Adults with diabetes on dialysis

Introduction

Kidney failure is among the most serious outcomes of diabetes mellitus. Diabetes is the leading cause of kidney failure, both worldwide and in the UK^​1,2​. In 2022, nearly 520,000 people in the UK were living with chronic kidney disease (CKD) as a complication of diabetes^​1​. Of the 8,556 adults who began renal replacement therapy (RRT) during 2023, diabetic kidney disease (DKD) — kidney damage caused by diabetes — was the recorded cause in 30.6% of cases, ranking above every other identifiable cause^​2​. 

People living with diabetes and are on dialysis have higher morbidity and mortality than those without. All-cause mortality is 40% higher, while cardiovascular mortality is 63% higher than in people on dialysis without diabetes^​3​. A study involving individuals with type 1 diabetes receiving RRT demonstrated improved survival over recent decades; however, it remains substantially below that of the general population^​4​.

Complications of diabetes also present differently in people on dialysis. Autonomic neuropathy can mask the typical symptoms of myocardial ischaemia, delaying recognition of coronary events^​5​. Diabetes is an independent risk factor for stroke in people receiving haemodialysis^​6​. Infection is a leading cause of death, with septicaemia occurring more frequently and carrying higher mortality in people with diabetes on haemodialysis than in those without^​7​. The Joint British Diabetes Societies (JBDS) classify all people with diabetes on dialysis as being at high risk of foot ulceration and amputation^​8​.

Managing diabetes in people on dialysis requires a multidisciplinary approach^​5,8​. Glucose homeostasis is substantially altered in this setting. Reduced kidney function, the uraemic environment and the dialysis procedure itself all contribute to the alteration of glucose homeostasis, producing both hyperglycaemia and hypoglycaemia^​5​. Routine glycaemic monitoring is less reliable in end-stage kidney disease (ESKD) because of associated laboratory abnormalities and comorbidities^​8​.

Glycaemic targets, therefore, must be set individually, balancing reduction of long-term complications against the risk of hypoglycaemia^​3,8​. Pharmacists in primary and secondary care are well placed to contribute to this multidisciplinary care through medication review, deprescribing of unsafe agents and insulin dose adjustment.

Diabetic kidney disease

DKD is progressive glomerular and tubulointerstitial injury caused by diabetes. It is identified by persistently raised albuminuria, reduced estimated glomerular filtration rate (eGFR), or both, with no alternative cause^​9,10​. Over time, this injury destroys nephrons, the functional filtering units of the kidney, and their loss drives the decline in kidney function^​9,10​.

Figure 1: Mechanism of glomerular hyperfiltration in diabetes

Hyperglycaemia also drives non-enzymatic glycation of structural proteins. The resulting advanced glycation end products cross-link collagen and thicken the glomerular basement membrane^​9,10​. Inflammatory and fibrotic injury follows. Oxidative stress and pro-inflammatory mediators promote mesangial matrix expansion and podocyte depletion, producing albuminuria. Glomerulosclerosis and tubulointerstitial fibrosis are the result. These changes are irreversible and each scarred glomerulus represents a nephron lost^​9,10​.

On testing, DKD typically follows a recognisable sequence. Hyperfiltration occurs first, followed by albuminuria and then a declining eGFR^​9,11​. Two measurements are used to detect DKD and to monitor its progression. The eGFR is calculated from serum creatinine and estimates the volume filtered by the glomeruli each minute, reflecting filtration capacity. The urine albumin-to-creatinine ratio (ACR) measures the albumin leaking into the urine, reflecting damage to the glomerular filtration barrier^​9,11​.

Progression can be slowed by targeting each underlying cause with medication (see Table 1^​9–12​).

Table 1: Medicines that slow the progression of diabetic kidney disease

ACE inhibitors, ARBs and SGLT2 inhibitors all produce a small fall in eGFR on initiation, reflecting the intended reduction in intraglomerular pressure rather than deterioration^​9–11​.

These interventions slow the rate of nephron loss. They do not restore nephrons already lost. The kidney does not generate new nephrons after birth, so once a glomerulus has been replaced by scar tissue, no mechanism exists to rebuild it^​9​.

When nephron loss is sufficient, uraemic solutes and fluid accumulate beyond residual clearance capacity. NICE recommends considering dialysis when uraemic symptoms (e.g. reduced energy, loss of appetite, unexplained weight loss) affect daily living, when biochemical measures indicate it, when fluid overload is uncontrollable, or at an eGFR of about 5 to 7mL/min/1.73m² in the absence of symptoms^​13,14​. Biochemical indications include acid-base or electrolyte abnormalities that do not respond to medical treatment^​14​.

NICE recommends that assessment for RRT begins at least one year before it is likely to be needed^​13​.  This allows time for shared decision-making about the type and timing of treatment, including conservative management, and for psychosocial preparation and planning of dialysis access^​13​. For example, an arteriovenous fistula should be created about six months before haemodialysis is expected to start, to allow it to mature^​13​.

Challenges of managing diabetes on dialysis

Dialysis changes the pharmacology, the physiology and the delivery of diabetes care. The kidney is a principal site of insulin degradation, so reduced renal clearance prolongs the half-life of exogenous insulin^​5,15​. Hepatic insulin clearance also falls in CKD^​5​. Reduced nephron mass diminishes renal gluconeogenesis, removing a source of endogenous glucose production during fasting^​5,15​. By the time a person starts dialysis, their insulin requirement is commonly lower than it was earlier in the course of their kidney disease^​5,15​.

Burnt-out diabetes

In some people these changes go further. Hyperglycaemia resolves spontaneously and HbA1c falls into the range seen in people without diabetes, irrespective of therapy. This is termed burnt-out diabetes^​15,16​. Up to one third of people with diabetes on maintenance dialysis have an HbA1c below 42mmol/mol (6.0%)^​16​. For comparison, NICE recommends an HbA1c target of 48 or 53mmol/mol for most adults with type 2 diabetes^​17​, and a value below 42mmol/mol lies below the range used to identify non-diabetic hyperglycaemia^​18​. These changes may appear to indicate improved glycaemic control. They are instead a cause for concern. Burnt-out diabetes is associated with recurrent hypoglycaemia and mortality is higher at the lowest HbA1c values in this population^​3,16​. Several factors contribute. Renal and hepatic insulin clearance are reduced. Renal gluconeogenesis is lost. Protein-energy wasting and malnutrition reduce substrate availability. Diabetic gastroparesis produces erratic carbohydrate absorption. Accumulated uraemic solutes exert biguanide-like effects, meaning they lower glucose in a manner similar to metformin, which acts mainly by suppressing hepatic glucose production^​15,16​. Burnt-out diabetes does not occur in type 1 diabetes, in which lifelong insulin therapy remains necessary^​8​.

Hypoglycaemia is more frequent and more dangerous in these patients. Counter-regulatory defences are impaired. Reduced renal gluconeogenesis limits the glucose response to falling concentrations^​5,15​. For example: 

• Autonomic neuropathy blunts the adrenergic warning symptoms that normally prompt a person to eat^​5​; 
• Awareness of hypoglycaemia is commonly reduced. Episodes may therefore go unrecognised until neuroglycopenia develops, meaning impaired brain function caused by an inadequate supply of glucose^​5,19​; 
• The first indication may therefore be confusion or loss of consciousness rather than sweating or tremor. People on dialysis treated with insulin have a 32% higher risk of hypoglycaemia than those on non-insulin agents^​3​.

Additional dialysis considerations

To further complicate management, dialysis sessions introduce their own glycaemic swings. With glucose-free dialysate, 20g to 40g of glucose is lost per haemodialysis session, producing a catabolic state comparable to fasting^​19​. Glucose concentrations are consequently lower on dialysis days than non-dialysis days, with the lowest readings usually post-dialysis^​19​. On non-dialysis days, glucose accumulates despite unchanged medication, so concentrations run higher^​19​. Meal timing and insulin administration around the session compound this^​8,19​. It should be noted that peritoneal dialysis increases the risk of hyperglycaemia, as it uses a glucose-based dialysate that is absorbed systemically; therefore, insulin requirements may be increased^​3,8​.

Detecting these swings is difficult, because numerous factors that commonly present in ESKD render HbA1c less reliable (see Table 2^{​3,16,20​}). HbA1c reports mean glycaemia over the lifespan of circulating erythrocytes (about two to three months), which is abnormal in kidney failure^​20​. 

Table 2: Factors distorting HbA1c in ESKD

These factors can act in opposing directions and, in most cases, more than one is present. The net effect in any individual cannot therefore be predicted from the HbA1c result alone^​3,20​.

Another consideration is HbA1c reports a single averaged value. It cannot describe within-day variability (i.e. fluctuation over 24 hours) or between-day variability (i.e. differences from one day to the next)^​8,19​. Both types of variability are characteristic of dialysis.

JBDS therefore advises that HbA1c is used with caution in all people with diabetes on dialysis, as it may not reflect prevailing glucose control and may not identify those at high risk of hypoglycaemia^​8​. Glycated albumin and fructosamine are not recommended as alternative measures, since data on their use in people on dialysis are inadequate^​8​. No HbA1c target has been established for the dialysis population, and KDIGO and other guideline bodies decline to specify one^​3,10​. JBDS instead proposes a glucose target range of 6 to 12mmol/L, with more than 70% of time spent within this range, and notes that an HbA1c above 80mmol/mol (9.5%) is likely to reflect uncontrolled diabetes^​8​. Despite these limitations, HbA1c remains the principal biomarker recommended in guidance for assessing long-term control in people on dialysis^​3,8​.

When interpreting HbA1c in a person on dialysis, pharmacists should consider:

• Whether anaemia, iron replacement, erythropoiesis-stimulating agents, recent blood transfusion or malnutrition may be distorting the result (see Table 2^{​3,16,20​});
• Whether a low or falling value reflects burnt-out diabetes or recurrent hypoglycaemia rather than improved control^​8,16​;
• Whether the result agrees with capillary glucose or CGM data, which measure glucose directly and are unaffected by erythrocyte factors^​3,8​.

Continuous glucose monitoring

Unlike HbA1c, continuous glucose monitoring (CGM) reveals short-term glycaemic change around the time of dialysis, and its results are unaffected by urea concentration, erythrocyte lifespan or erythrocyte production^​3,8​. It measures interstitial glucose directly, so none of the distorting factors above apply. It captures within-day and between-day variability, and distinguishes dialysis-day from non-dialysis-day patterns^​3,8​.

CGM eligibility is dependent on both national eligibility and individual risk. NICE recommends CGM for all adults with type 1 diabetes^​21​, and intermittently scanned CGM for adults with type 2 diabetes on multiple daily insulin injections who have recurrent or severe hypoglycaemia, impaired hypoglycaemia awareness, or who would otherwise need to self-measure at least eight times daily^​17​. NICE also recommends it for adults with insulin-treated type 2 diabetes who would otherwise need help from a care worker or healthcare professional to monitor their glucose^​17​. The NICE criteria do not name ESKD or dialysis specifically. Given how common hypoglycaemia and impaired awareness are in this group, many people on dialysis will meet these criteria. JBDS is the UK guidance that addresses CGM in people on dialysis specifically, and recommends that CGM is offered with training and support for its optimal use^​8​.

JBDS suggests three further positions relating to CGM:

• Real-time CGM is suggested for anyone on insulin with recurrent hypoglycaemia or loss of hypoglycaemia awareness; 
• Long-term CGM should be considered for anyone treated with insulin or a sulfonylurea, unless practical difficulties prevent continuous use, in which case 6–12 monthly diagnostic CGM can guide dose adjustment; 
• For those not eligible for intermittently scanned CGM, periodic diagnostic CGM is triggered by any of four findings: more than 5% of self-monitored readings below 4mmol/L, more than 20% above 14mmol/L, inability to self-monitor twice daily for 1-to-2-week periods, or HbA1c below 42mmol/mol (6.0%) or above 80mmol/mol (9.5%)^​8​.

Capillary blood glucose self-monitoring remains necessary alongside CGM. JBDS recommends that all people on dialysis treated with insulin or sulfonylureas have access to capillary self-monitoring, whether or not they use CGM^​8​. Meters using glucose oxidase or glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) methods should not be used in people on dialysis^​8​. GDH-PQQ meters, for example, can give falsely elevated readings in people using iodextrin peritoneal dialysis solutions, which may prompt excessive insulin dosing and hypoglycaemia^​8​.

Reviewing medicines safely in people receiving dialysis

In individuals living with diabetes who are receiving dialysis, insulin requirements fall, renally cleared agents accumulate, hypoglycaemia is more frequent and less readily recognised, and HbA1c is unreliable. The JBDS guideline on the management of adults with diabetes on dialysis responds by restricting therapeutic options and specifying how the remaining agents should be used^​8​.

JBDS does not recommend sulfonylureas, glinides, acarbose, metformin or SGLT2 inhibitors in people receiving dialysis, none of which are licensed in this setting^​8​. Sulfonylureas present the clearest hazard, as both the parent compounds and their active metabolites accumulate with declining clearance, and they stimulate insulin secretion independently of prevailing glucose concentration^​5,8​.

A regimen established earlier in CKD may therefore become unsafe once dialysis starts. For example, at an eGFR of 30mL/min/1.73m², KDIGO supports metformin at a reduced dose and continuation of an SGLT2 inhibitor^​10​. Neither is recommended once dialysis begins^​8​. Exposure to sulfonylureas and insulin rises as clearance falls, increasing the risk of hypoglycaemia^​5,8​. A full review of glucose-lowering therapy is therefore required when dialysis starts.

Opportunities for pharmacist review arise at several points in care. These include medicines reconciliation when dialysis starts or when the dialysis modality changes, hospital admission and discharge, and requests for repeat supplies of agents that are no longer recommended^​8​. A low or falling HbA1c, reported hypoglycaemia, weight loss, and changes to iron or erythropoiesis-stimulating agent therapy are further triggers, since each may signal a need to adjust treatment or to reinterpret glycaemic data^​3,8,16​.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are the principal exception. Linagliptin, sitagliptin, vildagliptin and alogliptin are all licensed for use in dialysis and are recommended by JBDS^​8​. DPP-4 inhibitors increase insulin secretion only when glucose concentrations are normal or raised, which limits their risk of hypoglycaemia when used alone^​22,23​. Sitagliptin, vildagliptin and alogliptin are eliminated mainly by the kidneys, so they accumulate in kidney failure and require dose reduction^​8,23​. Linagliptin is eliminated mainly in the faeces, with about 5% excreted in the urine, so no dose adjustment is required^​22​.

Caution is advised in the following instances. Pioglitazone is licensed to an eGFR of 4mL/min/1.73m² and has been used safely in maintenance haemodialysis, although it is not licensed in dialysis^​8​. Glucagon-like peptide 1 (GLP-1) receptor agonists are unlicensed below an eGFR of 15mL/min/1.73m² but have been safely used in this population. JBDS recommends their use with caution^​8​. Gastrointestinal intolerance is a particular consideration, since 70–90% of people receiving dialysis report gastrointestinal symptoms, and incretin-induced weight loss may be detrimental where nutritional status is already compromised^​3​.

Insulin in patients receiving dialysis

JBDS states that the aim of insulin therapy in this population is to improve quality of life and to avoid extremes of hyperglycaemia and hypoglycaemia^​8​. Dosing should reflect the dialysis schedule. JBDS suggests reducing insulin doses by 25% on haemodialysis days and basal insulin requirement has been shown to fall by about 25% on the day following haemodialysis^​3,8​. CGM provides a more reliable guide than any fixed adjustment^​8​.

Basal bolus regimens are suggested as best suited to the glycaemic variability observed in this group^​8​. Where a person cannot manage such a regimen, a once-daily longer-acting insulin should be considered^​8​. This may apply, for example, where cognitive impairment, reduced dexterity or visual impairment limits self-administration, or where a carer or community nurse administers insulin. Conversion from neutral protamine Hagedorn (NPH) to analogue insulin may be appropriate where hypoglycaemia is troublesome^​8​. In peritoneal dialysis, insulin should be administered subcutaneously only. JBDS does not recommend intraperitoneal administration, because efficacy data are lacking and the route carries known risks^​8​.

Hypoglycaemia

Prevention of hypoglycaemia requires attention to the dialysis session itself. JBDS recommends that capillary glucose is measured before and after haemodialysis. Where pre-dialysis glucose is below 7mmol/L in a person treated with insulin, 20g to 30g of low glycaemic index carbohydrate should be provided at the start of the session^​8​.

Treatment of hypoglycaemia must accommodate fluid, potassium and phosphate restrictions. Glucose should be reassessed 15 minutes after treatment, and where it remains below 4mmol/L, a further 15g of rapid-acting glucose should be given, followed by 10g to 20g of complex or low glycaemic index carbohydrate. Rapid-acting glucose for treating hypoglycaemia should always be accessible, including during travel to and from the dialysis unit. Both patients and staff should receive education in the recognition and management of hypoglycaemia^​8​.

JBDS recommends specialist diabetes input for any person receiving dialysis with acute or chronic glycaemic instability, or established on insulin therapy, and that all such individuals have access to a named diabetes specialist nurse^​8​.

Best practice

• Undertake a full review of glucose-lowering therapy at the point dialysis is initiated, and at each subsequent medication review. A regimen appropriate at an eGFR of 30mL/min/1.73m² may cause harm once dialysis has commenced^​8,10​.
• Discontinue sulfonylureas, glinides, acarbose, metformin and SGLT2 inhibitors in people receiving dialysis, none of which are licensed or recommended in this setting^​8​.
• Verify DPP-4 inhibitor dosing. Sitagliptin, vildagliptin and alogliptin require dose reduction; linagliptin does not^​8​.
• Interpret a low HbA1c as a warning rather than an indication of good control. A value below 42mmol/mol (6.0%) should prompt assessment for burnt-out diabetes and recurrent hypoglycaemia^​8,16​.
• Interpret any HbA1c result in the context of haemoglobin concentration, iron status and erythropoiesis-stimulating agent use, before acting upon it^​3,20​.
• Establish whether insulin doses differ between dialysis and non-dialysis days. Where they do not, review is indicated^​8,19​.
• Identify individuals eligible for CGM. Recurrent hypoglycaemia and impaired hypoglycaemia awareness are common in this population, and both constitute NICE eligibility criteria^​17,21​.
• Enquire directly about hypoglycaemia. Autonomic neuropathy blunts adrenergic warning symptoms, so the absence of reported symptoms does not indicate the absence of episodes^​5​.
• Confirm that rapid-acting glucose for treating hypoglycaemia is always accessible, including during travel to, and from, the dialysis unit^​8​.
• Confirm that the annual diabetes review, retinal screening and foot check have been undertaken, and refer where they have not^​8​.
• Escalate to the specialist diabetes team where glycaemic instability or insulin therapy is present, in accordance with JBDS^​8​.