NODAT: an acronym you don’t want to hear

This blog entry is based on a review paper from Toronto published online in April 2015.

The authors are clinicians from the renal department of St Michael’s Hospital, Toronto, and they draw on 93 papers for their information, the majority of which were published in the last 10 years. Condensing and commenting on the significance of this number of studies is not a short task, and I have not attempted to confirm their interpretation. My aim is to translate their paper into a straight forward and simplified summary.

What is NODAT?

New Onset Diabetes After Transplant
That is, in individuals who were not previously diabetic and it refers to diabetes that persists beyond the first month after the transplant. Diabetes is caused by the body’s inability to manage blood sugar, either because the pancreas doesn’t make enough insulin or because the insulin is not being listened to by the rest of the body (insulin insensitivity).

How common is it?

Because the criteria for making this diagnosis were not established until recent years quoted figures for prevalence range from 2% to 54% of kidney transplant recipients – now thats not very helpful. The more recent figures using the WHO diagnostic criteria claim it is diagnosed in 20% of kidney transplant recipients with the highest incidence in the first 12 months post transplant.

In UK from April 2013 – March 2014 there were 3257 kidney transplants.
20% of this is 650 patients diagnosed with NODAT per year.

In US there were 17,205 kidney transplants during 2014.
That means 3440 patients in US diagnosed in one year with NODAT.

Who get’s it?

There are risk factors that you can change (modifiable) and some you cannot (non-modifiable). You can do nothing about your age (over 45), racial background (South Asian or African-American) or family history (relatives with diabetes), or your diagnosis of PKD. Nor is anyone likely to want to turn down a transplant because the donor had risk factors – deceased male donor kidneys carry an increased risk for the recipient developing NODAT. But the biggest potentially modifiable risk factor is weight. The relationship between weight and risk of NODAT is linear for everyone over 45kg, and that’s probably most of us. What is less clear is whether this relates to pre-transplant weight or the post-transplant weight gain, most likely a combination of both. Some of the underlying pathophysiology is understood – in adiposity (a nicer term for obesity?) the hormone adiponectin is reduced and NODAT is known to be associated with low levels of adiponectin. Also the amount of adipose tissue(fat) relates to increased inflammation and NODAT is associated with raised CRP (C-reactive-protein) which is a marker for inflammation.

The next big risk factors are the drugs used for immunosuppression: corticosteroids and calcineurin inhibitors (tacrolimus and cyclosporin). Steroids are quite complex in their effects on the body (the terms will trip up many a medical student and probably could be used for elocution lessons: gluconeogenesis and glycolysis both increase, glycogenesis is reduced and insulin resistance goes up) but the net effect is to increase glucose in the blood, both fasting and the surge that occurs after meals. Even in the non-transplant settings steroids are associated with the development of diabetes. It is known that the dose and duration of treatment with steroids influences the risk – the low maintenance doses of 5mg/day are less of a concern than the high doses of around 1mg/kg/day that are given early and in acute rejection.

Most patients will receive either tacrolimus or cyclosporin. I shall not go into details of how these work but tacrolimus can have greater efficacy and might be safer so is more often prescribed but it is also 50% more diabetogenic. There are 2 mechanisms behind this: deficiency of calcineurin leads to decreased insulin production and these drugs also prevent body cells from taking up glucose from the blood by diminishing the glucose transporters that line up along the cell membranes. The end result of that is hyperglycaemia, or raised blood sugar. There are studies currently ongoing which suggest changing from tacrolimus to cyclosporin in NODAT patients can reverse the diagnosis in the early stages, which is promising, though cyclosporin may cause gum hypertrophy and increased body hair so it is a question of balance.

What does it matter – what is the clinical significance of NODAT?

There are 4 elements : reduced graft survival, increased mortality, costs, quality of life.

The paper uses data from several papers and they express their conclusions in different ways – for example, one study demonstrated that patients who developed NODAT had only 48% organ survival compared with 70% for those who did not have it; this is contrasted with another paper describing the outcomes as a 17% reduced graft survival – I can easily get myself tied in knots with the glass-half-full/half-empty views so I am leaving it as a simple “the new kidneys don’t last as long in patients who develop NODAT”. Of note, both these studies were quite old, as they would be for longitudinal data, but there are some prospective studies being undertaken so more statistics will become available in time.

The greatest risk for a transplant recipient is now cardiovascular disease and there can be no doubt that having diabetes increases the risks to the heart and blood vessels. So patients with NODAT carry a higher mortality from cardiovascular disease.

NODAT needs treating with the usual drugs used in diabetes and these can add exponentially to the costs of the transplant. One paper suggests increased costs of around $12,000 per year for a NODAT patient. Along with this will be more hospital visits, restricted diet and impaired exercise tolerance. So this diagnosis is something you really want to avoid if possible.

If it happens, how is it managed?

With good management up to 50% of recent transplant patients with NODAT can revert to normal glycaemia and accompanied lowered risks. The first and most important step is to diagnose it early – which is why most units test frequently both fasting blood sugar and random measures. Other units advocate self-testing by patients. Lifestyle modification (the in-term for exercise and diet to reduce weight) might not be top on your list when you have just had a transplant, you probably feel pretty battered at this point, but it is the same message you have been getting throughout, not rocket science, just a lot harder to implement with everything else that is going on. The rest is up to the nephrologists in charge of your medication – ? reduce the steroids ? change the calcineurin inhibitors ? consider magnesium oxide supplements ? use statins and monitor both blood sugar and blood pressure often.

End comment

Survival after kidney transplant has increased dramatically over the last 50 years. NODAT is important because it contributes to both failed transplants and increased mortality. Newer studies need to incorporate the development of NODAT as an end-point in order to monitor and develop different strategies for both preventing it and managing it.

Ok, so its a random picture - you try finding one that illustrates this text! There us a slight connection - the middle jar contains needles for a diabetic pump!

Ok, so its a random picture – you try finding one that illustrates this text! There us a slight connection – the middle jar contains needles for a diabetic pump!


Main paper:      Palepu S, Prasad GVR. New-onset diabetes mellitus after kidney transplantation: Current status and future directions. World Journal of Diabetes. 2015;6(3):445-455. doi:10.4239/wjd.v6.i3.445.

Selection of other papers cited:

Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation.
de Mattos AM, Olyaei AJ, Prather JC, Golconda MS, Barry JM, Norman DJ
Kidney Int. 2005 Feb; 67(2):714-20.

Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients.
Woodward RS, Schnitzler MA, Baty J, Lowell JA, Lopez-Rocafort L, Haider S, Woodworth TG, Brennan DC
Am J Transplant. 2003 May; 3(5):590-8.

Diabetes mellitus after kidney transplantation in the United States.
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ
Am J Transplant. 2003 Feb; 3(2):178-85.

Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity.
Radu RG, Fujimoto S, Mukai E, Takehiro M, Shimono D, Nabe K, Shimodahira M, Kominato R, Aramaki Y, Nishi Y, Funakoshi S, Yamada Y, Seino Y
Am J Physiol Endocrinol Metab. 2005 Feb; 288(2):E365-71.

Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents.
Pereira MJ, Palming J, Rizell M, Aureliano M, Carvalho E, Svensson MK, Eriksson JW
J Clin Endocrinol Metab. 2014 Oct; 99(10):E1885-94.

Sirolimus is associated with new-onset diabetes in kidney transplant recipients.
Johnston O, Rose CL, Webster AC, Gill JS
J Am Soc Nephrol. 2008 Jul; 19(7):1411-8

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?
Miles AM, Sumrani N, Horowitz R, Homel P, Maursky V, Markell MS, Distant DA, Hong JH, Sommer BG, Friedman EA
Transplantation. 1998 Feb 15; 65(3):380-4. graft srvival 48% cf 70%

Posttransplant hyperglycemia. Increased incidence in cyclosporine-treated renal allograft recipients.
Roth D, Milgrom M, Esquenazi V, Fuller L, Burke G, Miller J
Transplantation. 1989 Feb; 47(2):278-81.

The association of early post-transplant glucose levels with long-term mortality.
Valderhaug TG, Hjelmesæth J, Hartmann A, Røislien J, Bergrem HA, Leivestad T, Line PD, Jenssen T
Diabetologia. 2011 Jun; 54(6):1341-9.

Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.
Cosio FG, Pesavento TE, Kim S, Osei K, Henry M, Ferguson RM
Kidney Int. 2002 Oct; 62(4):1440-6.


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s