are present, assessment of Figure 2. Level of urinary albumin by various test methods and stage of diabeticnephropathy. ACR, albumin-to-creatinine ratio.
the level of kidney function may be clinically necessary but should

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Table 1Stages of diabetic nephropathy by level of urinary albumin level not be used to assess the stage of CKD. Because renal function can suspected of having acute kidney injury or nondiabetic renal be transiently depressed, a persistent reduction in eGFR is required disease. Screening should be delayed in the presence of conditions before it is considered to be abnormal.
that can cause transient albuminuria or a transient fall ineGFR.
Other Clinical Features and Urinary Abnormalities: When to Screening for CKD in people with diabetes should be performed Consider Additional Testing or Referral with a random urine ACR and a serum creatinine that is thenconverted into an eGFR (This can be delayed 5 years from Urinalysis findings of red blood cell casts are not a common the onset of type 1 diabetes but should begin immediately at the finding in renal disease due to diabetes, and white blood cell casts time of diagnosis of type 2 diabetes. An abnormal screening test or heme-granular casts are not compatible with a diagnosis of should be confirmed by repeat testing of the eGFR within 3 months, kidney disease due to diabetes. Although persistent microscopic and 2 more random urine ACRs ordered during that interval. If hematuria can occur in about 20% of people with diabetic either the eGFR remains low or at least 2 of the 3 random urine nephropathy, its presence should lead to the consideration of other ACRs are abnormal, then a diagnosis of CKD is confirmed. The urological or nephrological conditions. lists other clinical exception to this approach is when the random urine ACR indicates clues that may point to a renal diagnosis other than kidney disease albuminuria in the overt nephropathy range, as this level of due to diabetes. Such patients should undergo an appropriate proteinuria rarely resolves spontaneously, so confirmatory testing assessment for the cause of their disease. A rapid decline in eGFR or is usually unnecessary.
development of severe hypertension would suggest prompt referral Once a diagnosis of CKD has been made, a urine sample for to a specialist.
dipstick and microscopy should be ordered. In the absence of any Although 24-hour collections are not needed for routine significant abnormalities other than proteinuria, then a presump- screening in diabetes, they can be useful when there is doubt about tive diagnosis of kidney disease due to diabetes is made. The the accuracy of an eGFR, when screening for nonalbumin urinary presence of clinical or laboratory abnormalities suggesting nondi- proteins (e.g. multiple myeloma) or when estimating daily sodium abetic kidney disease indicates the need for appropriate workup or intake in an individual with refractory edema or hypertension.
Individuals should be counseled to discard the first morning urineon the day of collection and then collect all subsequent urine Prevention, Treatment and Follow Up for a 24-hour period, including the first morning urine of the nextday.
Optimal glycemic control established as soon as possible after diagnosis will reduce the risk of development of diabetic nephropathy Optimal BP control also appears to beimportant in the prevention of diabetic nephropathy, although People with diabetes should undergo annual screening for the the results have been less consistent Blockade of the presence of kidney disease when they are clinically stable and not renin-angiotensin-aldosterone system (RAAS) with either an Table 2Factors favouring the diagnosis of classical diabetic nephropathy or alternative renal diagnoses

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 In CKD from causes other than diabetic nephropathy, ACE inhi- Conditions that can cause transient albuminuria bition has been shown to reduce proteinuria, slow progressive lossof glomerular filtration rate and delay the need for dialysis The issue of whether ARBs and ACE inhibitors are similarly effectivein CKD that is not caused by diabetic nephropathy remains contro-versial A variety of strategies to more aggressively block the RAAS have been studied in kidney disease, including combining RAASblockers or using very high doses of a single RAAS blocker. Thesestrategies reduce proteinuria but have not been proven toimprove patient outcomes in diabetic nephropathy eandcome at a risk of increased acute renal failure, typically whena Aggressive RAAS blockade strategies should be restricted tospecialized clinics.
Treating Kidney Disease Safely angiotensin-converting enzyme (ACE) inhibitor or an angiotensinII receptor blocker (ARB) can reduce the risk of diabetic The "sick day" medication list (see Appendix 7) nephropathy independent of their effect on BP. This protectiveeffect has been demonstrated in people with diabetes and Several classes of medications used commonly in people with hypertension but not in normotensive people with diabetes diabetes can reduce kidney function during periods of intercurrent illness and should be discontinued when patients are unwell, in All people with CKD are at risk for cardiovascular (CV) events particular when they develop significant intravascular volume and should be treated to reduce these risks (see Vascular Protection contraction due to reduced oral intake or excessive losses due to chapter, p. S100) e. The degree of risk of CV events or vomiting or diarrhea. Diuretics can exacerbate intravascular progression to ESRD increases as albuminuria levels rise, and as volume contraction during periods of intercurrent illness. Blockers eGFR falls, with the combination of albuminuria and low eGFR of the RAAS interfere with the kidney's response to intravascular predicting a very high level of risk () volume contraction, namely, the ability of angiotensin II to contract The progression of renal damage in diabetes can be slowed the efferent arteriole to support glomerular filtration during these through intensive glycemic control and optimization of BP periods. Nonsteroidal anti-inflammatory drugs cause constriction Progression of diabetic nephropathy can be slowed through of the afferent arterioles, which can further reduce blood flow into the use of an ACE inhibitor or ARB , independent of their effect the glomerulus in patients who are volume contracted. For these on BP, and these 2 medication classes appear to be equally effective reasons, all of these drugs can reduce kidney function during times for cardiorenal protection . In type 1 diabetes, ACE inhibitors of intercurrent illness. Consideration should be given to providing have been shown to decrease albuminuria and prevent worsening patients with a "sick day" medication list, instructing the patient to of nephropathy , and ARBs have been shown to reduce hold these medications if they feel that they are becoming dehy- proteinuria . In type 2 diabetes, ACE inhibitors and ARBs have drated for any reason. A number of additional medications need to been shown to decrease albuminuria and prevent worsening of be dose adjusted in patients with renal dysfunction, so their usage nephropathy, and ARBs have been shown to delay the time to and dosage should be reevaluated during periods where kidney dialysis in those with renal dysfunction at baseline . In type function changes.
2 diabetes, ACE inhibitors have also been shown to reduce thechance of developing new nephropathy . These renal-protective effects also appear to be present in proteinuric indivi- The safe use of RAAS blockers (ACE inhibitors, ARBs, and direct renin duals with diabetes and normal or near-normal BP. ACE inhibitors inhibitors [DRIs]) have been shown to reduce progression of diabetic nephropathy inalbuminuric normotensive individuals with both type 1 Drugs that block the RAAS reduce intraglomerular pressure, and type 2 diabetes .
which, in turn, leads to a rise in serum creatinine of up to 30%, whichthen stabilizes Although these drugs can be used safely inpatients with renovascular disease, these patients may have an even larger rise in serum creatinine when these drugs are used e. In Stages of chronic kidney disease the case of severe renovascular disease that is bilateral (or unilateralin a person with a single functioning kidney), RAAS blockade canprecipitate renal failure. In addition, RAAS blockade can lead tohyperkalemia. For these reasons, the serum creatinine and potas-sium should be checked between 1 and 2 weeks after initiation ortitration of a RAAS blocker In patients in whom a significantchange in creatinine or potassium is seen, further testing should beperformed to ensure that these results have stabilized.
Mild-to-moderate hyperkalemia can be managed through die- tary counselling, Diuretics, in particular furosemide, can increaseurinary potassium excretion. Sodium bicarbonate (500 to 1300 mgorally twice a day) can also increase urinary potassium excretion,especially amongst individuals with a metabolic acidosis asdemonstrated by a low serum bicarbonate level. If hyperkalemia issevere, RAAS blockade would need to be held or discontinued P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Figure 3. Screening for chronic kidney disease (CKD) in people with diabetes. ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate.
P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 medications wishes to become pregnant, consideration should begiven to their discontinuation prior to conception.
Medication selection and dosing in CKD Many medications need to have their dose adjusted in the presence of low kidney function, and some are contraindicated inpeople with significant disease. Appendix 6 lists some medicationscommonly used in people with diabetes and how they should beused if kidney dysfunction is present.
Referral to a specialized renal clinic Figure 4. Relative risk of chronic kidney disease (CKD). Shading shows how adjusted Most people with CKD and diabetes will not require referral to relative risk is ranked for 5 outcomes from a meta-analysis of general population a specialist in renal disease. However, specialist care may be cohorts: all-cause mortality, cardiovascular mortality, kidney failure treated by dialysis necessary when renal dysfunction is severe, when there are dif and transplantation, acute kidney injury, and progression of kidney disease. GFR, glomerular filtration rate.
culties implementing renal-protective strategies or when there areproblems managing the sequelae of renal disease .
As the use of RAAS blockers during pregnancy has been asso- ciated with congenital malformations, women with diabetes of Other Relevant Guidelines childbearing age should avoid pregnancy if drugs from theseclasses are required If a woman with diabetes receiving such Targets for Glycemic Control, p. S31Monitoring Glycemic Control, p. S35Pharmacotherapy in Type 1 Diabetes, p. S56 Pharmacologic Management of Type 2 Diabetes, p. S61Type 1 Diabetes in Children and Adolescents, p. S153 1. In adults, screening for CKD in diabetes should be conducted using a random urine ACR and a serum creatinine converted into an eGFR [Grade Type 2 Diabetes in Children and Adolescents, p. S163 D, Consensus]. Screening should commence at diagnosis of diabetes in Diabetes and Pregnancy, p. S168 individuals with type 2 diabetes and 5 years after diagnosis in adults with Diabetes in the Elderly, p. S184 type 1 diabetes and repeated yearly thereafter. A diagnosis of CKD shouldbe made in patients with a random urine ACR 2.0 mg/mmol and/or aneGFR<60 mL/min on at least 2 of 3 samples over a 3-month period [Grade Relevant Appendices D, Consensus].
Appendix 6: Therapeutic Considerations for Renal Impairment 2. All patients with diabetes and CKD should receive a comprehensive, Appendix 7: Sick Day Medication List multifaceted approach to reduce cardiovascular risk (see VascularProtection, p. S100) [Grade A, Level 1A ].
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A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo

International Journal of Cancer A mixture of amino acids and other small molecules presentin the serum suppresses the growth of murine and humantumors in vivo ´ kos Schulcz2 and Tamas Cz€omp€oly1 1 Immunal Ltd., Cancer Research and Product Development Laboratory, H-7630 Pecs, Finn u. 1/1., Hungary2 Department of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, Rath Gy€orgy u. 7-9., Hungary

Performance comparison of benchtop high-throughput sequencing platforms Nicholas J Loman1, Raju V Misra2, Timothy J Dallman2, Chrystala Constantinidou1, Saheer E Gharbia2, John Wain2,3 & Mark J Pallen1 Three benchtop high-throughput sequencing instruments are The 454 GS Junior from Roche was released in early 2010 and is now available. The 454 GS Junior (Roche), MiSeq (Illumina)