#NephMadness 2024: Dual-Organ Transplant Region
Submit your picks! | NephMadness 2024 | #NephMadness
Selection Committee Member: Roslyn Mannon @mannonmom
Roslyn B Mannon is a Professor of Medicine, Vice-Chair for Research, and Associate Chief of Research in the Division of Nephrology, Department of Internal Medicine at the University of Nebraska Medical Center. She has published extensively on late allograft failure and post-transplant complications and therapeutics through a combination of preclinical mechanistic studies and interventional and observational clinical studies.
Writer: Sam Kant @kantsmd
Sam Kant is an Assistant Professor of Medicine at the Division of Nephrology and Comprehensive Transplant Center at the Johns Hopkins University School of Medicine.
Writer: Manal Alotaibi @Maealotaibi
Manal Alotaibi is an Assistant Professor at Umm Al-Qura University in Makkah, Saudi Arabia. She completed her nephrology fellowship at Northwestern University in Chicago, IL, and her transplant nephrology fellowship at Johns Hopkins University in Baltimore, MD. Her primary clinical interests are in glomerulonephritis (GN) and recurrent GN post-transplant. Additionally, she is currently a Glomcon fellow.
Competitors for the Dual Organ Transplant Region
Team 1: Simultaneous Liver-Kidney (SLK) Transplantation
versus
Team 2: Simultaneous Pancreas-Kidney (SPK) Transplantation
Image generated by Evan Zeitler using Image Creator from Microsoft Designer, accessed via https://www.bing.com/images/create, January, 2024. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.
Transplantation enters the tournament this year with tremendous confidence, with “Access to Transplantation” still wearing the 2023 NephMadness crown. Though many of the challenges still remain for patients to achieve successful kidney transplantation, this year’s teams tackle something different–with some of the same: Dual-Organ Transplantation. To paraphrase a 2009 song featuring and written by Taylor Swift, is 2 really better than 1? Read on to see if these teams, both their own version of a double team, can take on the 2024 NephMadness competition and achieve the unprecedented: a repeat NephMadness championship.
Team 1: Simultaneous Liver-Kidney (SLK) Transplantation
Copyright: LedyX / Shutterstock
Simultaneous liver-kidney (SLK) transplantation is a potentially compelling one-time surgery option for individuals with liver failure and coexisting kidney disease. Among patients with cirrhosis, acute kidney injury (AKI) prevalence is high–reported as up to 50%. SLK transplantation in the United States (US) has steadily increased since the Model for End-Stage Liver Disease (MELD) score became the primary determinant of liver allograft allocation in 2002. In 2021, 780 SLK transplants (8% of all liver transplants) were performed for both adults and pediatric patients.
On December 28, 1983, the first SLK transplant was performed in Austria in a 32-year-old man with cirrhosis due to hepatitis B infection and a failed prior kidney transplant. Historically, decisions regarding SLK transplantation have been transplant center-specific and motivated by concerns about persistent kidney failure after liver transplant alone (LTA), high likelihood of severe AKI after LTA that may require kidney replacement therapy (KRT), and post-transplant calcineurin inhibitor induced nephrotoxicity. Approximately 25% to 50% of liver transplant recipients experience AKI, with CKD developing in 30% to 90% of cases. After LTA, the risk of kidney failure requiring KRT is up to 5% per year among all recipients. In addition, patients who are placed on the wait list for a kidney transplant after having undergone a non-kidney organ transplant may have worse outcomes than those waiting for kidney transplant alone (KTA).
How Do We Decide: SLK or LTA?
Up until 2017, there were no standardized medical criteria to help make this decision, raising concerns that high quality kidneys were being allocated to candidates who may have regained kidney function following LTA. In other words, were some kidneys being “wasted” on liver transplant candidates who may have regained native kidney function following LTA alone (i.e. ultimately left with 3 working kidneys), leaving our very, very long list of KTA candidates without organs? Further, the quality of kidneys used for SLK is usually significantly better than those used for kidney transplantation alone, with a mean kidney donor profile index (KDPI) below 35% in 2014.
Determining the cause of AKI (and in this context, whether or not kidney function will recover after LTA) in patients with liver failure can be a real challenge. Distinguishing between hepatorenal syndrome (see coverage in NephMadness 2019), acute tubular necrosis (ATN), and other intrinsic kidney diseases is crucial. The nephrologist’s most beloved/hated tool, the fractional excretion of sodium, may not always be helpful in separating patients with cirrhosis with prerenal azotemia, HRS, or ATN. Though not used in standard clinical practice, urinary biomarkers such as neutrophil gelatinase-associated lipocalin, interleukin-18, kidney injury molecule-1, liver-type fatty acid binding protein, and albumin may be helpful in identifying ATN versus HRS. Cheap, non-invasive urine microscopy (see coverage in NephMadness 2021) may provide additional helpful data points. Kidney biopsies are not generally performed in patients with cirrhosis due to coagulopathy concerns, but a small study of liver transplantation candidates found that kidney biopsy can be safely performed.
Visual abstract by @whatsthegfr on Alsaad et al
After proposed changes in 2015, medical eligibility criteria were introduced in 2017 to identify liver transplant candidates less likely to recover kidney function following LTA. One of 3 criteria (to be confirmed by a transplant nephrologist) must be met for a patient to be eligible for SLK listing: CKD, sustained AKI, or metabolic disease (kidney failure due to hyperoxaluria, atypical hemolytic uremic syndrome, familial non-neuropathic systemic amyloid, or methylmalonic aciduria). Post-policy, SLK transplants accounted for 9.0% and 4.5% of total liver and kidney transplants, respectively, compared to 10.2% and 5.5% prior to the policy. Of the 494 and 557 SLK performed in 2014 and 2015, respectively, 19% would not have been performed on the basis of the new medical eligibility criteria.
Visual abstract by @DrPSVali on Asch et al
Transplant nephrologists are not (always) perfect, and it’s of course possible that the SLK medical eligibility criteria might “get it wrong.” If a patient does not recover kidney function following LTA, the Safety Net allows these patients to be prioritized for kidney transplantation if they meet criteria for kidney transplantation and were listed 60-365 days after liver transplantation.
Is SLK Better than LTA?
The data are conflicting, and we’ll never have that gold-standard randomized, controlled trial to get the answer. Patients who receive SLK have five-year survival rates ranging from 64% to 76%. A 2015 retrospective study of liver transplant recipients (n = 65,206) found inferior survival in the LTA group compared to SLK. A 2008 retrospective cohort study found that kidney graft survival after SLK was actually inferior to graft survival after kidney transplantation alone, whereas liver graft survival was not different with or without a kidney transplant. Following the liver transplantation procedure, the kidney allograft is placed in the recipient–and may lead to higher cold ischemia times for the kidney and potentially higher rates of delayed graft function and poorer kidney allograft outcomes.
Support for SLK came from a 2012 study of patients with cirrhosis and kidney failure who received LTA (n = 2,774) or SLK (n = 1,501) which found that SLK patients had significantly higher liver allograft and patient survival rates compared to LTA patients at 1-, 3-, and 5-years post-transplant. A smaller study found that 20% of SLK recipients (2004-2014) experienced “renal allograft futility,” defined as death or the need for kidney replacement therapy 3 months post-SLK. These recipients had higher MELD scores, longer length of hospitalization, poorer kidney and liver donor risk indices, longer kidney cold ischemia time, and inferior overall survival. A 2023 study compared 3,053 paired donor kidneys allocated to SLK vs KTA recipients and found lower kidney graft survival in SLK compared to KTA. In that same study, 516 paired donor kidneys had similar graft survival when comparing kidney-after-liver transplant with KTA recipients.
Visual abstract by @jmteakell on Schold et al
Unlike in KTA, where induction therapy is very common, a 2020 study found that 50% of SLK recipients (n = 5,172) received neither T-cell depleting nor interleukin-2 receptor antagonist induction therapy at the time of transplantation. Recipients of SLK have lower rates of both acute cellular and antibody-mediated rejection due to the immunomodulatory properties of the liver on the immune system. Interestingly, the liver allograft is also thought to facilitate removal and absorption of donor specific anti-HLA antibodies (HLA DSA), though more effectively for class I than class II anti-donor HLA antibodies. Though SLK transplantation may be performed more commonly in the setting of preformed HLA DSA, compared to KTA, a panel reactive antibody of more than 20% has been shown to be associated with lower patient survival among SLK recipients.
Visual abstract by @krithicism on Hibi et al
Is SLK better than LTA? Maybe we should let the next jump ball decide.
Disparities in SLK
As significant racial and ethnic disparities have been observed in the listing and outcomes of patients who receive KTA, it seems plausible that similar differences may exist in SLK. An analysis of SLK performed from 2002-2013 found that compared to non-Hispanic white patients, non-Hispanic Black patients who received SLK had a lower mortality risk in the first 2 years post-SLK, but higher mortality after 2 years. A similar analysis of SLK performed 2017-2019 (post-policy) found comparable post-transplant graft survival (composite of post-transplant death or need for re-transplant) between Black, Hispanic, and white patients.
In summary, SLK remains the therapy of choice for patients with both liver and kidney disease (i.e patients with liver failure that meet the 2017 medical eligibility criteria). To avoid “kidney allograft futility,” patient selection is key to identify candidates who will both tolerate and benefit from SLK. Though studies analyzing SLK performed since 2017 are beginning to emerge, more data are needed to fully understand SLK outcomes when compared to KTA, LTA, and kidney-after-liver transplant.
Check out this podcast episode of The Nephron Segment featuring NephMadness Exec Members Samira Farouk and Matt Sparks along with Roslyn Mannon and Lizzie Aby:
Episode 13: NephMadness & Dual-Organ Transplantation: Is 2 Better Than One?
Team 2: Simultaneous Pancreas-Kidney (SPK) Transplantation
Copyright: BigBlueStudio/Shutterstock
Diabetic kidney disease, prevalent in up to 50% of individuals living with diabetes, remains the most common cause of kidney failure. For these patients, there are several transplantation options (warning: alphabet soup ahead): SPK, deceased donor kidney transplant alone (DDKA), living donor kidney transplant alone (LDKA), and pancreas after kidney transplant (PAK, typically after a LDKA). Individuals who are eligible for kidney transplantation and are also insulin dependent can be considered for SPK or PAK. Notably, these criteria do not differentiate between individuals living with type 1 diabetes mellitus (T1DM) vs type 2 diabetes mellitus (T2DM).
Diabetes-related complications can have a significant impact on the quality of life for patients, and diabetes is associated with high health care costs ($412.9 billion in 2022!) and reduced work productivity. Not surprisingly, glycemic control can have a profound impact on reducing long-term diabetes complications and health care expenditure. In medicine, treating the root of the problem (here, impaired/absent insulin secretion or insulin sensitivity) is often the correct answer–so pancreas transplantation must be the fix, right? Though pancreas transplantation represents a potentially durable solution for achieving insulin independence and mitigating complications associated with diabetes, several questions remain. Data are conflicting on the impact of pancreas transplantation on diabetes microvascular complications like retinopathy and neuropathy, while it seems long-term macrovascular complications may be better after SPK compared to KTA. Are more beta cells really bett-a?
Pancreas transplantation, unlike kidney and liver transplantation, has been a bit of a “guideline free” zone. The first ever consensus conference for pancreas transplantation was held only a few years ago in 2019! In fact, immunosuppression for pancreas allografts is “off label” use. About 1,000 pancreas transplants were performed in the US in 2021, with 23% in those with T2DM. Of these, nearly 80% were SPK–with the remaining being either pancreas transplant alone (PTA) or PAK. Recipients of PAK (after LDKA) have increased kidney and pancreas allograft survival compared to SPK recipients, though overall survival has been shown to be similar in both groups. Since PAK isn’t in this fight, SPK might be poised to be this year’s NephMadness Cinderella story.
A Brief Word on the Surgery: Enteric vs Bladder Exocrine Drainage
Pancreas transplantation was first performed in 1966 by William Kelly and Richard Lillehei at the University of Minnesota. In this surgery, the donor’s pancreas, along with a piece of their duodenum, is transplanted into the recipient. The pancreas portal vein is typically anastomosed to the recipient vena cava or iliac vein (venous endocrine drainage). The native pancreas drains digestive enzymes via the pancreatic duct (exocrine drainage), which empties into the major duodenal papilla. While “enteric drainage” (connection of the donor duodenum to the recipient jejunum) of the pancreas allograft was attempted in the 1970s, bladder drainage (connection of the donor duodenum to the recipient bladder) became the predominant method of pancreatic drainage until the mid-1990s. Though bladder drainage reduced the incidence of surgical complications and aided in monitoring of pancreatic function via urinary amylase levels, it was associated with multiple complications including volume depletion, metabolic acidosis, hematuria, cystitis, and reflux pancreatitis. Recurrence of these complications often required conversion from bladder to enteric drainage, with the first successful conversion performed in 1987. Over 90% of pancreas allografts are now enterically drained, with the donor duodenal segment anastomosed to recipient’s proximal jejunum (with or without a Roux-en-Y loop).
Image created by @CTeodosiu.
Insulin released by the allograft beta cells (endocrine drainage) will bypass first-pass liver metabolism. In individuals with only a native pancreas, the liver clears up to 80% of native-pancreas secreted insulin and thus pancreas transplant recipients are left with a “hyperinsulinemic” state. The lack of hypoglycemia in SPK recipients suggests that these individuals may have some impaired insulin sensitivity (including patients with T1DM).
Should Patients with T2DM Receive SPK or PAK?
Overall, pancreas transplantation is safe with a low 3-4% 1-year mortality rate for either PAK or SPK. Ten-year mortality rates range from 20% for PAK to 23% for SPK. The 2021 SRTR/OPTN data found minimal difference in survival outcomes for T1DM vs T2DM after pancreas transplantation, reporting 92% and 89% 5-year survival for T1DM and T2DM, respectively.
For those with T1DM, SPK outcomes have been shown to be superior to DDKA and inferior to LDKA. Conversely, a 2010 study reported a longer term survival advantage (at 20 years) among SPK recipients when compared to LDKA. The 2019 consensus conference concluded that SPK improves both quality of life and long-term survival of those with insulin-dependent diabetes–“applied more strictly to patients with T1DM.” As data are lacking, the experts concluded that for those with T2DM, it was unclear if SPK improved survival when compared to LDKA. However, they noted that SPK was “convenient” over both dialysis and DDKA.
Visual abstract by @whatsthegfr on Young et al
A 2012 retrospective study of 6,416 patients revealed favorable SPK outcomes in some patients with T2DM, though there was no survival advantage when compared with DDKA. Again, outcomes were better with LDKA. A more recent study found that patients with T2DM have a survival benefit following SPK compared to those who only undergo DDKA or LDKA, with this advantage being contingent on a functional pancreas allograft at 3 months. A German study of T1DM and T2DM transplant recipients of SPK or KTA demonstrated actuarial pancreas graft survival for SPK recipients at 1 and 5 years was 83% and 79% for the T1DM group and 92% and 83% for the T2DM group, respectively. Kidney allograft survival at 5 years was lowest in the T2DM group that received a KTA (65%), compared to 80% for T1DM and 83% for those with T2DM after SPK. As with preemptive KTA, a large study of nearly 10,000 SPK recipients found improved 10-year survival in those who received preemptive (prior to initiation of dialysis) SPK compared to non-preemptive SPK.
SPK recipient selection for candidates with T2DM is not as straightforward as T1DM, and even controversial. For individuals who do not have living kidney donors, SPK is the “express lane” to kidney transplantation due to much shorter wait times compared to DDKA alone. Further, SPK kidneys are generally higher quality with lower KDPIs. Obesity (BMI >30 kg/m2) in SPK recipients has been shown to be associated with both kidney and pancreas allograft loss, increased post-transplant complications, and increased mortality. Critics of SPK in those with T2DM may point out that pancreas transplantation will not reverse the underlying pathology–insulin resistance. A low c-peptide level suggests true insulin deficiency and may support pancreas transplantation. A 2023 study of 76 SPK recipients found that higher pre-transplant c-peptide levels (suggestive of higher levels of endogenous/native pancreas insulin production) may be associated with poorer post-transplant outcomes. Unfortunately, a pancreas transplant can only correct insulin deficiency and not the complicated mechanisms of insulin resistance.
Before we move on, let’s take a moment here to acknowledge that there has recently been growth of newer, effective therapeutic and glucose monitoring options for patients with diabetes – underscoring the need for newer data in this area to identify the optimal candidates pancreas transplantation.
Early Pancreas Allograft Failure & Rejection
Rates of early pancreatic graft failure (within 3 months) can be up to 10%, with the most common cause being thrombosis. The majority of complications associated with SPK occur in the first year post transplantation. In the immediate postoperative period, there is a high risk of pancreas graft thrombosis (accounting for 80% of early graft loss) and reoperation (12-40%) for a variety reasons including thrombosis, bleeding, duodenal stump leak, severe pancreatitis/abscess, and small bowel obstruction. Nearly 50% of graft losses in the first post-transplant year are attributable to early technical failures and unfortunately usually require pancreatectomy.
Visual abstract by @whatsthegfr on Hopp et al
Recipients of pancreas transplants receive higher levels of immunosuppressive therapy as the pancreas allograft is thought to be more immunogenic, though data are limited in support of targeting higher immunosuppression levels. Rates of pancreas rejection in 2020 were lower in SPK (11% at one year) when compared to PTA (22%) and PAK (12.5%). Pancreas rejection is usually asymptomatic and presents most commonly with elevated serum levels of pancreatic enzymes (amylase, lipase). Amylase and lipase are typically checked with routine laboratory studies, as often as monthly at some centers. If amylase or lipase are elevated, potential etiologies other than rejection should also be addressed. Hyperglycemia, elevated hemoglobin A1C, low c-peptide levels, and elevated urinary amylase (if exocrine bladder drainage) are other possible presentations of pancreas rejection. Evidence of kidney allograft injury in an individual with an SPK can be considered as a possible indicator of concurrent rejection of both allografts in over 60% of cases, though isolated pancreas rejection can occur.
Pancreas biopsy is considered the gold standard for diagnosing rejection and treatment is guided by the pancreas-version of the Banff classification. Like acute cellular rejection of the kidney, Grade I pancreas rejection is typically treated with steroids and higher grades can be treated with both steroids and T-cell depleting therapy. Rejection is one of the leading causes of pancreas allograft failure and associated with decreased allograft survival. In a 2013 study, graft loss occurred in 20% of patients one year after pancreas allograft rejection. Of note, hyperglycemia may reflect later stages of pancreas allograft rejection as acute rejection as inflammation of the exocrine component occurs prior to islet cell injury. Hyperglycemia in patients with pancreas transplants may also be due to other etiologies, including acute pancreatitis or immunosuppression-related effects (eg, corticosteroids, calcineurin inhibitors, mTOR inhibitors).
In conclusion, SPK should be considered as an option for individuals with kidney failure and insulin dependence–particularly when a living kidney donor is not available. Though early pancreas graft failure rates are high, deceased donor kidney quality is better when paired with the pancreas and wait times for potential candidates for SPK is shorter. Whether for those with T1DM or T2DM, when the recipient is chosen thoughtfully, restoration of euglycemia with SPK can provide improved survival and potentially ameliorate complications associated with diabetes.
– Executive Team Members for this region: Samira Farouk @ssfarouk and Matt Sparks @Nephro_Sparks | Meet the Gamemakers
How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on May 31, 2024.
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