This single-center study from the University of Wisconsin-Madison included all adult SPK transplant recipients performed between 01/01/2001 and 12/31/2022. We excluded all recipients whose pancreas or kidney graft failed within 2 weeks of transplant, multiorgan transplant recipients (i.e., simultaneous liver - pancreas), or pancreas after kidney transplant recipients. In subgroup analysis, we analyzed SPK recipients even with graft failure within 2 weeks of transplant. This study was approved by the University of Wisconsin Institutional Review Board (IRB protocol number: 2014-1072). This study followed the Declaration of Helsinki. The clinical and research activities being reported were consistent with the Principles of the Declaration of Istanbul as outlined in “The Declaration of Istanbul on Organ Trafficking and Transplant Tourism.”

Only recipients with serum albumin levels measured within 45 days before transplant were included. In patients with multiple albumin levels measured within 45 days before transplant, we used the measurement closest to the transplant date. SPK recipients without albumin levels within the 45-day timeframe before transplant were excluded. Recipients were categorized based on pretransplant albumin levels as normal (≥4.0 g/dL), mild hypoalbuminemia (≥3.5–< 4.0 g/dL), and moderate hypoalbuminemia (<3.5 g/dL). Although, we initially planned to categorize the severe hypoalbuminemia group defined as <3.0 g/dL, this was not possible due to the extremely small sample size in this group with limited outcomes of interest, so for this reason they were included in the moderate hypoalbuminemia group. Pre or peri-transplant albumin transfusion to correct hypoalbuminemia has never been the current or past practice at our center, although few recipients may have received albumin infusion intraoperative or post-operative for various other indications. At no time during this study period or currently in our program was there a protocolized criterion for pretransplant serum albumin level to approve or disapprove SPK transplant eligibility.

Length of stay (LOS) after index transplant, kidney delayed graft function (DGF), and re-hospitalization within 30 days after discharge were perioperative outcomes of interest followed by the need for a return to the operating room (OR) related to transplant surgical complications, acute rejection of either grafts and uncensored and death-censored graft failure, within the 12 months post-transplant were short-term outcomes of interest. We limited outcomes to the first 12 months post-transplant to better correlate pre-transplant serum albumin levels and early post-transplant outcomes.

Donor characteristics such as age, sex, race, body mass index (BMI), death due to cardiovascular causes, terminal serum creatinine, kidney donor profile index (KPDI), donation after circulatory death (DCD), pancreas cold ischemia time (CIT), and kidney CIT were reported. Information on recipients included age, sex, race, BMI, diabetes type, induction therapy, pre-emptive transplant, and early steroid withdrawal. Immunologic factors reported were panel reactive antibody (cPRA) > 20%, average Human Leukocyte Antigen (HLA) mismatch (of 6), and whether primary or prior transplant.

DGF was defined as a need for dialysis within one-week post-transplantation. Re-hospitalizations within 30 days post initial discharge and any unanticipated return to the operating room within 12 months post-SPK were included. Return to the operating/procedure room for an anticipated ureteric stent removal was not considered a return to the OR. All episodes of rejections were biopsy-proven within 12 months of transplant. Kidney uncensored graft failure was defined as all causes of graft failure including death, while death-censored graft failure (DCGF) was defined as a return to dialysis or re-transplantation, all within 2 weeks–12 months post-transplant. Similarly, pancreas uncensored graft failure was defined as all causes of pancreas graft failure including death. And pancreas DCGF was defined based on the current United Network for Organ Sharing criteria for pancreas graft failure, which include removal of the pancreas graft, re-registration for a pancreas transplant, registration for an islet transplant after receiving pancreas, or an insulin requirement that is ≥0.5 units/kg/day for 90 consecutive days [16, 17].

At our institution, serum albumin concentration measurements are conducted utilizing bromocresol assays. Before 2008, albumin was measured using bromocresol green assays. Since 2008, our institution has used bromocresol purple to assess serum albumin concentrations.

Reference ranges were adjusted to reflect the methodology of each test; prior institutional comparison of both assays on patient samples showed an average negative 0.56-g/dL bias in the newer bromocresol purple assay. This difference was considered to be within allowable limits for general clinical use.

Our center-specific induction immunosuppression therapy was consistent throughout the study period, either a depleting agent (alemtuzumab or anti-thymocyte globulin) or a non-depleting agent (basiliximab) was utilized. Triple immunosuppression with tacrolimus, mycophenolic acid and prednisone taper was standard for all recipients. Few had early steroid withdrawal based on the immunological risk and patient request as previously described [18].

The two most common indications for kidney biopsy were an unexplained rise in creatinine and proteinuria or the development of denovo DSA against HLA as described before [19]. Similarly, the common indications for pancreas biopsy were an unexplained rise in pancreatic enzymes, development of denovo DSA, and unexplained hyperglycemia [20]. If possible, we attempt to perform both graft biopsies in the setting of dual graft dysfunction [20].

Similarly, the management of rejections was based on the severity and proximity from the transplant to the diagnosis of rejection as described before [19, 20]. Briefly, kidney T cell-mediated rejection (TCMR) was treated with steroid pulse plus/minus anti-thymocyte globulin. And antibody-mediated rejection (AMR) was treated with steroid pulse, intravenous immunoglobulin (IVIG), plus/minus rituximab, plus/minus plasmapheresis. Treatment of pancreas rejection was based on the type and severity of rejection and was graded by the Banff criteria. TCMR was treated with IV steroid pulse with or without anti-thymoglobulin 6–12 mg/kg in 4–10 divided doses, while mixed rejection was treated with steroids, anti-thymoglobulin, IVIG, and plasmapheresis. Early AMR was treated with steroids, IVIG, and plasmaphereis [20].

Continuous data were compared using Student’s t-test or the Wilcoxon rank-sum test, where appropriate. Categorical data were analyzed using Fisher’s exact test or chi-square test. p-Values ≤ 0.05 were considered statistically significant. Multivariable logistic regression and Cox proportional hazard models were used to analyze associations of the pre-transplant serum albumin levels with various outcomes of interest. Variables considered to be associated with outcomes of interest from baseline characteristics were included in adjusted models. Outcomes of interest were also analyzed by Kaplan-Meier survival analysis. Analyses were performed in Stata SE 18.0 ¹ .

A total of 7.3% of recipients had DGF (Table 2). 4.5% of recipients with normal albumin levels, 9% with mild, and 10% with moderate hypoalbuminemia group experienced DGF. Mild hypoalbuminemia (OR: 2.08; 95% CI: 0.93–4.67; p 0.07) and moderate hypoalbuminemia were not associated with risk of DGF (OR: 2.36; 95% CI: 0.99–5.63; p = 0.05) in an unadjusted model. This was further confirmed after adjustment of multiple variables in mild (OR: 1.69; 95% CI: 0.65–4.37; p = 0.28); moderate (OR: 1.52; 95% CI: 0.55–4.20; p = 0.42) hypoalbuminemia groups (Table 3).

The mean LOS among the entire cohort after index transplant was 11.1 ± 7.9 days (Table 2). The mean LOS in normal, mild, and moderate hypoalbuminemia recipients was 11.2 ± 6.5 days, 10.4 ± 6.0 days, and 12.1 ± 12.0 days, respectively. Mild hypoalbuminemia was not associated with increased or decreased LOS in unadjusted (OR: −0.78; 95% CI: −2.31, 0.76; p = 0. 32) or adjusted models (OR: −0.94; 95% CI: −2.49, 0.61; p = 0. 24). Moderate hypoalbuminemia was also not associated with LOS in unadjusted (OR: 0.92; 95% CI: −0.84, 2.61; p = 0. 31) or adjusted models (OR: 0.22; 95% CI: −1.61, 2.06; p = 0. 81) (Table 4).

A total of 34.2% were re-hospitalizations within 30 days after the initial discharge from the index transplant (Table 2). The rate of rehospitalization in normal, mild, and moderate hypoalbuminemia recipients were 32.4%, 35.3%, and 35.8% respectively. Mild hypoalbuminemia was not associated with re-hospitalization rates in unadjusted (OR: 1.13; 95% CI: 0.75–1.71; p = 0.55) or adjusted models (OR: 1.31; 95% CI: 0.86–2.82; p = 0.21). Similarly, moderate hypoalbuminemia was not associated with re-hospitalization rates in unadjusted (OR: 1. 16; 95% CI: 0.73–1.86; p = 0.53) or adjusted models (OR: 1. 34; 95% CI: 0.81–2.23; p = 0. 25) (Table 5). The most common indications for re-hospitalization were gastrointestinal symptoms including, nausea, vomiting, diarrhea, and abdominal pain followed by hypo or hypertension.

A total of 22.6% of recipients returned to the operating room within 2 weeks–12 months post-transplant (Table 2). 25.7% of patients with normal albumin levels, 20% with mild, and 20.8% with moderate hypoalbuminemia were reoperated within the stated timeframe. Mild hypoalbuminemia was not associated with increased reoperation rates in unadjusted (OR: 0.59; 95% CI: 0.29–1.18; p = 0.14) or adjusted models (OR: 0.54; 95% CI: 0.26, 1.12; p = 0.10). Similarly, moderate hypoalbuminemia was not associated with increased reoperation rates in unadjusted (OR: 1.04; 95% CI: 0.52–2.04; p = 0.92) or adjusted models (OR: 0.80; 95% CI: 0.38–1.66; p = 0. 54) (Table 6). This was further confirmed by the Kaplan-Meier survival analysis curve (Figure 1). The most common indications for return to the operating room were intraabdominal fluid collection followed by intrabdominal bleeding.

A total of 19.4% of SPK recipients developed pancreas rejection and 12.2% developed kidney rejection. Pre-transplant hypoalbuminemia, either mild or moderate was not associated with acute rejection in either adjusted or unadjusted models (Table 7). This was further confirmed by the Kaplan-Meier Survival analysis curve (Figures 2, 3).

A total of 7.3% of SPK recipients experienced uncensored graft failure and 4.7% experienced pancreas DCGF. Similarly, 3.3% experienced kidney uncensored graft failure, and 1.1% experienced kidney DCGF (Table 8). Pre-transplant hypoalbuminemia either mild or moderate was not associated with either uncensored or death-censored graft failure in either adjusted or unadjusted models. This was further confirmed by the Kaplan-Meier Survival analysis curve (Figures 4–7).

Also, 3.0% of SPK recipients experienced death with both functional grafts, and similar to the previous findings, neither mild nor moderate pre-transplant hypoalbuminemia was associated with death with both functional grafts (Table 8).

A total of 17 SPK recipients had early pancreas DCGF, 3 had early kidney DCGF, and 3 died with both functional grafts, all within 2 weeks post-transplant, and were not included in the main analysis of the study. When analyzing the data in this subgroup of SPK recipients, pretransplant hypoalbuminemia was not associated with those outcomes of interest either in the mild or moderate hypoalbuminemia group in the unadjusted model (Supplementary Table S1).

Also when including these recipients with early pancreas graft failure, pretransplant hypoalbuminemia was not associated with either grafts uncensored or DCGF or death either in the mild or moderate hypoalbuminemia group in the unadjusted model or adjusted model (Supplementary Table S2).

Simultaneous pancreas-kidney transplant (SPK) has become a growing form of treatment for those with diabetes mellitus and ESRD as it restores euglycemia and slows the progression of diabetes complications. In these patients, hypoalbuminemia has been proposed to be caused by chronic systemic inflammation and reduced synthesis of albumin. However, the role of pre-transplant hypoalbuminemia and its impact on post-transplant outcomes in patients undergoing SPK transplantation remains unclear. In this study, we studied 532 SPK recipients at our center with mild and moderate hypoalbuminemia. Outcomes of interest included kidney delayed graft function (DGF), length of stay (LOS) after transplant, re-hospitalization within 30 days after discharge, and need for a return to the operating room related to transplant surgical complications, acute rejection, and uncensored and death-censored graft failure, within the first years post-transplant. Mild or moderate hypoalbuminemia was not associated with DGF, LOS, re-hospitalization, return to the operating room, graft rejection, or graft failure. The outcomes of this study have significant clinical importance showing that mild or moderate hypoalbuminemia, was not associated with inferior outcomes, concluding that these patients are acceptable candidates for SPK.