Surprises from the 1994 Modification of Diet in Renal Disease (MDRD) study

Low-protein disappoints; attention drawn to proteinuria and blood pressure

The MDRD study was a landmark trial set up to prove the importance of dietary protein in slowing the progression of kidney failure.  This had been shown in animal models but human studies were not so clear.  It was combined with using two different blood pressure targets, as again these seemed important in animal studies but it was not clear how much we should lower blood pressure in patients.

Patients were recruited from nephrologists and by advertisement; they were known to have a kidney diagnosis. They were not simply people found to have reduced kidney function by random testing.  Diabetic nephropathy was excluded but diagnoses were varied.  25% had glomerulonephritis.  Almost as many had the genetic condition polycystic kidney disease (PKD, a group you might think whose outcome would not be altered so much by control of diet or blood pressure. 

The patients were divided into these groups with higher or lower protein intake, and higher or lower blood pressure: 

Study	GFR	Protein intake	Blood pressure
1 (n = 585)	25-55	Usual protein (1.3 g/kg/d)   or Low protein (0.58 g/kg/d)	140/90   or 130/80
2 (n = 255)	13-24	Low protein (0.58 g/kg/d)   or Very low (0.28 g/kg/d)	140/90   or 130/80

The very low protein diet was supplemented with essential keto acids and amino acids.  Glomerular filtration rate (GFR) was measured every 4 months by iothalamate clearance and normalised for surface area (/1.73m2). Follow up was for an average of 2.2 years. 

The Results were surprising
Diet had no impact on rate of loss of GFR or on the number of patients starting dialysis or dying, in either the low or the high GFR groups.
Blood pressure control had no overall effect, but there was a striking benefit from the lower blood pressure target for those with over 1g of proteinuria per day.  The benefits increased further as the amount of proteinuria rose. 

Decline in GFR in study 1.  Usual protein group is the dashed
line and low-protein the solid line.  No significant difference.
There was an early fall then slower gradient in the low-protein
group but no overall benefit. 

Deaths and ESRD in study 2.  Very low protein is the solid

line, low protein is the dashed line.  Figures from Klahr et
al as below, with permission from NEJM.

Diet enthusiasts have hoped that there might be a silver lining, but one has not emerged.  If there is any long term effect, it seems to be slight.  Worse, a 10 year analysis of what happened in the low-GFR group (Study 2) showed that those who had been allocated to the very low protein diet started dialysis no later than the low protein group, but were twice as likely to have died (Menon 2008).  The effect seemed to persist long after the study had finished.  Surely the last nail in the coffin of very low protein diets, and confirming Thomas Addis's caution about low protein diets in 1949, 'We are trying to do something dangerous'. 
What else did the trial achieve?  Well scores of other studies have come from analysing the details of the rich data collected in the MDRD study.  The best known is the MDRD equation, a formula for estimating GFR from serum creatinine which is now in near universal use.  
A couple of interesting subgroup analyses were mentioned in the original paper.  Patients with polycystic kidney disease did not appear to benefit from blood pressure control.  The 53 black patients had a higher rate of loss of GFR than other patients, but it was half the rate in those allocated to the lower blood pressure target group.

Why were the diet results so negative?  The conclusion should be qualified: it was not that diet is useless.  It was that lowered protein diets are not helpful in well supervised patients with good blood pressure control.  Even the higher blood pressure group in MDRD had pretty good blood pressure control.  Animals with renal failure probably have comparatively much higher pressures. 

How high can protein intake safely be?  With those animal experiments in mind, plus a number of concerning anecdotes about the effects of protein supplementation on kidney disease in some individuals, few dare to recommend exceeding 'moderate' protein intake. 
Personal view:  If blood pressure control is poor or supervision difficult, you might argue for lower intakes.  If you cannot or do not want to use dialysis to control symptoms in advanced uraemia, targets could be lower still.  

Further reading
Diets for chronic uraemia - on this blog
Klahr S et al.  The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease.  New Engl J Med 1994 330:877-84
Menon V et al.  Effect of a very low protein diet on outcomes: long-term follow-up of the MDRD study.  Am J Kidney Dis 2009 53:208-17.

Twins in transplantation

Groundbreaking - and lucky to have one

John Merrill shows the Herrick twins an early dialysis machine

On December 23rd 1954, 24 year-old Richard Herrick became the first successful kidney transplant recipient in Boston, Massachusetts. He was lucky both to be in Boston, and to have an identical twin brother Ronald who was prepared to take the risk to help him, as at that time the problems of rejection were known but not soluble.
Joseph Murray, the surgeon, had perfected the surgical technique in dogs.  The kidney was anastamosed onto the iliac blood vessels in the pelvis outside the peritoneum, as originally developed in France.  Much the same operation is used today.  Murray had already undertaken 20 transplants of cadaver kidneys into dying patients, usually into the groin and with admission to patients of their experimental nature, but none of them successfully. 
The recovery of Richard Herrick's health, anaemia and nutritional state were remarkable.  He died of a heart attack 8 years later, while his genetically identical brother lived 56 years longer until December 2010, perhaps an early pointer to the cardiovascular consequences of kidney disease.


Edith Helm was 20 and just married in Oklahoma in 1956 when she was told she was dying of renal failure.  However she had a twin, Wanda, and later that year travelled to Boston to become the first woman to receive a successful transplant.  Before the operation the sisters were visited by Richard Herrick.  As she was leaving the hospital in August 1956, she said 'Ive never been operated on before, never been east before, never been on a plane before. This has really been an experience'  She lived 54 more years until April 2011, going to work as a school cook, and becoming the first transplant patient to give birth, having a son and a daughter. 

A total of 12 identical twin grafts had been carried out in Boston by 1961, 35 around the world by 1965.  In long term follow-up, 4 of the first 7 died later of renal failure following the recurrence of nephritis in their grafts, in the absence of immunosuppression. 

The UK's first successful transplant was between 49 year old identical twins in October 1960.  Means to prove that they were identical are described in detail in Woodruff's 1961 paper, and were essentially the same as used by Murray and Merrill in Boston, based on appearance, fingerprint patterns (undertaken by local police in Boston), detailed blood grouping, haptoglobin variants, and finally on skin grafting.  A square of skin was taken from each twin and transplanted to the other.  This proof of immunological identity and tolerance between identical twins was first demonstrated in 1937.

Reciprocal skin grafts between the
Edinburgh identical twin brothers

Skin grafts like this were used to prove tolerance between a pair of non-identical (male and female) twins who had exchanged some bone marrow in utero.  Very unusually their blood showed two blood types: the man had 86% group A red cells and 14% group O, while the woman had 99% O and 1% A.  The skin grafts were not rejected (Woodruff 1959). This provided evidence that tolerance might be achievable without drugs one day.   Experience in twins suggests it could be at the expense of a higher incidence of disease recurrence. 

Many different approaches to suppressing rejection were investigated in these early days and modern regimens were arrived at step by step, with azathioprine being the first key success after the failure of irradiation treatment.


Further reading
Murray JE, MP Merrill, JH Harrison.  Renal homotransplantation in identical twins.  J Am Soc Nephrol 12:201-4 (reprinted from Surg Forum 1955 VI: 432-6)
Woodruff MFA, JS Robson, JA Ross, B Nolan, AT Lambie.  Transplantation of a kidney from an identical twin.  Lancet 1961 ii 1245-9
Murray JE. Human organ transplantation: background and consequences. (from Nobel Prize Lecture 1990).  Science 1992 256:1411-15
Woodruff MFA, B Lennox. Reciprocal skin grafts in a pari of twins showing blood chimaerism. Lancet 1959 ii 476-8
Tilney NL. Renal transplantation between identical twins: a review.  World J Surg 1986 10:381-8

Diets for chronic uraemia

1949-1993:  Addis to Giovannetti

It didn’t work for her: a 46 year old female patient who stopped

her diet. Note that it was lowering urea but not creatinine.

From Shaw et al 1965, by kind permission of OUP.

Low protein diets were shown to prolong the life of uraemic rats in experiments in the 1930s, and it was long held that the products of protein metabolism (which included Urea) were major contributors to the symptoms and signs of uraemia.  In the late 1940s, no-protein no-electrolyte diets, the Borst and Bull regimens, were introduced for conservative management of acute renal failure. 

Thomas Addis was a strong proponent of low protein intake for chronic uraemia too.  In his classic 1949 book Glomerular Nephritis he talked of ‘resting the kidney’, perhaps now interpreted as reducing hyperfiltration, and carefully explained how to achieve it in partnership with patients, dietitians and nurses in the real world. However he also commented

“We are trying to do something dangerous.  We are always on the edge of a possible deficiency”. 

Referring back to data from the 1920s, when the minimum protein intake compatible with neutral nitrogen (protein) balance was estimated, he prescribed 0.5g of protein per kg weight per day.  This was increased by any amount lost in urine, and a bit more was alllowed for growing children.  These principles became widely accepted and followed. 

Giordano in 1961 was probably the first to advocate a much lower protein intake, 18g, with supplementation of essential amino acids, but this idea became more widely associated with the name of Giovannetti after a 1964 paper in The Lancet.  It is interesting that this more extreme management came into vogue just at the time that dialysis and transplantation were beginning to develop.  Perhaps there was increased awareness of end stage renal disease, and it was all too obvious who could not be eligible for these new experimental and expensive treatments.  The aim was to reduce the symptoms and prolong the life of patients with advanced and terminal uraemia, when symptoms could be severe on more moderate protein restriction.

Giovannetti’s patients were 27-52 years old and had creatinine levels of 900-1600 micromol/l (10-18 mg/dl) on admission.  Some of them needed temporary dialysis (the only kind available most likely) to stop vomiting before they could start their diet, but then symptoms improved.  The severity of renal failure in their patients is apparent from their report.  Two of 8 died but the others remained alive at 10 months. 

The diet

Attempts to simplify the regimen, and make it more acceptable in the Northern Europe of the time by replacing the starch-based spaghetti with bread recipes designed for patients with phenylketonuria, were described by Berlyne and colleagues in Manchester in 1965.  Glomerular filtration rates varied from 1 to 5 ml/min.  Those with values greater than 2.5 ml/min tended to do better.  They reported lowered urea and phosphate and improved (but persistent) acidosis, and perhaps most importantly, reduced anorexia, nausea and vomiting.  In a later paper they also described less drowsiness so that patients tended to die in a bleeding-agitation syndrome, which doesn’t sound such a great success. On this diet death occurred when creatinine was over 1800 micromol/l (20 mg/ml), urea a mean of 80 mmol/l (230 mg/dl) (see Figure).  Urea:creatinine levels were generally lower on very low protein diets. 
All groups commented on the unpalatability of these diets (click on the diet sheet image to the right) and how difficult patients found it to adhere to them, and to maintain adequate intake, although they seemed to achieve their purpose in the short term. 

A number of mostly small and flawed human studies during the 1980s supported that low protein diets reduced the rate of loss of function in patients, a conclusion supported by further animal experiments.  However it was not until the Modification of Diet in Renal Disease (MDRD) study in 1994 that the real value of low protein diets in human kidney disease became known.  And the answer was not at all what was expected. 

Further info
Conservative dietary management from edren (www.edren.org)
Addis T.  Glomerular Nephritis.  Macmillan (New York) 1949. 
Shaw AB, FJ Bazzard, EM Booth, S Nilwarangkur, GM Berlyne.  The treatment of chronic renal failure by a modified Giovannetti diet.  Quart J Med 1965 34:237-53
Giordano C.  Treatment of uraemia using essential amino acid and low protein diets. 1963 Proceedings of the 2nd International Congress of Nephrology 752-7
Giordano C.  Protein restriction in chronic renal failure.  Kidney Int 1982 22:401-8
Giovannetti S, Q Maggiore.  A low-nitrogen diet with proteins of high biological value for severe chronic uraemia.  1964 Lancet 1964 i 1000-1003