Transplantation in diabetic patients with renal insufficiency

 

Transplantation in diabetic patients with renal insufficiencyIntroduction :

The leading cause of kidney failure in the United States, and also rising in France, diabetes is spreading in an almost “epidemic” mode. Its global prevalence of 4% in 1995 is expected to reach 5.4% in 2025 and the number of diabetic patients to increase from 135 to 300 million. In the United States, an estimated 29 million people will be reached by 2050.

In France, the prevalence of diabetes treated is 3.06% and there are about two million type 2 diabetic patients, 200,000 type 1 diabetic patients and 1,800,000 people who are unknown and untreated diabetics.

The reasons for this “epidemic” are to be found in the increase in obesity, the lowering of the glycemic definition threshold of diabetes and, for type 2 diabetes, the effectiveness of information campaigns designed to encourage screening. Along with this increase in the number of diabetic patients, the incidence of hypertensive patients is increasing. Diabetes and high blood pressure (HTA) contribute to the onset and progression of kidney failure. Earlier detection, combined with better treatment with treatments that work on the renin-angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin-2 antagonists), has certainly reduced the risk of passing to the nephropathy or the risk of evolution of it. However, the increase in the number of patients and the better management of early causes of death, particularly cardiovascular and cerebrovascular, combine to explain the number of diabetic patients reaching end-stage renal failure (see article EMC). “Diabetic nephropathies”).

For these patients, with end stage renal failure diabetic nephropathy, renal transplantation alone or combined renopancreatic takes its place. Despite the initial reluctance to explain the increased risk of cardiovascular and infectious complications in this population, the analysis of the results of transplantation compared with patients maintained on dialysis shows a clear improvement in life expectancy, which goes from 8 to 19 years, in favor of transplantation (see below).

Thus, organ transplantation is the alternative of choice for the management of IRCT in diabetic patients. This awareness led the American nephrologists to organize a task force on this subject in 2003, the results of which were published.

Evaluation of a diabetic patient before transplantation:

Stage of registration of patients on the waiting list:

Numerous studies have shown that the fate in dialysis or peritoneal dialysis of patients with type 1 or type 2 diabetes is significantly worse than patients whose initial nephropathy is not diabetes or who are not diabetic. These results are found both in patients whose initial nephropathy results from complications of diabetes and in patients with other nephropathy.

However, for the first, the other complications of diabetes, microangiopathy or macroangiopathy, have an additional negative influence on the prognosis. This derogatory prognosis is due in large part to cardiovascular complications.

In view of this observation, and since the survival of patients improves after transplantation (see below), their registration on the waiting list for a transplant must be early. It has been shown that, as with other nephropathies, a short wait time or pre-emptive transplant are success factors after transplantation. Unfortunately, US studies have shown that patients with diabetes are less likely to be referred for transplant than patients with another cause of chronic renal failure.

Optimal management involves active collaboration between referring physicians, cardiologists, diabetologists, nephrologists and transplant surgeons.

There is no proper French rule on when to conduct pre-transplant assessment examinations and then effectively transplant these patients.

However, recommendations have been published in the United States (KD / DOQI).

These specify that patients with chronic renal failure with a glomerular filtration rate of less than 30 ml / min should be referred for evaluation to a transplant center.

Patient Assessment Prior to Waiting List Patient Information:

This is an essential first step. This information must be as objective as possible. It covers not only the benefits but also the risks of transplantation (mortality, transplant failure, severe infection, morbidity, etc.).

An assessment of the candidate’s motivation and future therapeutic compliance is important, in collaboration with the treating nephrologist and diabetologist. In addition, the advantages and disadvantages of isolated renal transplantation or combined renopancreatic transplantation should be clarified.

Immunological evaluation:

This step includes the definition of the erythrocyte ABO group, the HLA (human leucocyte antigen) tissue group, and the search for anti-HLA lymphocytotoxic antibodies by various techniques (cytotoxicity, Elisa, Luminex®) and endothelial antibody antibodies. This evaluation is particularly important in the case of the indication of a combined renopancreatic transplantation since the rules of distribution of the organs taken give priority to the patients not immunized against the HLA molecules.

Medico-surgical evaluation:

It is advisable, as in the case of a transplantation in a non-diabetic patient, to study the entire medical file.

Physiological age, condition of urinary excretory pathways, quantification of eventual residual diuresis, vascular risk factors (particularly smoking), infectious, hepatic (hepatitis B, C), psychiatric history should be defined , surgical history and known allergies to drugs. As with all patients for enrollment, the status of immunization against cytomegalovirus, Epstein-Barr virus, hepatitis B and C viruses, HIV and HTLV should be clarified ( human T cell lymphoma virus), toxoplasmosis, syphilis and HHV-8 virus.

In case of transplantation in a diabetic patient, special attention is paid to the cardiovascular, trophic and infectious, ophthalmological status and, in some cases, the condition of the lower urinary tract.

Cardiovascular status:

Whether it is an isolated kidney transplant or a combined transplant, the most important evaluation is in the cardiovascular sphere. About 50 to 85% of diabetic patients over 45 have a cardiovascular pathology (compared to 35 to 50% in the dialysis population in general).

The peripheral vascular network is explored with non-invasive methods such as lower limb ultrasonography and supra-aortic trunks associated with an abdomen without preparation for calcification. If there are calcifications, the scanner without injection is an effective tool to verify the circumferential character or not. In case of a history of arterial disease of the lower limbs, plantar perforating pains or even amputation, it is necessary to obtain a more accurate imaging of the lower limbs. The relative place of arteriography or angio-MRI depends on the habits of the centers, the vascular surgeons and the patient’s renal state.

From a cardiac standpoint, coronary artery disease, which is often silent in this area, is common. Noninvasive explorations consist of thallium effort scintigraphy and stress ultrasound.

Coronary angiography is almost systematic in patients with non-invasive explorations who are over 45 years of age, or who have had diabetes for more than 25 years, or a history of severe heart disease (myocardial infarction, stent, etc.).Except for these last three points, if stress scan and stress echography are negative, it is possible not to perform coronary angiography.

In all cases, the discovery of coronary lesions must discuss a revascularization procedure to resume secondarily the process of registration on the waiting list. The role of coronary bypass graft versus angioplasty with active or non-active stent placement is dependent on the routine of the reference cardiology center. The question of the delay between the revascularization procedure and the listing on the waiting list is not decided, but is usually 6 months.Finally, renofancreatic combined transplantation may be complicated by the use of antiplatelet agents and may lead to the choice of isolated renal transplantation to reduce perioperative morbidity.

Trophic and infectious state:

The absence of any progressive infectious lesion (poor plantar perforation for example) must be rigorously confirmed in view of the surgical intervention and the immunosuppressive treatments. This contraindication is absolute in case of renopancreatic transplantation (TRP), relative in renal transplantation.

Importance of Diabetic Retinopathy:

The goal of renopancreatic transplantation is to enable perfect glycemic control. It is known that this balance may exacerbate retinopathy

severe diabetic. A recent ophthalmological examination and retinal angiography are therefore mandatory before registration on the renopancreatic transplantation waiting list.

State of the lower urinary tract:

When the surgical technique chosen involves a bladder diversion of pancreatic secretions in the case of renopancreatic transplantation, cystography or urodynamic examination is required to verify the absence of complications related to the vegetative neuropathy of diabetes.

Anesthetic consultation:

In this field in particular, a consultation with a referent anesthesiologist of a renopancreatic transplantation team is essential for the correct definition of the anesthetic risk.

Surgical consultation:

Special attention should be given to the surgical feasibility of transplantation since the vascular state of the lower limbs can be problematic.

Finally, if the indication of a combined renopancreatic transplantation is retained, the patient must be referred to a referral center approved for the practice of this type of intervention.

It is necessary to explain specifically the advantages and disadvantages of any of the techniques and to have consultation with the team surgeons because of the complexity of this procedure.

Registration on the transplantation waiting list:

In the case of type 2 diabetes or for isolated renal transplantation, waiting list and pretransplantation assessment are performed when glomerular filtration is approximately 15 ml / min.

For type 1 diabetes, the gait should occur earlier, when the glomerular filtration rate becomes less than 30 ml / min.American authors even suggest a figure of 40 ml / min, which seems excessive given the possibilities of current control of diabetic nephropathy.

Indications and contraindications:

The indications for transplantation have no particularity compared to other causes of chronic nephropathy.

These are patients with end-stage or pre-terminal chronic renal failure.

Choice of locomotion method: isolated renal transplantation or double renopancreatic transplantation:

This is the first question that should be asked during pre-transplant evaluation of a diabetic patient with IRCT. The possible alternatives are either a single transplant or a combined renopancreatic transplant at the same time, or a pancreatic transplant after kidney transplantation. The future may belong to the islet transplant Langerhans which has the advantage of being more simple technically and only compensate for the deficiency of insulin secretion. Although first results on islet transplantation after renal transplantation are beginning to be published, they are far from those obtained for diabetic patients without renal insufficiency. This excludes this possibility from the framework of our article.

The choice between renal transplantation or combined renopancreatic therapy is based on the patient’s medical indication and personal choice. Currently, in France, renopancreatic transplantation is conceivable only for patients with zero or extremely insulin secretion.

Before the proposal of a double transplant, it is therefore necessary, by the interrogation, to look for elements suggestive of insulin-dependent character from the outset. It is also essential to practice the determination of the plasma concentration of peptide C, a control of this insulin secretion. When it is impossible to dose or less than 0.5 ng / ml, the indication for renopancreatic transplantation may be used. It should be noted, however, that a team has already reported identical insulin-independence results in patients receiving a pancreas whose initial C-peptide was greater or less than 0.8 ng / ml. In addition, reflections are under way to evaluate the benefit of combined pancreatic transplantation in type 2 diabetic patients for whom insulin secretion reserves are incompatible with life after renal transplantation without insulin. The second limitation is pre-transplantation assessment, especially cardiovascular.

Finally, a psychological evaluation of the recipient potential and a frank discussion of the different alternatives must allow a free and informed decision.

Choice of locum method: type 2 diabetes

For patients with type 2 diabetes, in the case of overweight, obesity, chronological age over 45 years, and a history of cardiovascular disease, an isolated renal transplant should be offered. In the absence of these criteria, it is possible to propose a C-peptide assay, optionally coupled to dynamic tests for oral and / or intravenous glucose loading to measure the insulin secretion capacity of the pancreas. In collaboration with the diabetology team, the proposal for a renopancreatic transplant may be considered. More recently, a small study has shown that in patients with type 2 diabetes, pancreatic transplantation allowed 94% of them to become euglycemic, with in some cases a follow-up of more than 4 years.

Choice of the locum method: type 1 diabetes

With regard to patients with type 1 diabetes, and in the proven absence of C-peptide secretion, two options also open up. For these patients, kidney transplantation isolated from a live donor organ is currently considered the best option.

This type of transplant makes it possible to avoid dialysis or to reduce the time spent using this technique. However, the benefits of glycemic control offered by renopancreatic transplantation may be significant enough in some candidates to require open discussion between the transplant team and patients to reflect on these options. In the case of living donors, secondary pancreatic transplantation or islet transplantation may be proposed after stabilization of isolated renal transplantation.

After determining the need for biologic biologic transplantation, both options should be presented to the patient who is in the terminal stage of renal failure or who is on dialysis. The most effective attitude is to refer the patient to a referral center in renopancreatic transplantation for complete information and to choose between isolated or combined pancreas kidney transplantation.

Absolute contraindications:

Absolute contraindications to transplantation in patients with diabetes are few. They are limited to contraindications for transplantation in all patients. Uncontrolled infections, recent cancer and coronary heart disease can not be treated.

At present, there is no longer any absolute and definitive contraindication to renal transplantation. Two situations must however be considered with great circumspection: on the one hand the intimate conviction of a bad therapeutic compliance which almost inevitably strikes the chances of success of an organ transplant and, on the other hand, a history of psychosis because, during relapses, therapeutic compliance becomes uncertain and the future of transplantation uncertain.

Absolute but temporary contraindications are infections as long as they are not perfectly controlled and cancers in evolution. The necessary period of recession before considering a new transplant is 2 years for most cancers and 5 years for the most severe forms, but the prediction at the individual level is difficult. With regard to systemically discovered kidney cancers and in situ cancers, no wait is considered essential.

Relative contraindications (and in particular severe atherosclerosis) increase the risk of morbidity and mortality: their exact evaluation is all the more important.

Contraindications of combined renopancreatic transplantation:

There are more contraindications for combined renopancreatic transplantation, particularly because of the greater complexity of the surgical procedure on the pancreatic graft. They are also related to an increased risk of infection, linked to the derivation of the duodenum of the donor in the bladder or in the digestive tract of the recipient (see below).

Finally, combined transplantation is associated with an increased risk of rejection whose reason is only imperfectly understood.

At the end of this evaluation, if the patient’s cardiovascular status allows it and after long and clear discussions with him about treatment options, he or she may be placed on the waiting list. Thereafter, once a year, cardiac reassessment of diabetic patients, whether waiting for an isolated renal transplant or combined renopancreatic transplantation, should be performed regularly.

Although there is currently no specific evidence that good glycemic control and cardiovascular risk reduction improve pre- and post-transplantation outcomes, the management of patients with diabetes on the waiting list should be scrupulously advice from consensus conferences. In particular, it concerns glycemic control and lipid disorders, with a blood pressure of less than 130/80 mmHg, a glycated hemoglobin of less than 7% and a LDL (low density lipoproteins) fraction of cholesterol less than 100 mg / dl. Stopping smoking, exercise and good weight control are strongly recommended. The correction of anemia and phosphocalcic disorders of renal osteodystrophy is particularly important in this area.

Currently, the Biomedicine Agency is prioritizing the double kidney-pancreas transplant for patients with type 1 diabetes, who are under 45 years of age and who do not have HLA antibodies.

Renopancreatic combined transplantation techniques:

There is no surgical specificity for isolated kidney transplants in diabetic renal failure patients, except that the recipient’s vessels often leave something to be desired.

In contrast, for renopancreatic transplantation, historically, three main techniques have been applied. The three techniques are each in their own way a surgical challenge that involves the derivation of exocrine secretions from the transplanted pancreas. Indeed, with the exception of very rare external pancreatic insufficiencies associated with a deficiency of endocrine secretion (most often secondary to a total pancreatectomy), the goal of a pancreatic transplantation is only the replacement of a deficient insulin secretion.

An extremely comprehensive recent review takes stock of the techniques, their results and their respective advantages and disadvantages.

Technique of the segmental pancreas:

The segmental pancreas technique was developed by Professor Dubernard in Lyon. It relies on neoprene injection into the Wirsung canal to block pancreatic exocrine secretions, avoiding the extra sutures needed with other techniques.Since 1995, this technique has been gradually abandoned because of local complications and poorer metabolic results in the long term. These poorer results could be explained by the transplantation of a smaller mass of islets or the phenomena of chronic fibrosis secondary to the injection of neoprene.

Bladder drainage of pancreatic exocrine secretions:

The implantation of the pancreas with bladder drainage was the most used technique until 1998. Its principle is based on the suture of the duodenal collar of the donor in the bladder of the recipient, thus allowing the elimination of exocrine secretions by the urinary tract. bass.

The advantages of this technique are:

• a suture simpler than the digestive suture, especially when high doses of steroids, interfering with healing, are used;

• easy monitoring of amylasuria as a marker of rejection;

• the possibility of performing a biopsy of the organ transplanted cystoscopically.

The disadvantages are:

• the occurrence of local complications: hematuria by cystitis and chemical urethritis sometimes very painful, pancreatitis by reflux of urine in the duodenal collar and then in the Wirsung canal, recurrent urinary infections;

• the risk of dehydration due to the inevitable loss of bicarbonates.

The technique of bladder diversion is therefore burdened with a significant morbidity, source of many hospitalizations.

Secondly, it requires digestive bypass in 25% of patients at 5 years of age. This recovery is complex and leads to a risk of thrombosis of the vessels and loss of the pancreatic graft.

Digestive drainage of pancreatic exocrine secretions:

The implantation of the pancreas with digestive bypass is the most “physiological”. This historic technique had been abandoned because the large doses of steroids interfered with healing. The complications of digestive sutures were often responsible for graft loss and significant morbidity and mortality. It has been used again by the majority of centers since 1998. Indeed, surgical progress (automatic suture clamp) as well as the new powerful immunosuppressants that allow a reduction in corticosteroid doses have improved the immediate risks following the transplantation. Several techniques are described according to the higher or lower location of the anastomosis on the hail and the use or not of a loop in Y.

Advantages are :

• physiological drainage of exocrine secretions;

• the absence of urinary complications and dehydration.

The disadvantages are mainly related to the comfort of the patient in the immediate postoperative period.

A discussion remains open on the advantages and disadvantages of venous drainage in the basement system or the portal system. The latter is more physiological, but is associated more readily with venous thromboses formidable. The future will clarify the best technique. However, a recent study of the North American experience of the United Network for Organ Sharing (UNOS) registry of more than 10,000 patients showed that if portal drainage did not alter the incidence of rejection and survival of In patients treated with tacrolimus, there was no advantage over glycemic control.The difficulties inherent in the surgical technique are therefore not balanced by a frank metabolic advantage.

Immunosuppressive treatment:

Another discussion is that of optimal immunosuppressive therapy. Current trends point to the need for antireceptor monoclonal antibody-based induction of interleukin-2, superiority of mycophenolate mofetil over azathioprine and tacrolimus over ciclosporin. The Nantes team also reported the rapid elimination of steroids. This maneuver does not increase the risk of acute rejection. On the other hand, there was no benefit in terms of metabolic balance, whereas a particularly beneficial effect on this field was expected. In conclusion, the current consensus is the use of a long-term combination biologic induction therapy with treatment with mycophenolate mofetil, tacrolimus and possibly corticosteroids.

Biological induction:

A recent meta-analysis reported the results of five studies that evaluated induction therapies, with in particular three level-1 studies comparing daclizumab (a monoclonal antibody antireceptor to interleukin-2 or polyclonal anti-lymphocyte serum) to absence of induction.

All studies showed the superiority of induction therapy with a significant reduction in the incidence of acute renal or pancreatic rejection (from 76% to 36%). In contrast, the studies did not show any significant improvement in survival of patients or grafts in patients treated with biological induction.

Antiproliferative agent:

All prospective and retrospective studies suggest a benefit to the use of mycophenolate mofetil over azathioprine for the prevention of acute rejection. However, again, patient survival was comparable and between 93% and 100%, but graft survival was lower in the azathioprine group in one of the studies.

Calcineurin inhibitors:

The most important point is probably the type of calcineurin inhibitor used. If, initially, the increase in the incidence of post-transplant diabetes observed when tacrolimus was used had cast doubt on the appropriateness of its use in this population, recent studies, as well as a meta-analysis demonstrated that the use of tacrolimus in combination with mycophenolate mofetil significantly decreased the incidence of acute rejection. In addition, pancreatic survival at one year is significantly higher in patients treated with tacrolimus.

Corticosteroids:

There is growing interest in the use of low doses of steroids, with early cessation or even the complete absence of steroid use in this population due to the additional metabolic, bone, and infectious complications in this area. Rapid elimination after 6 days was reported in 126 patients. The results were comparable in terms of acute rejection. One study even reported comparable results for patients receiving or not receiving steroids after combined transplantation.It should be noted, however, that the non-use of steroids was also not associated with an improvement in the metabolic profile. The same group showed that there was no difference between a strategy with a steroid withdrawal at 3 months and a strategy favoring the absence of steroids immediately.

Post-transplant surveillance:

 

The monitoring of the grafted pancreas is based on the regular measurement of glycemia and glycated hemoglobin. The majority of teams also offer a C-peptide and insulin dosage every 3 months to check graft viability. Unfortunately, the appearance of abnormalities of these markers is very late compared to the evolution of the rejection. The practice of pancreatic graft biopsy is increasingly performed. In addition to potential technical problems, interpretation of lesions is sometimes difficult. In addition, immunological monitoring is performed on the renal graft even if there are rare cases of dissociated rejections of either organ. For renal transplantation, whether renopancreatic transplant or kidney transplant, surveillance is identical to that provided for transplantation due to non-diabetic nephropathy.

On the other hand, patients, still diabetic or former diabetics, are still patients at risk, especially infectious and cardiovascular. The diabetic disease present must continue to be followed by diabetologists, ophthalmologists and possibly cardiologists, etc. This can be particularly difficult to manage psychologically in the case of successful combined transplantation. The myth of definitive healing then collapses (K. de Vion, personal communication). Patients often have difficulty understanding this “Yes, you are cured of your diabetes but, etc. This once again emphasizes the importance of good information before transplantation.It happens that the transplanted patient refuses to see his diabetologist after transplantation, it is then the nephrologist to take charge of this. specific follow-up.

We must therefore insist on the proven results. There is a disappearance of acute disorders of glycemic regulation (risk of hypoglycemia or ketosis). Regarding the chronic complications of diabetes, renopancreatic transplantation allows stabilization of retinopathy, neuropathy (and sometimes even its regression) and cardiovascular disorders (see below). It also prevents the recurrence of diabetic nephropathy on the graft.

Current results of organ transplantation in diabetic patients with end-stage renal disease:

Type 2 diabetes:

For patients with type 2 diabetes, the comparison is twofold. This is to clarify the results of transplantation in this population compared to non-diabetic transplant patients and to compare these results with diabetic dialysis patients.

Results of transplantation compared with non-diabetic transplant patients:

Regarding the first part of the comparison, the survival of patients after isolated renal transplantation in type 2 diabetic patients is comparable to that of non-diabetic patients.

The only prognostic factor found was the age of the recipient. In contrast, in terms of morbidity, diabetic patients required more hospitalization and had a greater incidence of amputation than in the general population.

Results of transplantation compared to dialysis in diabetic patients:

With respect to the comparison with dialysis, the survival of patients with type 1 and type 2 diabetes is consistently higher. This is for example the results of the study published by Wolfe et al. in 1999. Life expectancy after transplantation was more than doubled in transplant patients compared to dialysis patients, from 8 to 19 years. Many studies have reported comparable results. The improvement in survival is mainly related to an improvement in cardiovascular morbidity and the lack of role of traditional risk factors in multivariate analysis, showing the importance of the part related to transplantation.

Diabetes type 1:

Results of combined renopancreatic transplantation compared to isolated renal transplantation:

A more difficult question is that of comparing the survival of type 1 diabetic patients who chose a combined transplant versus isolated kidney transplantation. Studies are sometimes contradictory, especially because of a control group that is difficult to define. Based in one case on the data of UNOS, and in the other on those of USRDS (United States Renal Data System), two teams published respectively in 2001 and 2003 two opposite results. In the first case, combined transplantation allowed longer survival than isolated transplantation. In the second case, after multivariate analysis, combined transplantation was no longer beneficial. It is important to note, however, that in no study (even the latter) double transplantation had a deleterious effect on patient survival. An approach to the importance of pancreatic transplantation for cardiovascular outcome is to appreciate its influence on cardiac function in patients with type 1 diabetes. Pancreatic transplantation with portal drainage induces early improvement of cardiovascular risk factors and improves heart function.

With respect to graft survival, the studies all show good concordant results.

The survival of the renal graft is greater than 90% one year after transplantation and 80% at 5 years. Israni et al. also report superiority of renal transplant survival in combination transplantation compared with isolated renal transplantation. The absence of recurrence of diabetic disease on the graft during combined transplantation as well as organs from young donors may explain these findings. These first results deserve to be confirmed.

Pancreatic graft survival in 2003 was 83% at one year with total insulin-independence of patients. These results tend to improve to more than 90% in some publications. At 5 years and 914 renopancreate transplant patients between 1994 and 2002, 71.6% of grafts were still functional. These results should be further improved in the future by the steady progress of the transplantation technique and immunosuppressive treatments. It should be noted that, even though chronic rejection phenomena are beginning to appear, the main cause of pancreatic graft loss is related to immediate technical failures after transplantation, particularly of the thrombotic type.

Consequences of pancreatic transplantation on acute and chronic complications of diabetes:

Acute complications of diabetes:

These complications obviously include ketoacetic or hyperosmolar comas and hypoglycemia. After successful pancreatic transplantation, blood glucose levels fluctuate between 0.8 and 1 g / l with a glycated hemoglobin value consistently below 6%.

The impact of pancreatic transplantation on alpha cell function is more complex. Pancreatic transplantation restores a normal glucagon response to insulin-induced hypoglycemia, even if the transplant is not orthotopic and the central nervous system-mediated responses can not be considered normal. Nevertheless, transplantation completely restores glucagon secretion and therefore increases hepatic glucose production in induced hypoglycaemia studies. It should be noted that preliminary studies have shown that this response did not exist after islet transplantation, since alpha cells were not grafted at the same time.

Chronic complications of diabetes:

This question is probably more important than the previous one since it is the first reason for morbidity and mortality in long-term diabetic patients. This is of course nephropathy, neuropathy, retinopathy, macrovascular damage and loss of quality of life observed.

Nephropathy. Studies comparing renal transplant recipients or combined grafts showed stabilization of glomerular basement membrane thickness and mesangial accumulation in double transplant recipients. These are two early signs of diabetic nephropathy. A more controversial article concluded that 10 years after transplantation, diabetic nephropathy had disappeared from the kidneys of isolated pancreatic transplant recipients. The analysis of renal function is more difficult because of the nephrotoxicity of immunosuppressants. In fact, an analysis comparing the evolution of the histological results of renal transplants with or without pancreatic grafts showed a more marked fibrotic evolution in the group of pancreatic transplant patients. This could be related to an accentuation of nephrotoxicity lesions induced by calcineurin inhibitors.

Neuropathy. It has been reported regularly that fine vegetative function tests show that pancreatic transplantation is associated with improved gastroparesis and cardiac involvement in these patients. This was documented by a 10-year study reporting stabilization of clinical examination, nerve conduction velocity, and autonomic function. Patient survival increases significantly in transplanted diabetic patients with autonomic insufficiency syndrome.

Retinopathy. Early studies failed to demonstrate a beneficial effect of pancreatic transplantation on these complications, although there were indirect arguments to suggest that this was the case. A more recent study has shown a statistically significant improvement in retinopathy. In this study of baseline data and the need for complementary laser therapy, patients receiving isolated renal transplantation had less favorable outcomes than patients receiving double transplantation.

Macrovascular disorders. Even in large-scale studies, it has been difficult to detect a difference between intensive and less intensive treatments. This is also the case for studies on renopancreatic combined transplantation. However, such a benefit has been reported recently in a longitudinal study. Coronary atherosclerosis, as measured by quantitative coronary angiography, showed that, while the lesions continued to worsen with pancreatic graft loss, there was no change in diameter on average 4 years after successful transplantation.

Quality of life. In terms of quality of life, the benefits of isolated transplantation or combined versus dialysis transplantation are unclear. In combination transplantation compared to isolated transplantation, it frees the patient from the need for antidiabetic therapy, regular monitoring of blood glucose levels and adherence to a diet. Resumption of a normal life is possible, which represents a real psychological shock in these diabetic people with sometimes more than 25 years of illness behind them. All studies are therefore in the direction of improving the quality of life. However, the part of each transplanted organ (kidney and pancreas) in this improvement is difficult to specify. One study showed a better quality of life in patients with a functional pancreas than in those who had lost their pancreatic graft. These studies take into account many criteria including the adverse effects of the immunosuppressive treatments used as well as the surgical procedure.

Conclusion:

Transplantation is the therapy of choice for the management of a diabetic patient with IRCT. These are renopancreatic transplantation for type 1 diabetic patients and isolated renal transplantation in type 2 diabetics, with rare exceptions.

The hopes rest on improving the results and opening the transplant to more diabetic patients.

There, as elsewhere, there is a shortage of organs. This is all the more true as the limits of indications are constantly being pushed back and the necessary organs must come from young donors.

The second great hope lies in the transplantation of the islets of Langerhans, which greatly reduces the surgical problems currently responsible for perioperative morbidity and mortality.

The surgical procedure is simple: percutaneous approach of the portal vein followed by an intrahepatic injection of purified islets. The development and marketing of immunosuppressive molecules theoretically less and less toxic to islets should promote this technique. The insulin-independence results continue to improve, exceeding in the short term 80% in some teams.

However, islet transplantation is currently mainly performed in patients with type 1 diabetes whose renal function is preserved. Some teams are beginning to successfully transplant diabetic kidney patients or patients who have had kidney transplants and have lost their pancreas in a second time. It is the sequential use of different substitution techniques that should allow the future to best serve the benefit of diabetic patients, even if recent results are more disappointing.

 

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