Role of deceased donor kidney procurement biopsies in organ allocation

Abstract

Purpose of review:

There has been an increased emphasis by the transplant community and the federal government to increase the utilization of deceased donor kidneys. Procurement biopsies during allocation are the most common reason for kidney discards. This manuscript reviews the evidence of procurement biopsies practices and utility.

Recent findings:

Procurement biopsies are performed in over half of all the kidneys recovered in the United States and account for more than one third of the kidney discards. However, there is a significant heterogeneity across the organ procurement organizations regarding the indications for biopsy, biopsy techniques and their reporting. Procurement biopsy findings are not reproducible and poorly correlate to post-implantation histology, although reasons for these limitations are not clear. Procurement biopsy findings are not associated with post-transplant outcomes after accounting for readily available donor clinical characteristics.

Summary:

Procurement biopsies contribute to deceased donor kidney discards but do not predict post-transplant outcomes. Research to establish the best practices for procurement biopsies is needed to improve organ utilization.

Introduction

Kidney transplant offers a significant advantage over dialysis in terms of survival and quality of life.⁽¹⁾ However, in the United States, the majority of patients with end-stage kidney disease never receive a transplant.⁽²⁾ Despite the rising number of deceased donor transplants performed in the United States, the demand for the organ donors has continued to far exceed the supply. The increasing gap between supply and demand for kidneys has resulted in efforts to increase the use of organs from donors with less-than-ideal clinical characteristics. ^(3–5) Coupled with the need to use these less-than-ideal organs is the increased need for reliable assessments of organ quality during allocation.

Traditional organ quality assessments were largely based on donor history. In 2002, the “extended criteria donor” designation was established to increase the use of organs from donors aged >60 years or with comorbidities in an effort to improve appropriate organ allocation. Given the challenges of mere dichotomization, a continuous assessment of organ quality, the Kidney Donor Risk Index (KDRI), was introduced and is presented as a percentile score called the Kidney Donor Profile Index (KDPI). However, these scores have limited prognostic capabilities, with the KDPI having a C-statistic of only 0.6, and their introduction has not eliminated clinicians’ desire to obtain additional information about organ quality.^(6–9) This search for additional information results in a frequent desire to incorporate histological information from a procurement biopsy.

Procurement biopsies are performed during the allocation of deceased donor kidneys to ascertain the extent of histological injury (acute and chronic), including glomerulosclerosis (GS), interstitial fibrosis/tubular atrophy (IFTA), and arteriosclerosis/arteriolosclerosis (AS). Currently, about half of recovered deceased donor kidneys undergo procurement biopsies in the United States.⁽¹⁰⁾ However, the utility of these biopsies is at best unclear and might be contributing potential inappropriate discard of kidneys. Despite their widespread use, there is a growing concern regarding the reliability of the data obtained from biopsy interpretations and their reproducibility in repeat biopsies. There is also considerable variation in when and how these biopsies are performed, what scoring systems are used to evaluate them, and how results are reported.⁽¹¹⁾ Moreover, procurement biopsies add cost and may increase cold ischemia time, driving inefficiencies in the allocation process. Given that procurement biopsies have also emerged as one of the leading factors contributing to deceased donor kidney discard in the United States, understanding the most appropriate role for these biopsies during allocation is imperative to increasing access to transplantation.^{(12, 13)}

Utilization of Procurement Biopsies in the United States

Procurement biopsies are performed on approximately half of deceased donor kidneys in the United States in an attempt to identify organ suitability for transplantation, especially in kidneys from expanded criteria donors (older donors, age > 60 years; or donors over the age 50 and at least two of the following: history of hypertension, terminal creatinine of > 1.5 mg/dl, death from stroke ) ^{(10, 11)} Current UNOS guidelines recommend that a recovering organ procurement organization (OPO) should provide the receiving transplant center with biopsy information for donors with KDPI >85% and donors with diabetes, hypertension and/or acute kidney injury. A wedge biopsy 10 mm long by 5 mm wide, and 5 mm deep to be taken from the kidney cortex should sample at least 25 glomeruli; and frozen or fixed sections of slide may accompany the kidney along with biopsy report or telepathology if available. A biopsy report, usually read by a donor hospital pathologist, travels with the organ, gets uploaded into DonorNet, and/or is directly called to the accepting transplant surgeon.

There is, however, a significant degree of variation in the practice of biopsy among OPOs and a growing recognition that standardization of biopsy techniques, sample processing and interpretation are essential if the procurement biopsy is to be a valid tool in the assessment of organ quality. Recent analyses have highlighted the significant heterogeneity in the proportion of kidneys that are biopsied across OPOs (23% to 78% of all allografts recovered).⁽¹⁰⁾ This wide variation in OPO biopsy practice patterns persisted even after adjustment for the usual donor factors that might prompt a biopsy – underscoring the wide variation in the clinical thresholds for a biopsy. Other recent reviews focused on OPO clinical thresholds and practices highlighted the differences in how the OPOs consider procurement biopsies and the extent to which this clinical practice is also influenced by the preferences of transplant centers that are considering these organs.⁽¹¹⁾ They also noted considerable variability in biopsy technique, procedures for biopsy interpretation and reporting of findings to transplant programs – underscoring the complete absence of any standardization at any step in the process.⁽¹¹⁾

Biopsy scoring system

The clinical consideration of procurement biopsy results often has historically emphasized the degree of GS present, due to early findings by Gaber, et al. that allografts with >20% GS had inferior survival in an analysis that since been called into question.⁽¹⁴⁾ These findings have not been replicated in other adjusted analyses using procurement biopsy data either from single center studies or in studies using US transplant registry data.^{(15, 16)} Despite the lack of evidence to support this threshold in the evaluation of organ quality, it continues to be used by transplant centers widely as a bypass filter and appears to be the primary driver among histologic findings of discard.

In recognition of the limitations that result from consideration of GS alone, multiple procurement biopsy scoring systems have been proposed which combine different pathological findings with or without donor criteria to predict post-transplant outcomes (Table 1). Many of these studies were based on small, single-center cohorts with limited, if any, subsequent validation. A recent systematic review showed that only about half of the studies demonstrated an association between the biopsy scores and clinical outcomes.⁽¹⁷⁾

Table 1.

Components of commonly used procurement biopsy-based (Remuzzi, MAPI, Leuven) and donor history-based (Nyberg, KDRI) deceased donor kidney quality scoring systems.^{(24, 47–49)}

Characteristics included	Remuzzi	MAPI	Leuven	Chronic donor damage score	Nyberg	KDRI
Clinical	None	None	Age	None	Age	Age
					Hypertension	Weight
					Creatinine clearance	Height
					Cause of death	Ethnicity
					HLA mismatch	Hypertension
						Diabetes
						Creatinine
						Cause of death
						HCV status
						DCD status
Pathologic	GS	GS	GS	GS	None	None
	Arterial Narrowing	Arteriolar hyalinosis	Arteriolar narrowing	Arteriolar
				narrowing
	IFTA	Banff> cv2 lesion	IFTA	IFTA
		Cortical scar		Cortical glom volume
		Periglomerular Scarring		Cortical interstitial volume
				Intimal arterial volume
Scoring system	0–12 points	0–15 points	ROC curve: Cut off 47 points	0 to > 3 points	0–39 points	KDPI 0–100 points

Abbreviations: GS, glomerulosclerosis; IFTA, interstitial fibrosis/tubular atrophy

In 1999, in a consensus statement, an international group of pathologists presented a biopsy-based scoring system which would allow the assessment of whether kidneys from donors older than 60 years have sufficient nephron mass to be allocated for transplant and whether single or dual transplantation be pursued.⁽¹⁸⁾ The scoring system (“Remuzzi score”) combined histopathological parameters including GS, IFTA, and AS and divided the results into scores from 0–3 based on severity and chronicity in each compartment. Biopsy scores of 0–3 could be transplanted as single kidneys, 4–6 as dual transplants and >7 were considered of insufficient quality to transplant. In a prospective cohort study utilizing Remuzzi scoring to compare outcomes among 62 patients who received kidneys from donors >60 years of age based on above histology criteria to 124 matched recipients of kidneys without the prior biopsy, the former showed better 3-year graft survival.^(18–21)

The Maryland Aggregate Pathology Index (MAPI) score combined various pathological findings to assign an aggregate score (using GS, IF, arterial hyalinosis, arterial-wall-to-lumen ratio) which was significantly associated with graft survival.⁽²²⁾ This was subsequently validated in a cohort of 205 preimplantation biopsies from 2 centers and showed that MAPI score was associated with graft outcomes at 3 years, suggesting that such a scoring has the potential to better characterize marginal kidneys, increase utilization and predict clinical outcomes.^{(23) (24)}

The Leuven score, which combines age of the donor with biopsy findings (IFTA according to Banff 2007 classification, GS), was compared with KDPI in a multicenter, retrospective analysis by Hall et al, who demonstrated that it did not outperform KDPI in predicting posttransplant outcomes.⁽²⁵⁾ Leuven scores >47 had 85% specificity and 81% sensitivity for 5-year graft failure. The authors concluded that, given the modest association, neither the Leuven score nor KDPI should be used in isolation for determining organ acceptance decisions.

Value of Procurement Biopsies

Limitations of histological scoring systems likely stem from the inability of procurement biopsies to provide reliable and reproducible findings that are associated with clinical outcomes.^(26–28) These limitations appear to be unique to procurement biopsies, as high-quality reperfusion biopsies performed after implantation yield findings that are associated with post-transplant outcomes.⁽²⁹⁾ In a large retrospective, single-center study, Carpenter et al. showed that deceased donor kidney reperfusion biopsy findings were associated with death-censored allograft survival even after adjusting for donor characteristics while procurement biopsies available on the same kidneys were not.⁽³⁰⁾ There are differences between the ability of reperfusion biopsy and procurement biopsies to discriminate optimal and suboptimal histology – and the resulting misclassification that is observed in procurement biopsies impedes the ability of these biopsies to discriminate organ quality and inform organ offer decisions.

The inherent unreliability of procurement biopsy findings in current practice is well described, with ample evidence that sequential procurement biopsies performed on the same kidney can often yield different results.⁽³¹⁾ Muruve, et. al performed multiple wedge biopsies on nine discarded kidneys and noted wide variability in GS between biopsies, underscoring the challenge of variation that stems from the small samples under consideration.⁽³²⁾ A recent analysis of kidneys that underwent multiple biopsies during the allocation process and were eventually accepted for transplantation noted large differences between the biopsies.⁽³³⁾ While this study was a single center study and the overwhelming majority of the second biopsies were performed at one OPO by an experienced group of pathologists with considerable experience with procurement biopsies, these findings underscore the challenges that stem from non-standardized processes across OPOs. Notably, predicators of discordant biopsy results included lack of concordance with the contralateral kidney and inconsistent degree of sclerosis across all biopsy compartments. Advanced sclerosis on the first biopsy was also associated with different findings on the second biopsy but this is likely an artifact that stems from a selection bias which results in those kidneys with concordant severe vascular disease on both biopsies being discarded. Similarly, agreement between findings on procurement biopsies and reperfusion biopsies is poor. An observational case control study comparing 83 kidneys discarded due to biopsy findings with 83 transplanted contralateral kidneys and 83 randomly matched controls found significant overlap in the biopsy findings between kidneys that were discarded and kidneys that were transplanted.⁽³⁴⁾ A comparison of sequential biopsies from the same kidney also demonstrated significant differences in this study, raising the question of the reliability of biopsies for making acceptance decisions.

Multiple mechanisms have been proposed to explain such findings, including wedge biopsy technique, tissue processing quality, and pathologist expertise, although evidence supporting each of these hypotheses is mixed. Azancot et al in an insightful analysis of 162 deceased donor kidneys, demonstrated that the scoring by on-call pathologists did not correlate with 12-month kidney function and was not able to distinguish between kidneys that did well over the longer term and those that did not.⁽³⁵⁾ However, pathologists with renal experience given the same slides the following morning were able to score the biopsies in a manner that was both associated with 12 month kidney function and was able to discriminate those kidneys that did well from those that did not. This analysis suggests the challenges faced by pathologists with limited renal pathology experience. However, Liapsis et al also demonstrated moderate-to-poor correlation in 124 procurement biopsies read by 32 renal pathologists, suggesting that interrater reliability is questionable even among renal pathologists.⁽³⁶⁾ Wedge biopsies, unlike needle core biopsies, are large biopsies with significant amounts of subcapsular tissue that tends to have more glomerulosclerosis. Differences in the tissue and location is thought to influence how to interpret the findings suggesting that perhaps some of the apparent limitations of the biopsy stem from the technique used to obtain the tissue sample. However, a recent large single-center retrospective study of 392 deceased donor kidney biopsies ⁽³⁷⁾ demonstrated lack of influence of biopsy technique (core vs wedge) and pathologist training (renal vs nonrenal) on concordance between procurement and gold-standard reperfusion biopsy histologic classification, confirming the absence of an effect of the type of biopsy that had been demonstrated in earlier smaller studies.^{(31, 32, 36–38)}

Impact on Kidney Utilization

A lack of procurement biopsy reliability and association with outcomes is especially troubling given that procurement biopsies have emerged as one of the leading causes of deceased donor kidney discard in the United States.⁽¹³⁾ In a large, national study of discarded kidneys, biopsy findings were reported as the primary reason for 38% of all the discards in the United States.⁽¹³⁾ Even after adjustment for donor and clinical factors, biopsy was noted to be significantly associated with discard rate in a recent, retrospective registry analysis of kidneys procured from 2014–2018.⁽¹⁰⁾

Notably, the practice of procurement biopsy is not routine outside of the US. In the absence of routine procurement biopsy use, organs with comorbidities affecting kidneys are more likely to be accepted in the Eurotransplant region, which has significantly lower rates of discard and aggressive utilization patterns than in USA.(39–42) In a recent registry analysis involving more than 10,000 recipients over 20 years period using ANZDATA (Australia and New Zealand Dialysis and Transplant Data) showed procurement biopsy rate of only 15%.(43) Differences in practice patterns, regulatory requirements, donor demographics and differential reliance on biopsies for ruling in and ruling out transplantable kidneys make inter-country comparison difficult to interpret. For example, UK’s practice of recovering organs is conditional on organ acceptance by transplant centers whereas in USA, recovering process occurs prior to the organ acceptance.(41) While procurement biopsies are performed in transplant centers across France and Belgium, the results of these biopsies are not utilized for guiding offer acceptance decisions.(39, 42) A recent analysis validated this approach by demonstrating that the inclusion of histology findings did not improve the association of clinical factors with longer term graft outcomes – despite the fact that these biopsies were done using 16-gauge needles, were fixed in formalin, embedded in paraffin, and interpreted by renal pathologists at the academic centers.⁽⁴²⁾ These findings are particularly intriguing given that it would suggest that procurement biopsies even in the most ideal settings are not providing any additional information for the clinicians in decision making process. Although procurement biopsy quality data may limit comparability between the biopsy results of the two different countries, it underscores the need to standardize the biopsy process to better understand the comparative extent of lost transplant opportunities attributable to biopsy-associated discards in the United States.⁽⁴⁴⁾

Conclusions

All current organ quality assessments have limitations in their ability to predict long-term allograft outcomes. Given a need to identify which marginal organs can be safely transplanted, it is inevitable that surgeons will seek out all available information when making organ acceptance decisions. Although ostensibly objective assessments of organ quality, procurement biopsies are poorly reproducible and add little to the assessment of deceased donor kidney quality yet are a major factor contributing to organ underutilization. Reducing the rate of deceased donor kidney discards and will require an improvement in our ability to identify and accept deceased donor kidneys that will do well in the long run, but to do so, procurement biopsies will need to be used to rule in kidneys for acceptance rather than using these results for ruling out kidneys when offered. This approach would require strict consistent criteria for the circumstances when a biopsy can be performed – for example if there are no creatinine trends and a single elevated creatinine concentration in a deceased donor without a clear medical history. Standardization of biopsy technique and its subsequent processing are early steps that may help achieve consistency across all OPOs. These changes would potentially prevent the inappropriate decline of kidneys and the downstream detrimental impact of declined offers.⁽⁴⁵⁾

The common goal of the transplant community is to improve access to transplantable kidneys for patients in need – and this will require, as articulated in the Advancing American Kidney Health Initiative, efforts that gear towards lowering the national discard of deceased donor kidneys in the United States.⁽⁴⁶⁾ Limiting the reliance on procurement biopsies and updating their performance and interpretation to best practices will improve organ utilization, increase the efficiency of the allocation process, and reduce the exceedingly high kidney discard rate in the United States.

Key Points:

• Procurement biopsies are the leading cause of deceased donor kidney discards in the United States

• There is wide variation in the clinical threshold for procurement biopsies across the Organ Procurement Organizations in the United States

• Procurement biopsy findings do not improve the prediction of clinical outcomes beyond the other readily available donor characteristic