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Keywords:

  • Dual kidney transplant;
  • graft survival;
  • order donors;
  • preimplantation biopsy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

Using kidneys from expanded criteria donors (ECD) increased transplant activity but resulted in a reduced graft survival. The relatively poor long-term outcome of ECD grafts may be the consequence of an imbalance between the number of viable nephrons supplied and the metabolic demand of the recipient. Providing more nephrons by dual transplants may improve outcomes but fails, per se, to confer the same benefit of single transplants from young donors. A biopsy-based score system has been presented by a panel of pathologists to assess whether kidneys from donors older than 60 years still contain enough viable nephrons to be made available for transplantation, and whether single or dual transplantation should be used. Allocating kidneys from older donors to a single or dual transplant on the basis of this scoring system allowed achieving a graft survival similar to that of single transplants from ideal donors and remarkably superior to that of single transplants from older donors not evaluated histologically before implantation. Thus, preimplantation histologic evaluation maximizes the success of ECD transplants and protects recipients from receiving organs at increased risk of premature failure. This may limit the number of patients who eventually must resume dialysis and need second transplants.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

Kidney transplantation is the preferred therapy for most patients with end-stage renal disease (ESRD) and is superior to dialysis in terms of long-term mortality risk. As eligibility criteria have been eased in parallel with improved posttransplantation results, and the number of patients with ESRD has increased, the pool of deceased donor renal transplant candidates has increased dramatically. Living-donor transplantation has increased in the United States, but the number of deceased donors has increased only modestly. Recent increases in kidneys from deceased donors have been principally from older donors or those with other characteristics associated with a risk of poor graft outcome (1). In 2002, the term expanded criteria donor (ECD) has been introduced to identify donors aged 60 years or older or donors aged 50–59 years with at least two comorbidities among history of hypertension, cerebrovascular death or serum creatinine level greater than 1.5 mg/dL (2,3). Seventeen percent of deceased-donor transplants in the United States now use ECD kidneys (3). The relative risk for graft loss at 3 years, however, is 70% higher than after a non-ECD transplant (2). In a retrospective analysis of 100 000 patients added to a kidney waiting list from 1995 to 2002 and referred to the U.S. national registry, survival of ECD transplant recipients was only marginally better as compared to that of candidates who remained on the waiting list, and in particular those younger than 40 years did not have any significant ECD survival benefit (4). As for ideal kidney transplant recipients, in the early posttransplantation period, mortality is higher for ECD transplant recipients than for those still on the waiting list. This reflects the excess mortality associated with surgery and postoperative complications. In ECD transplant recipients, however, it takes more than 7 months for the elevated risk of death to return to that of the standard-therapy group, while in ideal transplant recipients this takes only 3 months (5). After this point, the risk is lower for ECD recipients than for wait-listed patients, but, because of the excess death accumulation, cumulative survival in the ECD transplant group does not equal that in the standard-therapy group until 3.5 years posttransplantation. Only beyond 3.5 years, cumulative survival favors the ECD recipient. In ideal kidney recipients this survival benefit is achieved just at 8 months posttransplantation (5). These observations have important implications for candidates who must decide whether to accept an ECD kidney and highlight the importance of strategies aimed at maximizing the success of transplantation with ECD kidneys (6).

Strategies to Improve the Outcomes of Grafts from ECDs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

Shortening the cold ischemia time (7), using pulsatile perfusion during machine preservation (8), and reducing exposure to nephrotoxic drugs such as calcineurin inhibitors (9), may decrease renal dysfunction soon after transplantation and possibly improve long-term outcomes of ECD grafts. Transplanting a pair of kidneys from the same donor into the same recipient has also been suggested to improve renal function recovery and reduce the gap between the filtration power of ECD grafts and the metabolic demand of an average recipient (10). Moreover, evidence is available that in rats, providing more nephrons by transplanting two kidneys into the same recipient, may also prevent progressive deterioration in renal function observed in control animals given a single kidney (11). These findings suggest that nephron dosing with the intent to meet the metabolic demand of the recipient may help protect a renal graft from long-term, progressive loss of renal function (11). Simultaneous transplant of both kidneys from the same donor has been first proposed by Johnson and coworkers as a method to optimize function from donor kidneys with suboptimal mass (10). Compared to single kidney graft recipients, graft function in 15 dual graft recipients was better at 12 weeks after transplantation. Graft function was better in 26 dual than in 10 single transplant recipients 1 year posttransplantation, when kidneys from donors more than 65 years old were used (12). Two-year graft survival was significantly better (96% vs. 73%) in 28 recipients of dual transplants than in 21 recipients of single grafts from donors older than 55 years, who had diabetes mellitus, hypertension, increased serum creatinine levels or intrinsic renal parenchymal disease (13). On the same line, a comparative analysis of 238 dual transplant recipients referred to the Dual Kidney Transplant Registry and 3746 single transplant recipients from donors over 54 years of age reported to the United Network for Organ Sharing (UNOS) database, found higher survivals (75% vs. 65%) and better kidney function 3 years posttransplantation in the dual kidney transplant group (DKG) (14). At 3 years, however, survival of dual kidney transplants was 15% less than the average survival of single kidney transplants referred to the UNOS Registry considered as a whole. Older donor and recipient age, and higher incidence of primary nonfunction, likely explained the worse outcomes of dual transplants. Thus, the dual transplant procedure may help improving the results of kidney transplants from ECDs, but fails, per se, to confer the same benefit of single transplants from young donors without evidence of renal disease.

Optimizing Selection and Allocation of Kidneys from ECDs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

As early as 1980, studies have documented that the quality of organs from deceased donors in kidney transplantation represents one of the crucial factors affecting graft survival (15). Subsequently, there have been numerous research papers evaluating various potential donor risk factors for graft loss in transplantation highlighting the importance of the organ characteristics independent of the transplant recipient. Studies have addressed donor disease history, anatomical characteristics of transplanted organs, donor and recipient matching and donor demographic characteristics (3). The ECD designation has served major importance to the transplant community by labeling those deceased donor kidneys with a high relative risk for graft loss, as well as shortening waiting times for patients consented to receive these organs. Perhaps even more important, the ECD policy was considered to lower discard rates of those organs with a perceived higher risk of graft loss (2). The ECD label included those organs which had an associated relative risk greater than 1.7 from the model generated by the Scientific Transplant Registry for the outcome of overall graft loss (2). This model incorporated donor age, donor history of hypertension, donor serum creatinine and donor cause of death (in particular cerebrovascular death), but did not include a histologic indicator of the structural integrity of the ECD kidney. However, following the pioneeristic experience with emergency autopsies of senile donor kidneys reported by Ende and Zukoski more than 40 years ago (16), several studies evaluated the reasonable concept that preimplantation biopsy of kidneys from older or ECD potential donors can help identify usable kidneys (6). Preliminary uncontrolled studies suggested that kidneys from donors more than 60 but less than 75 years old could be considered for a single transplant if the average rate of glomerulosclerosis is less than 15%, or for a dual transplant if it is more than 15% but less than 50% (17). By this approach, 1-year graft survival ranged from 90% to 95% in recipients of single or dual transplants, respectively. In another series of 26 patients, kidneys were selected and allocated to single or dual transplant on the basis of a scoring system including donor age, serum creatinine, kidney weight and degree of glomerulosclerosis. For each considered parameter, the score was 0 or 1 according to values below or above a predefined cut-off level (65 years for age, 1.8 mg/dL for serum creatinine, 30% for the degree of glomerulosclerosis and 300 g for the weight of both kidneys). A sum of 1 or less resulted in a single kidney transplantation, a sum of 2 in a dual kidney transplantation and a sum of more than 2 in refusal of the organ. At 1 year, single as compared to dual transplant recipients had a similar graft survival (92%), but a worst graft function (18).

Unfortunately, the above studies applied different criteria for selection and allocation of ECD kidneys on the basis of the histology changes, which made interpretation of outcome data difficult and controversial. Some studies considered only, or mainly, the severity of the glomerular changes (17,18), others identified the vascular pathology as the strongest predictor of recipient graft function (19). Moreover, some studies found that renal pathology findings predict graft outcome regardless of donor kidney function (20), while others found that ECD designate provides a description of kidney quality that may obviate biopsy (7). Even more important, the consistency of the histology findings was most likely affected by the different modalities adopted for tissue sampling. To this respect, frozen as compared to permanent sections may save time, but have limitations (20), while needle core biopsy, as opposed to wedge biopsy, may have advantages (21). Indeed, the full cortical thickness, including arteries near the corticomedullary junction, can be sampled by needle core biopsies (Figure 1). By contrast, wedge biopsies often lack these vessels and frequently yield samples in which the superficial cortex is overrepresented. This may result in an overestimate of the overall histology score since, in older people, glomerular and tubulointerstitial scarring tend to localize in the superficial cortex. Thus, histologic evaluations on core biopsies should markedly reduce variability in prognosticating outcomes for recipients of ECD kidneys (21). By this technique (Figure 1), the average number of glomeruli retrieved from each kidney may range from 40 (22) to 80 (23), a sample that is considered more than adequate for a definite histologic diagnosis (20). Notwithstanding, histology score and subsequent graft outcomes are independent of the number of glomeruli retrieved with the biopsy sampling (Perico N., Bergamo, June 2006, personal communication).

image

Figure 1. Sampling strategy for independent glomerular scoring in donor kidney biopsies. Kidney tissue specimens from donor kidney are serially sectioned at 3 μm. Three sections are considered (A) that are 180 μm apart (corresponding to a number of 60 sections). Since mean glomerular diameter estimated from donor kidney biopsies (A. Remuzzi, manuscript in preparation) in the same experimental setting is 163 μm, only one independent section is expected for each glomerular tuft.

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Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

To help standardizing the preimplantation histologic evaluation of older or ECD kidneys, an international panel of pathologists suggested a biopsy-based scoring system for kidneys, with scores ranging from a minimum of 0 (no lesions) to a maximum of 12 (marked changes in vessels, glomeruli, tubules and connective tissue) (24). Kidneys with a score of 3 or lower were predicted to contain enough viable nephrons to be used for single transplants. Those with a score of 4, 5 or 6 could be used as dual transplants, on the assumption that the sum of viable nephrons in the two kidneys approached the number in one ideal kidney. Those with a score of 7 or higher were discarded, since it was assumed that they would deliver an insufficient dose of nephrons, even in a dual transplantation. This score was developed to replace the Banff 97 scoring system that standardizes renal-graft-biopsy interpretation, but does not apply to native kidneys. Moreover, it does not consider the degree of glomerular sclerosis, one of the strongest predictors of subsequent graft outcome (20). The suggested scoring system for preimplantation biopsy samples was validated in comparative analyses with autoptical samples taken at the same time from the same kidneys (25) and its predictive value was tested in prospective studies of single (19) or dual (24) ECD renal transplants. A prospective, matched-cohort study (1), found that 3-year graft survival in 62 recipients of one or two kidneys from deceased donors over 60 years selected and allocated on the basis of the above scoring system (94%) was identical to that in 124 recipients of single grafts from ‘ideal’ donors less than 60 years old (94%) and was remarkably superior to that of 124 recipients of single grafts from donors older than 60 who were not evaluated histologically before implantation (77%). At multiple regression analysis biopsy-guided kidney allocation was the only independent predictor of improved outcome. Moreover, in the above series, the biopsy-based strategy increased the number of available kidneys by 24%, which enhanced the chances of receiving a graft and shortened the waiting time for kidneys from deceased donors. This may be an additional advantage—in particular for those transplant networks that with the current selection strategies have relatively low recruitment rates for older donors—since waiting time on dialysis is the strongest modifiable risk factor for poor renal transplant outcomes (26). On the other hand, no graft was lost because of complications of tissue sampling and cold ischemia was comparable in the study cohorts, indicating that evaluation of a preimplantation biopsy specimen is compatible with the routine activities of organ procurement and allocation, at least when there are no major logistic challenges in getting timely and consistent biopsy results. Indeed, practical difficulties in circulating kidneys and histology samples between different centers may represent for some transplant networks a major limitation to the systematic application of a biopsy-guided strategy for organ selection and allocation. An additional problem is that, so far, no study formally compared the predictive value of the histology score and of donor kidney function. Prospective studies are clearly needed to assess whether the two parameters may independently contribute to improve the assessment of ECD kidneys and guide their allocation to the single or dual transplant procedure.

Regardless of the above, biopsy-guided allocation of ECD kidneys may be an effective and safe strategy for prolonging graft survival and limiting the number of patients who eventually must resume dialysis and who need second transplants. This may have important social and economical implications since about 20% of patients waiting for a kidney from a deceased donors are people whose first transplants have failed. Moreover, renal transplant patients who resume dialysis have a shorter life expectancy than those who remain independent of dialysis and those who are undergoing dialysis while waiting for their first transplant.

Of interest, dual transplant outcomes with the above biopsy-based strategy appear to be better than those of dual transplants reported to the UNOS registry (27). Notwithstanding the younger age of donors in the UNOS registry (60 years on average as compared to 69), only 60% of the recipients of dual transplants reported to the UNOS registry had functioning kidneys at 3 years as compared with 94% of those who received histologically evaluated kidneys. A reasonable explanation for this striking difference is that in the UNOS series, ECD kidneys were allocated without a preimplantation biopsy (Table 1). When further analyses considered dual transplant recipients who had had their grafts evaluated histologically before implantation, data showed a graft survival similar to that of single transplants from younger donors (27). This is consistent with evidence from more recent, single-center study that 3- and 5-year graft survival of single transplants from low-risk, ‘ideal’ donors (89% and 79%) was similar to that of single (82% and 78%) or dual (88% and 78%) transplants from older donors allocated on the basis of the DKG score and of donor-calculated creatinine clearance (28).

Table 1.  Outcomes of single or dual kidney transplants from expanded criteria donors allocated or not allocated on the basis of a preimplantation histologic evaluation
Follow-upHistologic evaluation YESHistologic evaluation NO
ReferenceTransplant(n)Graft survival (%)ReferenceTransplant(n)Graft survival (%)
1 yearDietl et al.Dual(26)94Alfrey et al.Dual(15)87
Transplantation 2000Single(10)94Transplantation 1997Single(37)81
Andres et al.Dual(21)95 
Transplantation 2000Single(40)90 
  
Weighted averageDual(47)94 
Single(50)91 
2 yearsJerius et al.Dual(28)96Lu et al.Dual(50)85
J UrolSingle(21)73Arch Surg 1999Single(73)84
3 yearsRemuzzi et al.Dual(54)94Alfrey et al.Dual(238)75
N Engl J Med 2006Single(8)87Transplant Proc. 2001Single(4726)65
Deshpande et al.Dual(50)88Bunnapradist et al.Dual(287)64
JASN 2005Single(47)82JASN 2003Single(2350)69
  
Weighted averageDual(104)91Weighted averageDual(525)69
Single(55)83 Single(7076)66

An additional advantage of the preimplantation histologic evaluation is that discarding kidneys on the basis of too severe histology changes protects recipients from receiving organs at increased risk of premature failure. This may explain why in the DKG series (1) 2-year graft survival (94%) was superior to that in previous series (82%) routinely allocating all ECD kidneys to the dual transplant procedure (27,29). Thus, biopsy-guided allocation of ECD kidneys may help improve graft outcomes, in particular in those centers with high procurement rates from older donors who currently use ECD kidneys almost exclusively for single transplants. On the other hand, allocating kidneys with no or minimal histology changes to the single transplant procedure avoids subtracting normal or relatively normal kidneys from the already limited organ pool for unnecessary dual transplants. Altogether, the above encouraging results, underline the need for prospective studies formally evaluating whether the inclusion of an histology marker of kidney structural integrity in the model for ECD organ procurement and allocation may serve to enhance the opportunities for successful transplantation for those in need.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

The most widespread and successful efforts to enhance the supply of organs available for transplantation have involved expansion of the donor pool to include marginal donors. There are now considerable data and experience to support the policy that no ECD kidneys should be discarded, providing that preimplantation kidney biopsy is acceptable. Indeed, based on biopsy findings, up to 35% and 44% of kidneys from deceased donors older than 60 years may be adequate for a single or dual transplant, respectively (23). Using these kidneys should increase the current organ supply by another 25–30%.

According to Delmonico and Burdick, ‘in the future, the selective and increasing use of kidneys from expanded criteria donors is likely to be supported if the kidney functions well before recovery, if the morphologic features of the kidney are adequate according to the biopsy results, and if the flow to the kidney by pulsatile perfusion is acceptable’ (6). Thus, if transplantation procedures of ECD kidneys continue their increasing success, an entirely new field of responsibility may fall to the pathologist in evaluating the graft. A rapid and reliable decision will have necessarily to be made on the histology specimen without delaying graft procurement and allocation. This will afford to the preimplantation histologic evaluation acute and immediate clinical value similar to that of the frozen section on the surgical specimen. Exactly the case of the emergency autopsies for the selection of donor kidneys performed by Ende and Zukoski in the early sixties (16).

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References

The Authors wish to thank Dr. T. Bertani (Azienda Ospedaliera ‘Ospedali Riuniti’, Bergamo, Italy) and Dr. A. Katz (St. Michael's Hospital, Toronto, Ontario, Canada) who developed the scoring system for preimplantation histologic evaluation of ECD kidneys referred to the Dual Kidney transplant Group (DKG) and Dr. T. Bertani and Mr. G. Marchetti, (Azienda Ospedaliera ‘Ospedali Riuniti’, Bergamo, Italy), Dr. J. L. Ravetti (Ospedale San Martino, Genoa) and Dr. M. Valente (Azienda Ospedaliera Giustinianeo, Università degli Studi, Padua) who performed the scoring analyses in the context of the work-up of ECD kidneys referred to the group.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Strategies to Improve the Outcomes of Grafts from ECDs
  5. Optimizing Selection and Allocation of Kidneys from ECDs
  6. Standardizing Selection and Allocation of ECD Kidneys on the Basis of the Preimplantation Histologic Evaluation
  7. Conclusions
  8. Acknowledgments
  9. References
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