Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease

The National Strategic Framework for Renal Services introducedthe routine reporting of estimated glomerular filtration rates(eGFR) on serum urea and electrolyte tests. Estimated glomerularfiltration rates might reduce renal failure induced by lithiumand cardiovascular mortality but there are many false positives.We propose how eGFR might be used in lithium monitoring.

INTRODUCTION

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INTRODUCTION

The National Strategic Framework for Renal Services, part two,has recommended a change to the routine reporting of serumurea and electrolyte results with the introduction of reportingof estimated glomerular filtration rates (eGFR).¹ In manyparts of the UK, eGFR is already reported routinely as partof urea and electrolyte results. Estimated glomerular filtrationrate is calculated using the four-variable ‘modificationof diet in renal disease’ equation:¹

Formula
Sadly, the National Strategic Framework for RenalServices completely neglected consideration of lithium as adrug that could be toxic for the kidney, and did not developany guidance in relation to lithium and eGFR. Psychiatristswho usually work in separately managed health organisationsfrom renal physicians and chemical pathology laboratories havenot been educated about the change in reporting of urea andelectrolytes. Yet, a recent survey from France shows that 5%of patients taking lithium aged 40–69 years are in stage4 of chronic kidney disease,² when patients become symptomaticfrom the disease and may require dialysis or transplantation,compared with 0.4% of the general population.³ Therefore,psychiatrists require education about eGFR now that changeshave been made to the routine reporting of serum urea and electrolytes.

The benefits of reporting eGFR

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The benefits of reporting...

The National Strategic Framework for Renal Services promotesthe reporting of eGFR on routine serum urea and electrolytesbecause eGFR is a more sensitive indicator of grade 3 chronickidney disease than elevated or rising urea and creatininelevels. Stage 3 chronic kidney disease is asymptomatic but itis associated with a 40% increase in cardiovascular mortalityin the community when all other cardiovascular risk factorsare controlled for.⁴ Improved detection of chronic kidneydisease using eGFR will mean that more people will have thedisease detected at an early stage. A Canadian study found thatof 2781 out-patients referred by community physicians to anurban laboratory network for serum creatinine measurement,182 (6.5%) had both abnormal serum creatinine levels and abnormaleGFR ( $≤$ 50 ml/min^–1), but a further 387 patients (14%)had normal serum creatinine and abnormal eGFR.⁵ Assuming that by 2014/2015, half of the 40% of late referrals could be avoided,this could lead to about 568 more renal patients per annumsurviving at least 2 years longer.¹ Although only a smallproportion of these will have end-stage disease induced by lithium,mortality from cardiovascular disease might be delayed or prevented in many more patients prescribed lithium.

Is lithium worth prescribing?

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Is lithium worth prescribing?

The first reaction to high rates of poor renal function in patientson long-term lithium medication might be to discontinue lithiumtherapy. However, alternative drugs with both antimanic andanti-depressant properties may not be efficacious in a patientwith bipolar disorder who has remained well on lithium; alternativedrugs also have potential long-term undesirable effects. Furthermore,lithium has a demonstrated effect on reducing suicide, suicidalityand cardiovascular mortality that may be superior to other antimanicand antidepressant drugs.^6,7 The addition of lithium to antidepressantsis one of the few evidence-based adjunctive strategies forthe management of unipolar depression that has not respondedto other first- and second-line treatments. A full discussionof benefits and adverse effects of lithium can be found inNational Institute for Health and Clinical Excellence (NICE)guidelines for bipolar disorder and a recent paper in this Journal.^8,9

The unreliability of a single eGFR estimation

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The unreliability of a...

Unfortunately a single estimation of eGFR is not a reliableestimate of stage 3 chronic kidney disease and this may beespecially true in patients taking lithium. The percentagesof patients taking lithium with eGFR results below the usualstated normal level ( $≤$ 59 ml/min^–1) in age groups 20–39,40–59, 60–69 and $≥$ 70 years were 36%, 53%, 73% and77% respectively.² A single abnormal eGFR is clearly not sufficientto establish chronic kidney disease. The eGFR estimate maybe inaccurate in people over 70 years of age, people less than18 years old, pregnancy, amputees, malnourishment and dehydrationstates, and also in people of African–Caribbean origin. However, people from African–Caribbean backgrounds areat increased risk of renal failure because of their increasedrisk of hypertension.¹ Laboratories will modify their estimationon eGFR according to an agreed formula if they are suppliedinformation on ethnicity. Even a recent fall, muscle injuryor an injection may lead to a substantially increased eGFR, which is exquisitely sensitive to changes in creatinine levelfor any reason.

Recommendations for the correct use of eGFR

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Recommendations for the correct...

How can we detect progressive deterioration in renal functionin patients taking lithium using eGFR? Any approach shouldbe compatible with current guidelines for lithium testing sothat large increases of unnecessary investigation are avoided.As part of routine safety and monitoring procedures that psychiatristsshould follow, patients on lithium receive 3-monthly checks on lithium levels, 6-monthly checks on urea and electrolytelevels, and thyroid function tests, together with regular butunspecified checks on weight.⁸ More frequent tests are requiredif there is evidence of clinical deterioration, abnormal results,a change in sodium intake, other risk factors such as startingmedication known to affect renal function (e.g. non-steroidal anti-inflammatory drugs, diuretics and angiotensin-convertingenzyme inhibitors) or symptoms (such as thirst) indicatingabnormal renal or thyroid function.⁸ In addition, a recentreview encouraged yearly assessment of urine production (below4 litres in 24 h) in patients taking lithium.⁹ Therefore recommendationsfor serial eGFRs over 6 months if the first eGFR is $≤$ 59 ml/minare compatible with existing NICE guidelines on lithium monitoring. However, some clinicians are concerned that the use of evenserial eGFR levels generates a ‘disease’ that maymerely be age-related kidney function decline.¹⁰

We recommend an approach to eGFR advocated by the UK ConsensusConference on Early Chronic Kidney Disease,¹⁰ organised bythe Royal College of Physicians of Edinburgh with the UK and Scottish Renal Associations. We have adapted their recommendationsfor patients taking lithium, although none of these bodiesspecifically considered patients prescribed lithium in drawingup their recommendations.

Whether or not the eGFR is less than 60 ml/min, a rise in creatinineon three or more occasions will require further investigation,including urinalysis for proteinuria, haematuria, glucose,review of medical history (including urological history andmedication) and blood pressure. If a urine dipstick test suggeststhere is protein in urine, then the laboratory should be requestedto perform a protein:creatinine ratio test on a sample of urine.
In all patients with eGFR of 30–59 ml/min, repeat eGFRand other urea and electrolyte measurements every 3 monthsunless there is a clinical indictor for even more frequentestimation. Every patient should have urinalysis for proteinuria,haematuria, glucose, review of medical history (including urologicalhistory and medication) and blood pressure measurement. Allrisk factors for cardiovascular disease should be actively treatedand monitored according to national guidelines developed forprimary care.
Referral for specialist renal opinion shouldoccur in any patient where:
1. the eGFR is decreasing by morethan 4 ml/min per year as shownby a progressive fall on threeor more serial tests withoutevidence of acute renal failureor dehydration;
2. there isa progressive rise in serum creatininelevel on threeor more serial tests;
3. there is proteinuria(plasma:creatinine ratio $≥$ 1);
4. there is haematuria;
5. thereare symptoms of chronic renalfailure; symptoms such astirednessdue to anaemia from renaldisease are unlikely unlessrenalfunction falls below 45 ml/min;
6. eGFR is below 30 ml/min.
In patients with a glomerular filtration rate of 30–59ml/min who do not require specialist renal referral, 3-monthlyurea and electrolyte monitoring should be accompanied by measuresto decrease other risk factors for renal impairment and cardiovasculardisease such as obesity, hypertension, diabetes mellitus, smoking,high alcohol consumption, adverse lipid profiles, urologicalproblems and the prescription of drugs with adverse renal effects such as nonsteroidal anti-inflammatory drugs, diuretics andangiotensin inhibitors.
Among patients with slowly progressiverenal disease diagnosedby a renal physician, the adverse effectsof lithium on thekidney might be reduced by lowering the therapeuticdose, havingdrug holidays through periods of prolonged remission,or usingalternative antimanic or antidepression treatments.

Future directions

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Future directions

More research is required on the clinical significance and optimaluse of eGFR in patients taking lithium, and the stage at whichmore active intervention is required to prevent end-stage chronickidney disease due to lithium. Such research may be particularlyrequired in the elderly, where the false-positive rate foreGFR may be especially high. From a clinical perspective, mentalhealth services are employing nurses to help with the physicalhealth monitoring of patients with serious mental illness, particularlythose who may not attend primary care services. A fresh challenge to our clinical services and health purchasers is the integrationof monitoring and proactive physical healthcare with the restof clinical care for patients with serious mental illness acrossprimary and secondary care services.

REFERENCES

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