How to measure renal function in clinical practice
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38975.390370.7C (Published 05 October 2006) Cite this as: BMJ 2006;333:733
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Sir,
The creatinine present in serum and urine is derived from non -
enzymatic conversion of muscle creatine. The cooking process has a similar
effect, converting a proportion of the meat creatine into creatinine. When
the meal is then eaten, the change in serum creatinine within the first
few hours depends on the initial creatine content of the meat, the amount
eaten and the absorptive capacity of the gut.
Indeed, in previous experiments in the 1980's, when young, healthy
individuals were fed both raw and cooked meat, there was no change in
serum creatinine after eating as much as 500g raw mince. After the meals
containing cooked meat, however, their serum creatinines increased by up
to 60%.
Competing interests:
None declared
Competing interests: No competing interests
Somewhat tremulously I suggest that whether the meat is cooked or
uncooked - or "rare" - is immaterial in this context. Admittedly I have
not carried out a clinical trial.
JK Anand
Competing interests:
None declared
Competing interests: No competing interests
Editor,
The recent clinical review by Traynor et al [1] highlighted the
important and topical issue of the estimation of glomerular filtration
rate (eGFR) based on serum creatinine concentration and the relevant
Modification of Diet in Renal Disease (MDRD) equation [2]. Reporting of
eGFR by biochemistry laboratories is now recommended by national and
international bodies such as the Department of Health in England [3], the
National Kidney Foundation, the American Society of Nephrology, the
National Kidney Disease Education Programme, Kidney Health Australia and
Kidney Disease: Improving Global Outcomes (KDIGO). eGFR will hopefully
assist in the diagnosis, management and staging of chronic kidney disease
(CKD).
Traynor et al state that serum creatinine concentration, and
therefore eGFR, may only be slightly affected by ingestion of meat. We
believe it is important to highlight that ingestion of cooked meat may, in
fact, have a considerable influence on serum creatinine concentration and
eGFR. In the MDRD study data used to generate the eGFR equations, samples
were taken from predominantly fasting subjects (AS Levey, personal
communication). In clinical practice, however, samples for serum
creatinine concentration and eGFR are generally used in situations where
the patient’s recent dietary intake is not considered.
We recently carried out a study to investigate the impact of meals on
serum creatinine concentration and eGFR. Participants (n = 32; median age
54.5 years; age range 18 – 86 years) had blood samples taken before and
after normal helpings of meat-containing meals supplied by our hospital
canteen. Blood samples were analysed for creatinine concentration using a
common analytical technique (kinetic Jaffe method) and eGFR was
calculated. Results were classified according to the National Kidney
Foundation guidelines for CKD [4]. Ethical approval had been obtained from
the local ethics committee.
Results showed that, following a cooked meat meal, serum creatinine
concentration increases significantly. Median serum creatinine
concentration increased from 80.5 µmol/L preprandially to 101.0 µmol/L 1-2
hours after eating (p<0.0001), and 99.0 µmol/L 3-4 hours after eating
(p<0.0001). Furthermore, median eGFR decreased from 84.0 mL/min/1.73m2
preprandially to 59.5 mL/min/1.73m2 1-2 hours after eating (p<0.0001)
and 64.0 mL/min/1.73m2 3-4 hours after eating (p<0.0001).
Crucially, this led to apparent changes in CKD staging. In 12 of the
32 participants (six males age 47 – 76 years; six females age 36 – 84
years), the lowest eGFR in the postprandial period fell into a worse CKD
category than the preprandial eGFR. In 11 cases, CKD staging was altered
from better than CKD 3 (which includes normal GFR, CKD 1 and CKD 2) to CKD
3. In these cases, preprandial eGFRs ranged from 67 mL/min/1.73 m2 to 97
mL/min/1.73 m2 and the 60 mL/min/1.73 m2 threshold was crossed. In the
other case, staging changed from CKD 3 to CKD 4.
Our results suggest that the risk of misdiagnosis or incorrect
staging of CKD is high after a meal containing cooked meat. This may
result in inappropriate additional investigation and referral of
unsuitable patients to renal clinics. The cost implications over a large
population may be significant. We recommend that national guidelines
incorporate the advice that serum creatinine measurement, for the purpose
of eGFR calculation and CKD staging, should be carried out when a patient
has fasted or specifically avoided a cooked meat meal on the day of blood
sampling.
A complete account of the methods and results from our study is due
for publication early in 2007 [5].
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. BMJ 2006; 333: 733 – 737
2. Levey AS, Coresh J, Greene T, Stevens LA, Zhang Y, Hendriksen S,
Kusek J, Van Lente F. Using standardized serum creatinine values in the
Modification of Diet in Renal Disease study equation for estimating
glomerular filtration rate. Ann Intern Med 2006; 145: 247 – 254
3. Department of Health. National Service Framework for Renal
Services. Part Two: Chronic Kidney Disease, Acute Renal Failure and End of
Life Care. 2005; Available at:
http://www.dh.gov.uk/assetRoot/04/10/26/80/04102680.pdf
4. K/DOQI clinical practice guidelines for chronic kidney disease:
evaluation, classification, and stratification. Kidney Disease Outcome
Quality Initiative. Am J Kidney Dis 2002; 39: S1 – 246
5. Preiss DJ, Godber IM, Lamb EJ, Dalton RN, Gunn IR. The influence
of a cooked meat meal on estimated glomerular filtration rate. Ann Clin
Biochem (in press).
Competing interests:
None declared
Competing interests: No competing interests
Sir,
Plasma creatinine and urea levels as well as predictive formulas for
glomerular filtration rate that use these levels are not more than rough
estimations of renal function. In particular in critically ill patients in
whom renal function may deteriorate rapidly the impreciseness of these
surrogate measures of renal function causes practical problems. Thus, a
more accurate and practical (and preferably endogenous) indicator of renal
function is needed. Such a substance should be produced by the human body
at a constant rate, should be solely eliminated from the human body by
glomerular filtration and should be freely filtered in the glomerulus. In
addition, such a substance should not be secreted or reabsorbed by the
renal tubules, and should not be influenced by disease state or
medication. Finally, it should rapidly follow changes in glomerular
filtration rate.
As cystatin C fulfills many of the abovementioned conditions, we
hypothesize cystatin C to be an ideal endogenous marker of renal function.
Traynor et al., however, suggest the role for cystatin C measurement to be
limited (1). Indeed, while the generation rate of cystatin C is reported
to be stable in non-critically ill patients (2), the production of
cystatin C may be influenced by critical illness itself. In addition,
several disease states may have an effect on serum cystatin C levels,
including thyroid dysfunction (3,4) and the use of corticosteroids (5-7).
The latter may particularly apply for critically ill patients, since
recent studies suggest that corticosteroids should be more frequently
prescribed in this group (8). The abovementioned drawbacks have recently
been criticized, i.e. Åhlstrom et al. showed that abnormal concentrations
of serum cystatin C and plasma creatinine appeared in the same time frame
(9). Furthermore, hydrocortisone (100-300 mg per day, in the majority of
cases prescribed for suspected relative adrenal insufficiency due to
septic shock) did not seem to affect serum cystatin C concentrations.
Others recently confirmed these findings (10).
In conclusion, evaluation of serum cystatin levels may prove to be a
useful way to monitor renal function, particularly in critically ill
patients. Nevertheless, further studies are needed before cystatin C
becomes the new gold-standard for renal function in the intensive care
unit.
References
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. Bmj 2006;333(7571):733-7.
2. Sjostrom P, Tidman M, Jones I. Determination of the production
rate and non-renal clearance of cystatin C and estimation of the
glomerular filtration rate from the serum concentration of cystatin C in
humans. Scand J Clin Lab Invest 2005;65(2):111-24.
3. den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Is cystatin C
a marker of glomerular filtration rate in thyroid dysfunction? Clin Chem
2003;49(9):1558-9.
4. Jayagopal V, Keevil BG, Atkin SL, Jennings PE, Kilpatrick ES.
Paradoxical changes in cystatin C and serum creatinine in patients with
hypo- and hyperthyroidism. Clin Chem 2003;49(4):680-1.
5. Bjarnadottir M, Grubb A, Olafsson I. Promoter-mediated,
dexamethasone-induced increase in cystatin C production by HeLa cells.
Scand J Clin Lab Invest 1995;55(7):617-23.
6. Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J. Serum
cystatin C, a potent inhibitor of cysteine proteinases, is elevated in
asthmatic patients. Clin Chim Acta 2000;300(1-2):83-95.
7. Poge U, Gerhardt T, Bokenkamp A, Stoffel-Wagner B, Klehr HU,
Sauerbruch T, et al. Time course of low molecular weight proteins in the
early kidney transplantation period--influence of corticosteroids. Nephrol
Dial Transplant 2004;19(11):2858-63.
8. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B,
Korach JM, et al. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. Jama
2002;288(7):862-71.
9. Ahlstrom A, Tallgren M, Peltonen S, Pettila V. Evolution and
predictive power of serum cystatin C in acute renal failure. Clin Nephrol
2004;62(5):344-50.
10. Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F,
Janssen O, et al. Early detection of acute renal failure by serum cystatin
C. Kidney Int 2004;66(3):1115-22.
Competing interests:
None declared
Competing interests: No competing interests
Traynor et al.(1) recently emphasized a widely publicized limitation
of estimating equations for interpreting normal glomerular filtration rate
(GFR): current equations lack precision for GFR estimates greater than 60
ml per minute per 1.73m2. Consequently, they recommend that such values
“not [be] used routinely.”
These GFR values, however, also correspond to serum creatinine values
within “normal” reference ranges. As such creatinine interpretation errors
continue. Recently at our institution, yet another patient with previously
“normal” renal function presented with acute renal failure from severe
glomerulonephritis. Although long-standing microscopic hematuria was
evaluated with renal imaging and cystoscopy, no further renal-disease
specific investigation was pursued for years. Presumably, the patient’s
apparently “normal” renal function falsely assured his providers that no
significant renal dysfunction existed. Subsequently, his renal function
deteriorated undetected.
Is it time to also change serum creatinine reporting to include an
explicit reminder that “normal” reference values lack the discriminatory
power to identify patients with abnormal renal function? With such a
warning our patient, and hundreds of others like him, might have fared
better.
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. BMJ 2006;333(7571):733-7.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
The comprehensive review of the measurement of renal function in clinical practice by Traynor and colleagues1 is helpful but I feel that the calculation and routine reporting of estimated glomerular filtration rate (eGFR) on the basis of the 4-variable MDRD is having some unfortunate effects2.
I have recently encountered two elderly patients with serum creatinine levels below 120 mmol/L whose eGFR were reported to be around 50 mL/min. In both cases the general practitioner contacted me, worried about declining renal function. It seems that the routine reporting of eGFR may be a fine example of the law of unintended consequences. Anxiety is caused where there is no need. In all my years lecturing about hypertension up and down the land, I had never, until last week been interrupted by a spontaneous round of applause. Usually the applause is desultory and at the end only. This astonishing event occurred when I voiced the opinion that the routine reporting of eGFR on the basis of serum creatinine, age and gender was “dangerous nonsense”. Clearly the good general practitioners of the Scarborough area were irritated by biochemistry reports suggesting impending renal doom in their patients. I suggest that this formula should only be applied in older patients if the serum creatinine is greater than 130 or 140 mmol/L, but even at that threshold I would seriously question its value. Or maybe the whole idea of calculating eGFR on the basis of the 4 variable MDRD is fundamentally flawed.
Yours sincerely
D G Beevers
Department of Medicine, City Hospital, Birmingham
References:
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal function in clinical practice. BMJ 2006; 333: 733-7
2. Levey AS, Greene T, Kusek JW, Beck G. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000; 11: A0828.
Competing interests:
None declared
Competing interests: No competing interests
We read the clinical review by Traynor et al in the 7th October 2006
edition of BMJ 1 with interest.
In their box giving ‘Tips for non-specialists’, they recommend that
potentially nephrotoxic agents such as angiotensin converting enzyme
inhibitors (ACEI), angiotensin receptor antagonists (ARA) and non-
steroidal anti-inflammatory drugs be reviewed if glomerular filtration
rate (GFR) is less than 60 ml/min. While the advice is of course sound, we
are concerned that non-specialists might wrongly interpret it as
suggesting ACEI /ARA should be stopped in all such patients.
ACEI and ARAs have been shown beyond any doubt to protect long term
renal function in patients with non-diabetic CKD with proteinuria 2 and
diabetics with microalbuminuria 3 or overt proteinuria 4. Furthermore,
these drugs are safe in advanced stages of renal failure up to and
including stage 4, provided precautions are followed such as excluding
patients with renovascular disease, ensuring a low potassium diet, and
measuring serum creatinine and potassium levels for a few weeks after
initiation or change in dose 4 5.
Given that the number of patients with early CKD far outweighs the
number on renal replacement therapy, the emphasis in the last few years
has rightly shifted to trying to prevent the progression of these earlier
stages. In achieving this goal, non-specialists will play a major role in
early recognition and appropriate management of CKD. Hence it is vital
that they are given clear and unambiguous information regarding the use
and continuing benefit of ACEI and ARA.
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. Bmj 2006;333(7571):733-7.
2. Randomised placebo-controlled trial of effect of ramipril on decline in
glomerular filtration rate and risk of terminal renal failure in
proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di
Studi Epidemiologici in Nefrologia). Lancet 1997;349(9069):1857-63.
3. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner
P. The effect of irbesartan on the development of diabetic nephropathy in
patients with type 2 diabetes. N Engl J Med 2001;345(12):870-8.
4. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al.
Renoprotective effect of the angiotensin-receptor antagonist irbesartan in
patients with nephropathy due to type 2 diabetes. N Engl J Med
2001;345(12):851-60.
5. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, et al. Efficacy
and safety of benazepril for advanced chronic renal insufficiency. N Engl
J Med 2006;354(2):131-40.
Competing interests:
None declared
Competing interests: No competing interests
In a recent issue Traynor et al. have reviewed renal function
measurements in clinical practice [1]. They put special emphasis on the
creatinine-based 4-variable (“simple”) MDRD equation that allows
estimation of glomerular filtration rate by using serum creatinine
concentration, age, sex and ethnic background of the patient. This
equation is very convenient as it enables the laboratory to report an
estimated GFR instead of serum creatinine concentrations.
This is not without risk, however. As creatinine production is
proportional to muscle mass, there is large interindividual variability in
serum creatinine concentrations. Here, Traynor et al misquote the study by
Keevil et al. [2], who in fact reported significantly lower
interindividual variability for serum cystatin C, which is largely
independent of age, gender and body composition. This can only in part be
corrected for by the simplified MDRD-equation as it does not take the
individual body habitus into account. Cystatin C appears to be
particularly well suited to assess GFR in patients with altered or
variable creatinine production such as children, patients with malignancy,
anorexia nervosa, chronic liver disease etc (for review see Bokenkamp et
al. [3]).
In their summary the authors state that an estimated GFR of 60-89
ml/min/1.73m2 requires no further testing. Recent data have shown,
however, that even such mild reduction in GFR is an independent risk
factor for cardiovascular disease [4]. It has been widely accepted that
creatinine fails to detect mild impairment of renal function due to
increasing tubular excretion with diminishing GFR. Recent longitudinal and
large prospective epidemiological studies [5] have demonstrated that serum
cystatin C detects diminishing GFR earlier than serum creatinine and the 4
-parameter MDRD equation and is associated with adverse cardiovascular
outcomes [3].
In the light of these studies, the practice advised by the authors
may need to be re-considered in the near future.
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. BMJ 2006;333:733-7
2. Keevil BG, Kilpatrick ES, Nichols SP, Maylor PW. Biological
variation of cystatin C: implications for the assessment of glomerular
filtration rate. Clin Chem 1998;44:1535-9.
3. Bokenkamp A, Herget-Rosenthal S, Bokenkamp R. Cystatin C, kidney
function and cardiovascular disease. Pediatr Nephrol 2006;21:1223-30
4. Manjunath G, Tighiouart H, Coresh J, Macleod B, Salem DN, Griffith
JL, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for
cardiovascular outcomes in the elderly. Kidney Int 2003;63:1121-9
5. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen
C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS. Cystatin C
and prognosis for cardiovascular and kidney outcomes in elderly persons
without chronic kidney disease. Ann Intern Med 2006;145:237-46.
Competing interests:
A.B. received honoraria from Dade Behring, Marburg, Germany and DAKO, Glostrup, Denmark
Competing interests: No competing interests
The introduction of routine reporting of eGFR with every serum
creatinine requested seems to have led to three outcomes in general
practice: worried patients, increased workload, and confused clinicians.
While the NSF for Renal Services does not suggest that eGFR should be
used as a screening tool for renal disease amongst unselected patients,
but rather should be used to give further information about patients
already known to be at risk of renal disease, this is effectively what has
happened. In common with other doctors, general practitioners request
baseline biochemistry in situations ranging from investigation of
symptoms, to "work-up" of known disease, to monitoring of long-term
illness and so on. Of the 30 eGRs in my practice lablinks inbox today ,
originating from unselected patients of varying health, social class and
ethnic origin, 18 were less than 90 (and in only two of these cases was
the creatinine outside the normal range) and require further follow up. The
high risk patients will mostly have had their urine dipped already--perhaps we should routinely dip the urine of everyone having blood taken
for serum creatinine to avoid the worry of recall.
Whilst accepting that
eGFR is not a population screening test, no screening test would ever
have been introduced without extensive data relating to the performance of
the test in the population concerned, and without much clearer
information to clinicians.
Competing interests:
None declared
Competing interests: No competing interests
The MDRD-formula in pregnancy
To the Editor:
In their comprehensive review Traynor et al [1] conclude that the 4v-
MDRD-formula has become a standard method to measure renal function in
routine medical practice.
Although it may be true that the endogenous creatinine clearance (CrCl) is
no longer much used in clinical practice, in pregnancy it is still
considered the gold standard to estimate glomerular filtration rate (GFR).
In contrast to the Cockcroft-Gault (CG) formula [2], the performance of
the MDRD-formula has never been studied in pregnancy.
We compared CrCl to both the MDRD-formula and the CG-formula in 200 women
(median age: 30 years [range:19-41]) collecting 24-hour urine (n=301
samples) in the third trimester of pregnancy.
CrCl was calculated using the equation: (urinary creatinine [umol/L]x1000)
x urinary volume [mL]/1440 min)/ plasma creatinine [umol/L]. GFR was
estimated using the CG-formula: 140 - age [years] x weight [kg] / 0.953 x
plasma creatinine [umol/L] and the MDRD-formula: 186 x ((plasma creatinine
-27 [umol/L]) / 88.4)1.154 x age [years]-.203 x 0.742. In the MDRD-formula
27 umol/L is substracted since plasma creatinine was measured using the
Jaffé method in stead of enzymatic determination [1,3].
Correlation of both formulas with CrCl was poor (Figure 1). Pearson’s
correlation coefficients for the MDRD-formula and the CG-formula were 0.61
and 0.69 respectively.
Since the increase in body weight in pregnancy does not reflect an
increase in muscle mass formulas calculating GFR based on plasma will
overestimate GFR in pregnant women. As a result both the GC-formula and
the MDRD-formula are not useful in pregnancy. Correlation to CrCl is even
less in the latter.
Figure 1: Relationship between endogenous creatinine clearance (CrCl) and estimated GFR using the MDRD-formula and the Cockcroft-Gault(CG)-formula in pregnant women.
References:
1. Traynor J, Mactier R, Geddes CC, Fox JG. How to measure renal
function in clinical practice. BMJ 2006;333:733-737.
2. Quadri KH, Bernardini J, Greenberg A, Laifer S, Syed A, Holley JL.
Assessment of renal function during pregnancy using a random urine protein
to creatinine ratio and Cockroft-Gault formula. Am J Kidney Dis
1994;24:416-420.
3. Mazzachi BC, Peake MJ, Ehrhardt V. Reference range and method
comparison
studies for enzymatic and Jaffé creatinine assays in plasma and serum and
early
morning urine. Clin Lab 2000;46:53-55.
Friso M.C. Delemarre(1)*
Christian H.H. Schoenmakers(2)
Departments of (1)Obstetrics and Gynaecology and (2)Clinical
Chemistry, Elkerliek Hospital, Helmond, The Netherlands
*Address correspondence to this author at: Department of Obstetrics
and Gynaecology, Elkerliek Hospital, P.O. Box 98, 5700 AB Helmond, The
Netherlands. e-mail fdelemarre@elkerliek.nl
Competing interests:
None declared
Competing interests: No competing interests