Chronic kidney disease controversy: how expanding definitions are unnecessarily labelling many people as diseased

We read with interest the article by Moynihan et al [1] and, as nephrologists, we disagree with some of his statements.

Chronic kidney disease is defined as the presence of renal anomalies of structure or function, present for at least 3 months, with implications for health. Based on the GFR, chronic kidney disease is classified into six stages: (1, 2, 3A, 3B, 4, and 5) and in three categories according to the proteinuria. [2]

In consideration of the prevalence of the CKD that is up to 60% in the US in the elderly population [3-4], that is also confirmed by Gubbio’s Study, which shows how reduced eGFR changes exponentially from a very low percentage (1%) in 'age 18-34 years up to higher percentages in the age ≥ 75 years, it is clear that this condition should be at least identified [5].

In the elderly population, by definition, more fragile, suffering from comorbidities and in multiple therapy, regardless of whether it is a physiological process of aging or a pathological process more or less evolutionary, it is essential to identify a reduced GFR and taking it into consideration to prevent potentially avoidable complications.

The identification of chronic kidney disease is necessary to prevent progression but especially to reduce the risk of cardiovascular morbidity and mortality.

In fact, if CKD is clinically silent in the early stages, it is possible to detect abnormal laboratory parameters already in II K-DOQI stage i. e. PTH increase; in stage III appears hyperparathyroidism, anemia and acidosis. On the contrary hyperkalemia and hyperphosphatemia occur only in the later stages of the disease. [6]

Worth noting that in the presence of comorbidities such metabolic complications may occur at an earlier stage (such as anemia in earlier stage in diabetics). [7]

The risk of cardiovascular disease in CKD patients in early stages is far greater than the risk of progression to end stage renal disease, cardiovascular mortality is twice higher in patients with stage 3 and three times higher in stage 4, compared to no renal subjects . [8-9].

Only in patients with severely impaired renal function, the risk of end stage renal disease exceeds that of cardiovascular events. [10]

It is also known as a reduced estimated GFR was associated with an increased risk of death, cardiovascular events and hospitalization regardless of known risk factors, history of cardiovascular disease, and the presence of documented proteinuria. [11-12]

In support of increased CV risk in patients with reduced GFR also the European guidelines for hypertension in 2013 point out that the identification of certain types of organ damage is essential for the diagnostic and prognostic evaluation of patients with hypertension.

In this contest, plasma creatinine, estimated glomerular filtration rate (eGFR) and proteinuria are therefore considered routine examinations throughout the hypertensive population, like the ECG. [13]

The higher cardiovascular risk is shown not only by meta-analysis but also from prospective studies, for example, the Dana’s study et al. which shows that myocardial infarction is often unrecognized in patients with GFR <60ml/min and how it is associated with worseprognosis. [14-15] and many others.

Not recognizing a patient with CKD may determine the risk of medication errors that may exacerbate the severity of the disease, prolong the hospital stay and potentially accelerate disease progression. [16]

As is evident in the Balthasar study of the non-recognition CKD leads to gross errors and potentially avoidable in drug delivery. [17] In the aging population use of drugs and especially antibiotics and proton pump inhibitor and cardiovascular drugs (ie digossin) could be very dangerous if are not properly dosed and the eGFR properly estimated by suitable method.

Overall aging people use many drugs and the concurrent use may increase risk of Acute Kidney In risk of acute kidney injury with increase mortality and cost (20)

Finally, chronic renal failure, both as a reduced GFR as the presence of proteinuria is one of the major risk factors for acute renal failure.

The risk is even worse in patients with multiple diseases, in the case of dehydration, especially in the categories of very young or elderly patients. [18-19]

The CKD has to be taken into account when prescribing drugs can cause acute kidney injury and early diagnosis should lead to a more judicious use of NSAIDs in acute and chronic conditions and contrast in CT and angiography.

Moynihan speaks of overdiagnosis, but given the low incidence of dialysis patients in UK, compared to the European average, there is a doubt: it there really a CKD "overdiagnosis" in the UK?

Second focus: “should be the problem the overdiagnosis or the undertreatment ”?

We think that CKD should always be diagnosed as soon as possible.

This does not mean to label a patient as sick. It means for the patient but also for the physician to be aware of the presence of a predisposing condition to risks often predictable and in some cases potentially avoidable.

Furthermore, according to guidelines, treatment should be individualized.

REFERENCE

1. Moynihan R et al. Chronic kidney disease controversy: how expanding definitions are unnecessarily labelling many people as diseased. Bmj 2013;347:f4298.
2. K-DOQI guidelines 2012
3. Coresh J e al. Prevalence of chronic kidney disease and decreased kidney function in the adult in US population: Third National Healt and Nutrition Examination Survey. Am J Kid Dis. 41(1);1-12 , 2003
4. Coresh J et al. prevalence of chronic kidney disease in the United States. JAMA 298: 2038-2047, 2007
5. Cirillo M et al.Cohort Profile: The Gubbio Population Study.
Int J Epidemiol. 2013 Mar 29
6. Moranne O. et al. Timing of onset of CKD-related metabolic complications. JASN 20:164-171, 2009
7. Ravanna R. et al. Impact of diabetes on haemoglobin levels in renal disease. Diabetologia 50(1):26-31, 2007.
8. Matsushita K, van der Velde M, Astor BC, et al, for the CKD Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073–81.
9. Van der Velde M, Matsushita K, Coresh J, et al, for the Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011; 79: 1341–52.
10. Packham DK, Alves TP, Dwyer JP, et al. Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC database. Am J Kidney Dis 2012; 59: 75–83
11. Go A. et al. Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization N Engl J Med;351:1296-305 2004
12. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention Lancet 2013; 382: 339–52
13. Mancia G et al. Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertension 2007;25:1105-1187
14. Dana V. et al.Prevalence and prognosis of unrecognized myocardial infarctions in chronic kidney disease Nephrol Dial Transplant 2012, 27: 3482–3488
15. Dalrymple LS et al. Chronic kidney disease and the risk of end-stage renal disease versus death. J Gen Intern Med 2011;26(4):379-85
16. Medication errors in chronic kidney disease: one piece in the patient safety puzzle Jeffrey C. Kidney International. 2009, 76, 1123 – 1125.
17. Balthasar L. et al. Occurrence of adverse, often preventable, events in community hospitals involving nephrotoxic drugs or those excreted by the kidney Kidney International 2009, 76, 1192–1198
18. Norbert H Lameire at al. Acute kidney injury: an increasing global concern, Lancet 2013; 382: 170–79
19. Coca SG et al.Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012; 81: 442–48.
20 Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S.:
Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.BMJ. 2013 Jan 8;346:e8525. doi: 10.1136/bmj.e8525.

Thank you to the authors for opening up this confusing issue for wider discussion.I share the concerns of the authors to a huge extent and having read the rapid responses, felt that I should be voicing my views.

To be very clear about the rest of this post, I am sure nobody wants to stop monitoring eGFR. Everybody should continue to adjust drug doses and watch out for AKI in those with low eGFR. That is not the issue here. The focus here is on the word "disease".

Over-diagnosis and medicalisation of every measurable abnormality is increasingly becoming fashionable, if not the norm. Arguing that the label of a "disease" is required to trigger concern and interest in physicians to address the associated cardiovascular issue is not reasonable. That would merely be a reflection of our current sweeping responses to anything and everything that we cannot police or influence on a day to day basis. Specialists will have to balance the vested interests that they have in trying to help identify all eligible patients with high inclusivity against the need to be pragmatic for the sake of the generalists who will be dealing with much of the population to whom the controversial diagnostic criteria will apply to, while taking care not to dumb down criteria to cater to those less engaged. A balance is also required to ensure that specificity is not sacrificed for the sake of sensitivity, lest the false positive diagnosis of a potentially progressive chronic disease causes great emotional distress with knock on effects on various aspects ranging from loss of a productive life to treatment-seeking behaviour.

The major criticism of the paper has been its lack of recognition of the CVD predictive value of CKD. If we are interested in a low eGFR due to its impact on future CVD rather than ESRD (accepting that many do not progress to ESRD, but all have higher risk for CVD), are we then labelling a risk factor as a disease? Is there an IFG and IGT analogy given that there is higher risk for CVD being predicted by all levels of eGFR in a progressive fashion? Are we getting too wound up about a "surrogate marker' of a generalised vascular problem? Should there be a push to label microalbuminuria as a disease since it predicts CVD?

eGFR, like any other value, will have to be treated on a case by case basis. It will have to be interpreted in the different contexts of risk prediction, prognostication, trend monitoring, drug dose adjustments, as well as institution of CVD preventative measures. This is particularly relevant when discussing the issue of whether to label a stable marginal decline of eGFR below 60 ml/minute in a very elderly person without a demonstrable abnormality in the urine or in renal anatomy, as a disease. Many of us would like to believe that a drop in eGFR with age is a manifestation of the natural ageing process. People who offer counter-arguments that low eGFR predicts increased CVD risk and hence is unlikely to be a natural ageing process but instead is an indicator of vascular damage seem to conveniently forget the fact that vascular damage is also part of ageing. The current extreme desire in the medical community to prevent and treat vascular damage in all instances has made it politically incorrect to even suggest that it would be reasonable to avoid cardiovascular preventative measures in the very elderly. If our real concern is the possibility of denying cardiovascular preventative treatment to huge numbers of frail elderly, then we should be looking harder at the NNT(numbers needed to treat) concept to guide us through these difficult discussions. While we know that low HDL predicts higher cardiovascular mortality, we have not shown that treating it improves CVD mortality. Have we shown that treating CKD improves mortality? Given that CKD implies lack of improvement of renal function further-allowing for recognised fluctuations within a stage- any impact of treatment on CVD improvement would be due to appropriate statin, anti platelet, anti-hypertenisve and anti-hyperglycaemic usage. Do we really need a "disease" label to make us use all those? Aren't there enough other markers that can trigger their use appropriately?

We probably will never know the NNT for 80 and 90 year olds to get CVD benefits with current treatment, although all of us suspect triple figure numbers. But one thing that many of us who deal with elderly patients on a daily basis have a gut feeling for is the NNH (Numbers Needed to Harm). NNH figures are likely to be much lower (greater harm) in the real world than in research settings, as elderly patients with multiple co-morbidities are exposed to polypharmacy with monitoring tempered by a multitude of social reasons.

While the desire to highlight the importance of low eGFR from a cardiovascular view point is very justifiable, we should resist the temptation to forget primum non nocere and avoid accepting heavy collateral damage at an individual level in the search for improved public health and life prolongation. Can we talk about CKC or CKA? Chronic Kidney Change or Chronic Kidney Abnormality? Could we introduce the requirement of a second factor of microalbuminuria for diagnosis in the very elderly in the CKD IIIa stage? Should we be revisiting the age related eGFR trends set up years ago when lower life expectancies were the norm?

We found the recent article published by Moynihan et al[1], which roundly criticised the revised chronic kidney disease (CKD) diagnostic framework as devoid of clinical utility, and greatly inaccurate, largely because of the authors’ incomplete appraisal of the large body of evidence used in the formulation of the revised framework. The authors have overlooked, and indeed misinterpreted, published evidence that supports the framework as important in identifying elevated cardiovascular risk, leading to improved models of care. We seek to correct the inaccurate assertions, and to highlight the evidence in support of the importance of the early recognition and treatment of CKD.

1. Age matters.
The authors argue that “an eGFR of 60 ml/min/1.73 m2 is within the normal reference range for men over 60 years and women over 50 years and cannot be used to define a diseased population.” From a practical viewpoint, a revised idealised population reference interval in the elderly would exclude subjects with clearly reduced renal function. In a way, this then establishes a circular argument as the nature of CKD, clinically silent in the early stages, and without suitable exclusion criteria, makes it impossible to define a “renally healthy” population. Moreover, establishment of multiple population reference intervals risks normalising the process of loss of renal function leading to underdiagnosis of CKD.

2. Early recognition and treatment affects outcome.
The CKD Prognosis Consortium recently published findings of their collaborative meta-analyses from general[2 3], high-risk [4] and kidney disease populations [5] (45 cohorts in total comprising 1,555,332 participants summarised in Levey et al[6]) in which an eGFR < 60 mL/min/1.73 m2 was significantly associated with incrementally increased risks of all-cause mortality, cardiovascular mortality, end-stage kidney disease, acute kidney injury and progression of CKD without consistent age interactions [6]. In particular, for the allegedly controversial category of stage 3a CKD (eGFR 45-59 mL/min/1.73 m2) with normal albuminuria, the increased relative hazards of all outcomes except all-cause mortality were demonstrated, and were similar both above and below the age of 65 years in the general population cohorts. A subsequent individual-level meta-analysis of 2,051,244 participants from 33 general population or high vascular risk cohorts and 13 CKD cohorts from around the world found that age did not modify end-stage kidney disease (ESKD) risk at lower eGFR or higher albuminuria, “supporting a common definition and staging of CKD based on eGFR and albuminuria for all age groups”[7] These observations are not consistent with the author’s interpretation that decreased GFR with ageing is ‘normal’ or ‘physiological.’ In support of the prognosis consortium, the Australasian Creatinine Consensus Working Group recently concluded that age-related decision points for eGFR are not recommended in adults [8].

Unfortunately, most of the arguments in the article by Moynihan et al. focus primarily on the relatively uncommon clinical outcome of ESKD. Of more importance for patients with CKD is the demonstrated natural history that they are up to 20-fold more likely to die, typically from premature cardiovascular disease, than survive to the point of ESKD. This is not mentioned at all in the critique of the CKD diagnostic framework. Furthermore, robust evidence supports the early identification of this cohort, as treatment of patients with early CKD with anti-hypertensive agents (especially with ACEi or ARB) [9] reduces their risks of ESKD and cardiovascular disease, and that treatment with statins also reduces their risk of cardiovascular disease [10].

3. Improved diagnosis and improved outcomes.
In the absence of any hard evidence to support their assertions, the authors assert that that the current revised CKD diagnostic framework leads to overdiagnosis, and needless burden of disease. However, in quoting a study from 1999 that estimated a 1 in 6 prevalence of CKD in Australia, the authors have neglected a subsequent study, detailing a revised estimated prevalence of one in 10 of the Australian population[11].

Furthermore, citing a study published in 2008, Moynihan et al assert that the framework has resulted in increased unnecessary referrals, stating that “the advent of the 2002 framework has substantially increased specialist referrals for chronic kidney disease, with referrals ….up 40% in two hospitals in Brisbane, Australia.” Unfortunately, the authors did not consider the complete results of the Australian study, which went on to report that “a greater absolute number of CKD patients were appropriately being referred for nephrologist review in the post-eGFR period” and that “the intervention therefore resulted in net benefit.”[12]

4. Microalbuminuria is important too.
The presence of microalbuminuria as part of the CKD diagnostic framework was also criticized by the authors, as “a third of people who are identified as having kidney damage on the basis of moderate microalbuminuria may shed that label when re-tested up to two months later.” The authors have overlooked the requirement for the presence of albuminuria to be detected on at least two occasions, three months apart to fulfil the diagnosis of CKD. Moreover, the previous literature suggesting microalbuminuria alone does not add to Framingham risk of CVD, has only been assessed in a populations not enriched with CKD [13].

5. CKD framework is better.
In their section titled “How to do better,” Moynihan et al offer no viable alternative diagnostic framework other than the vague advice that “clinicians consider the age of the patient and the trajectory of eGFR or urinary albumin test results.” In their box recommendations, they suggest looking for other poorly defined changes to support a diagnosis of CKD such as anaemia (very crude and somewhat late feature of CKD), abnormal urinalysis results (without specifying what we should be looking for other than proteinuria) and abnormalities on renal ultrasonography (also a very crude and insensitive method for detecting CKD).

In short, the recent BMJ article by Moynihan et al has neglected and misinterpreted a significant body of evidence underpinning the recently refined recommendations for the diagnosis of CKD. We acknowledge that false positives are an issue with any diagnostic classification, however the available evidence would suggest that the current definition minimizes the overidentification of those at risk of associated mortality. Moreover, the evidence argues against modifications according to race, age or gender, just as the definitions of hypertension, hypercholesterolaemia and diabetes are not modified according to age - conditions that are also very common in the elderly, conditions that also connote increased risks of adverse renal and cardiovascular outcomes.

“It is better to light a candle than to curse the darkness.” Chinese proverb

References

1. Moynihan R, Glassock R, Doust J. Chronic kidney disease controversy: how expanding definitions are unnecessarily labelling many people as diseased. Bmj 2013;347:f4298.
2. Chronic Kidney Disease Prognosis C, Matsushita K, van der Velde M, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375(9731):2073-81.
3. Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney international 2011;80(1):93-104.
4. van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney international 2011;79(12):1341-52.
5. Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney international 2011;79(12):1331-40.
6. Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney international 2011;80(1):17-28.
7. Hallan SI, Matsushita K, Sang Y, et al. Age and association of kidney measures with mortality and end-stage renal disease. JAMA : the journal of the American Medical Association 2012;308(22):2349-60.
8. Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations. The Medical journal of Australia 2012;197(4):224-5
9. Lv J, Ehteshami P, Sarnak MJ, et al. Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2013;185(11):949-57.
10. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. European heart journal 2013;34(24):1807-17.
11. White SL, Polkinghorne KR, Atkins RC, et al. Comparison of the prevalence and mortality risk of CKD in Australia using the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study GFR estimating equations: the AusDiab (Australian Diabetes, Obesity and Lifestyle) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation 2010;55(4):660-70.
12. Noble E, Johnson DW, Gray N, et al. The impact of automated eGFR reporting and education on nephrology service referrals. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2008;23(12):3845-50.
13. Chang A, Kramer H. Should eGFR and albuminuria be added to the Framingham risk score? Chronic kidney disease and cardiovascular disease risk prediction. Nephron. Clinical practice 2011;119(2):c171-7;.

We read the paper by Ray Moynihan and colleagues with some sympathy for the view that the classification of a large proportion of the population as having chronic kidney disease (CKD) carries a risk of causing anxiety and expense without proven benefit (1). We believe, however, there are strong grounds for continuing to use this classification, if only to identify an elevated risk of cardiovascular disease which for those in early-stage CKD is far greater than the risk of progression to end-stage renal disease (2). The suggestion that the presence of CKD has minimal impact on cardiovascular risk relative to smoking is difficult to reconcile with more recent population-based evidence showing coronary risk in people with CKD is comparable to that of diabetics (3). We would also caution against the notion that because a “disorder” has a high prevalence it is incorrect to classify it as a “disease”. Elevation of both blood pressure and cholesterol are at least as prevalent as CKD but are undeniably potent risk factors for cardiovascular disease and are therefore considered as disease states. Effective treatments addressing both these traditional risk factors have substantially reduced cardiovascular mortality in recent decades.

Despite powerful evidence of a graded inverse association between eGFR and proteinuria with cardiovascular risk, a causative relationship cannot be assumed. Nevertheless, a similar view was held by cardiologists for many years regarding cholesterol before the advent of statin therapy put this argument beyond reasonable doubt. The current lack of CKD-specific cardiovascular risk reducing treatment reflects our poor understanding of the pathophysiology of cardiovascular disease associated with this disease but does not invalidate CKD as a cardiovascular risk factor. Mechanisms of action such as activation of the renin-angiotensin-aldosterone system and abnormal calcium phosphate metabolism appear to be important and there are early signs that specific treatments might prove to be effective in future trials (4). In addition, non-specific risk reducing measures such as ACE inhibitors and statins have proven efficacy in patients with early-stage CKD (5, 6).

While the identification of CKD using low eGFR may lead to patient angst, the same is true of elevated blood pressure and cholesterol but few would argue that we should abandon their measurement. We urge that eGFR should continue to be measured, recorded and used as a risk factor for cardiovascular disease. By including CKD in cardiovascular risk models we have an important opportunity to better inform patients of prognosis as well as help guide primary prevention (7). Whilst we do not currently know the precise eGFR at which cardiovascular risk begins to increase, the majority of evidence points towards a level <60 ml/min/1.73m2 with some studies suggesting a threshold as high as <90ml/min/1.73m2 (8). At what level of eGFR, cardiovascular risk reducing therapy should be started will hinge as much or more on economics and societal values as on the simple relationship to risk.

References

1. Moynihan R, Glassock R, Doust J. Chronic kidney disease controversy: how expanding definitions are unnecessarily labelling many people as diseased. Bmj 2013;347:f4298.
2. Dalrymple LS, Katz R, Kestenbaum B, Shlipak MG, Sarnak MJ, Stehman-Breen C, et al. Chronic kidney disease and the risk of end-stage renal disease versus death. J Gen Intern Med 2011;26(4):379-85.
3. Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 2012.
4. Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol 2009;54(6):505-12.
5. Tonelli M, Isles C, Curhan GC, Tonkin A, Pfeffer MA, Shepherd J, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004;110(12):1557-63.
6. Ninomiya T, Perkovic V, Gallagher M, Jardine M, Cass A, Arima H, et al. Lower blood pressure and risk of recurrent stroke in patients with chronic kidney disease: PROGRESS trial. Kidney Int 2008;73(8):963-70.
7. Collins GS, Altman DG. Predicting the 10 year risk of cardiovascular disease in the United Kingdom: independent and external validation of an updated version of QRISK2. Bmj 2012;344:e4181.
8. Van Biesen W, De Bacquer D, Verbeke F, Delanghe J, Lameire N, Vanholder R. The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years. Eur Heart J 2007;28(4):478-83.