Chronic Kidney Disease – An Exemplar for Collaboration Between the Clinic and the Laboratory

Chronic kidney disease (CKD) is a term introduced about 10 years ago that defines any persistent kidney condition irrespective of cause, and is associated with a widely accepted staging system that allows severity to be described. This nomenclature has given kidney disease a language and a basis that has transformed our ability to describe and analyse kidney conditions and has led to a proliferation of information particularly in the population health area. Intrinsic to this CKD staging system is the fact that because the majority of kidney conditions are asymptomatic until most kidney function is lost, staging is entirely reliant on biochemical markers of kidney damage and kidney function.¹

The introduction and wide clinical acceptance of CKD staging has stimulated interest and attention on the accuracy of the measurement and reporting of the biochemical markers used for its definition. This focus has highlighted the variability in serum creatinine and proteinuria results that had been previously accepted as satisfactory by clinicians. As these markers began to be used to determine CKD staging with its implication for prognoses and changes to clinical management of CKD, concerns developed about the lack of accuracy and potential for misinformation that arose as a consequence.²

In the area of creatinine measurement this has led to significant change in laboratory techniques that has improved the precision of creatinine measurement and encouraged alignment to an international standard. A strong influence in favour of change has been the two creatinine ‘consensus’ processes that have published specific recommendations regarding the measurement and reporting of creatinine and the use of eGFR (estimated glomerular filtration rate).^3,4 A third Australian ‘consensus’ process on creatinine measurement and reporting is just concluding that has made further recommendations on creatinine measurement and its use for estimating GFR. Proteinuria measurement is also under the spotlight as the clinical significance of its presence is more widely appreciated and moves are afoot to embed proteinuria into an amended CKD staging system. A separate proteinuria ‘consensus’ process is also coming to conclusion with far reaching recommendations arising from it that follow the UK NICE Guidelines in suggesting that albuminuria measurement is to be preferred to proteinuria for the initial testing of people for CKD.

These changes have impacted greatly over the last decade on the clinical practice of nephrology and could not have occurred without close collaboration between the laboratory and clinical worlds. This collaboration has been particularly effective in Australia and New Zealand and has led to an early and widespread uptake of the concept of eGFR automatically reported from serum creatinine. To extend and consolidate the collaboration and in recognition of further projected changes to the measurement and reporting of serum creatinine and urine protein, the AACB organised a symposium in August 2010 that brought together clinicians and pathologists to consider these matters. Papers presented at this meeting are published here and represent a state-of-the-art account of this dynamic and evolving area.

Dissatisfaction with the simple CKD staging system introduced in 2002 that graded severity of CKD into five stages, centred on the reliance on an accurate determination of eGFR and fixed cut-points to determine the stages. This had the effect of potentially allowing miscategorisation of a significant number of people into having a serious condition (CKD stage 3) when in fact they were in all other respects normal. Polkinghorne reviews this controversy and outlines the concepts behind a revision to the staging of CKD that splits CKD stage 3 into two levels and incorporates proteinuria as a determinant of outcome. Intrinsic to the improved staging is the use of a new formula to estimate GFR that reduces the bias previously experienced with MDRD (Modification of Diet in Renal Disease) in the crucial range of 60–90 mL/min/1.73m².

Polkinghorne and colleagues have importantly described that those reclassified from CKD stage 3 to ‘normal’ with the new CKD-EPI (CKD Epidemiology Collaboration) formula were predominantly women with a favourable cardiovascular risk profile.⁵ Subsequent to this symposium, a seminal paper outlining the new staging system and the justification for it has been published.⁶ Clinical action plans to match the new stages are in the process of development.

The significant difficulties in using serum creatinine to reliably measure kidney function have led to attempts to develop an alternative biomarker not affected by muscle bulk and creatinine generation. MacIsaac reviews the most likely and best developed alternative, cystatin C, and highlights its better correlation with measured GFR in the range >60 mL/min. Despite its being known for more than 20 years to have advantages over creatinine, there remain issues with standardisation of its measurement and cost. There is also an appreciation that there are extra renal factors that influence its circulating level and these include age, body weight, gender, smoking, C-reactive protein, abnormal thyroid status, malignant and inflammatory states and steroid therapy. MacIsaac concludes ‘although cystatin C is well-established as a research tool, it is unlikely that it will make the transition to routine clinical practice in the near future. In the meantime, creatinine-based methods will almost certainly remain the most clinically applicable way of estimating GFR.’

The use of eGFR for determining drug dose adjustment for people with reduced GFR has been a particular area of concern for clinical pharmacologists and others keen to improve the quality use of medicines. Doogue reviews the principles of drug dosing adjustment in people with reduced kidney function and concludes ‘Recognition of renal function as a prescribing issue is more important than the precision of different estimates of renal function’. The new consensus recommendation on eGFR and drug dosing endorses its use by practitioners for drug dose adjustments whilst highlighting the need to refer to the product information for detailed guidance, particulary for drugs with a narrow therapeutic index.

Jones further reviews this drug-dosing area and in his chapter details the concerns about switching to eGFR from the historically entrenched use of Cockcroft-Gault in the drug-dosing world. He makes the case for removing the normalisation of body surface area (automatically included in the usual reporting of eGFR) to allow for a better approximation of the eGFR to the measured GFR in individuals at the extremes of body size. He states ‘Based on the above discussion I believe that the most appropriate formula for GFR estimation for drug dosing decisions is CKD-EPI formula, as this provides the most accurate estimate of GFR, with removal of body surface area normalisation if needed.’ He endorses the US National Kidney Disease Education Program recommendation that either eGFR or Cockcroft-Gault can be used for drug dosing adustments with normalisation for body surface area being removed in very large or very small people.⁷

Florkowski reviews inherent problems with using the serum creatinine as a marker of kidney function and the history of the use of eGFR for measurement of kidney function. The multiple issues affecting its performance as an accurate and reliable estimate of GFR are outlined. The advantages of the new CKD-EPI formula in reducing the bias seen with the MDRD formula and providing a closer approximation to measured GFR in the area >60 mL/min are emphasised. He states ‘we need to remember that all equations for GFR estimation are essentially mathematical abstractions that relate patients to the populations from which the equations were derived. Inevitably, therefore, there is no ideal “one size fits all” equation, and clinicians need to be mindful of all the potential limitations in their application and to interpret results in a full clinical context.’

Few clinicians have appreciated the lack of precision evident in measuring proteinuria in the laboratory and the lack of standardisation, variation in reference intervals and reporting methods–all compounding the recognised issues in timed urine collections. Johnson reviews all these issues and outlines the case for shifting to urine albumin measurement as a preferred approach to the detection and staging of CKD. Since his paper was completed, the ‘consensus’ process on proteinuria (that Johnson co-Chairs) has made the recommendation for Australia to move to urine albumin/creatinine ratio (urine ACR) in place of proteinuria measurement for the intial detection of CKD. Urine albumin excretion has large biological variation and hence the requirement to repeat it up to three times in any individual to clarify its status. It is also not possible to reliably convert a urine albumin measurement to urine protein because the relationship is complex and not linear. Nevertheless the advantages of urine albumin measurement outweigh the disadvantages and the new CKD staging system is reliant on it.

Martin in her paper emphasises these issues related to albumin and protein measurement and states ‘available data suggest that Australasian laboratory performance is adequate in terms of precision and accuracy above current decision limits for urine albumin. In contrast, the complexity of proteins in urine makes standardisation of urine total protein measurement impossible. As well, urine total protein measurement is insufficiently sensitive to detect clinically important concentrations of urine albumin.’ Thus the scene is set (once the ‘consensus’ recommendations are endorsed and published) for an important change to clinical practice in Australia – dipstick testing for proteinuria is out and urine ACR is in.

Jones addresses the reporting of urine protein and albumin results and concludes that ‘from the data presented here. it is clear that the information being transmitted by Australasian laboratories to our clients is needlessly confusing and potentially confounding.’ He looks to the ‘consensus’ process on proteinuria for guidance around the reporting methods, units used and reference intervals. This is another advantage of using ACR where the variation in reporting has been less marked.

The advantages of point-of-care-testing for creatinine were presented by Shephard who has extensive experience in this area and in urine testing. He outlined the particular difficulties in point-of-care creatinine measurement on finger prick size samples and the lack of precision found with currently available techniques. The attractiveness of on-site serum creatinine testing in the Clinic immediately pre-visit or for self monitoring is evident but awaits further technical development.

The meeting concluded with a useful review by Hickman of the use of cardiac biomarkers in dialysis patients and the complexities associated with their interpretation due to the inflammatory state these people exhibit even whilst apparently well. Endre reviewed the use of biomarkers for the early diagnosis of acute kidney injury and concluded ‘Sufficient new biomarkers have been discovered and evaluated to expect that not one biomarker but a panel of biomarkers applied according to phase of injury, baseline renal function and comorbidities will be necessary for the early diagnosis of acute kidney injury’. This is an area of acute interest and increasing appreciation of the role it plays in increasing mortality and its contribution to later CKD.

Overall this was a Symposium that brought together clinicians and pathologists meeting on the common ground of kidney disease. The need for close consultation and the interdependence of one on the other in order to achieve change to clinical and laboratory practice was evident.

This Symposium and indeed the ‘consensus’ processes in creatinine and protein measurement and reporting that are just concluding are models for other areas of medicine to follow. The essential features allowing this process to be successful are committing to the use of available expertise wherever it exists, ensuring the process is open to all stakeholders and displaying an approach based on mutual respect, and a commitment to an evidence base for all recommendations. The AACB are to be applauded for having brought together the CKD stakeholders at this particular time and at a stage when the parameters for the diagnosis and management of CKD are being set for the next decade or so.