Slide 1

Thank you Mr Chairman and I also would like to thank the organising committee and especially Anders Alvestand who invited me to give this speech on my favourite subject the diabetic foot. Nephropathy and diabetes are associated with increased risk for a foot ulcer and also a several-fold increased risk for amputation.

Slide 2

So what are the risk factors for chronic foot ulcers in patients with nephropathy?

Slide 3

As you can see, the peripheral neuropathy is a very important risk factor that can be due to high PTH which can induce, as some researchers have shown, neuropathy, it can be due to hypoxia, neurotoxins and diabetes per se. Ischemia is the next most common cause of chronic foot ulcers in diabetes and nephropathy. Microangiopathy is important especially Mönckeberg sclerosis, calciphylaxis, and hypertension. Hypoxia is also due to hemodialysis, peripheral oedema and anaemia.
Malnutrition is an independent risk factor for non-healing ulcers.
Oxidative stress is now well studied and is a very important factor leading to chronic foot ulcers, which can be induced by hemodialysis, abnormal glucose tolerance and hyperlipidemia, as well as chronic inflammation.

Slide 4

So what about foot ulcers in diabetes? This was published in Lancet a couple of years ago. It is one of the most feared complications for diabetic patients. So in different countries 8-25% of the population with diabetes will have during life time chronic foot ulcers. This 20-40 times increased risk for amputation if you have diabetes. While we are talking here for one hour in this symposium there will be 120 patients that will be amputated below the knee due to diabetes and foot ulcers. Several millions will have this problem at the moment and the costs are very high but we can reduce the complications. They can be prevented by care and identifying the risk.

Slide 5

The development of chronic foot ulcers are dependent on all the factors that the diabetic patient can suffer from. Neuropathy, microangiopathy, macroangiopathy, impaired coagulation, urology, hyperglycemia per se which I’ll show you, infection, malnutrition, impaired immune response. All these factors lead to the chronic foot ulcer in both diabetes and in patients with nephropathy.

Slide 6

The most common causes of amputation today are ischemia, ischemia in combination with infection and have nephropathy, especially ESRD. In Karolinska Hospital, 50% of amputations were associated with nephropathy or ESRD in the males and 30% in the females. Non-healing foot ulcers can also be a cause for amputation after several years.

Slide 7

Wound healing is delayed in diabetes. For a neuropathic foot ulcer with good pulses, good circulation, the mean healing time is half a year. For neuroischemic foot ulcer, the median healing time is one year.

Slide 8

So why does acute foot ulcer lead to a chronic ulcer? Many factors; hyperglycemia are probably the most important as well as impaired oxygenation. Infection, increase in protease activity; decreased growth factor activity, malnutrition are important factors and also non-compliance.

Slide 9

Here’s a chronic wound in type 1 diabetic patients, it has been there for 5 years.

Slide 10

Here’s a chronic wound in a type 2 diabetic patient which have been there for 5-6 years.

Slide 11

Hyperglycemia is the main cause of foot ulcers.

Slide 12

We can see here amputation in the left corner down, you can see that amputation in the lower left corner. The higher the HbA1C, the higher the risk for amputation in type 2 diabetic patients.

Slide 13

If you take fibroblasts from the diabetic patient’s foot ulcer, the fibroblasts don’t grow normally. The lower line here represents a diabetic foot ulcer fibroblast, while the normal fibroblasts or the non-diabetic fibroblasts from chronic bones grow better (upper lines).

Slide 14

If I take animals with high glucose, the DBDB mice, you can see that the mice don’t heal their wounds, in spite treatment with growth factors.

Slide 15

If you grow the fibroblasts in high glucose, the hatch bars, they don’t respond to growth hormones or insulin compared to those who are grown in normal glucose.

Slide 16

But if you treat the fibroblasts with anti-oxidants like vitamin E or Q10, they grow normally again.

Slide 17

If you treat them in a hyperbaric oxygen they also grow normal again.

Slide 18

Hypoxia is a very important factor.

Slide 19

This was shown many decades ago. You can see that if you have low oxygenation (the hatch bars) of the tissue, you don’t heal the wound compared to normal oxygenation.

Slide 20

We showed some years ago that patients with low oxygenation measured as the TcPCO2 at the wound area had a high risk for amputation and non-healing during a follow up for 1 year.

Slide 21

We have also shown that capillary blood flow is reduced if high blood glucose.

Slide 22

Hypoxia is very dangerous for the patient and for the wound. Hypoxia Inducible Factor, HIF-1 alpha is the most important transcriptional factor for adaptation to hypoxia.

Slide 23

HIF is regulating a lot of genes important for adaptation.

Slide 24

We found that in diabetic chronic foot ulcers a very low expression of the HIF 1 alpha compared to those with non-diabetic chronic ulcers.

Slide 25

We found the same when we cultured cells in high glucose an hypoxia.

Slide 26

The diabetic’s condition impaired the response to hypoxia with low expression of target genes.

Slide 27

So we treated diabetic mice with factors that could stabilise HIF-1 alpha and then we could normalise the wound healing in these mice.

Slide 28

Hyperglycemia also causes oxidative stress that causes hypoxia through impairment of NO synthesis, for example.

Slide 29

We believe that in diabetes and nephropathy there are too many radicals which cannot be neutralised by enough anti-oxidants due to different factors like inflammation or genetic polymorphism.

Slide 30

We know from Brownlee’s theory that if we can block the ROS production in the mitochondria, we can also normalise the signalling pathways

Slide 31

This has also been shown by Ceriello.

Slide 32

There is an international consensus regarding treatment of diabetic ulcers. The team work is very important. The team work of specialists have to see that there is optimal oxigenation of the tissue, optimal metabolic control and nutrition, infection control and normal off-loading. All these factors are important for wound healing.

Slide 33

So how to improve skin circulation? If no palpable foot pulses or a low ankle pressure or low TcPO2, we have to refer the patient immediately to a vascular surgeon. But we can also do other things if the surgeon can’t improve the circulation, such as improve the microcirculation; using aspirin, stop smoking, treat the oedema, the pain, the anaemia. We have to treat polycythaemia, heart failure and hyperlipidemia. Also it’s very important to have a non-weight bearing treatment/off-loading. We have shown that treatment with low molecular weight heparin, Fragmin, improved oxygenation of the tissue and wound healing as did treatment with hyperbaric oxygen.

Slide 34

Here’s a patient with nephropathy and a ulcer that came from a small crack in the heel. He healed with medical treatment including Fragmin.

Slide 35

Here’s another patient with Mönkeberg sclerosis and ulcers of the toes and heels. He had also nephropathy and diabetes.He healed most of the ulcers. He healed without vascular surgery. Only one toe was amputated.

Slide 36

We showed that Fragmin, low molecular heparin, could reduce amputations by 70% and improved healing.

Slide 37

We also showed that hyperbaric oxygen is very important if we cannot do anything else to rescue the leg. It’s only good if the patients have low basal TcPO2 at the wound bone area but respond with a several-fold increase in oxygen after inhalation of 100% oxygen.

Slide 38

This is a hyperbaric oxygen chamber.

Slide 39

And this is a young girl with an arterial thrombosis of the tibial artery. They were going to amputate but she was treated successfully in the hyperbaric chamber, the ulcer healed.

Slide 40

This is a type 2 diabetic patient that came acute with newly diagnosed diabetes, foot ulcer and nephropathy And you can see there is a severely infected ischemic wound.

Slide 41

Slide 42

He was treated with vascular surgery, surgical debridement and HBO and it healed in a couple of months.

Slide 43

We showed in another study that if you treat the patient with HBO, you can also save the legs, with 70% less amputation when we followed the patient for 3 years.

Slide 44

A good metabolic control is also very important and insulin is required in most cases to achieve normal blood glucose,

Slide 45

Slide 46

Infection control is also very important. Surgical debridement is the first choice and then of course, high doses of antibiotics for several weeks and the results for the wound culture healing decides how long you shall continue with the antibiotics.

Slide 47

Off-loading on the wound is also very important and to check the effect of offloading equipment, you can use this very easy lipstick test.

Slide 48

This is a patient with a foot ulcer for 5 years.

Slide 49

I checked the offloading of his insoles and shoes with a lipstick on his dressings on the ulcer.

Slide 50

When I saw these marks on the insoles I knew that the off-loading was not adequate.

Slide 51

So we changed the insoles and then the wound healed in a couple of months after being there for 5 years.

Slide 52

Wound dressings are important but there is no consensus on what kind of wound dressings you should use. But don’t use occlusive dressings and never wet dressings on ischemic ulcers. It’s always important to document the wound area and the characteristics of the wound at each visit.

Slide 53

Finally regular examination of the foot at risk and foot care, as well as early treatment of newly discovered foot ulcers by a multidisciplinary team can reduce amputations up to 80% of the cases.

Slide 54

Thank you for your attention.