Pancreas After Kidney Transplants Research Articles

Experience from 100 consecutive pancreas transplants amidst low national transplant activity: a retrospective study at a single center in Korea.

Since 1992, over 800 pancreas transplants have been performed in Korea. However, this number is significantly lower compared to the number of kidney or liver transplants. Between 2015 and July 2023, Pusan National University Yangsan Hospital conducted 100 pancreas transplants, accounting for about 20% of all transplants performed in Korea during this period. The study comprised 27 simultaneous pancreas and kidney (SPK) transplants, 23 pancreas after kidney (PAK) transplants, and 50 pancreas transplant alone (PTA) cases. Duodenoduodenostomy was the primary surgical technique employed for exocrine drainage, along with various modifications of the venous outflow anastomosis. The availability of brain-dead donors for kidney transplants was lower compared to isolated pancreas transplants. Patients undergoing SPK transplants faced significantly longer waiting times than those receiving PTA or PAK transplants. The rate of surgical complications was acceptable, with a notably low thrombotic graft failure rate of 1.0%. In the PTA group, acute rejection of the graft pancreas occurred frequently (18.0%), though this was not statistically significant (P=0.328). The pancreas transplantation survival rates were 91.0%, 78.5%, and 75.4% at 1, 5, and 9 years, respectively. The PTA group exhibited a lower graft survival rate than the SPK and PAK groups, with marginal statistical significance (P=0.059). Graft survival rates have improved over time due to advancements in surgical techniques and immunosuppressant strategies. By sharing our experiences, we aim to enhance the activity and success of pancreas transplantation in Korea.

Pancreas transplantation: review.

Pancreas transplant (PTx) is the only treatment that establishes normal glucose levels for patients diagnosed with diabetes types 1 and 2. The paper aims to review and analyze graft survival, patient survival, and the impact on diabetic complications. We describe that the graft survival was 82-98% at 1 year, 90% at 5 years, and 75-54% at 10 years for simultaneous pancreas-kidney recipient; 71% pancreas after kidney (PAK), and 62% PTx alone at 1 year. Patient survival: At 1 year for recipients was 96.9% simultaneous pancreas-kidney transplantation (SPK); for PAK transplantation recipients, 96.3%; and for PTx alone recipients, 98.3%. In general, the pancreas transplantation improves and reverses diabetic complications. Finally, the pancreatic transplant is a morbid procedure and emerges as a significant alternative in diabetes management, directly competing with conventional insulin therapies. Results so far suggest that the most effective transplant model is the SPK. While more patients could benefit from this procedure, surgical complications and the need for immunosuppression pose significant challenges.

Association of human leukocyte antigen mismatches between donor-recipient and donor-donor in pancreas after kidney transplant recipients.

The effects of HLA mismatching on pancreas outcomes among pancreas after kidney (PAK) recipients are undefined. Outcomes might potentially differ depending on whether there is a mismatch between pancreas donor and recipient (PD-R) or pancreas donor and kidney donor(PD-KD). All primary PAK at our centre were included in this study. Patients were divided into two groups based on the degree of HLA mismatching: low (L-MM) as 0-4 and high (H-MM) as 5-6. We analysed all (N=73) PAK for PD-R mismatch and the subset of PAK for PD-KD mismatch (N=71). Comparing PD-R L-MM (n=39) and H-MM (n=34) PAKs, we observed no difference in the rate of pancreas graft failure. There was also no difference in the rate of rejection (L-MM 33% vs. H-MM 41%) or the severity of rejection. However, we observed a significantly (P<0.01) shorter time to acute pancreas rejection in the H-MM group (6.8±8.7 mo) versus the L-MM cohort (29.0±36.2 mo) (P<0.001). Similar to the PD-R mismatched cohort, we did not observe a detrimental effect of HLA mismatching on graft outcomes in the PD-KD cohort; time to rejection was again shorter in the H-MM subset. In this study, we found no impact of HLA mismatch on either pancreas graft survival or rejection rates, though rejection occurred earlier in high mismatched PAK transplants.

Risk factors for surgical site infection after kidney and pancreas transplantation.

To evaluate the incidence of surgical site infection (SSI) in a cohort of pancreas transplant recipients and assess predisposing risk factors for SSI DESIGN: Retrospective cohort study SETTING: Single transplant center in CanadaPatientsPatients who underwent any simultaneous pancreas and kidney (SPK) or pancreas after kidney (PAK) transplant procedures between January 2000 and December 2015 METHODS: In this retrospective cohort evaluation of SPK or PAK recipients, we assessed the incidence of SSI and risk factors associated with superficial, deep, and organ/space SSI. Multivariate logistic regression was used to identify independent risk factors for SSI in SPK and PAK recipients. In total, 445 adult transplant recipients were enrolled. The median age of these patients was 51 years (range, 19-71 years), and 64.9% were men. SSIs were documented in 108 patients (24.3%). Organ/space SSIs predominated (59 patients, 54.6%), followed by superficial SSIs (47 patients, 43.5%) and deep SSIs (3 patients, 2.8%). Factors predictive of SSIs in the multivariate analysis were cold pancreas ischemic time (odds ratio [OR], 1.002; P=.019) and SPK transplant (compared to PAK transplant recipients; OR, 2.38; P=.038). Patients with SSIs developed graft loss more frequently (OR, 16.99; P<.001). Organ/space SSIs remain a serious and common complication after SPK and PAK. Prolonged cold ischemic time and SPK transplant were the risk factors predictive of SSIs. Appropriate perioperative prophylaxis in high-risk patients targeting the potential pathogens producing SSIs in kidney and/or pancreas transplant recipients and a reduction in cold ischemia may prove beneficial in reducing these SSIs.

OPTN/SRTR 2016 Annual Data Report: Pancreas.

The number of pancreas transplants performed in the United States increased by 7.0% in 2016 over the previous year, the first such increase in more than a decade, largely attributable to an increase in simultaneous kidney pancreas transplants. Transplant rates increased in 2016, and mortality on the waiting list decreased. The declining enthusiasm for pancreas after kidney (PAK) transplants persisted. The uniform definition of graft failure was approved by the OPTN Board of Directors in 2015 and will be implemented in early 2018. Meanwhile, SRTR continues to refrain from reporting pancreas graft failure data. The OPTN/UNOS Pancreas Transplantation Committee is seeking to broaden allocation of pancreata across compatible ABO blood types in a proposal out for public comment July 31 to October 2, 2017. A new initiative to provide guidance on the benefits of PAK transplants is also out for public comment.

Duodenal leaks after pancreas transplantation with enteric drainage - characteristics and risk factors.

Pancreas-kidney transplantation with enteric drainage has become a standard treatment in diabetic patients with renal failure. Leaks of the graft duodenum (DL) remain a significant complication after transplantation. We studied incidence and predisposing factors of DLs in both simultaneous pancreas-kidney (SPK) and pancreas after kidney (PAK) transplantation. Between January 2002 and April 2013, 284 pancreas transplantations were performed including 191 SPK (67.3%) and 93 PAK (32.7%). Patient data were analyzed for occurrence of DLs, risk factors, leak etiology, and graft survival. Of 18 DLs (incidence 6.3%), 12 (67%) occurred within the first 100 days after transplantation. Six grafts (33%) were rescued by duodenal segment resection. Risk factors for a DL were PAK transplantation sequence (odds ratio 3.526, P = 0.008) and preoperative immunosuppression (odds ratio 3.328, P = 0.012). In the SPK subgroup, postoperative peak amylase as marker of preservation/reperfusion injury and recipient pretransplantation cardiovascular interventions as marker of atherosclerosis severity were associated with an increased incidence of DLs. CMV-mismatch constellations showed an increased incidence in the SPK subgroup, however without significance probability. Long-term immunosuppression in PAK transplantation is a major risk factor for DLs. Early surgical revision offers the chance of graft rescue.

Pancreas after kidney transplantation: why is the most logical option the least popular?

Despite recent improvements in outcomes for pancreas transplantation in general, including graft survival following pancreas after kidney (PAK) transplantation, there has been a consistent decline in the number of PAK transplants performed in the USA. The purpose of the present review is to analyze the advantages and disadvantages of PAK transplantation compared with simultaneous pancreas and kidney (SPK) transplantation and to review recent publications in an attempt to explain this phenomenon. PAK transplantation has historically been associated with inferior pancreas allograft survival compared with SPK transplantation. Under modern immunosuppression protocols, pancreas allograft survival has improved substantially with rare immunological graft loss. According to several recent publications, it is controversial whether there is a survival advantage related to performing the pancreas transplant once the recipient has had a living donor renal transplant (LDRTx). Considering that patient survival following SPK transplantation is significantly superior to that of recipients of LDRTx with type 1 diabetes alone and that LDRTx has demonstrated clear superiority in terms of renal allograft and patient survival over cadaveric renal transplantation, it would seem that PAK transplantation should be revisited as the option of choice for uremic recipients with diabetes.

Long-Term Outcomes of Pancreas After Kidney Transplantation in Small Centers: Is It Justified?

BackgroundCurrently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied. MethodsIn this retrospective analysis, we report short- and long-term outcomes in a small center performing 2–9 PT annually. ResultsForty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy. ConclusionsCompared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.

Kidney, Pancreas and Islet Transplant Options for Patients with Diabetic Nephropathy

Recent progress in surgery and immunosuppression has expanded the “transplant menu” for patients with diabetic nephropathy which is now including: Kidney Transplantation from a Deceased Donor (DDKT) or a Living Donor (LDKT), Simultaneous Pancreas Kidney (SPK), Pancreas Transplantation Alone (PTA), Pancreas after Kidney (PAK) and Islet transplantation. As pre-emptive transplantation presents a clear survival advantage over dialysis, all diabetic patients with chronic kidney disease (CKD) should be referred for early evaluation by a transplant center. For type 1 diabetes mellitus (T1DM) patients, LDKT and SPK transplantation offer superior and approximately equivalent long-term patient and allograft survival. PAK transplant rates tend to decline due to surgical and immunological complications, but it may still be considered for well selected candidates with preserved kidney allograft function. For type 2 diabetes mellitus (T2DM) patients, not only LDKT, but even DDKT are superior to dialysis. SPK transplantation should be offered only in selected cases with special metabolic characteristics similar to T1DM. PTA should be considered only for selected cases of T1DM with well preserved renal function (eGFR>80 ml/min/1.73 m2 and minimal proteinuria), as it may a cause of rapid deterioration of renal function. Islet transplantation should still be considered as an experimental procedure for T1DM, and has no place in patients with advanced CKD, but it may be applied in already immunosuppressed patients following KT. However, the best transplant option for patients with diabetic nephropathy therapy should always be individualized, taking under consideration the patients’ preferences and expectations, their overall medical condition and the transplant center’s experience with all these procedures.

The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan-Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review.

For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic control without significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directly with the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK). We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion. Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7-205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function. The mixed results may be attributable to limited sample sizes. Also, some PRO measures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important for QoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet/pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

Renal Allograft Failure Predictors After PAK Transplantation: Results From the New England Collaborative Association of Pancreas Programs

The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection. Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure. Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year. In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.

Epidemiology of Infections Requiring Hospitalization During Long-Term Follow-Up of Pancreas Transplantation

BACKGROUND.: Pancreas transplantation (PT) provides the best glycemic control option for diabetes mellitus but is associated with significant morbidities related to infectious disease. METHODS.: We performed a retrospective study of a cohort of consecutive PT recipients in whom PT was performed from 1998 to 2006 (n=216) and followed up them until July 2008. Data regarding infections, rejection, infection chemoprophylaxis, graft failure, absolute lymphocyte counts (ALCs), and mortalities were collected. RESULTS.: Simultaneous pancreas and kidney, pancreas transplantation alone, and pancreas after kidney (PAK) transplantations were performed in 42, 67, and 107 patients, with a mean (standard deviation) age at transplantation of 46.8 (8.03), 40.6 (10.1), and 43.7 (8.19) years. Of the simultaneous pancreas and kidney, pancreas transplantation alone, and PAK transplant recipients, 54.7%, 37.3%, and 58.8% were men. Overall, 63% developed a serious infection during the median follow-up of 6.4 years. Mean (range) number of infectious episodes was 2.3 (1-12), with mostly bacterial infections both within (68%) and after 1 year (78%). Incidence of bacterial and viral infections was greatest in the first 3 months after transplantation. Fungal infections were more constant. Bladder exocrine drainage was associated with higher risk of infection (hazard ratio=2.5, P<0.001). Infection within the first 3 months after transplantation was related to higher mortality after the first 3 months (hazard ratio=3.19). ALC was associated with the risk of first infections (P=0.005) and bacterial infections (P<0.001). CONCLUSIONS.: Incidence of infections after PT was 63% and mostly bacterial. Bladder drainage increases infection risk and low ALC partially predicts episodes. Limitations include retrospective design, unequal composition of PT groups, and lack of data between kidney and PT for PAK.

The case for pancreas after kidney transplantation

Pancreas after kidney (PAK) transplantation has historically demonstrated inferior pancreas allograft survival compared to simultaneous pancreas and kidney (SPK) transplantation. Under our current immunosuppression protocol, we have noted excellent outcomes and rare immunological graft loss. The goal of this study was to compare pancreas allograft survival in PAK and SPK recipients using this regimen. This was a single center retrospective review of all SPK and PAK transplants performed between January 2003 and November 2007. All transplants were performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included induction with rabbit anti-thymocyte globulin (thymoglobulin), early steroid withdrawal, and maintenance with tacrolimus and sirolimus or mycophenolate mofetil. Study end points included graft and patient survival and immunosuppression related complications. Transplants included PAK 61 (30%) and SPK 142 (70%). One-yr patient survival was PAK 98% and SPK 95% (p = 0.44) and pancreas graft survival was PAK 95% and SPK 90% (p = 0.28). Acute cellular rejection was uncommon with 2% requiring treatment in each group. Survival for PAK using thymoglobulin induction, early steroid withdrawal and tacrolimus-based immunosuppression is at least comparable to SPK and should be pursued in the recipient with a potential living donor.

Trends in Organ Donation and Transplantation in the United States, 1998–2007

The articles in this report are based on the reference tables in the 2008 OPTN/SRTR Annual Report. Table numbers are noted in brackets and may be found online at: http://www.ustransplant.org.

Thrombotic microangiopathy following pancreas after kidney transplants

Advances in immunosuppressive therapy and refinement in surgical techniques have allowed pancreas after kidney (PAK) transplantation to become a viable therapeutic option for patients with brittle type I diabetic recipients of a living donor or previous deceased kidney alone transplant. Although maintenance immunosuppressive therapy is not significantly changed after the addition of a pancreas, a temporary booster in immunosuppressive therapy and an increase in the dose of calcineurin inhibitor (CNI) are required after PAK transplantation. The latter has been implicated in the observed variable decline in kidney allograft function. We herein report two cases of kidney allograft dysfunction following PAK transplant due to biopsy-proven transplant, thrombotic microangiopathy (TMA). Whether PAK transplantation pre-disposes a subset of patients to the development of post-transplant TMA is not known. Diagnostic kidney biopsies should be considered in PAK transplant recipients with worsening kidney allograft function.

Prevalence and Clinical Course of BK Virus Nephropathy in Pancreas After Kidney Transplant Patients

The influence of BK virus nephropathy (BKVN) in pancreas after kidney (PAK) transplantation is unclear. A retrospective analysis of PAK transplants performed at our center was conducted to determine the impact of BKVN. Among 40 PAK transplants performed using sequential immunosuppression, four patients developed BKVN, as defined by a >20% rise in serum creatinine and BK viremia (BK plasma load >4 log copies/mL), at a median of 19 months following PAK. In all four patients, treatment of BKVN consisted of reduction in tacrolimus, cessation of mycophenolate mofetil, and introduction of leflunomide. With this approach, two patients experienced improvement or stabilization of renal function. The remaining two patients progressed to dialysis dependence despite treatment. Plasma BK load ≤5 log copies/mL was associated with graft preservation. Gender, age, delay between transplants, cumulative Thymoglobulin dose, and type of kidney donor were not associated with BK virus infection. Pancreas graft rejection or dysfunction was not observed with the above immunosuppression modification. Mean amylase and lipase ≥6 months following BKVN treatment remained normal. BKVN is an important cause of kidney allograft loss in PAK patients. Screening and early treatment of BKVN may enable preservation of kidney and pancreas grafts.

Steroid Withdrawal for Pancreas after Kidney Transplantation in Recipients on Maintenance Prednisone Immunosuppression

Steroid withdrawal from patients taking prednisone for their renal allograft at the time of reinduction of immunosuppression for subsequent pancreas after kidney (PAK) transplantation has not been explored. Our expectation was that lymphocyte depletion, in conjunction with an augmentation of immunosuppression at the time of pancreas transplantation would protect the recipient from rejection of the renal allograft when chronic maintenance steroids are withdrawn. Pancreas transplantation was performed using systemic venous drainage and enteric exocrine drainage. Regardless of preoperative immunosuppression, all patients received induction with antithymocyte globulin, a brief taper of intravenous solumedrol over four to five days, maintenance therapy with tacrolimus and sirolimus and either resumption of chronic maintenance steroids or complete withdrawal of steroids. A total of 30 PAK transplants were performed in 29 recipients and divided into two groups: continuation of chronic steroids (n = 10) or steroid-free (n = 19). One pancreas allograft was lost and there was a single mortality in the steroid free group. There was no significant difference in renal function or incidence of infections. Steroids can be safely withdrawn following pancreas after kidney transplantation for recipients already on maintenance prednisone in the setting of rabbit antithymocyte globulin induction and tacrolimus and sirolimus maintenance immunosuppression.

Organ donation and transplantation trends in the USA, 2003

This summary provides an overview of solid organ transplantation in the USA, produced as part of the 2003 OPTN/SRTR Annual Report. The Annual Report is prepared by the Scientific Registry of Transplant Recipients (SRTR) in collaboration with the Organ Procurement and Transplantation Network (OPTN) under contract with the Health Resources and Services Administration (HRSA). A wide range of activities related to solid organ transplantation in the USA are thoughtfully addressed in this publication with the intention of providing useful information to patients, the transplant community, the public, and the Federal Government.

Immunosuppression: practice and trends

Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.