Secondary complications of diabetes

C H A P T E R

47 Secondary complications of diabetes Fanny Buron⁎, Olivier Thaunat⁎,†,‡ ⁎

Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France †Claude Bernard University (Lyon 1), Lyon, France ‡French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France O U T L I N E Introduction

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Cardiovascular disease

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Nephropathy

591

Conclusion

594

Retinopathy

593

References

594

Neuropathy

593

Introduction Diabetes mellitus is associated with the development of microvascular complications (including nephropathy, retinopathy, and neuropathy) and damage to large blood vessels, which increases the incidence of cardiovascular complications. Intensive insulinotherapy has been proven to slow down the development of secondary complications of diabetes. As islet transplantation allows for a better metabolic control than insulinotherapy, it is reasonable to speculate that this therapy improves diabetes complications. However, the low activity of islet transplantation makes available data scarce and reduces the quality of evidence. In this chapter, we provide an overview of available data regarding the impact of islet transplantation on diabetic nephropathy, retinopathy, neuropathy, and cardiovascular disease.

Nephropathy The effect of islet transplantation on diabetic nephropathy is difficult to assess. Indeed, kidney function reflects several parameters and the possible improvement in diabetic nephropathy could be masked by the neph-

Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1 https://doi.org/10.1016/B978-0-12-814833-4.00047-2

rotoxicity of immunosuppressive drugs (in particular calcineurin inhibitors, which are also responsible for hypertension). Proteinuria, which is one of the classical features of diabetic nephropathy, may also be due to other causes, including toxicity of immunosuppressive drugs (mainly mTOR inhibitors). Another layer of complexity comes from the fact that candidates for islet transplantation either have minimal lesions of diabetic nephropathy on native kidneys (islets transplanted alone, ITA) or they receive a kidney allograft devoid of these lesions along with islet transplantation [simultaneous islets and kidney (SIK), or islets after kidney (IAK)]. Therefore, in all cases, lesions of diabetic nephropathy are minimal on functional kidneys, which makes the evaluation of their regression harder to highlight. Chronic kidney disease (CKD) is a classical complication of solid organ transplantation, even in nondiabetic recipients, mainly because of nephrotoxicity of immunosuppressive drugs (in particular calcineurin-inhibitors).1 After pancreas transplantation alone, the cumulative incidence of end-stage renal disease (ESRD) is about 15% at 5  years (data coming from the Scientific Registry of Transplant Recipients concerning 1597 PTA performed between 1990 and 2008).2 For ITA, available data comes from smaller studies (<50 patients) with relatively short follow-up (summarized in Table 1). Although the results are not fully concordant, they generally point toward a

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47.  Secondary complications of diabetes

TABLE 1  Kidney function after islet transplantation: Summary of available studies Nb of patients

Date of islet transplantation

Follow-up (months)

Immunosuppressive regimen Main result

Geneva

5 ITA 5 IAK

2002–04

8–20

Daclizumab TAC and SRL

Decline in KF: 4/5 ITA, 2/5 IAK Increased albuminuria: 2/5 ITA

Maffi et al. (2007)4

Milan

19 ITA

2001–05

24

Daclizumab TAC and SRL

Decline in KF: 2/19 Increased albuminuria: 4/19

Senior et al. (2007)5

Edmonton

41 ITA

1999–2003

Up to 48

Daclizumab TAC and SRL

Decline in KF: 47% at 1 year, 92 % at 3 years Increased albuminuria: 24%

Leitao et al. (2009)6

Miami

35 ITA

2000–07

Up to 72

Daclizumab or alemtuzumab TAC and SRL

Stable KF Transient increase in albuminuria

Gillard et al. (2014)7

Leuven

48 ITA

2002–10

Up to 60

ATG TAC and MMF

Initial 20% reduction in eGFR, reversible after TAC withdrawal Reduction in albuminuria, also reversible

Lablanche et al. (2015)8

Swiss-French GRAGIL Network

24 ITA 20 IAK

2003–10

60

Daclizumab TAC and SRL

ITA: stable KF IAK: decline in KF

Authors

Center

Andres et al. (2005)3

ATG, antithymocyte globulins; eGFR, estimated glomerular filtration rate; KF, kidney function; MMF, mycophenolate mofetil; SRL, sirolimus; TAC, tacrolimus.

decrease in kidney function after islet transplantation, which seems to be less important in the most recent studies. Accordingly, the last published annual report of the CITR (concerning 819 ITA and 192 IAK/SIK performed in 1999–2013) shows significant decline in median CKDEPI estimated glomerular filtration rate (eGFR) in both ITA (90 mL/min/1.73 m2 baseline vs 70 mL/min/1.73 m2 at 5 years) and IAK recipients (55 mL/min/1.73 m2 baseline vs 45 mL/min/1.73 m2 at 5  years). This decline is also less important in the most recent era. The percentage of patients with more than 30% increase in serum creatinine is estimated to be 25% at 6 months and 32% at 5 years for ITA recipients and 15% at 6 months and 30% at 5 years for IAK/SIK recipients, respectively.9 The main risk factors for developing CKD after islet transplantation are similar to those identified in solid organ transplantation1 or pancreas transplantation10: low kidney function and proteinuria before transplantation4,5 and diabetes duration before transplantation.5 The selection of recipients and the management of the aggravating factors of CKD reduce the risk of CKD.6 Nephrotoxicity due to tacrolimus could be reversible when it is stopped because of islet failure,7 but this could lead to increased risk of sensitization against donors-specific HLA molecules.11 Immunosuppression protocols have evolved with the introduction of mycophenolate mofetil that is not nephrotoxic. Comparing outcome in ITA (n = 15) and PTA (n = 10) recipients, Moassesfar et  al. found that overall kidney function was comparable but with a significant decrease in posttransplant kidney function in the PTA group that was not seen in the ITA group, possibly because of tacrolimus minimization in the last group.12 Lehman et al.

reported no difference in kidney function decline in SPK/PAK recipients (n = 94) and SIK/IAK recipients (n = 38) with up to 13 years of follow-up.13 To summarize, islet transplantation is followed by a decline in kidney function that is less important in the most recent era due to a better selection of recipients and the use of less nephrotoxic immunosuppressive protocols. The burden of the immunosuppressive drugs on renal function makes difficult the evaluation of the potential beneficial impact of islet transplantation on diabetic nephropathy. However, there are arguments in favor of this improvement. In animal models, early diabetic nephropathy reverses after islet transplantation.14,15 Renal histology could help but there is no data on kidney biopsy in islet transplantation. However, results are expected to be comparable to PTA, where regression of diabetic nephropathy has been shown.16 It should be noted that this regression is slow and could be limited in the case of islet transplantation due to the shorter duration of function of islet grafts (as compared with pancreas). In a prospective crossover cohort study, Vancouver’s group compared the slope of eGFR in 45 type 1 diabetic patients with intensive medical therapy or ITA. They showed that the rate of decline in GFR was slower after ITA than on medical therapy with a follow-up of more than 3 years.17 In another study, Milan’s group compared type 1 diabetic patients who received either a kidney alone (KA) or SIK, and showed that both survival and function of kidney grafts were better after SIK (n = 24) than after KA (n = 44).18 However, it is fair to underline

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Neuropathy

that these two types of recipients are likely not identical, which limits the clinical value of the comparison. Finally, Peixoto et  al. studied kidney function after islet graft failure and immunosuppression discontinuation in 12 patients. After a mean follow-up of 10 years, the eGFR was comparable to that estimated at the time of islet graft failure and microalbuminuria regressed after discontinuation of immunosuppression in four out of five subjects.19 Although the number of patients is low, this study highlights the slow progression of diabetic nephropathy and the reversibility of immunosuppression nephrotoxicity if stopped early. In conclusion, recipients of islet transplantation are exposed to immunosuppression nephrotoxicity, as recipients of other solid organ transplants. Risk factors for decline in kidney function are mainly kidney function at transplantation and duration of diabetes before transplantation. There is probably a beneficial impact of islet transplantation on diabetic nephropathy but this impact is difficult to evaluate because of the confounding effect of immunosuppression and because diabetic nephropathy is usually at a very early stage in patients selected for islets transplantation (Fig. 1).

Retinopathy There is a known risk of worsening of diabetic retinopathy immediately after islet transplantation, as after any rapid improvement in blood glucose control. Risk factors include higher baseline levels of HbA1c, longer diabetes durations, and severity of diabetic retinopathy.20 Ryan et  al. from the Edmonton's group reported 4 out of 47 patients with deterioration in eye disease within 5  months postislet transplantation.21 It is thus important to optimize diabetes control and stabilize diabetic retinopathy before islet transplantation procedure. Apart from this early risk, islet transplantation seems to allow stabilizing (sometimes even improving) diabetic retinopathy (Fig.  1). In eight ITA recipients with 1–2 years of follow-up, Miami's group reported stabilization of diabetic retinopathy for all patients at 1-year posttransplantation.22 In a prospective, crossover, cohort study comparing islet transplantation with intensive medical therapy in 45 patients, Vancouver’s group showed significantly more progression of retinopathy in medically treated patients (10 out of 82 eyes after a median follow-up of 47  months, 12.2%) than in islet transplantation group (0 out of 51 eyes after a median follow-up of 66 months).17 Finally, Milan’s group found a significant increase in arterial and venous retinal blood flow velocities 1 year after ITA in 10 recipients as compared as baseline values measured before ITA and a control group of 10 matched type 1 diabetic patients.23

FIG. 1  Graphical summary of the impact of islet transplantation on secondary complications of diabetes. In the clinical setting, the beneficial impact of an optimal glycemic control provided by grafted islets must be weighed against the detrimental impact of immunosuppressive drugs, which are mandatory to prevent rejection. The net effect of islet transplantation, estimated on the basis of the available evidence from the literature is shown for each secondary complications of diabetes.

Neuropathy As for diabetic retinopathy, there is a risk of early worsening of diabetic neuropathy after rapid improvement in blood glucose following islet transplantation. Optimal control of diabetes is therefore required before islet transplantation. Data from animal models suggest that on the long term islet transplantation restores the nerve conduction velocities (NCV).15 Clinical data are more difficult to interpret and one should keep in mind that the evaluation of the impact of islet transplantation on diabetic neuropathy is blurred by the known neurotoxicity of calcineurin inhibitors.24 In eight ITA recipients with 1–2  years of follow-up, Miami’s group reported stability of NCV in two patients, improvement in two patients but worsening in four patients.22 Lille’s group studied evolution of neuropathy before and 5  years after islet transplantation in 13 ITA and 8 IAK recipients on an intention-to-treat basis. They showed improvement in sensory NCV and action potentials 5 years after islet transplantation. There was a negative correlation between CGM mean glucose and both motor and sensory NCV and action potentials. Motor action potentials and NCV were negatively correlated with tacrolimus, triglycerides, and mean systolic blood pressure.25 Comparing 18 IAK vs 9 kidney alone recipients (all patients under immunosuppressive therapy), Milan’s group found an improvement in the NCV score at 4 years in the IAK group but not in the kidney alone group. There was also a nonsignificant trend for improvement

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47.  Secondary complications of diabetes

in motor and sensory action potentials in the IAK group vs a worsening in the kidney alone group. Finally, the authors observed reduced glycation end products levels and the expression of their specific receptors in perineurium and vasa nervorum in skin biopsies of the IAK group.26 In their prospective, crossover, cohort study comparing islet transplantation with intensive medical therapy in 44 patients (mean follow-up of 74 and 53 months, respectively), Vancouver’s group showed a positive slope of NCV in islet recipients and a negative slope in the medical group (but the difference was not significant). A subgroup analysis conducted in patients with diabetic neuropathy (n = 29, 66%) showed a significantly better slope of NCV in the islet recipient group27 (Fig. 1).

Cardiovascular disease Data regarding the impact of islet transplantation on cardiovascular disease are scarce. The possible beneficial impact of islet transplantation on macroangiopathy must again be weighed against the known detrimental impact of immunosuppressive drugs on cardiovascular risk. Animal models show that islet transplantation in diabetic rats significantly increases the number of cardiomyocytes.15 Milan’s group observed a significantly better patient survival rate, lower cardiovascular death rate, and lower intima-media thickness progression in 21 successful IAK recipients vs 13 unsuccessful IAK recipients (mean follow-up of 4.5  years, all patients being under immunosuppressive drugs because of kidney transplantation).28 They also showed an improvement in ejection fraction and brain natriuretic peptide levels at 3  years compared to 17 IAK recipients and 25 kidney alone recipients.29 Chicago’s group showed a reduction in carotid intima-media thickness in 15 ITA recipients followed 1–5  years.30 The same group observed a minimal increase in coronary artery calcium levels pre- and posttransplantation (mean follow-up of 2.3 years) in 11 ITA recipients.31 Moreover, Milan’s group observed no change in cerebral vasculopathy assessed by magnetic resonance imaging in 12 ITA recipients at 15 months of follow-up32 (Fig. 1).

Conclusion The impact of islet transplantation on secondary complications of diabetes is currently difficult to assess because of (i) the confounding detrimental side effects of immunosuppressive drugs and (ii) the low quality

of available clinical evidence. Large-scale collaborative works are therefore necessary to reach a definitive conclusion in this field. Waiting for a definitive answer, data from animal models (where immunosuppressive drugs can be avoided) and available small clinical studies all suggest that islet transplantation probably improve, or at least stabilize, secondary complications of diabetes (Fig. 1).

References 1. 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. 2. Singh SK, Kim SJ, Smail N, Schiff J, Paraskevas S, Cantarovich M. Outcomes of recipients with pancreas transplant alone who develop end-stage renal disease. Am J Transplant. 2016;16(2):535–540. 3. Andres A, Toso C, Morel P, et al. Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen. Transpl Int. 2005;18(11):1226–1230. 4. 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. 5. Senior PA, Zeman M, Paty BW, Ryan EA, Shapiro AM. Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant. 2007;7(1):91–98. 6. Leitão CB, Cure P, Messinger S, et al. Stable renal function after islet transplantation: importance of patient selection and aggressive clinical management. Transplantation. 2009;87(5):681–688. 7. Gillard P, Rustandi M, Efendi A, et al. Early alteration of kidney function in nonuremic type 1 diabetic islet transplant recipients under tacrolimus-mycophenolate therapy. Transplantation. 2014;98(4):451–457. 8. Lablanche  S, Borot  S, Wojtusciszyn  A, et  al. Five-year metabolic, functional, and safety results of patients with type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL Network. Diabetes Care. 2015;38(9):1714–1722. 9. Collaborative Islet Transplant Registry. Ninth Annual Report. December, https://citregistry.org/system/files/9AR_Report. pdf; 2016. 10. Kim SJ, Smail N, Paraskevas S, Schiff J, Cantarovich M. Kidney function before pancreas transplant alone predicts subsequent risk of end-stage renal disease. Transplantation. 2014;97(6):675–680. 11. Pouliquen  E, Baltzinger  P, Lemle  A, et  al. Anti-donor HLA antibody response after pancreatic islet grafting: characteristics, risk factors, and impact on graft function. Am J Transplant. 2017;17(2):462–473. 12. Moassesfar  S, Masharani  U, Frassetto  LA, et  al. A comparative analysis of the safety, efficacy, and cost of islet versus pancreas transplantation in nonuremic patients with type 1 diabetes. Am J Transplant. 2016;16(2):518–526. 13. Lehmann R, Graziano J, Brockmann J, et al. Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: a prospective 13-year follow-up. Diabetes Care. 2015;38(5):752–759. 14. He Y, Xu Z, Zhou M, et al. Reversal of early diabetic nephropathy by islet transplantation under the kidney capsule in a rat model. J Diabetes Res. 2016;2016:4157313. 15. Remuzzi  A, Cornolti  R, Bianchi  R, et  al. Regression of diabetic complications by islet transplantation in the rat. Diabetologia. 2009;52(12):2653–2661.

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16. Fioretto  P, Steffes  MW, Sutherland  DE, Goetz  FC, Mauer  M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;339(2):69–75. 17. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. 2011;91(3):373–378. 18. Fiorina  P, Venturini  M, Folli  F, et  al. Natural history of kidney graft survival, hypertrophy, and vascular function in end-stage renal disease type 1 diabetic kidney-transplanted patients: beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care. 2005;28(6):1303–1310. 19. Peixoto  E, Vendrame  F, Arnau  A, et  al. Ten years of preserved kidney function after islet transplant graft failure. Diabetes Care. 2016;39(12):e209–e211. 20. Feldman-Billard  S, Larger  E, Massin  P. Standards for screeningand surveillance of ocular complications in people with diabetes SFD study group. Early worsening of diabetic retinopathy after rapid improvement of blood glucose control in patients with diabetes. Diabetes Metab. 2018;44(1):4–14. 21. Ryan  EA, Paty  BW, Senior  PA, et  al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54(7):2060–2069. 22. Lee TC, Barshes NR, O'Mahony CA, et al. The effect of pancreatic islet transplantation on progression of diabetic retinopathy and neuropathy. Transplant Proc. 2005;37(5):2263–2265. 23. Venturini M, Fiorina P, Maffi P, et al. Early increase of retinal arterial and venous blood flow velocities at color Doppler imaging in brittle type 1 diabetes after islet transplant alone. Transplantation. 2006;81(9):1274–1277. 24. Arnold  R, Pussell  BA, Pianta  TJ, Lin  CS, Kiernan  MC, Krishnan  AV. Association between calcineurin inhibitor

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treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant. 2013;13(9):2426–2432. 25. Vantyghem MC, Quintin D, Caiazzo R, et al. Improvement of electrophysiological neuropathy after islet transplantation for type 1 diabetes: a 5-year prospective study. Diabetes Care. 2014;37(6):e141–e142. 26. Del Carro U, Fiorina P, Amadio S, et al. Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care. 2007;30(12):3063–3069. 27. Fensom B, Harris C, Thompson SE, Al Mehthel M, Thompson DM. Islet cell transplantation improves nerve conduction velocity in type 1 diabetes compared with intensive medical therapy over six years. Diabetes Res Clin Pract. 2016;122:101–105. 28. 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. 29. Fiorina  P, Gremizzi  C, Maffi  P, et  al. Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients. Diabetes Care. 2005;28(6):1358–1365. 30. Danielson KK, Hatipoglu B, Kinzer K, et al. Reduction in carotid intima-media thickness after pancreatic islet transplantation in patients with type 1 diabetes. Diabetes Care. 2013;36(2):450–456. 31. Madrigal JM, Monson RS, Hatipoglu B, et al. Coronary artery calcium may stabilize following islet cell transplantation in patients with type 1 diabetes. Clin Transpl. 2017;31(10). 32. D'Addio F, Maffi P, Vezzulli P, et al. Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes. Diabetes Care. 2014;37(1):267–276.

B. Islet allo-transplantation