- Email: [email protected]
Simultaneous islet-kidney and islet-after-kidney transplantation
C H A P T E R
35 Simultaneous islet-kidney and islet-after-kidney transplantation Roger Lehmann Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zürich, Switzerland
O U T L I N E Introduction
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Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia 426 Treatment algorithm for beta-cell replacement therapy depends on kidney function
429
Conclusions
429
References
431
427
Introduction Both transplantation of isolated islets of Langerhans, as well as whole organ pancreas transplantation, are treatment options in the care of patients with type 1 diabetes mellitus. Both transplantation options can be conducted alone or in combination with a kidney. Whereas simultaneous pancreas-kidney transplantation (SPK) is an intervention with proven benefits in terms of survival,5 conflicting results in pancreas transplantation alone have been published.6, 7 By providing a source of endogenous insulin secretion, both transplantation options aim at improving glycemic control. Yet, while insulin independence is routinely achieved in the majority of pancreas transplantation and is still present in 60%–70% of patients 5 years after transplantation,8 recipients of islet transplantation need more than one transplantation to achieve insulin independence in most cases and insulin independence is lost in more than 70% after 2 years.9 However, in selected cases, the insulin independence rate at 5 years with modern immunosuppression (anti-TNFα treatment) was the same in islet and pancreas transplantation.10 On the other hand, the
Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00035-6
Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA)
rate of complications is high in pancreas transplantation with up to 40% of patients undergoing re-laparotomy during the first 3 months,11 whereas laparotomy rate in islet transplantation is as low as 1%–3%.3, 9, 12 Data on transplantation outcome of SPK transplantation directly compared to simultaneous islet-kidney (SIK) transplantation is rare. However, there are only few data regarding their long-term effect, in particular when compared to each other.3, 12 We reported a 5-year follow-up of SPK vs SIK transplantation,12 and a comparison of pancreas vs islet transplantation alone was presented recently, but this study did not include information on glycemic control,13 therefore the recently published 13-year old follow-up represents the first trial, which proved that the transplanted kidney can be protected by both islet or pancreas transplantation (either as simultaneous transplantation or after kidney transplantation).4 In this review, we carefully elaborated a comprehensive treatment algorithm for either simultaneous pancreas-kidney or islet-kidney transplantation, or for pancreas- or islet-after-kidney transplantation (Fig. 1). A joint transplant team with expertise in islet-, pancreas-,
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© 2020 Elsevier Inc. All rights reserved.
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35. Simultaneous islet-kidney and islet-after-kidney transplantation
TABLE 1 Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA) Criteria
Islet transplant
Pancreas transplant
Patient decision
High operative risk (coronary heart disease, cerebrovascular disease, calcified large arteries, …)
Possible after careful work-up
Contra-indicated
Not possible
High recipient age (>50–55 years)
Possible
Generally not accepted
Not possible
Despite education and technology (pump, CGM) never HbA1c < 8.0%
Usually lower insulin independence rate
Higher insulin independence rate
Possible
Never accepted T1D, hates injections, and glucose measurements
Not optimal option
Preferred treatment option
Possible
Recipient age 18–50 years
Possible
Possible
Possible
Low perioperative complications, short hospitalisation
Preferred
Not optimal
Possible
Long-term protection of transplanted kidney from diabetic Possible nephropathy
Possible
Possible
Prevention of severe hypoglycemia
Possible
Possible
Possible
Islet transplantation: no reimbursement
Not optimal solution
Possible
Possible (if costs covered)
and kidney transplantation sees and evaluate the transplant candidates. They explain the procedure and possible complications and respect the patients’ transplant preference (Table 1) when it is compatible with indications and contraindications.
Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia Pancreas and now more frequently also islet transplantation can correct most of the symptoms and stabilize the complication of T1D14 and in particular prevent hypoglycemia, improve impaired glucose counter-regulation, and return hypoglycemia awareness, and thus ameliorate problematic hypoglycemia in T1D.3, 15 The risks of the transplant procedure and the need for life-long immunosuppressive therapy and limited availability of organs represent major limitations to widespread implementation in patients with problematic hypoglycemia refractory to educational and technological measures. While pancreas transplantation is an established treatment modality and islet transplantation remains investigational in the United States, islet transplantation is approved and reimbursed in many other countries (Canada, Switzerland, France, Italy, Sweden, Denmark, Norway, and Australia). Because not all patients are surgical candidates for pancreas transplantation (Table 1), and because not all pancreata are technically suitable for whole organ transplantation, islet and pancreas transplantation are evolving as complementary approaches to β-cell replacement. The goal is either to eliminate problematic hypoglycemia or to protect the transplanted kidney from glucose-related damage in T1D.4
The majority of pancreas transplants are performed simultaneously with a kidney (SPK) transplant in those with renal failure and show superior long-term graft function than when transplanted after a kidney transplant or alone.16 In a patient already immunosuppressed for a kidney transplant, when the added surgical risks are acceptable, the addition of a pancreas transplant may be considered to normalize glycemia, stabilize diabetes complications, and prevent recurrent diabetic nephropathy. In the presence of problematic hypoglycemia, a stronger case may be made for pancreas-after-kidney (PAK) or islet-after kidney (IAK) transplant where elimination of severe hypoglycemia is achieved for the life of the graft at the expense of a higher complication rate in the case of pancreas transplantation, or with a small additional risk with the minimal invasive islet transplantation. With SPK and as shown recently also in simultaneous islet-kidney (SIK) transplantation, the majority of recipients can expect amelioration of problematic hypoglycemia for more than a decade.3, 16, 17 Most islet transplants are performed either alone (ITA) for problematic hypoglycemia or as simultaneous islet-kidney (SIK) or islet-after-kidney (IAK) transplant in T1D patients experiencing advanced diabetic nephropathy. While the durability of insulin-independence is superior with SPK, similar rates can be observed with pancreas transplant alone (PTA) compared with islet transplant alone (ITA).10, 13 In fact, in selected centers, over 50% of ITA recipients may remain insulin-independent after 5 years.10 While unselected Collaborative Islet Transplant Registry data indicate the majority of islet recipients may return to requiring some insulin therapy by 3 years following transplantation, amelioration from problematic hypoglycemia is observed for the duration of graft function, currently retained in 90% of recipients at 4–13 years.3, 18
B. Islet allo-transplantation
Treatment algorithm for beta-cell replacement therapy depends on kidney function
Islet and pancreas transplantation are the only approaches to date that have documented both sustained recovery from hypoglycemia-associated autonomic failure (HAAF) and restored glucose counter-regulation (by endogenous glucose production) in long-standing T1D (mean 25–30 years of disease duration). Even partial islet graft function has been associated with improvement in the endogenous glucose production response to insulin-induced hypoglycemia,19 explaining protection from problematic hypoglycemia by islet grafts even when insulin may be required to maintain near-normoglycemia. Documentation of protection from problematic hypoglycemia by pancreas or islet transplantation in T1D also comes from studies involving CGM. SPK recipients have been shown to exhibit normal mean glucose and no time spent in hypoglycemia (<60 mg/dL/<3.3 mmol/L).20 Similarly, in a study of SPK and IAK recipients, both transplant groups had significantly reduced mean glucose, glucose variability and time with glucose values <60 mg/dL/<3.3 mmol/L compared to a group with a comparable duration of T1D managed by insulin pump treatment. Subsequent studies have shown that the significant reductions in mean glucose, glucose variability, and time spent in hypoglycemia according to new international guidelines (<54 mg/dL/<3.0 mmol/L) relative to T1D were similar for both insulin-independent and insulin-requiring islet recipients,20 and sustained for as long as 18 months.21 Importantly, Vantyghem et al.22 have shown that minimal islet graft function is necessary to abrogate hypoglycemia (<54 mg/dL/<3.0 mmol/L), and confirmed that even suboptimal function (requiring insulin) significantly improves mean glucose and glucose variability. That glycemic control benefits are imparted by the islet graft has been further supported by the demonstration of significant continuous associations with stimulated C-peptide levels in islet transplant recipients.23 This avoidance of hypoglycemia with islet or pancreas transplantation as documented by CGM best explains the documented reversal of HAAF, which in turn, assists in the recovery of glucose counter-regulation and hypoglycemia symptom recognition, reversing the vicious cycle of hypoglycemia begets hypoglycemia in T1D.24 In summary, in a program for T1D kidney transplant recipients, islet transplantation is considered simultaneously with or after kidney transplantation for patients who are not surgical candidates for, or not willing to accept the additional risks of pancreas transplantation (Table 1).3 At 512 and 13 years,4 while the insulin- independence rate was higher with recipients of pancreas vs islet transplantation, the islet transplant group experienced significantly less operative complications, and both forms of transplantation significantly improved glycemic control and reduced severe hypoglycemia by >90%.4
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Treatment algorithm for beta-cell replacement therapy depends on kidney function The proposed treatment algorithm (Fig. 1) takes into account the number of patients with T1D with problematic or recurrent severe hypoglycemia, existing educational tools and technologies to reduce hypoglycemia, and available resources for these treatment strategies and transplantation in T1D and might, therefore, require adaptation by individual countries or reimbursement plans. The strategy is different if the patient has endstage kidney disease. Now kidney replacement treatment has the highest priority and beta-cell replacement has the benefit of protecting the transplanted kidney from hyperglycemic damage and of preventing severe hypoglycemia (Fig. 1). If the careful evaluation indicates a possibility for transplant intervention, kidney function is the main determinant of whether islet or pancreas transplantation alone should be considered (e-GFR >60 mL/min), or if a living-kidney transplantation should be performed first, followed by islet or pancreas transplantation. If no living donor is available, either a combined islet- or pancreas transplantation simultaneous with a kidney may be indicated (Fig. 1). Reduced kidney function is by itself a risk factor for severe hypoglycemia.25 An e-GFR between 30 and 60 mL/min pretransplant as compared to e-GFR > 90 mL/min/1.73 m2 increases the risk for developing the end-stage renal disease after the introduction of calcineurin inhibitor-based immunosuppression by 2.25-fold.1, 2 Very recently, a 13-year follow-up of simultaneous pancreas- or islet-kidney transplantation or pancreas-/islets after kidney transplantation in the same institution showed that the very high rate of severe hypoglycemia in this group of patients could be reduced significantly from 3.5 to 0.05 and 0.1 per patient years in the SPK/PAK and SIK/IAK groups, respectively.3 In combined transplantation the focus is to avoid severe hypoglycemia and protect the transplanted kidney from hyperglycemic damage, which can be achieved by both approaches (pancreas- and islet transplantation),3 whereas in islet cell replacement alone the focus is primarily avoidance of severe hypoglycemia and normal or near-normal glucose control and only secondarily insulin independence26 as the fourth step of the previously proposed treatment algorithm for problematic hypoglycemia.4 Another crucial factor is the reimbursement policy of each country or insurance plan. If an expensive technology option does not deliver the expected results within a 6-month period, it may be discontinued. While in many countries health insurance reimburses insulin pump treatments, CGM is not. The same is true for β-cell replacement, while in many countries pancreas transplantation is reimbursed, a much smaller number of countries
B. Islet allo-transplantation
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35. Simultaneous islet-kidney and islet-after-kidney transplantation
FIG. 1 Evidence-based treatment algorithm for patients with T1D and severe hypoglycemia with and without reduced kidney function. Adapted from Choudhary P, Rickels MR, Senior PA, Vantyghem M-C, Maffi P, Kay TW, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 2015;38(6):1016–1029.
reimburse islet transplantation. Cost-effectiveness of these technologies have not been tested in larger populations and it will take many years (10–15 years)27 to prove cost-saving or at least cost-effectiveness, whereas QoL improves in most trials. Individualized treatment targets must balance the risk of complications and the risk of hypoglycemia, trying to achieve the lowest attainable HbA1c without problematic hypoglycemia. According to the literature, it should be possible to achieve an A1c between 7.2% and 8.0% with educational programs and technology (without beta-cell replacement). In keeping with this treatment goal, it is important to regularly assess the frequency and risk of hypoglycemia. Many patients rarely or never inform their general practitioner/specialist about their hypoglycemia.28 Providers should directly inquire about hypoglycemic episodes and, if present, use the tools available to quantitate impaired awareness hypoglycemia,29, 30 hypoglycemia severity, and glycemic lability.31 Measurement of glycemic variability using simple measures such as standard deviation (>40 mg/dL/>2.8 mmol/L),22 or the coefficient of variation, or more complex measures such as low blood glucose index (LBGI)32 can also be valuable (Table 3).
The first step in patients identified with problematic hypoglycemia is to evaluate possible underlying causes of hypoglycemia and to evaluate if the actual HbA1c is at the individual target. If the patient is not a target, the first line of intervention is structured education or hypoglycemia-specific education (Fig. 1). The evidence base supports use of educational programs such as intensified insulin treatment and teaching or functional insulin therapy (FIT),34 DAFNE program,35 and BGAT,36 which can reduce severe hypoglycemia rate by about 50%–70% and restore hypoglycemia awareness is up to 40%. The second line of intervention is the use of insulin pump treatment, continuous glucose measurement (CGM) or sensor augmented pump treatment (SAP) (Fig. 1). Even though insulin pump treatment, continuous glucose measurement have been successful in reducing severe hypoglycemia, many patients are reluctant to use these devices or do not use CGM on most days of the week. In patients with T1D, who use CGM 60% or more per week, it has been shown to reduce HbA1c without increasing hypoglycemia.37 Which sequence of technology would be the most beneficial with regards to elimination of severe hypoglycemia (CGM followed by insulin pump, followed by SAP with or without low
B. Islet allo-transplantation
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Conclusions
TABLE 2 Glucose control (HbA1c) and decline of function of transplanted kidney (e-GFR) in simultaneous islet-kidney, simultaneous pancreas-kidney transplantation vs kidney transplantation alone with deceased donors (Switzerland) or living-donors (Norway) University Hospital Zurich, Switzerland Category HbA1c (%) e-GFR (mL/min)
Pancreas-kidney
Islet-kidney
Kidney alone
Oslo, Norway Pancreas-Kidney
Living-donation Kidney
5.8
6.5
8.1
5.5
8.3
−1.0
−1.3
−2.5
−1.1
−2.3
glucose suspension or even semiautomatic insulin pump or pump treatment followed by CGM, followed by SAP, or SAP with LGS from the beginning or semiautomatic pump treatment) has not been tested in larger trials. Therefore, the sequence of technology may depend on the availability and preference of the patient (Fig. 1). The third line of intervention uses a sensor-augmented pump with low glucose suspension or semiautomatic pump and/or very frequent contact if the composite treatment target is still not met (Fig. 1). Byrne et al. demonstrated that specialized clinics with the provision of expertise in hypoglycemia management are essential to focus limited transplant resources on those who need it most. In 36 patients with recurrent severe hypoglycemia referred to a specialized hypoglycemia service, problematic hypoglycemia resolved in 47.2% with optimal medical therapy, with a further 25% achieving clinically relevant improvement. Of these highly selected patients, however, 27.8% required transplantation despite access to all therapies.38
Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/ PAK, or ITA/PTA) If both transplant options are available, a joint transplantation team consisting of personnel responsible for islet or pancreas, and kidney transplantation evaluates possible candidates. The candidate should be informed about the procedure and associated complications and should be carefully worked up to assess the operative risk and whether any assessments before surgery are necessary (e.g., coronary angiogram, MRI/CT scan, angiogram peripheral arteries,…). If the recipient has a high operative risk or a high age, then pancreas transplantation is usually not the recommended transplant option (Table 1). If islet transplantation is not reimbursed in the specific country, and the patient is not taking part in a trial, which covers the cost, then only pancreas transplantation remains an option. In most cases, the advantages and disadvantages of both procedures are discussed, and if the patient is a possible candidate for both islet and pancreas transplantation, then the patient can decide on the favored transplant option (Table 1).
Conclusions Hypoglycemia is a common and greatly feared complication of type 1 diabetes (T1D).7 Severe hypoglycemia affects about 30% of the population of type 1 diabetes. The cumulative risk for end-stage renal disease is 2.2% after 20 years and 7% after 30 years from the diagnosis of 1 diabetes mellitus and has significantly decreased markedly during the last five decades.39 With an organ donation rate of 10–35 per million people only 1%–2% of patients with type 1 diabetes mellitus can be transplanted.4 Therefore, there has to be a careful treatment algorithm for patients with severe hypoglycemia, to reduce the number for a potential islet or pancreas transplant to 1%–2%. Since end-stage renal disease in type 1 diabetes is getting less common over time, patients with ESRD can be offered a simultaneous islet or pancreas-kidney transplantation or islet or pancreas after kidney transplantation. The IPITA/EPITA Study group defined a successful outcome for beta-cell replacement recently.33 With both treatment options, an optimal or good beta-cell graft functional status can be achieved with an HbA1c of ≤6.5 or <7.0%, no severe hypoglycemia events, a C-peptide level higher than at baseline and either insulin independence or <50% of baseline insulin requirement (Table 4). With regard to the indication for beta-cell replacement and the goals and ideal state after beta-cell replacement, some goals can be achieved with SAP or now with the first semiautomated SAP on the market (Medtronic 670G) like a HbA1c < 7.0%, with no severe episodes of hypoglycemia with a Clarke or Gold Score < 4 and the time below a glucose level of 54 mg/dL or 3.0 mmol/L less than 1%, a glucose coefficient of variation <30% and a time with a glucose between 70 and 180 mg/dL or 3.9–10 mmol/L above 70%. The ideal goal of an HbA1c < 6.5% and >90% of values between 70 and 180 mg/dL or 3.9–10 mmol/L can today only be achieved with successful beta-cell replacement (Table 3). What emerged as an important finding in simultaneous islet-kidney or islet-after-kidney transplantation was that the long-term decline in kidney function of the transplanted kidney is the same for islet- and pancreas transplantation,3 but is much higher in kidney transplantation alone (living donation or deceased donor) in
B. Islet allo-transplantation
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35. Simultaneous islet-kidney and islet-after-kidney transplantation
TABLE 3 Indications and targets for beta-cell replacement Metric
Indication
Goal
Ideal
HbA1c, %
>7.5–8.0
<7.0 < inline-image>
≤6.5
SH, events per year
One or more
None
None
Clarke or Gold score
≥4
<4
0–1
Time < 54 mg/dL (<3.0 mmol/L), %
≥5
<1
0
Glucose SD, mg/dL (mmol/L)
≥40 (2.2)
<40 (2.2)
NE
Glucose coefficient of Variation, %
≥30
<30
NE
Time < 70 mg/dL (<3.9 mmol/L), %
NA
<5
<5
Time 70–180 mg/dL, (3.9–10 mM) %
NA
>70 < inline image>
>90
Time > 180 mg/dL (<10 mmol/L), %
NA
<20–30
<5
Adapted from Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation 2018;31:343–352.
TABLE 4 IGLS definition by EPITA/IPITA Study group of a successful outcome for beta-cell replacement β-Cell graft functional status
HbA1c, %
Severe hypoglycemia, Insulin requirements, events per yr U kg−1 day−1 C-peptide
Optimal
≤6.5
None
None
>Baseline
Yes
Good
<7.0
None
<50% baseline
>Baseline
Yes
Marginal
≥7.0
≥50% baseline
>Baseline
No
Failure
Baseline
Baseline
Baseline
Baseline
No
Treatment success
Adapted from Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation 2018:31:343–352.
patients with type 1 diabetes and end-stage renal disease (Table 2).3, 40 Therefore, it is obvious that every patient with end-stage renal disease and type 1 diabetes should be evaluated not only for kidney transplantation but also for beta-cell replacement. The choice of the preferred treatment option depends on age and operative risk of the recipient (Table 1), but also on the characteristics of the donor, patient preferences, and on the reimbursement situation in each country. Since the number of patients with type 1 diabetes and end-stage kidney disease is decreasing and the time until it develops increasing, the available donor organs for a simultaneous transplantation or beta-cell replacement after kidney transplantation would be sufficient in most countries, whereas the number of patients with severe hypoglycemia and normal or moderately reduced kidney function (e-GFR > 60 mL/ min) that cannot be treated by beta-cell replacement alone exceeds the number of available pancreas donors.4 In this category, educational steps and technology have to be improved to be able to achieve similar results without the need for beta-cell replacement. Hypoglycemia is a common and greatly feared complication of type 1 diabetes (T1D).7 Severe hypoglycemia (severe hypoglycemia), an event requiring the assistance
of another person for recovery due to profound neuroglycopenia, is experienced by one-third of patients with T1D at least once yearly. Many of these events are single episodes caused by insulin dosing errors, exercise, and alcohol. Conversely, problematic hypoglycemia describes a condition in which episodes of severe hypoglycemia are unpredictable, cannot be easily explained or prevented, and therefore have a significant direct or indirect negative impact on the patient’s health and quality of life (QoL). Recurrent severe hypoglycemia (two or more episodes annually) is reported by 21% of patients with T1D41 and by 66% of patients in whom T1D is complicated by impaired awareness of hypoglycemia.30 Four to 10% of all deaths are attributed to severe hypoglycemia in people with T1D;42, 43 the risk of death at 5 years is increased 3.4fold in diabetic patients who report severe hypoglycemia.43 The fear of hypoglycemia creates conflict within the individual, and relatives, diminishing motivation to attain strict glycemic control despite the knowledge that achieving this aim would minimize the risk of diabetic complications.44 As outlined above, β-cell replacement is a very effective treatment to achieve the composite targets of
B. Islet allo-transplantation
References
eliminating severe hypoglycemia while achieving near-normal HbA1c (<7.0%), but life-long immunosuppression with all of its associated possible complications represents one of the two limiting factors. The second rate-limiting factor is organ shortage since in the United States and Europe the organ donation rate of between 10 and 35 per million people45, 46 is well below the number of people on the waiting list. On the other hand, about 30% of all patients with type 1 diabetes mellitus (prevalence in Western countries: 0.3%) have problematic hypoglycemia, i.e., 1000 per million people have severe hypoglycemia.41, 47 Since the availability of suitable organs for β-cell replacement is very limited today (for 1%– 2% of all patients with severe hypoglycemia), optimal education programs coupled with the available medical and technological devices in a specific country have to take care of the majority of the patients. Therefore, until new sources of β-cells are available for clinical use, β-cell replacement by means of a whole pancreas or isolated islet transplantation will be limited to a carefully selected group of patients with severe hypoglycemia refractory to medical and technical measures and represents the fourth line intervention (Fig. 1). In conclusion, problematic hypoglycemia requires intervention. Educational, technological, and transplant interventions have shown promise in decreasing the risk of severe hypoglycemia in T1D.4 Looking at the success story of simultaneous islet- kidney or pancreas-kidney transplantation to avoid severe hypoglycemia by more than 90%,4 islet or pancreas transplantation alone appears to be the logical choice for treatment of severe hypoglycemia. However, the high number of people with severe hypoglycemia and T1D (30%) and the low number of possible organs suited to be transplanted, requires a thorough workup of the problems leading to severe hypoglycemia and to reduce the number of patients for a possible islet or pancreas transplantation alone substantially (1%–2%). Since the age of patients with end-stage renal disease is increasing and the cumulative risk for this disease is decreasing in T1D39 due to better treatment options, islet-kidney or islet-after-kidney transplantation emerges more and more as the prefered treatment option in this category due to absolute or relative contraindications for pancreas transplantation.
References 1. Maffi P, Bertuzzi F, De Taddeo F, et al. Kidney function after islet transplant alone in type 1 diabetes. Impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care. 2007;30(5):1150–1155. 2. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931–940. 3. Lehmann R, Graziano J, Brockmann J, et al. Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation
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in type 1 diabetes: a prospective 13-year follow-up. Diabetes Care. 2015;38:752–759. 4. Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38(6):1016–1029. 5. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation. 2001;71(1):82–90. 6. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant. 2004;4(12):2018–2026. 7. Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA. 2003;290:2817–2823. 8. Gruessner RW, Gruessner AC. The current state of pancreas transplantation. Nat Rev Endocrinol. 2013;9(9):555–562. 9. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–1330. 10. Bellin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012;12:1576–1583. 11. Page M, Rimmele T, Ber CE, et al. Early relaparotomy after simultaneous pancreas-kidney transplantation. Transplantation. 2012;94(2):159–164. 12. Gerber PA, Pavlicek V, Demartines N, et al. Simultaneous islet–kidney vs pancreas–kidney transplantation in type 1 di abetes mellitus: a 5 year single centre follow-up. Diabetologia. 2008;51(1):110–119. 13. Maffi P, Scavini M, Socci C, et al. Risks and benefits of transplantation in the cure of type 1 diabetes: whole pancreas versus islet transplantation. A single center study. Rev Diabet Stud. 2011;8(1):44–50. 14. Fiorina P, Folli F, Bertuzzi F, et al. Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. Diabetes Care. 2003;26(4):1129–1136. 15. Rickels MR. Recovery of endocrine function after islet and pancreas transplantation. Curr Diab Rep. 2012;12(5):587–596. 16. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant. 2012;17(1):100–105. 17. Sollinger HW, Odorico JS, Becker YT, D’Alessandro AM, Pirsch JD. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg. 2009;250(4):618–630. 18. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436–1445. 19. Ang M, Meyer C, Brendel MD, Bretzel RG, Linn T. Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes. Diabetologia. 2014;57(3):623–632. 20. Rodriguez LM, Knight RJ, Heptulla RA. Continuous glucose monitoring in subjects after simultaneous pancreas- kidney and kidney-alone transplantation. Diabetes Technol Ther. 2010;12(5):347–351. 21. Gorn L, Faradji RN, Messinger S, et al. Impact of islet transplantation on glycemic control as evidenced by a continuous glucose monitoring system. J Diabetes Sci Technol. 2008;2(2):221–228. 22. Vantyghem MC, Raverdy V, Balavoine AS, et al. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab. 2012;97(11):E2078–E2083.
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23. Brooks AM, Oram R, Home P, Steen N, Shaw JA. Demonstration of an intrinsic relationship between endogenous C-peptide concentration and determinants of glycemic control in type 1 diabetes following islet transplantation. Diabetes Care. 2015;38(1):105–112. 24. Cryer PE. Hypoglycemia begets hypoglycemia in IDDM. Diabetes. 1993;42(12):1691–1693. 25. Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo Clin Proc. 2014;89(11):1564–1571. 26. Lehmann R, Spinas GA, Moritz W, Weber M. Has time come for new goals in human islet transplantation? Am J Transplant. 2008;8(6):1096–1100. 27. Gerber PA, Locher R, Zuellig RA, et al. Glycemia, hypoglycemia, and costs of simultaneous islet-kidney or islet after kidney transplantation versus intensive insulin therapy and waiting list for islet. Transplantation. 2015;99:2174–2180. 28. Ewing DJ, Campbell IW, Burt AA, Clarke BF. Vascular reflexes in diabetic autonomic neuropathy. Lancet. 1973;2:1354–1356. 29. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care. 1995;18(4):517–522. 30. Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994;17(7):697–703. 31. Ryan EA, Shandro T, Green K, et al. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004;53(4):955–962. 32. Kovatchev BP, Cox DJ, Gonder-Frederick LA, Young-Hyman D, Schlundt D, Clarke W. Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the low blood glucose index. Diabetes Care. 1998;21(11):1870–1875. 33. Rickels MR, Stock PG, de Koning EJP, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation. 2018;31:343–352. 34. Muhlhauser I, Bruckner I, Berger M, et al. Evaluation of an intensified insulin treatment and teaching programme as routine management of type 1 (insulin-dependent) diabetes. The Bucharest-Dusseldorf study. Diabetologia. 1987;30(9):681–690. 35. Hopkins D, Lawrence I, Mansell P, et al. Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience. Diabetes Care. 2012;35(8):1638–1642. 36. Cox D, Gonder-Frederick L, Polonsky W, Schlundt D, Julian D, Clarke W. A multicenter evaluation of blood glucose awareness training-II. Diabetes Care. 1995;18(4):523–528.
37. Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ. 2011;343:d3805. 38. Byrne ML, Hopkins D, Littlejohn W, et al. Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service. Horm Metab Res. 2015;47(1):9–15. 39. Helve J, Sund R, Arffman M, et al. Incidence of end-stage renal disease in patients with type 1 diabetes. Diabetes Care. 2018;41(3):434–439. 40. Lindahl JP, Reinholt FP, Eide IA, et al. In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone. Diabetologia. 2014;57(11):2357–2365. 41. Pedersen-Bjergaard U, Pramming S, Heller SR, et al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev. 2004;20(6):479–486. 42. Skrivarhaug T, Bangstad HJ, Stene LC, Sandvik L, Hanssen KF, Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia. 2006;49(2):298–305. 43. Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire register of diabetes in children and young adults. Diabetes Care. 2008;31(5):922–926. 44. Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10(12):711–722. 45. Klein AS, Messersmith EE, Ratner LE, Kochik R, Baliga PK, Ojo AO. Organ donation and utilization in the United States, 19992008. Am J Transplant. 2010;10(4 Pt. 2):973–986. 46. Matesanz R, Dominguez-Gil B, Coll E, de la Rosa G, Marazuela R. Spanish experience as a leading country: what kind of measures were taken? Transpl Int. 2011;24(4):333–343. 47. Weinstock RS, Xing D, Maahs DM, et al. Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D exchange clinic registry. J Clin Endocrinol Metab. 2013;98(8):3411–3419.
B. Islet allo-transplantation
35 Simultaneous islet-kidney and islet-after-kidney transplantation Roger Lehmann Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, Zürich, Switzerland
O U T L I N E Introduction
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Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia 426 Treatment algorithm for beta-cell replacement therapy depends on kidney function
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Conclusions
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References
431
427
Introduction Both transplantation of isolated islets of Langerhans, as well as whole organ pancreas transplantation, are treatment options in the care of patients with type 1 diabetes mellitus. Both transplantation options can be conducted alone or in combination with a kidney. Whereas simultaneous pancreas-kidney transplantation (SPK) is an intervention with proven benefits in terms of survival,5 conflicting results in pancreas transplantation alone have been published.6, 7 By providing a source of endogenous insulin secretion, both transplantation options aim at improving glycemic control. Yet, while insulin independence is routinely achieved in the majority of pancreas transplantation and is still present in 60%–70% of patients 5 years after transplantation,8 recipients of islet transplantation need more than one transplantation to achieve insulin independence in most cases and insulin independence is lost in more than 70% after 2 years.9 However, in selected cases, the insulin independence rate at 5 years with modern immunosuppression (anti-TNFα treatment) was the same in islet and pancreas transplantation.10 On the other hand, the
Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00035-6
Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA)
rate of complications is high in pancreas transplantation with up to 40% of patients undergoing re-laparotomy during the first 3 months,11 whereas laparotomy rate in islet transplantation is as low as 1%–3%.3, 9, 12 Data on transplantation outcome of SPK transplantation directly compared to simultaneous islet-kidney (SIK) transplantation is rare. However, there are only few data regarding their long-term effect, in particular when compared to each other.3, 12 We reported a 5-year follow-up of SPK vs SIK transplantation,12 and a comparison of pancreas vs islet transplantation alone was presented recently, but this study did not include information on glycemic control,13 therefore the recently published 13-year old follow-up represents the first trial, which proved that the transplanted kidney can be protected by both islet or pancreas transplantation (either as simultaneous transplantation or after kidney transplantation).4 In this review, we carefully elaborated a comprehensive treatment algorithm for either simultaneous pancreas-kidney or islet-kidney transplantation, or for pancreas- or islet-after-kidney transplantation (Fig. 1). A joint transplant team with expertise in islet-, pancreas-,
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35. Simultaneous islet-kidney and islet-after-kidney transplantation
TABLE 1 Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA) Criteria
Islet transplant
Pancreas transplant
Patient decision
High operative risk (coronary heart disease, cerebrovascular disease, calcified large arteries, …)
Possible after careful work-up
Contra-indicated
Not possible
High recipient age (>50–55 years)
Possible
Generally not accepted
Not possible
Despite education and technology (pump, CGM) never HbA1c < 8.0%
Usually lower insulin independence rate
Higher insulin independence rate
Possible
Never accepted T1D, hates injections, and glucose measurements
Not optimal option
Preferred treatment option
Possible
Recipient age 18–50 years
Possible
Possible
Possible
Low perioperative complications, short hospitalisation
Preferred
Not optimal
Possible
Long-term protection of transplanted kidney from diabetic Possible nephropathy
Possible
Possible
Prevention of severe hypoglycemia
Possible
Possible
Possible
Islet transplantation: no reimbursement
Not optimal solution
Possible
Possible (if costs covered)
and kidney transplantation sees and evaluate the transplant candidates. They explain the procedure and possible complications and respect the patients’ transplant preference (Table 1) when it is compatible with indications and contraindications.
Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia Pancreas and now more frequently also islet transplantation can correct most of the symptoms and stabilize the complication of T1D14 and in particular prevent hypoglycemia, improve impaired glucose counter-regulation, and return hypoglycemia awareness, and thus ameliorate problematic hypoglycemia in T1D.3, 15 The risks of the transplant procedure and the need for life-long immunosuppressive therapy and limited availability of organs represent major limitations to widespread implementation in patients with problematic hypoglycemia refractory to educational and technological measures. While pancreas transplantation is an established treatment modality and islet transplantation remains investigational in the United States, islet transplantation is approved and reimbursed in many other countries (Canada, Switzerland, France, Italy, Sweden, Denmark, Norway, and Australia). Because not all patients are surgical candidates for pancreas transplantation (Table 1), and because not all pancreata are technically suitable for whole organ transplantation, islet and pancreas transplantation are evolving as complementary approaches to β-cell replacement. The goal is either to eliminate problematic hypoglycemia or to protect the transplanted kidney from glucose-related damage in T1D.4
The majority of pancreas transplants are performed simultaneously with a kidney (SPK) transplant in those with renal failure and show superior long-term graft function than when transplanted after a kidney transplant or alone.16 In a patient already immunosuppressed for a kidney transplant, when the added surgical risks are acceptable, the addition of a pancreas transplant may be considered to normalize glycemia, stabilize diabetes complications, and prevent recurrent diabetic nephropathy. In the presence of problematic hypoglycemia, a stronger case may be made for pancreas-after-kidney (PAK) or islet-after kidney (IAK) transplant where elimination of severe hypoglycemia is achieved for the life of the graft at the expense of a higher complication rate in the case of pancreas transplantation, or with a small additional risk with the minimal invasive islet transplantation. With SPK and as shown recently also in simultaneous islet-kidney (SIK) transplantation, the majority of recipients can expect amelioration of problematic hypoglycemia for more than a decade.3, 16, 17 Most islet transplants are performed either alone (ITA) for problematic hypoglycemia or as simultaneous islet-kidney (SIK) or islet-after-kidney (IAK) transplant in T1D patients experiencing advanced diabetic nephropathy. While the durability of insulin-independence is superior with SPK, similar rates can be observed with pancreas transplant alone (PTA) compared with islet transplant alone (ITA).10, 13 In fact, in selected centers, over 50% of ITA recipients may remain insulin-independent after 5 years.10 While unselected Collaborative Islet Transplant Registry data indicate the majority of islet recipients may return to requiring some insulin therapy by 3 years following transplantation, amelioration from problematic hypoglycemia is observed for the duration of graft function, currently retained in 90% of recipients at 4–13 years.3, 18
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Treatment algorithm for beta-cell replacement therapy depends on kidney function
Islet and pancreas transplantation are the only approaches to date that have documented both sustained recovery from hypoglycemia-associated autonomic failure (HAAF) and restored glucose counter-regulation (by endogenous glucose production) in long-standing T1D (mean 25–30 years of disease duration). Even partial islet graft function has been associated with improvement in the endogenous glucose production response to insulin-induced hypoglycemia,19 explaining protection from problematic hypoglycemia by islet grafts even when insulin may be required to maintain near-normoglycemia. Documentation of protection from problematic hypoglycemia by pancreas or islet transplantation in T1D also comes from studies involving CGM. SPK recipients have been shown to exhibit normal mean glucose and no time spent in hypoglycemia (<60 mg/dL/<3.3 mmol/L).20 Similarly, in a study of SPK and IAK recipients, both transplant groups had significantly reduced mean glucose, glucose variability and time with glucose values <60 mg/dL/<3.3 mmol/L compared to a group with a comparable duration of T1D managed by insulin pump treatment. Subsequent studies have shown that the significant reductions in mean glucose, glucose variability, and time spent in hypoglycemia according to new international guidelines (<54 mg/dL/<3.0 mmol/L) relative to T1D were similar for both insulin-independent and insulin-requiring islet recipients,20 and sustained for as long as 18 months.21 Importantly, Vantyghem et al.22 have shown that minimal islet graft function is necessary to abrogate hypoglycemia (<54 mg/dL/<3.0 mmol/L), and confirmed that even suboptimal function (requiring insulin) significantly improves mean glucose and glucose variability. That glycemic control benefits are imparted by the islet graft has been further supported by the demonstration of significant continuous associations with stimulated C-peptide levels in islet transplant recipients.23 This avoidance of hypoglycemia with islet or pancreas transplantation as documented by CGM best explains the documented reversal of HAAF, which in turn, assists in the recovery of glucose counter-regulation and hypoglycemia symptom recognition, reversing the vicious cycle of hypoglycemia begets hypoglycemia in T1D.24 In summary, in a program for T1D kidney transplant recipients, islet transplantation is considered simultaneously with or after kidney transplantation for patients who are not surgical candidates for, or not willing to accept the additional risks of pancreas transplantation (Table 1).3 At 512 and 13 years,4 while the insulin- independence rate was higher with recipients of pancreas vs islet transplantation, the islet transplant group experienced significantly less operative complications, and both forms of transplantation significantly improved glycemic control and reduced severe hypoglycemia by >90%.4
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Treatment algorithm for beta-cell replacement therapy depends on kidney function The proposed treatment algorithm (Fig. 1) takes into account the number of patients with T1D with problematic or recurrent severe hypoglycemia, existing educational tools and technologies to reduce hypoglycemia, and available resources for these treatment strategies and transplantation in T1D and might, therefore, require adaptation by individual countries or reimbursement plans. The strategy is different if the patient has endstage kidney disease. Now kidney replacement treatment has the highest priority and beta-cell replacement has the benefit of protecting the transplanted kidney from hyperglycemic damage and of preventing severe hypoglycemia (Fig. 1). If the careful evaluation indicates a possibility for transplant intervention, kidney function is the main determinant of whether islet or pancreas transplantation alone should be considered (e-GFR >60 mL/min), or if a living-kidney transplantation should be performed first, followed by islet or pancreas transplantation. If no living donor is available, either a combined islet- or pancreas transplantation simultaneous with a kidney may be indicated (Fig. 1). Reduced kidney function is by itself a risk factor for severe hypoglycemia.25 An e-GFR between 30 and 60 mL/min pretransplant as compared to e-GFR > 90 mL/min/1.73 m2 increases the risk for developing the end-stage renal disease after the introduction of calcineurin inhibitor-based immunosuppression by 2.25-fold.1, 2 Very recently, a 13-year follow-up of simultaneous pancreas- or islet-kidney transplantation or pancreas-/islets after kidney transplantation in the same institution showed that the very high rate of severe hypoglycemia in this group of patients could be reduced significantly from 3.5 to 0.05 and 0.1 per patient years in the SPK/PAK and SIK/IAK groups, respectively.3 In combined transplantation the focus is to avoid severe hypoglycemia and protect the transplanted kidney from hyperglycemic damage, which can be achieved by both approaches (pancreas- and islet transplantation),3 whereas in islet cell replacement alone the focus is primarily avoidance of severe hypoglycemia and normal or near-normal glucose control and only secondarily insulin independence26 as the fourth step of the previously proposed treatment algorithm for problematic hypoglycemia.4 Another crucial factor is the reimbursement policy of each country or insurance plan. If an expensive technology option does not deliver the expected results within a 6-month period, it may be discontinued. While in many countries health insurance reimburses insulin pump treatments, CGM is not. The same is true for β-cell replacement, while in many countries pancreas transplantation is reimbursed, a much smaller number of countries
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FIG. 1 Evidence-based treatment algorithm for patients with T1D and severe hypoglycemia with and without reduced kidney function. Adapted from Choudhary P, Rickels MR, Senior PA, Vantyghem M-C, Maffi P, Kay TW, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 2015;38(6):1016–1029.
reimburse islet transplantation. Cost-effectiveness of these technologies have not been tested in larger populations and it will take many years (10–15 years)27 to prove cost-saving or at least cost-effectiveness, whereas QoL improves in most trials. Individualized treatment targets must balance the risk of complications and the risk of hypoglycemia, trying to achieve the lowest attainable HbA1c without problematic hypoglycemia. According to the literature, it should be possible to achieve an A1c between 7.2% and 8.0% with educational programs and technology (without beta-cell replacement). In keeping with this treatment goal, it is important to regularly assess the frequency and risk of hypoglycemia. Many patients rarely or never inform their general practitioner/specialist about their hypoglycemia.28 Providers should directly inquire about hypoglycemic episodes and, if present, use the tools available to quantitate impaired awareness hypoglycemia,29, 30 hypoglycemia severity, and glycemic lability.31 Measurement of glycemic variability using simple measures such as standard deviation (>40 mg/dL/>2.8 mmol/L),22 or the coefficient of variation, or more complex measures such as low blood glucose index (LBGI)32 can also be valuable (Table 3).
The first step in patients identified with problematic hypoglycemia is to evaluate possible underlying causes of hypoglycemia and to evaluate if the actual HbA1c is at the individual target. If the patient is not a target, the first line of intervention is structured education or hypoglycemia-specific education (Fig. 1). The evidence base supports use of educational programs such as intensified insulin treatment and teaching or functional insulin therapy (FIT),34 DAFNE program,35 and BGAT,36 which can reduce severe hypoglycemia rate by about 50%–70% and restore hypoglycemia awareness is up to 40%. The second line of intervention is the use of insulin pump treatment, continuous glucose measurement (CGM) or sensor augmented pump treatment (SAP) (Fig. 1). Even though insulin pump treatment, continuous glucose measurement have been successful in reducing severe hypoglycemia, many patients are reluctant to use these devices or do not use CGM on most days of the week. In patients with T1D, who use CGM 60% or more per week, it has been shown to reduce HbA1c without increasing hypoglycemia.37 Which sequence of technology would be the most beneficial with regards to elimination of severe hypoglycemia (CGM followed by insulin pump, followed by SAP with or without low
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Conclusions
TABLE 2 Glucose control (HbA1c) and decline of function of transplanted kidney (e-GFR) in simultaneous islet-kidney, simultaneous pancreas-kidney transplantation vs kidney transplantation alone with deceased donors (Switzerland) or living-donors (Norway) University Hospital Zurich, Switzerland Category HbA1c (%) e-GFR (mL/min)
Pancreas-kidney
Islet-kidney
Kidney alone
Oslo, Norway Pancreas-Kidney
Living-donation Kidney
5.8
6.5
8.1
5.5
8.3
−1.0
−1.3
−2.5
−1.1
−2.3
glucose suspension or even semiautomatic insulin pump or pump treatment followed by CGM, followed by SAP, or SAP with LGS from the beginning or semiautomatic pump treatment) has not been tested in larger trials. Therefore, the sequence of technology may depend on the availability and preference of the patient (Fig. 1). The third line of intervention uses a sensor-augmented pump with low glucose suspension or semiautomatic pump and/or very frequent contact if the composite treatment target is still not met (Fig. 1). Byrne et al. demonstrated that specialized clinics with the provision of expertise in hypoglycemia management are essential to focus limited transplant resources on those who need it most. In 36 patients with recurrent severe hypoglycemia referred to a specialized hypoglycemia service, problematic hypoglycemia resolved in 47.2% with optimal medical therapy, with a further 25% achieving clinically relevant improvement. Of these highly selected patients, however, 27.8% required transplantation despite access to all therapies.38
Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/ PAK, or ITA/PTA) If both transplant options are available, a joint transplantation team consisting of personnel responsible for islet or pancreas, and kidney transplantation evaluates possible candidates. The candidate should be informed about the procedure and associated complications and should be carefully worked up to assess the operative risk and whether any assessments before surgery are necessary (e.g., coronary angiogram, MRI/CT scan, angiogram peripheral arteries,…). If the recipient has a high operative risk or a high age, then pancreas transplantation is usually not the recommended transplant option (Table 1). If islet transplantation is not reimbursed in the specific country, and the patient is not taking part in a trial, which covers the cost, then only pancreas transplantation remains an option. In most cases, the advantages and disadvantages of both procedures are discussed, and if the patient is a possible candidate for both islet and pancreas transplantation, then the patient can decide on the favored transplant option (Table 1).
Conclusions Hypoglycemia is a common and greatly feared complication of type 1 diabetes (T1D).7 Severe hypoglycemia affects about 30% of the population of type 1 diabetes. The cumulative risk for end-stage renal disease is 2.2% after 20 years and 7% after 30 years from the diagnosis of 1 diabetes mellitus and has significantly decreased markedly during the last five decades.39 With an organ donation rate of 10–35 per million people only 1%–2% of patients with type 1 diabetes mellitus can be transplanted.4 Therefore, there has to be a careful treatment algorithm for patients with severe hypoglycemia, to reduce the number for a potential islet or pancreas transplant to 1%–2%. Since end-stage renal disease in type 1 diabetes is getting less common over time, patients with ESRD can be offered a simultaneous islet or pancreas-kidney transplantation or islet or pancreas after kidney transplantation. The IPITA/EPITA Study group defined a successful outcome for beta-cell replacement recently.33 With both treatment options, an optimal or good beta-cell graft functional status can be achieved with an HbA1c of ≤6.5 or <7.0%, no severe hypoglycemia events, a C-peptide level higher than at baseline and either insulin independence or <50% of baseline insulin requirement (Table 4). With regard to the indication for beta-cell replacement and the goals and ideal state after beta-cell replacement, some goals can be achieved with SAP or now with the first semiautomated SAP on the market (Medtronic 670G) like a HbA1c < 7.0%, with no severe episodes of hypoglycemia with a Clarke or Gold Score < 4 and the time below a glucose level of 54 mg/dL or 3.0 mmol/L less than 1%, a glucose coefficient of variation <30% and a time with a glucose between 70 and 180 mg/dL or 3.9–10 mmol/L above 70%. The ideal goal of an HbA1c < 6.5% and >90% of values between 70 and 180 mg/dL or 3.9–10 mmol/L can today only be achieved with successful beta-cell replacement (Table 3). What emerged as an important finding in simultaneous islet-kidney or islet-after-kidney transplantation was that the long-term decline in kidney function of the transplanted kidney is the same for islet- and pancreas transplantation,3 but is much higher in kidney transplantation alone (living donation or deceased donor) in
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35. Simultaneous islet-kidney and islet-after-kidney transplantation
TABLE 3 Indications and targets for beta-cell replacement Metric
Indication
Goal
Ideal
HbA1c, %
>7.5–8.0
<7.0 < inline-image>
≤6.5
SH, events per year
One or more
None
None
Clarke or Gold score
≥4
<4
0–1
Time < 54 mg/dL (<3.0 mmol/L), %
≥5
<1
0
Glucose SD, mg/dL (mmol/L)
≥40 (2.2)
<40 (2.2)
NE
Glucose coefficient of Variation, %
≥30
<30
NE
Time < 70 mg/dL (<3.9 mmol/L), %
NA
<5
<5
Time 70–180 mg/dL, (3.9–10 mM) %
NA
>70 < inline image>
>90
Time > 180 mg/dL (<10 mmol/L), %
NA
<20–30
<5
Adapted from Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation 2018;31:343–352.
TABLE 4 IGLS definition by EPITA/IPITA Study group of a successful outcome for beta-cell replacement β-Cell graft functional status
HbA1c, %
Severe hypoglycemia, Insulin requirements, events per yr U kg−1 day−1 C-peptide
Optimal
≤6.5
None
None
>Baseline
Yes
Good
<7.0
None
<50% baseline
>Baseline
Yes
Marginal
≥7.0
≥50% baseline
>Baseline
No
Failure
Baseline
Baseline
Baseline
Baseline
No
Treatment success
Adapted from Rickels MR, Stock PG, de Koning EJP, Piemonti L, Pratschke J, Alejandro R, et al. Defining outcomes for beta-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation 2018:31:343–352.
patients with type 1 diabetes and end-stage renal disease (Table 2).3, 40 Therefore, it is obvious that every patient with end-stage renal disease and type 1 diabetes should be evaluated not only for kidney transplantation but also for beta-cell replacement. The choice of the preferred treatment option depends on age and operative risk of the recipient (Table 1), but also on the characteristics of the donor, patient preferences, and on the reimbursement situation in each country. Since the number of patients with type 1 diabetes and end-stage kidney disease is decreasing and the time until it develops increasing, the available donor organs for a simultaneous transplantation or beta-cell replacement after kidney transplantation would be sufficient in most countries, whereas the number of patients with severe hypoglycemia and normal or moderately reduced kidney function (e-GFR > 60 mL/ min) that cannot be treated by beta-cell replacement alone exceeds the number of available pancreas donors.4 In this category, educational steps and technology have to be improved to be able to achieve similar results without the need for beta-cell replacement. Hypoglycemia is a common and greatly feared complication of type 1 diabetes (T1D).7 Severe hypoglycemia (severe hypoglycemia), an event requiring the assistance
of another person for recovery due to profound neuroglycopenia, is experienced by one-third of patients with T1D at least once yearly. Many of these events are single episodes caused by insulin dosing errors, exercise, and alcohol. Conversely, problematic hypoglycemia describes a condition in which episodes of severe hypoglycemia are unpredictable, cannot be easily explained or prevented, and therefore have a significant direct or indirect negative impact on the patient’s health and quality of life (QoL). Recurrent severe hypoglycemia (two or more episodes annually) is reported by 21% of patients with T1D41 and by 66% of patients in whom T1D is complicated by impaired awareness of hypoglycemia.30 Four to 10% of all deaths are attributed to severe hypoglycemia in people with T1D;42, 43 the risk of death at 5 years is increased 3.4fold in diabetic patients who report severe hypoglycemia.43 The fear of hypoglycemia creates conflict within the individual, and relatives, diminishing motivation to attain strict glycemic control despite the knowledge that achieving this aim would minimize the risk of diabetic complications.44 As outlined above, β-cell replacement is a very effective treatment to achieve the composite targets of
B. Islet allo-transplantation
References
eliminating severe hypoglycemia while achieving near-normal HbA1c (<7.0%), but life-long immunosuppression with all of its associated possible complications represents one of the two limiting factors. The second rate-limiting factor is organ shortage since in the United States and Europe the organ donation rate of between 10 and 35 per million people45, 46 is well below the number of people on the waiting list. On the other hand, about 30% of all patients with type 1 diabetes mellitus (prevalence in Western countries: 0.3%) have problematic hypoglycemia, i.e., 1000 per million people have severe hypoglycemia.41, 47 Since the availability of suitable organs for β-cell replacement is very limited today (for 1%– 2% of all patients with severe hypoglycemia), optimal education programs coupled with the available medical and technological devices in a specific country have to take care of the majority of the patients. Therefore, until new sources of β-cells are available for clinical use, β-cell replacement by means of a whole pancreas or isolated islet transplantation will be limited to a carefully selected group of patients with severe hypoglycemia refractory to medical and technical measures and represents the fourth line intervention (Fig. 1). In conclusion, problematic hypoglycemia requires intervention. Educational, technological, and transplant interventions have shown promise in decreasing the risk of severe hypoglycemia in T1D.4 Looking at the success story of simultaneous islet- kidney or pancreas-kidney transplantation to avoid severe hypoglycemia by more than 90%,4 islet or pancreas transplantation alone appears to be the logical choice for treatment of severe hypoglycemia. However, the high number of people with severe hypoglycemia and T1D (30%) and the low number of possible organs suited to be transplanted, requires a thorough workup of the problems leading to severe hypoglycemia and to reduce the number of patients for a possible islet or pancreas transplantation alone substantially (1%–2%). Since the age of patients with end-stage renal disease is increasing and the cumulative risk for this disease is decreasing in T1D39 due to better treatment options, islet-kidney or islet-after-kidney transplantation emerges more and more as the prefered treatment option in this category due to absolute or relative contraindications for pancreas transplantation.
References 1. Maffi P, Bertuzzi F, De Taddeo F, et al. Kidney function after islet transplant alone in type 1 diabetes. Impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care. 2007;30(5):1150–1155. 2. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931–940. 3. Lehmann R, Graziano J, Brockmann J, et al. Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation
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B. Islet allo-transplantation