Chronic renal disease
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7355.85 (Published 13 July 2002) Cite this as: BMJ 2002;325:85All rapid responses
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Insomnia is a common symptom in patients with advanced renal failure and on dialysis, which resolves with transplantation. Patients typically describe an inability to sleep through the night but do not feel tired or 'underslept' as a result. Despite not feeling tired, patients are often very disturbed by their inability to sleep.
The cause of insomnia in renal failure has remained a mystery.
Orexin is a neuropeptide produced in the hypothalamus. it is deficient in patients (and animals) with narcolepsy. Levels of orexin rise in the morning and keep the brain awake.
[JM. Siegel Ph.D., R. Moore, M.D., T. Thannickal Ph.D., and R. Nienhuis, B.S. A Brief History of Hypocretin/Orexin and Narcolepsy. Neuropsychopharmacology 25:S14-S20, 2001 http://www.npi.ucla.edu/sleepresearch/NEUROPSYCHOPHARMACOLOGY25/NEUROPSY....
Levels of orexin are significantly increased in patients on dialysis.
[Sugimoto T, Nagake Y, Sugimoto S, Akagi S, Ichikawa H, Nakamura Y, Ogawa N, Makino H. Plasma orexin concentrations in patients on hemodialysis. Nephron 2002 Apr;90(4):379-83
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis....
It seems logical to conclude that insomnia in patients with advanced renal failure may be due to high circulating levels of orexin. If so, novel treatment for this disturbing symptom may be possible.
Yours sincerely
Dr Hugh Rayner
Consultant in Renal Medicine
Birmingham Heartlands Hospital,
Birmingham UK
B9 5SS
hugh.rayner@heartsol.wmids.nhs.uk
Competing interests:
None declared
Competing interests: No competing interests
In the above response (author's reply) the serum creatinine is in
micromoles/L and not in mmol/L. In the original letter that was written
using Microsoft word, I used micro (u) symbol but when I posted the reply
(cut and paste) as rapid response, on bmj.com the micron somehow got
changed to mmol/L. So, please use micromol/L than mmol/L when using the
equations.
Thank you.
Competing interests: No competing interests
The Editors:
I thank Cohen, O’Riordan, Lamb and Ravnskov for their comments on
chronic renal disease1. Cohen is puzzled with the Cockcroft-Gault
equation2 but correctly illustrates with an example how glomerular
filtration rate (GFR) is different in a young and an old person with the
same serum creatinine concentration. He claims, “Experience tells us
otherwise.” However, literature and experience tells us that daily
production of creatinine is decreased in the elderly as a result of
reduced muscle mass3 therefore serum creatinine is not an accurate index
of renal function. In addition to age, there are numerous other factors
that affect the serum creatinine level and are described in the review.
Directly determined glomerular filtration rate is the best index of renal
function4 but the methods are too complex and cumbersome for routine
clinical use. Hence, a number of equations have been developed over the
years to estimate GFR and each has their limitations. Equations
empirically combine all the average factors while allowing for the
differences in creatinine production between individuals, therefore are
superior to serum creatinine concentration in estimating renal function.
Cockcroft-Gault equation was developed in 1976 and since have been widely
tested and commonly used for estimating GFR. This equation takes into
account increased creatinine production with increasing weight and
decreased creatinine production with increasing age. The original paper
describes very well how factor ‘140’ was derived. In the original equation
the denominator was [72 x serum creatinine (mg/dl)] and in SI units the
denominator [serum creatinine (mmol/L) x 0.81] is equivalent.
I sincerely thank O’Riordan and Lamb for pointing out an error in the
MDRD equation (box 1) of this review. The unit of serum creatinine used in
the equation is in mg/dl and one need to convert serum creatinine from
mmol/L to mg/dl by multiplying with 0.011 before using this equation.
Hence, the correct MDRD equation in SI units is [GFR = 186.3 x (serum
creatinine in mmol/L x 0.011)-1.154 x age-0.203 x (0.742 if female) x
(1.21 if African-American)]. I agree with them that this equation is
cumbersome and not practical in primary care practice.
Age is a susceptibility factor (factors that increase the risk for
kidney damage) as stated (box 2) and is not a risk on its own. I agree
that serum creatinine of 150 mmol/L may represent a significant renal
dysfunction in select group of patients (elderly, malnourished, Asian
populations) therefore estimation of GFR is recommended in all patients to
stage the degree of renal dysfunction and new staging system is based on
GFR than serum creatinine concentration. National Service Framework
suggests referral at 150 mmol/L.
It is true that serum cystatin C concentration is a better marker
that serum creatinine for detection of subtle changes in GFR, especially
in the elderly5. However, limited sample size, statistical methodology,
lack of information on cystatin C assay calibration, and conflicting
results make the available data inadequate for recommending cystatin C
measurement for widespread clinical application at present6.
Ravnskov’s comments on the effect of hydrocarbons in causation and
progression of renal disease are appreciated. I thank him for his summary
but the literature does not support his title “Chemic exposure – a common
cause of end-stage renal failure.” I don’t think that the nephrology
community ignores chemical exposure, as a cause of renal disease, as he
eludes in his letter however strong evidence to support this theory is
lacking. Due to space limitations and hydrocarbons role being
controversial the role of nephrotoxic agents was mentioned in general
terms.
References:
1. Parmar MS. Chronic renal disease. BMJ 2002; 325:85-90
2. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum
creatinine. Nephron 1976; 16:31-41
3. Fliser D, Franek E, Joest M, Block S, Mutschler E, Ritz E: Changes in
renal function in the elderly – influence of hypertension and cardiac
function. Kidney Int 1997;51:1196-1204
4. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal
function: New insights into old concepts. Clin Chem 1992; 38:1933-1953
5. Fliser D, Ritz E. Serum cystatin C as a marker of renal dysfunction in
the elderly. Am J Kid Dis 2001; 37:79-83
6. Deinum J, Derkx FH. Cystatin for estimation of glomerular filtration
rate. Lancet 2000; 356:1624-1625
Competing Interests: None to declare
Competing interests: No competing interests
In his review about prevention of renal failure
(1) Dr. Parmar mentioned nephrotoxic agents as an initiation factor. There are many
indications that exposure to toxic chemicals is more important as a progression factor,
however. An analysis of the accumulated evidence from more than 25 years of research
performed by many research groups has shown that more than 50 % of patients with end-stage renal failure due to
glomerulonephritis have been exposed to various types of hydrocarbons (2-4). In addition,
four follow-up studies have shown that progression of renal failure may be prevented if
the exposure is discontinued (3). Exposure to hydrocarbons may also have importance in
many patients with diabetic nephropathy and in patients with parenchymal renal disease of
unknown etiology. Other chemicals known to induce serious kidney disease with progressive
renal failure include silicates, gold, lead, mercury, non-steroidal anti-inflammatory
drugs and lithium, and in almost all such cases discontinuation of the exposure has led to
improvement (1,2).
The significance of chemical exposure is by and large ignored by
the nephrologic community. One of the reasons may be that some case control studies found
no difference between the exposure of glomerulonephritis patients and control individuals
suggesting that the studies that did show a difference were biased. However, the studies
with negative findings included patients with normal renal function or early disease only.
A meta-analysis of all case control studies found that exposure correlated inversely with
renal function indicating that the most important effect of hydrocarbons is a worsening of
renal function (4), also implying that the negative studies in fact are in support.
Another cause of skepticism is that many nephrologists have the
impression that few patients are exposed. But physicians may be unfamiliar with the
working conditions of their patients, and patients may be unaware of being exposed. To
reveal relevant exposure an interrogation of the patient by an expert in occupational
hazards is mandatory. If this is performed systematically in all patients with renal
failure due to parenchymatous renal disease, much exposure will be revealed and end-stage
renal failure with all its gloomy consequences may be prevented in a large number of
patients.
- Parmar MS. Chronic renal disease. BMJ 2002;325:85-90
- Ravnskov U. Hydrocarbon exposure may cause glomerulonephritis and worsen
renal function: evidence based on Hill´s criteria for causality. QJM 2000; 93:
551-6. - www.ravnskov.nu/index
- Ravnskov U. Hydrocarbons may worsen renal function in glomerulonephritis: a
meta-analysis of the case-control studies. Am J
Indust Med 2000; 37: 599-606.
Competing interests: No competing interests
Dear Editor
We welcome Parmar’s (1) excellent review of chronic renal disease,
emphasising the need for early detection and treatment of complications to
slow progression and improve quality of life. We were also pleased to see
the inadequacies of using serum creatinine to estimate glomerular
filtration rate (GFR) highlighted. As stated, the use of Cockcroft and
Gault or Modification of Diet in Renal Disease (MDRD) equations improves
GFR estimation. However, in reality the calculations are cumbersome and
not widely used in the UK, particularly in a primary care setting. Most
importantly, even in the 21st century, the integration of clinical
(weight, race) and biochemical (creatinine) data is beyond the information
technology provision between most primary and secondary care trusts. It
should be noted that the MDRD formula as described by Parmar requires
creatinine concentration to be expressed in units of mg/dL, as is the
convention in North America (although the Cockcroft and Gault formula is
described in international units). This is slightly misleading: readers in
the UK should multiply creatinine concentration (in umol/L) by 0.011
before using the formula.
We would like to comment on the statement that age is a risk factor
for chronic renal disease (Box 2). Whilst we recognise that the incidence
of renal failure increases with age, this is not an inevitable consequence
of ageing (2). Is the author suggesting that all older people should
undergo evaluation for kidney disease, or should additional risk factors
be present? Applying the interventions described to older people, many of
whom will have reduced GFR (2), has considerable resource implications.
The assessment of renal function is not straightforward in this
population. It should be acknowledged that a serum creatinine
concentration of 150-180 umol/L represents a very significant degree of
renal insufficiency (3), well beyond the point at which many of the
described interventions should have been implemented. Finally, the MDRD
formula has not, to date, been validated in an older population.
A single blood test, cystatin C, correlates well with gold standard
GFR, is sensitive for the detection of moderate chronic renal failure (4),
including amongst older people (5), and circumvents the analytical
problems of serum creatinine and the complexities of formulaic estimates.
Given the wealth of recent published research into the use of cystatin C
we were surprised not to read about it in an otherwise excellent and up to
date article.
Yours sincerely
Dr Shelagh E O’Riordan Consultant Geriatrician, Health Care of the
Older Person, East Kent Hospitals NHS Trust, Kent and Canterbury Hospital,
Canterbury, Kent CT1 3NG
Dr Edmund J Lamb Consultant Clinical Scientist, Department of
Clinical Biochemistry, East Kent Hospitals NHS Trust, Kent and Canterbury
Hospital, Canterbury, Kent CT1 3NG
Corresponding author:
Dr S O’Riordan, telephone 01227-766877; e-mail
Shelagh.O’Riordan@ekht.nhs.uk
References:
1. Parmar MS. Chronic renal disease. BMJ 2002;325:85-90
2. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of
decline in renal function with age. J Am Geriatr Soc 1985; 33: 278-285
3. Duncan L, Heathcote J, Djurdjev O, Levin A. Screening for renal disease
using serum creatinine: who are we missing? Nephrol Dial Trans
2001;16:1042-1046
4. Bostom AG, Dworkin LD. Cystatin C measurement: improved detection of
mild decrements in glomerular filtration rate versus creatinine-based
estimates. Am J Kidney Dis 2000;36:205-207
5. Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal
dysfunction in the elderly. Am J Kidney Dis 2001;37:79-83
Competing interests: none to declare
Competing interests: No competing interests
Editor-Parmar, in his Clinical Review of Chronic Renal Disease1,
provides us with the formula for estimating creatinine clearance in
ml/min/1.73m2. This is the glomerular filtration rate (GFR)
What is puzzling with this Cockcroft-Gault formula is the effect of age.
A 20 year-old male with a normal serum creatinine of 90 umol/l and a
weight of 75kg would give a creatinine clearance of: 120x75 =123ml/min.
90x0.81
which is normal. If this same man maintains his weight and normal serum
creatinine at the same level, but progresses to 75 years of age, his GFR
would be: 65x75 = 66ml/min.
90x0.81
which shows early chronic renal failure. In order to retain normal renal
function, his serum creatinine would have needed to have fallen as he got
older, i.e. his renal function needed to improve. Experience tells us
otherwise.
On the other hand, whilst maintaining his normal serum creatinine level of
90 umol/l., the older man can improve his GFR by putting on weight!
So how reliable is this formula?
How are the 140 and the o.81 factors derived?
Maurice Cohen -
1.- Parma. M.S. Chronic Renal Disease. BMJ 2002; 325:85-90
No competing interests
Competing interests: No competing interests
Re: insomnia in chronic renal disease
Insomnia is associated with many chronic diseases, including renal
failure, and with the administration of many medications and drugs
including anti-depressants (1).
Almost all these may be either the product of or the cause of an
impairment of mitochondrial oxidative phosphorylation (2,3). An impairment
in ox phos has also been implicated in drug addiction and jet-lag, sleep
being proposed to be analogous to the dark phase in photosynthesis in
which carbohydrates are synthesised (4,5,6). More specifically it has been
proposed that sleep is needed to replenish intra-glial glycogen stores
and/or neurotransmitter pools.
It is further proposed that insomnia might also be the product of a
biological need to prevent the rate of ATP resynthesis falling to
unacceptably low levels. An extreme example would be the transient waking
of a patient during obstructive apoea. In which case patients with chronic
renal failure are likely to be especially afflicted as observed in the
rapid response to this paper (7).Patients with chronic renal failure
appear to have chronic impairment of mitochondrial ox pos (2).
1. Stepanski EJ. Etiology of insomnia, in Sleep Medicine, Lee-Chlong
TL, Sateia MJ, Carskadon MA, Eds., Hanley and Belfus Inc, Philadelphia
2001.
2.Metformin, "lactic acidosis" and renal failure
Richard G Fiddian-Green
bmj.com/cgi/eletters/326/7379/4#28486, 6 Jan 2003
3.Depression: a metabolic perspective.
Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7370/934#26529, 26 Oct 2002
4.Addiction: an unsatisfied demand for metabolic energy?
Richard G Fiddian-Green
bmj.com/cgi/eletters/326/7385/400#29712, 17 Feb 2003
5. Intra-glial glycogen stores and jet lag
Richard G Fiddian-Green (4 March 2003) Rapid response to:
The prevention and treatment of jet lag
Andrew Herxheimer and Jim Waterhouse
BMJ 2003; 326: 296-297
6. Treating dementia with light and near infrared waves
Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7376/1312#29607, 12 Feb 2003
7. Chronic renal disease Malvinder S Parmar
BMJ 2002; 325: 85-90
Competing interests:
None declared
Competing interests: No competing interests