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Original Clinical Science—General

Long-term Effects of Pancreas Transplantation on Diabetic Retinopathy and Incidence and Predictive Risk Factors for Early Worsening

Kim, Yoon Jeon MD, PhD1; Shin, Sung MD, PhD2; Han, Duck Jong MD, PhD2; Kim, Young Hoon MD2; Lee, Joo Yong MD, PhD1; Yoon, Young Hee MD, PhD1; Kim, June-Gone MD, PhD1

Author Information
doi: 10.1097/TP.0000000000001958

Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus (DM), is a leading cause of vision loss worldwide.1 Although the mechanisms of DR are yet to be fully elucidated, chronic hyperglycemia has been noted as a core pathogenic cause of the disease. Accordingly, the Diabetes Control and Complications Trial demonstrated that the risk of development and progression of DR was much lower in strictly controlled diabetic patients.2,3 Interestingly, the Diabetes Control and Complications Trial also reported a higher incidence of progression of eye disease in the intensive-therapy group during the first year of improved glycemic control.2 Several previous studies also confirmed such early worsening of DR after intensive glycemic control; this phenomenon appears to be transient, and generally does not lead to vision-threatening diseases such as development of neovascularization or macular edema.4-6

Within the last decade, pancreas transplantation has benefited from advancements in immunosuppressants and surgical techniques and emerged as a clinical therapy for restoring normoglycemia without the risk of severe hypoglycemia or halting secondary complications.7,8 However, clinical data regarding the effect of pancreas transplantation on DR remain insufficient,9-11 and the majority of previous studies have focused on the effect of simultaneous pancreas-kidney (SPK) transplant performed during the end stage of diabetic nephropathy and retinopathy. Furthermore, only limited data is available with regard to the effects of pancreas transplantation, especially pancreas transplant alone (PTA), on earlier stage of DR. Moreover, even though abrupt normalization of glucose control induced by pancreas transplantation may aggravate DR in early posttransplant phase, little is known about the possible early worsening of DR after normalized glucose control obtained by pancreas transplantation.

One of the main causes of visual deterioration in DR is macular edema. The recent introduction of optical coherence tomography (OCT) and anti-vascular endothelial growth factor (VEGF) agents enabled easy detection and efficient treatment of macular edema; however, there is little information regarding the development of macular edema after pancreas transplantation. To compensate for the current scarcity of data on the aforementioned DR-related conditions and pancreas transplantation, we evaluated the long-term effects of pancreas transplantation on the progression of DR. In addition, we assessed the incidence of early worsening of DR after pancreas transplantation and the possible predictive factors for early worsening.

MATERIALS AND METHODS

Study Subjects

We selected patients with either type 1 or 2 diabetes who underwent successful pancreas transplantation from January 2007 to October 2015 with follow-up periods of longer than 1 year, and reviewed their medical record in a consecutive manner. Among them, those who received medical evaluation by both the transplant surgeons and ophthalmologists at our center were included in this retrospective cohort study. Criteria for exclusion were as follows: patients who developed early graft loss due to technical failure, severe venous thrombosis, or noncompliance; patients who underwent pancreas transplantation after total pancreatectomy due to chronic pancreatitis; or patients who received a segmental pancreas graft from a living donor. Eyes that had concomitant ocular disease other than DR were also excluded from the analysis.

Pancreas transplantation and postoperative anticoagulation were performed as previously described.12,13 Upon retrieval of a pancreas graft, the abdominal organs were perfused with histidine-tryptophan-ketoglutarate (15-20 L) through the aorta. The graft portal vein was anastomosed end-to-side to the recipient's external iliac vein. The superior mesenteric and splenic arteries reconstructed from donor iliac arterial Y graft were anastomosed to the recipient's common iliac or external iliac artery. Drainage of the exocrine pancreatic secretions was performed by either bladder or enteric drainage. Patients were administered with continuous intravenous heparin (400-1000 U/h) during the procedure. The level of activated partial thromboplastin time (aPTT) was checked every 6 hours; after the surgery, the patients were administered with oral warfarin for 3 months. The target level of aPTT and PT (international normalized ratio) was 1.5-fold to twofold of the upper reference range. All patients underwent CT angiography for monitoring of vascular patency within 48 hours after pancreas transplantation. If a thrombosis was detected, heparin was administered intravenously at a dose twice the normal upper level of aPTT, followed by weekly monitoring of graft patency using CT angiography. During follow-up periods, there was no change in our anticoagulation protocol.

The main immunosuppression protocol consisted of antithymocyte globulin (ATG) induction, maintenance with tacrolimus and mycophenolate mofetil, and small amounts of steroids. The total ATG dose was 4.5 to 5.0 mg/kg regardless of the type of transplant. The first dose (1.5 mg/kg) was intraoperatively administered and followed by 1 mg/kg ATG on postoperative days 1, 2, 4, and 6. A target tacrolimus level of 9 to 11 μg/L was achieved within seven days in 90% of the patients. Nine of the 153 recipients received basiliximab (Simulect) as induction therapy.

All procedures conformed to the principles of the Declaration of Helsinki, and the study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, Korea (2017-0035).

Evaluation of DR and Definition of DR Progression

At each of their initial and after visits to a retina clinic, all patients underwent a comprehensive ophthalmologic examination that included a review of their ophthalmologic history, measurement of best-corrected visual acuity (BCVA), slit lamp biomicroscopy, and funduscopic examinations through dilated pupils by retinal specialists. OCT images were taken using a Spectralis (Heidelberg Engineering) to assess the presence of macular edema. When necessary, fluorescein angiography was performed to assess vascular abnormalities and the extent of capillary nonperfusion area. The degree of DR was classified by the criteria of the Early Treatment Diabetic Retinopathy Study.14 In addition, history of ocular treatment, ie panretinal photocoagulation (PRP) or pars plana vitrectomy (PPV), were additionally applied to the categorization to reflect ocular vasoproliferative properties.

The initial posttransplant follow-up examination was carried out within 3 months after transplant, and the frequency of the eye examination was at least once a year or more depending on the degree of DR. Ocular treatment was based on the discretion of retinal specialists. The patients received PRP when DR progressed to very severe nonproliferative diabetic retinopathy (NPDR) or proliferative DR (PDR). Vitrectomy was performed if tractional retinal detachment or nonclearing vitreous hemorrhage developed. If central-involved macular edema developed combined with decreased BCVA of 20/30 or less, intravitreal anti-VEGF injection was performed.

Clinically significant DR progression was defined as (i) development or aggravation of macular edema requiring anti-VEGF injections and/or (ii) progression of DR severity requiring PRP and/or PPV. Depending on the timing of deterioration, progression within 1 year of posttransplantation was considered as early worsening. Patients who showed regression of DR severity were also identified. When calculating the progression rate, we counted either eye matching at least 1 of the above definitions of progression. On the other hand, when analyzing characteristics and risk factors for progression of DR, only 1 eye from each patient was included to obviate duplication of the same systemic characteristics of 1 patient. If only 1 eye experienced progression, the progressed eye was included in the analysis. If both eyes with the same DR stage experienced progression, either eye was selected. If both eyes experienced progression and were rated at different stages, the grade of the better eye was used to represent progression in eyes with earlier stage of DR.

Analysis

Variables regarding demographic characteristics, systemic and metabolic indices, surgical factors, and ocular status were recorded for each patient. Endocrine function evaluated at before and 1 month, 6 months, 1 year, 3 years, and 5 years after the pancreas transplantation was used in the analysis. As for BCVA, measurements at pretransplant and the last follow-up visit were used.

Descriptive statistics (number and percentage of each categorical variable and the mean ± standard deviation of each continuous variable) were initially evaluated to determine the baseline characteristics of subjects. Wilk-Shapiro test was used to explore the distribution of numerical data. To compare the posttransplant metabolic and ocular variables during the follow-up period with pretransplant values, paired t test was used.

The incidence of overall progression and early worsening of DR was also evaluated. With standards described above, to demonstrate the characteristics of subjects with early worsening of DR compared with those without, Student t test or Mann-Whitney U test were used, depending on the normality of their distribution. To compare categorical data, the χ2 test was used. Risk factors for early worsening were calculated as well. Odds ratios (ORs) for associations among potential risk factors were obtained using binary logistic regression analysis in the overall and each categorization of early worsening as the dependent variable. Univariate analyses were performed separately for each variable and variables with probability values less than 0.1 in univariate analysis were included in multivariate regression analysis model. A forward elimination process was used to develop the final multivariate model, and ORs with 95% confidence intervals were calculated. Kaplan-Meier graphs were used to provide overall incidence, timing, and associated variables regarding DR progression. All statistical analyses were performed using SPSS version 18.0 software (SPSS Inc., Chicago, IL).

RESULTS

Demographic and Baseline Characteristics of Study Patients

Between January 1, 2007, and October 31, 2015, 206 pancreas transplantations were performed at Asan Medical Center. Among them, 153 pancreas transplants was included in our study cohort, which consisted of 51 SPK, 26 simultaneous deceased donor pancreas and living donor kidney (SPLK), 25 pancreas after kidney transplants (PAK), and 51 PTA patients. The mean patient age at the time of transplant was 36.2 ± 10.7 years and 88 patients (57.5%) were women. Age at onset for DM was 20.4 ± 9.1 years, and DM duration at the time of transplant was 15.7 ± 7.9 years. Among the enrolled recipients, 121 (79.0%) were type 1 diabetes, and 32 recipients (21.0%) were type 2 diabetes. One hundred three (67.3%) transplants underwent bladder drainage, whereas enteric drainage was performed in the remaining 50 patients.

Regarding perioperative metabolic changes, the levels of HbA1c were significantly lower after transplantation compared with those before transplantation during the 5-year follow-up period (all P < 0.001). Likewise, the posttransplant levels of C-peptide were significantly higher than pretransplant values during the same time points (all P < 0.001).

The Incidence and Characteristics of Eyes With DR Progression After Pancreas Transplantation

Among the 306 eyes of 153 enrolled recipients, 3 eyes were excluded from our analysis due to the following reasons: 1 eye had no light perception due to chronic retinal detachment and 2 eyes developed CMV retinitis and endogenous endophthalmitis during postoperative periods. Mean follow-up period was 4.2 ± 2.2 years (1.0-9.75 years). Of 303 eyes, 221 (72.9%) eyes had advanced DR with a history of PRP/PPV. During the follow-up period, 24 eyes showed varying degrees of regression in DR severity and 217 eyes remained stable. Meanwhile, 62 eyes of 39 patients (20.5%) experienced DR progression (Table 1). Most cases of progression (57 cases (92.0%)) occurred during the first year of posttransplantation (Figure 1A). Notably, 10.8% of patients with no baseline DR showed development of DR, and the progression rate continued to grow as the severity of DR increased to severe NPDR (57.1%). Of 45 eyes that had DR findings without previous ocular treatments at baseline, 11 eyes received PRP/PPV during the follow-up period. Although none of eyes that underwent PPV experienced progression during the entire period, eyes that underwent PRP experienced different progression rate according to the timing of PRP before pancreas transplantation (Figure 2). The interval between PRP and pancreas transplantation was inversely proportional to the rate of DR progression. Specifically, 59.0% of eyes that underwent PRP within 1 year before transplantation showed progression; this rate was as high as that of severe NPDR without a history of PRP.

T1-31
TABLE 1:
Incidence of DR progression after pancreas transplantation during the entire follow-up period according to baseline severity of DR
F1-31
FIGURE 1:
Kaplan-Meier survival curves illustrating the cumulative incidence of overall progression of DR comprising (A) both i and ii, (B) (i) development or aggravation of central-involved macular edema requiring anti-VEGF injections, and (C) (ii) an increase of DR severity scales requiring PRP and/or PPV.
F2-31
FIGURE 2:
Incidence of early worsening according to the timing of PRP before transplant surgery.

Macular edema requiring anti-VEGF injections occurred in 32 eyes of 17 patients. Among them, 15 patients (88.2%) had macular edema in both eyes. Median time to the worsening after pancreas transplantation was 2.2 months (range, 0.2-9 months; Figure 1B). Interestingly, all of the aggravation developed within 3 months after surgery, pancreas transplantation, or enteric conversion. Fourteen (82.4%) patients had experienced hypotensive episodes before having macular edema. Five patients showed multiple splint retinal hemorrhages in both eyes, which is similar to nonischemic central retinal vein occlusion. Most (90.6%) eyes with macular edema were resolved with anti-VEGF treatments (median numbers of injection 2, 1-4), resulting in good visual outcomes (0.25 ± 0.16 at baseline vs 0.32 ± 0.28 at the last follow-up visit; P = 0.521).

As for the group with PRP/PPV, 43 eyes of 29 patients (14 patients in both eyes) experienced progression. Among 15 patients with unilateral progression, 8 patients already had histories of PPV in their fellow eyes. The median time to progression event was 6.5 months (range, 0.3-48 months; Figure 1C). Thirty-eight eyes (88.4%) had progression within 1 year posttransplant. Mean BCVA at the last follow-up was not significantly deteriorated when compared to baseline BCVA after proper ocular treatment (0.18 ± 0.11 at baseline vs 0.41 ± 0.62 at the last follow-up visit; P = 0.121).

Clinical Characteristics and Associated Risk Factors for Patient With Early Worsening of DR After Pancreas Transplantation

Because most progressions occurred during the first year posttransplant, we compared the clinical characteristics of patients in terms of experiencing early worsening. As described above, 1 eye from each patient was selected in the analysis.

Early worsening group had a greater proportion of patients who were young, had type 1 diabetes, had early development of DM, had poor pretransplant glycemic control, and subsequent large difference in the HbA1C level between pretransplant and posttransplant periods, received PTA other than SPK/SPLK or PAK, received bladder drainage, or had advanced DR with recent history of PRP within 1 year posttransplant (Table 2). There was no significant difference in terms of sex, DM duration, and induction and steroid treatment regimen between the 2 groups. Analysis of patients with macular edema showed that those with worsening had lower body mass index (BMI) in addition to the same characteristics noted in the overall early worsening group (Table 1 SDC,https://links.lww.com/TP/B491). As for PRP/PPV analysis, on the other hand, type 1 diabetes, young onset age, and bladder drainage were not significantly different according to progression.

T2-31
TABLE 2:
Baseline demographic and clinical characteristics: Comparison between eyes with early worsening of DR after pancreas transplantation and those without early worsening

Table 3 shows univariate and multivariate ORs for each putative risk factor in DR progression as the dependent outcome variable. In the multivariate analysis, severe NPDR-PDR with recent PRP (OR, 78.140; P <0.001) and type of transplantation as PTA (OR, 7.727; P = 0.002) were found to be significant risk factors for overall early worsening of DR. Kaplan-Meier survival curves are provided to illustrate the cumulative incidence of DR progression according to the transplantation type (Figure 3A) and baseline DR severity (Figure 3B). Moreover, multivariate analysis using either macular edema or PRP/PPV as dependent variables was performed separately. In the analysis of macular edema, low BMI (OR, 0.770, P = 0.050) was another significant risk factor in addition to other variables noted in the overall worsening. In the analysis of PRP/PPV, the same risk factors were identified as the overall group.

T3-31
TABLE 3:
Univariate and multivariate logistic regression with forward elimination for predicting early worsening of DR after pancreas transplantation
F3-31
FIGURE 3:
Kaplan-Meier survival curves illustrating the cumulative incidence of DR progression according to transplantation type (A) and baseline DR severity (B).

Subgroup Analysis in Patients Who Underwent PTA

A subgroup analysis was performed to determine the clinical characteristics of early worsening in PTA recipients because a large proportion of early worsening occurred in PTA recipients (Table 2 SDC,https://links.lww.com/TP/B491). Patients who underwent PTA had less advanced DR, and 34 (66.6%) of 51 patients had no history of PRP/PPV. Early worsening group showed a greater proportion of patients who had longer duration of DM (P = 0.006), lower baseline GFR (P = 0.007), posttransplant deterioration of renal function (reduction of GFR >50% of baseline value, P < 0.001), and larger differences of HbA1C between before and 6 months after surgery (P = 0.012). In addition, progression rate differed according to the pretransplant severity of DR (P = 0.001)—the highest progression rate was noted in DR severity more advanced than severe NPDR with a recent history of PRP within 1 year from transplantation.

DISCUSSION

Changes in DR after pancreas transplantation is becoming an important issue because pancreas transplant is more frequently offered to nonuremic patients with brittle DM to reduce the need for a kidney transplant.8 Our study demonstrated that, the degree of DR remained stable over time in most patients after achieving normoglycemia after transplantation. However, the effect of transplantation on DR differs depending on the pretransplant DR severity and pancreas transplantation type. In particular, the most critical time for progression of DR was the first year of metabolic normalization, and such early worsening of DR (18.8 %) was associated with potential risk factors of pretransplant vulnerable status of DR. Also, the largest proportion of early worsening occurred in PTA recipients. In long-term follow-up, progression of DR was reduced and DR was stabilized.

Even though some previous studies evaluated the changes in DR after pancreas transplantation, they are difficult to interpret due to the limited numbers of patients and varying follow-up periods.15 Several early reports showed no effect of pancreas transplantation on DR status, while some reported progression of retinal lesions.9-11,16 Other studies have shown beneficial effects of pancreas transplantation on DR, including slower progression of vascular proliferation and less need for PRP.17-21 In 1 of the early stages of research, Ramsay et al9 observed that progression of DR occurred in eyes with milder stages of DR during a 2-year follow-up period. When they extended the follow-up period, however, the authors also noticed the possibility that recipients with successful pancreas transplantation showed less deterioration compared with control group, which is in line with the results of our study.

Several factors may be involved in early worsening of DR after pancreas transplantation. Above all, it has been suggested that relative hypoglycemia might have a central role, because a rapid lowering of blood glucose in younger individuals with type 1 diabetes leads to an upregulation of insulin-like growth factor-1, a molecule that may have angiogenic effects.22 Moreover, because retinal circulation and oxygen supply in DR is compromised, their major remaining retinal energy source is reduced due to strict glucose regimen, resulting in VEGF upregulation as a compensatory mechanism.23 In our study, early worsening occurred more frequently in patients who had poor pretransplant glycemic control and subsequent large difference in HbA1C level between the pretransplant and posttransplant periods.

Early worsening is generally observed as mild-to-moderate DR worsening in about 10% of individuals with type 1 diabetes.4-6 We consider that the relatively higher incidence rate of patients experiencing early deterioration of DR in our study is probably related to the very dramatic glycemic control. Because we cannot find the control group with such dramatic glycemic control, it is difficult to directly compare the efficacy of our treatment with that of other medical treatment options. In addition to the rapid glycemic control, there might be a role of intrinsic changes related to surgery in early worsening after pancreas transplantation. First, in diabetic patients with underlying dysregulation of vascular tone, both orthostatic hypotension and recumbent hypertension can be induced after a major surgery.24 Fluctuating blood pressure causes spasm of retinal arterioles, leading to capillary closure and retinal ischemia. Also, hemodynamic responses are prone to be unstable especially in recipients with bladder drainage who are predisposed to volume depletion.8,25 Furthermore, hemodynamic changes also result from the use of immunosuppressant agents.26 Our study demonstrated that macular edema particularly developed at acute postoperative phase of transplantation and enteric conversion in both eyes of patients who had low BMI, which suggested a close relationship between early worsening and hemodynamic instability. Second, retinal acidification may be caused by hyperchloremic metabolic acidosis secondary to bicarbonate loss through urine, the major unique metabolic complication of bladder drainage. Previous reports demonstrated that retinal acidosis plays a role in the pathogenesis of DR, and VEGF could be independently induced by retinal acidification27,28; this implies that retinal acidic change might be another transplant-related factor for DR progression. In this regard, the early worsening group in our study cohort showed a greater portion of patients who underwent bladder drainage.

All of the changes mentioned above may commonly contribute to the high level of VEGF in the early postoperative phase of pancreas transplantation. VEGF, a strong angiogenic factor, may promote retinal nonperfusion by leukostasis, hence VEGF-induced positive feedback loop can be formed, resulting in significant retinal neovascularization and vascular leakage. The levels of VEGF are positively correlated with disease activity.29 A main regulating factor of VEGF is hypoxia. Because baseline retinal circulation and oxygen supply in DR is compromised in diabetic patients, fluctuation in blood supply and hypotension can induce hypoxic condition with underlying dysregulation of vascular tone. In this context, hypoxia aggravated by hypotensive episodes in diabetic patients may upregulate VEGF, which contribute as the major mechanism of DR progression after pancreas transplantation. For the same reason, the most vulnerable DR stage was more advanced than severe NPDR with recent PRP. Because PRP takes some time (months or more) for the laser effect to appear and stabilize, recent PRP within 1 year indicates that disease activity may be active and yet to be stabilized. And VEGF level is temporally increased after PRP treatment,30 Taking into account that not only patients with recent PRP ≤ 1 year but also patients without PRP show higher progression rate than those with PRP > 1 year, stabilizing DR at the timing of transplant surgery can be beneficial. In addition, treatment of macular edema with anti-VEGF agents showed substantially beneficial effects with relatively small number of injections.

Our study demonstrated that the degree of DR remained stable over time and could be reversed in some patients after pancreas transplantation. Notably, long term glycemic control was excellent without the risk of hypoglycemia after pancreas transplantation. This is 1 of the most important issues when treating DR patients. Among several important risk factors for DR, chronic exposure to hyperglycemia is believed to critical in both type 1 and type 2 DM. Therefore, achieving good glycemic control with pancreas transplantation is essential for managing DR patients.

However, because advanced DR is common in patients who undergo pancreas transplantation, reversal of disease with normoglycemia in these patients is unlikely due to irreversible injury from disease and previous treatment. Olsen et al31 suggested that a “point of no return” may be reached in advanced cases where improvement is unlikely. Thus, some researchers suggested that compared to those with more established chronic retinal lesions, patients with indications of PTA who receive pancreas transplantation early in the course of diabetic complication would benefit more from pancreas transplantation in terms of DR progression.17,32 To date, little information is available regarding the effects of pancreas transplantation on the earlier stage of DR, especially those of PTA on DR. According to our data, a significant portion of PTA patients experienced DR progression. These are consistent with previous findings that progression was observed in patients with a lower retinopathy score.9,26 With this in mind, we suggest that special cautions be taken when treating pancreas transplant candidates who have milder stages of DR, and especially those who have plan for receiving PTA with early decrease in renal function and longer duration of DM. We believe that these changes can be related to problems with orthostatic changes and/or difficulties in keeping up with the volume requirements, resulting in hypotension and BP fluctuation. In advanced cases that progressed to severe NPDR or more, it is important to be aware of the possibility of ocular deterioration within 1 year posttransplantation. Subsequently, close ophthalmologic follow-up after transplantation is necessary in patients with high risk. Of note, patients with no visible DR change may develop significant changes. Fortunately, owing to recent development of treatment modalities for DR, visual acuity can be restored with prompt management.

To our knowledge, this is the first study that compares various types of pancreas transplantation to determine vulnerable pretransplant DR severity and posttransplant phase for DR progression. The present study contains a significant portion of PTA patients, which allows for reasonable prognosis of milder DR severity at transplant surgery. Our study also possesses information regarding macular edema diagnosed based on OCT and treated with anti-VEGF agents, and thus provides valuable data on the main cause of decreased vision in DR. A potential limitation of this study is its retrospective design. Because patients who developed visual problems tended to visit more often, the frequency of exacerbations in our study might be higher than the actual value. Another limitation is that there is a lack of control group; some previous reports adopted a control group with patients who underwent pancreas transplant but had early graft failure. However, because recent surgical success rate has been rapidly increasing, it was difficult to find a reasonable control group with poor glycemic control after transplant. Lastly, the timewise scope of the study is quite short to determine the long-term progression of DR. Therefore, we encourage further prospective studies with long-term follow-up periods to determine the effect of pancreas transplantation on DR progression.

In conclusion, the degree of DR remained stable over time in most patients; on the other hand, early worsening of DR after pancreas transplantation occurred in patients who had pretransplant vulnerable status of DR and who underwent PTA, particularly within the first year of metabolic normalization. Therefore, to minimize posttransplant deterioration in patients at risk, thorough follow-up ophthalmologic examinations and timely ocular management are necessary.

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