Diabetes and End-Stage Kidney Disease: Insights and Challenges
Diabetic nephropathy is the leading cause of end-stage kidney disease (ESKD) worldwide.1 ESKD is defined as a glomerular filtration rate (GFR) of <15 mL/min/1.73m2 accompanied by signs and symptoms of uraemia or a need for initiation of kidney replacement therapy (dialysis or transplantation).2 Over the past 10 years the prevalence of type 2 diabetes (T2D) has significantly increased amongst people with ESKD on long-term dialysis, primarily due to improved survival and access to dialysis.3 Importantly, the co-existence of diabetes and ESKD is associated with a higher risk of cardiovascular disease-related and all-cause mortality, compared to either condition alone.4
Progressive loss of kidney function and the resultant uraemic milieu have profound effects on glucose homeostasis, the use of insulin and non-insulin glucose-lowering medications (GLMs) and the accuracy of glycaemic management indicators such as glycosylated haemoglobin (HbA1c). These pose several challenges in the management of people with diabetes and ESKD as discussed further in this article.
Alterations in Glucose Homeostasis with ESKD
People with ESKD, regardless of diabetes status, have a propensity to develop hypoglycaemia5 and this is associated with an increased risk of vascular events and mortality.6 Multiple reasons exist to explain this phenomenon (Figure 1).
Firstly, the kidney contributes approximately 20% of total gluconeogenesis (the rest occurring in the liver) under physiological conditions and is crucial in the counterregulatory response to hypoglycaemia.7 Secondly, circulating insulin, particularly exogenous analogues which do not undergo hepatic first-pass metabolism, are cleared and degraded by the kidney.8 As kidney function declines, the half-life of insulin and renally-excreted non-insulin GLMs are prolonged.9 Thirdly, 20 – 50% of people on long-term dialysis experience protein-energy malnutrition (PEM) due to loss of appetite and poor food intake, systemic inflammation and nutrient loss during dialysis; the resultant depletion of protein and glycogen stores reduces substrate availability for gluconeogenesis and glycogenolysis.10 Finally, haemodialysis (HD) can lower blood glucose through glucose loss into dialysate and improved insulin sensitivity.11
Interferences with Measures of Glycaemic Management
HbA1c testing is the standard of care for long-term monitoring of glycaemic management. This biomarker is produced when glucose attaches to haemoglobin within new erythrocytes proportional
to the ambient blood glucose concentration (glycosylation) and reflects the mean blood glucose concentration over the 120-day lifespan of the erythrocyte.12 Therefore, factors that interfere with glycosylation or the erythrocytes lifespan can affect the accuracy of HbA1c testing.
People with ESKD often have anaemia from multifactorial causes including iron deficiency, poor nutrition, diminished erythropoiesis from chronic disease and loss of renal erythropoietin, microscopic bleeding and shortened erythrocyte lifespan in uraemia.13 Once dialysis is commenced, most people will receive therapies targeting these pathophysiological changes including erythropoietin analogues, iron supplementation and infrequently, blood transfusions; these have all been shown to falsely lower HbA1c levels.13,14 Conversely, ESKD-specific factors that falsely elevate HbA1c include the production of carbamylated haemoglobin in the setting high levels of urea and metabolic acidosis.15 With the advent of newer assays, these appear to be less significant.16
Considering these biases, it is apparent that HbA1c in ESKD is often artefactually lower than the true value and significantly underestimates hyperglycaemia.16 Nevertheless, in the absence of reliable alternative biomarkers, the Kidney Disease Improving Global Outcome (KDIGO) guidelines still recommend use of HbA1c to monitor glycaemic management in people with ESKD.17
Continuous Glucose Monitoring
Continuous glucose monitoring (CGM) systems which measure interstitial glucose are now increasingly used for glycaemic monitoring in people with type I diabetes (T1D) and insulin-requiring T2D. These systems can provide either real-time (rt) monitoring (Dexcom or Medtronic) or intermittent (flash glucose) monitoring (i.e. Freestyle Libre), with data displayed on either an insulin pump, Smartphone app or a glucose reader.
In addition to real-time glucose readings, CGM can provide valuable information about glycaemic patterns not reflected by traditional HbA1c measurements or finger-prick capillary blood glucose monitoring, such as the magnitude, timing and frequency of glycaemic excursions. Importantly, wide fluctuations in blood glucose levels, also known as glycaemic variability, may be associated with micro- and macrovascular complications as well as mortality.18 Studies in people with diabetes but without ESKD have shown that CGM can improve glycaemic management19 as well as treatment satisfaction20 and quality of life.21 It may also may help to reinforce the effects of lifestyle modifications, such as exercise and low-carbohydrate diet.22
In people with diabetes and ESKD, CGM represents an emerging solution to both short- and long-term glycaemic monitoring given the limitations of HbA1c and heightened risk of hypoglycaemia, especially around the time of dialysis.23 People with ESKD have high rates of recurrent asymptomatic hypoglycaemia24 which can self-perpetuate by further impairing both hypoglycaemic awareness and the counterregulatory response.25 Promisingly, small studies using CGM in people with diabetes and ESKD have shown better glycaemic management and improved detection of hypoglycaemia. This is attributed at least in part to CGM alarms which can notify the user or caregiver of low blood glucose levels enabling appropriate treatment changes.24,26,27 However, the accuracy of these systems in the presence of fluid shifts during dialysis, uraemia and acidosis, is yet to be defined and trials are currently underway.28,29
Effects on Morbidity and Mortality
Both diabetes and ESKD are recognised cardiovascular risk factors.30 A large retrospective analysis of data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry has shown that cardiovascular disease-related and all-cause mortality are higher among people with diabetes and ESKD compared to those without. In fact, if diabetic nephropathy was the cause of ESKD, the risk of cardiovascular disease-related mortality was 25% higher.4
ESKD also appears to increase the risk of lower limb complications including foot ulceration and lower extremity amputation, even in the absence of clinically apparent peripheral vascular disease.31 For example, one study showed a fivefold increase in the prevalence of foot ulceration in people treated with dialysis.32 Prolonged pressure on insensate heels or toes from dialysis chairs, changes in skin microcirculation during dialysis, lack of regular foot inspection, poor attendance at podiatry appointments and behaviours such as walking barefoot may explain this observation.32,33
The use of glucose-containing dialysate is a key issue in people with diabetes and ESKD undergoing peritoneal dialysis (PD). The glucose in these solutions, which acts as an osmotic agent to remove excess fluid, is readily absorbed from the peritoneal cavity and can lead to multiple adverse metabolic effects including hyperglycaemia, hyperinsulinaemia, dyslipidaemia, appetite suppression and weight gain.34 A retrospective study of 716 people on PD also found that higher dialysate glucose concentrations were associated with higher cardiovascular and all-cause mortality.35 Icodextrin, a glucose-polymer and alternative osmotic agent, is currently recommended for people with diabetes as its slow absorption and metabolism liberates little to no free glucose. Studies have demonstrated that icodextrin improves glycaemic management and other metabolic parameters in this cohort.36 However icodextrin requires long dwell times and glucose based dialysates in variable concentrations are still the mainstay in rapid exchanges. Hence mixed, intermittent or bolus doses of insulin are often required to counter the glycaemic load during rapid exchanges and small basal doses are adequate for the long dwells if icodextrin is used.
In appropriate candidates, kidney transplantation (KT) is the preferred treatment for ESKD. Unfortunately, KT recipients with T2DM have poorer survival with the risk of death increased twofold, largely attributed to cardiovascular disease or infection.37 In a study of 2872 KT recipients with diabetes, suboptimal glycaemic management pre-transplant, defined by a time-averaged HbA1c >8%, was associated with higher mortality after transplant.38 In addition, people with pre-existing diabetes are more likely to have suboptimal glycaemic management and higher glycaemic variability in the post-transplant period.39
Dysglycaemia following KT is common, especially in the first 3 – 6 months, even in those without pre-existing diabetes.40 A significant proportion of people will go on to develop new-onset diabetes after transplantation (NODAT) influenced by risk factors such as older age, obesity, family history of diabetes and use of glucocorticoids and calcineurin inhibitors.41 People with NODAT experience an accelerated rate of diabetes complications and poorer post-transplant outcomes including major cardiovascular events, graft failure, infection and death.42-44
People with ESKD are a heterogenous population, however, a substantial proportion are older adults and have established micro- and macrovascular complications. Therefore, intensive glycaemic management (i.e. HbA1c <7%) is generally inappropriate and has been shown to double the risk of major hypoglycaemic events.45 Apart from the Joint British Diabetes Societies for Inpatient Care (JBDS-IP), which recommend a HbA1c target range of 7.5 – 8.5% for people on HD, most international guidelines do not specify a HbA1c target range.46 Rather, they encourage personalising HbA1c based on age, severity of chronic kidney disease (CKD), presence of diabetes-related complications, life expectancy and risk of hypoglycaemia (Figure 2).47 Importantly, studies in people on HD have demonstrated a U-shaped association between HbA1c and mortality, whereby mortality increased as HbA1c moved further away from 7 – 7.9%.48
Insulin has traditionally been the primary glucose-lowering agent used to manage hyperglycaemia in people with diabetes and ESKD. In general, the total daily dose of insulin often requires adjustment with the commencement of long-term dialysis and certain expert authors recommend a 25 – 50% reduction from previous amounts.49 Day-to-day requirements also require consideration due to the glucose-lowering effects of HD. Indeed, using euglycaemic clamp technique, Sobngwi et al. demonstrated a 25% reduction in basal insulin requirements on the day after HD.23 In addition, a small study of 17 people using CGM showed that mean glucose levels were lower on dialysis days compared to non-dialysis days, independent of energy intake.50 Therefore, it may be reasonable to reduce the basal insulin dose on the day of dialysis.
People with diabetes and ESKD may also experience episodes of hyperglycaemia several hours after treatment has completed, particularly if glycaemic control is suboptimal immediately prior starting HD. Large intradialytic falls in blood glucose levels should be avoided as this can stimulate a counterregulatory response which, alongside loss of insulin during dialysis, can promote hyperglycaemia especially in individuals with exhausted pancreatic b-cell reserves.51
The use of non-insulin GLMs in ESKD has typically been limited by the potential for adverse effects and lack of large-scale clinical trial data. Metformin and certain sulfonylureas (i.e. glibenclamide) are contraindicated due to the risk of lactic acidosis and prolonged hypoglycaemia, respectively.52 If used, short-acting gliclazide and glipizide are the preferred options and should be started at a low dose with careful titration.53 The newer incretin-based therapies, such as some dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, are now emerging as potential future therapeutic options in ESKD based on preliminary pharmacokinetic studies. DPP-4 inhibitors are typically well tolerated, reduce post-prandial glucose excursions and do not increase the risk of hypoglycaemia when used as monotherapy.54 With the exception of linagliptin, which requires no dose reduction in severe renal impairment, the DPP-4 inhibitors currently vary in their suitability for use in people with diabetes and ESKD.52 Clinicians should therefore be guided by the product information when prescribing these medications. GLP-1 agonists are not currently recommended due to a lack of clinical trial experience, however small pharmacokinetic studies with liraglutide and semaglutide have demonstrated both tolerability and safety in people with ESKD.55,56 Exenatide is contraindicated with a creatinine clearance < 30 ml/min due to significant accumulation and increased rates of nausea and vomiting.57 Sodium-glucose cotransporter 2 (SGLT-2) inhibitors depend on urinary glucose excretion and have negligible glucose-lowering properties in ESKD.58
Providing satisfactory nutrition is a complex issue in people with co-existent diabetes and ESKD as multiple dietary restrictions are often imposed. In general, people with ESKD should consume a diet rich in fruit, vegetables, wholegrains, fibre, unsaturated fat and plant-based protein. Processed meats, refined carbohydrates and sweetened beverages should be avoided, and salt intake should also be reduced to help regulate blood pressure and volume control.17,59 Importantly, people with ESKD are at risk of hyperkalaemia and hyperphosphataemia due to the retention of potassium and phosphate, respectively. Hyperkalaemia is associated with an increased risk of life-threatening ventricular arrhythmias and persistent hyperphosphataemia can lead to disorders of bone mineralisation and vascular calcification.59,60 Therefore, dietary intake of these electrolytes should be monitored in consultation with an accredited practicing dietitian (APD). To prevent PEM and hypoglycaemia, protein and carbohydrate consumption may need to be liberalised to ensure adequate energy intake.61,62 Fluid intake should generally be restricted to 1 – 2L per day but needs to be individualised based on residual kidney function, interdialytic weight gain and signs and symptoms of fluid overload (i.e. hypertension).63,64
People with diabetes and ESKD are often physically inactive and have reduced levels of fitness compared to the general population.65 Some may spend up to two-thirds of their day being sedentary and unsurprisingly, this is associated with increased risk of mortality, development of disability and loss of independence.66-68 All people with ESKD should be encouraged to increase their physical activity and guidelines recommend moderate-intensity exercise (i.e. brisk walking) for at least 150 minutes per week.69 However, it is important that clinicians firstly evaluate baseline fitness and identify potential limitations, such as musculoskeletal or significant cardiovascular disease, prior to prescribing physical activity. If present, these individuals should be referred to a physiotherapist and/or exercise physiologist, to help supervise as well as guide the amount and type of physical activity.68,69
Lastly, people with ESKD have substantially higher rates of major depression compared to the general population.70 Studies have shown that depression in people with ESKD can result in functional impairment, reduced quality of life, higher all-cause mortality and more frequent and longer stays in hospital.70 Recognition and appropriate management of depression is crucial in optimising self-management in patients with diabetes and ESKD. In a large study of 4 463 people with T2D, depression was associated with reduced levels of physical activity, unhealthy eating, smoking and poor adherence to non-insulin GLMs and other important medications (i.e. antihypertensives).71
ESKD provides several challenges for the management of diabetes and these people require the support of a multidisciplinary team. Particular care should be taken to avoid hypoglycaemia through ensuring adequate nutrition, avoiding intensive glycaemic management and reviewing therapeutic goals and interventions periodically.
- People with ESKD and diabetes are at risk of hypoglycaemia, increased cardiovascular-related and all-cause mortality and higher prevalence of lower limb complications.
- HbA1c is recommended but is less reliable in ESKD and may underestimate the degree of hyperglycaemia; CGM represents a promising solution and trials are currently underway to better define their accuracy in ESKD.
- Total daily dose of insulin should be adjusted once people with ESKD are started on dialysis and basal insulin requirements are typically lower in the period following HD.
- Incretin-based therapies, especially DPP-4 inhibitors, are increasingly used due to their tolerability and favourable pharmacokinetic profile in ESKD.
- Multidisciplinary team input is essential with attention to glucose variability, insulin dose adjustment, nutrition and cardiovascular risk management.