Growing Pains from The Islet Cell Transplant World (2006)

Type one diabetes (T1D) is a disease with profound implications for patients' quality of life, morbidity and mortality. The incidence of T1D is increasing and its treatment, although improving, continues to be challenging. Tight glycemic control can decrease the incidence and progression of diabetic complications (1Gale EA Spring harvest? Reflections on the rise of type 1 diabetes.Diabetologia. 2005; 48: 2445-2450Crossref PubMed Scopus (70) Google Scholar). However, this therapeutic goal is not easy to achieve, often interferes with quality of life and can be associated with severe hypoglycemia. Consequently, the need to develop better treatment strategies for T1D, including clinical islet cell transplantation (CICT), remains imperative. For many years, CICT remained in the ‘excellent idea that does not work’ category of procedures. However, the Edmonton group with their initial report of successful CICT (2Shapiro AM Lakey JR Ryan EA et al.Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.N Engl J Med. 2000; 343: 230-238Crossref PubMed Scopus (4428) Google Scholar) greatly increased the hopes of patients and MDs that this procedure was close to becoming a clinical reality. This seminal paper resulted in the rapid expansion in the number of programs attempting CICT to more than 60 worldwide with more than 600 islet transplantation procedures performed to date. This initial (over?)enthusiasm has been somewhat dampened by the limited success of newer CITC programs and by the longer term follow-up of the original Edmonton cohort. The reality is that although ‘simple on paper’, CICT is a complex procedure that to be successful requires optimal functioning of a complex, expensive program that may not be easily reproduced from site to site. Furthermore, the number of patients who remain insulin independent declines progressively after the first year post-transplant (3Ryan EA Paty BW Senior PA et al.Five-year follow-up after clinical islet transplantation.Diabetes. 2005; 54: 2060-2069Crossref PubMed Scopus (1382) Google Scholar). These reports, together with the manuscript from Senior et al in this issue of AJT, should make us reflect on the difficulties of developing this complex procedure and on the enormous advantages that open reporting of outcomes, good and not so good, have in a developing field. In this issue of AJT, Senior et al report on two serious negative renal outcomes after CICT: (1) variable declines in kidney function and/or (2) increases in proteinuria. This study did not assess whether these two outcomes are inter-related, a reasonable assumption. The variable declines in kidney function after CITC make us ponder the status of these patients' kidneys prior to the transplant. For example, previous studies have shown that in individuals with diabetes and microalbuminuria the renal histologic changes may range from normal to advanced diabetic glomerulosclerosis (4Fioretto P Steffes MW Mauer M Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria.Diabetes. 1994; 43: 1358-1364Crossref PubMed Google Scholar). Thus, likely the CICT recipients reported here had variable baseline kidney pathology that may have determined their variable tolerance to a subsequent nephrotoxic insult. Supporting this postulate, In Senior's study the decline in GFR after CITC is more marked in patients with lower GFR prior to the transplant. Thus, to better inform patients of the risks of CITC, a complete assessment of kidney status, including direct GFR measurements and perhaps kidney biopsies, should be done prior to the procedure. It is reasonable to assume that the worsening in kidney function after CICT is due, at least in part, to the use of calcineurin inhibitors (CNI). To minimize this risk the Edmonton protocol uses ‘low’ dose CNI combined with rapamycin. Paradoxically, we have learned since then that this combination of drugs is more nephrotoxic than each separately (5Meier-Kriesche HU Steffen BJ Chu AH et al.Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival.Am J Transplant. 2004; 4: 2058-2066Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Furthermore, the use of ‘low’ dose CNI is not necessarily kidney sparing (6Isnard BC Tezenas Du MS Beaufils H et al.Long-term renal effects of low-dose cyclosporine in uveitis-treated patients: Follow-up study.J Am Soc Nephrol. 2002; 13: 2962-2968Crossref PubMed Scopus (53) Google Scholar). It should be noted that Senior et al assessed changes in kidney function by estimating glomerular filtration rate (GFR) based on serum creatinine. The evidence indicates that these estimates are not very accurate, particularly when trying to assess changes in GFR over time (7Perkins BA Nelson RG Ostrander BE et al.Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: Results of a 4-year follow-up study.J Am Soc Nephrol. 2005; 16: 1404-1412Crossref PubMed Scopus (282) Google Scholar). Thus, measuring GFR directly will be needed to assess the true impact of CITC on kidney function. Equally disturbing is the finding that the number of patients with proteinuria increases following CITC. It seems unlikely that this event represents worsening of diabetic glomerulosclerosis. However, we would add promptly that ‘unlikely’ does not mean not possible. Indeed, we should remember that tight glycemia control may result in worsening of other diabetic complications namely retinopathy (8Lauritzen R Larsen H-W Frost-Larsen K Dechert T Effect of 1 year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics.Lancet. 1983; 1: 200-203Abstract PubMed Scopus (332) Google Scholar) and neuropathy (9Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial.Ann Neurol. 1995; 38 (DCCT.): 869-880Crossref PubMed Scopus (260) Google Scholar). Still, it seems more likely that the worsening of proteinuria after CITC is due to sirolimus. This drug has been associated with de novo proteinuria (10Sennesael JJ Bosmans JL Bogers JP Verbeelen D Verpooten GA Conversion from cyclosporine to sirolimus in stable renal transplant recipients.Transplantation. 2005; 80: 1578-1585Crossref PubMed Scopus (53) Google Scholar). Furthermore, in patients who already have proteinuria sirolimus may lead to poor native (11Fervenza FC Fitzpatrick PM Mertz J et al.Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies.Nephrol Dial Transplant. 2004; 19: 1288-1292Crossref PubMed Scopus (102) Google Scholar) and allograft (12Diekmann F Budde K Oppenheimer F Fritsche L Neumayer HH Campistol JM Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction.Am J Transplant. 2004; 4: 1869-1875Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar) kidney outcomes. The reporting transparency from the Edmonton group needs to be recognized and commended. The Senior report should make us consider several issues and perhaps reconsider the role of CITC, in its current status, in the treatment of T1D. The main indication for CITC in the patients reported here was severe hypoglycemia. Can this indication justify the reported renal risk of the procedure? This question is particularly relevant considering the low rate of success (insulin independence) of CITC after 5 years (5Meier-Kriesche HU Steffen BJ Chu AH et al.Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival.Am J Transplant. 2004; 4: 2058-2066Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). The answer to this question needs to be individualized for each patient and the decision to proceed with CITC needs to be made, we believe, based on a thorough assessment of kidney status prior to transplantation.