Evaluation of the older cadaveric kidney donor: the impact of donor hypertension and creatinine clearance on graft performance and survival.

BACKGROUND: The use of older donors for cadaveric renal transplantation (CRT) remains controversial because older donors are associated with decreased graft survival, yet offer the opportunity for donor pool expansion. We investigated the impact of two age-related donor factors, hypertension and calculated creatinine clearance (C(Cr)), as predictors of graft outcome in recipients of CRTs from donors > or =55 years of age. METHODS: We reviewed 33,595 recipients of CRTs reported to UNOS since 4/1/94, of which 4,732 were from donors aged > or =55 years. Outcome measures were graft survival, serum creatinine, and incidence of delayed graft function with 3 years of follow-up. We first analyzed the effect of hypertension on outcome from donors > or =55 years: 2679 donors had no hypertension, 1058 had hypertension < or =10 years, and 557 had hypertension > 10 years. Next, the effect of donor C(Cr) as a risk predictor was investigated. Based on this analysis, recipients of older donors were grouped into two cohorts for comparison: 2570 donors with C(Cr)<80 ml/min and 2162 donors with C(Cr) > or =80 ml/min. RESULTS: Actuarial graft survival from donors aged <55 years was 88.0, 83.4, and 78.5% at 1, 2, and 3 years, vs. 80.6, 73.5, and 65.3% from donors > or =55 years (P<0.0001). When stratified by hypertension, older donors hypertensive > 10 years had survivals of 77, 66, and 57% vs. 81, 73, and 65% from donors without hypertension (P<0.017) and 80, 74, and 66% from donors hypertensive <10 years (P<0.017). When stratified by C(Cr), older donors with C(Cr) <80 ml/min had survivals of 77, 69, and 62% vs. 83, 76, and 66% from donors with C(Cr) > or =80 (P<0.0001). Finally, older donors with both hypertension > 10 years and C(Cr) <80 ml/min had survivals of 77, 61, and 53%. CONCLUSIONS: Long-standing hypertension and low calculated creatinine clearance are risk factors for decreased graft survival of CRTs from older donors. When both factors are present, graft survival is significantly decreased.

The effect of age and prolonged cold ischemia times on the national allocation of cadaveric renal allografts.

BACKGROUND: National sharing of cadaveric renal allografts for perfectly matched kidneys (0 antigen mismatch) has improved outcome in the recipients of these kidneys despite increasing cold storage times. However, there may be limits to outcome improvement of matched kidneys based on age and cold storage time. MATERIALS AND METHODS: To determine if national sharing of kidneys based on matching improves outcome regardless of donor age and cold storage time, we evaluated the United Network for Organ Sharing (UNOS) Scientific Registry for all recipients of cadaveric kidney transplants between January 1, 1990 and July 31, 1998. We divided the recipients into four groups based on donor age and cold storage time. Group 1 comprised young donors (donor age <55 years) with average (<24 h) cold storage time; group 2, young donors with long (>/=24 h) cold storage time; group 3, older donors (donor age >/=55 years) with average cold storage time; and group 4, older donors with long cold storage time. RESULTS: A total of 64,046 recipients were evaluated: 35,061 (55%) in group 1, 21,264 (33%) in group 2, 4308 (7%) in group 3, and 3414 (5%) in group 4. Early graft performance progressively decreased from group 1 to group 4. Delayed graft function (DGF: dialysis requirement in the first 7 days posttransplant) was 18, 29, 33, and 42% (P < 0.0001); serum creatinine at 3 years (in mg/dl) was 1.70 +/- 0.8, 1.73 +/- 0.9, 2. 31 +/- 1.0, and 2.42 +/- 1.1 (P < 0.0001); 1-year graft survival was 87, 84, 79, and 77% (P < 0.0001); and 3-year graft survival was 77, 74, 63, and 62% (P < 0.0001, for groups 1 and 2 vs groups 3 and 4, respectively). The trends in DGF persisted through the groups in 0 antigen mismatched kidneys. CONCLUSIONS: Early function is adversely affected by prolonged cold storage, despite matching, in recipients of younger and older donor kidneys. Long-term function does not appear to be affected by prolonged cold storage. Recipients of kidneys from donors >/=55 years of age have significantly worse short- and long-term outcome and may not benefit from national sharing.

Outcome in recipients of dual kidney transplants: an analysis of the dual registry patients.

BACKGROUND: A novel but controversial method to increase the utilization of aged donor kidneys is the transplantation of both kidneys as a dual transplant. Initial single-center reports demonstrated outcomes similar to single kidneys from younger donors. In this report, we compare outcome in recipients of kidneys from donors > or =54 years of age who received a single kidney transplant reported to the United Network for Organ Sharing Scientific Registry versus a dual kidney transplant reported to the Dual Kidney Registry. METHODS: A retrospective analysis was performed, comparing four donor and nine recipient and outcome variables between recipients of a single versus a dual transplant between March 1993 and March 1999. RESULTS: Dual versus single transplants from donors > or =54 years of age have a significantly decreased incidence of delayed graft function, and lower serum creatinines up to 2 years after transplant despite having kidneys from significantly older donors with poorer HLA matching. CONCLUSIONS: Dual kidney transplants improve graft performance and outcome in recipients of kidneys from donors > or =54 years of age.

Severe glomerular sclerosis is not associated with poor outcome after kidney transplantation.

BACKGROUND: The increased utilization of expanded criteria kidney donors has necessitated the reevaluation of multiple donor risk factors to insure the best outcome from this valuable resource. Reports of decreased graft survival in recipients of kidneys from donors with > or =20% glomerular sclerosis (GS) have led many transplant centers to refuse these donor kidneys. The purpose of this study is to compare outcome in recipients of cadaveric donor kidneys with > or =20% GS versus those with <20% or no GS at our center. METHODS: We retrospectively reviewed 18 donor and 19 recipient and outcome variables in 89 recipients of kidneys, which were biopsied at the time of transplantation, between February 1995 and November 1998. We evaluated outcome based upon the percent of GS and the degree of vasculopathy. RESULTS: Donors with > or =20% GS were older and had more hypertension. Recipients of kidneys with > or =20% GS were older, had higher serum creatinine values at 1 and 2 years, but similar rates of delayed graft function and 2-year graft survival. Vasculopathy did not correlate to any important donor criteria except the percent GS. However, serum creatinine was significantly higher in recipients of kidneys with moderate vasculopathy versus none, up to 2 years after transplantation. There was no significant difference in graft loss based upon vasculopathy. CONCLUSION: Kidneys from donors with > or =20% GS provide excellent outcome similar to kidneys from donors with no GS.

Excellent outcome in recipients of dual kidney transplants: a report of the first 50 dual kidney transplants at Stanford University.

HYPOTHESIS: Recipients of dual kidney transplants from older expanded criteria donors (ECDs) have outcomes similar to recipients of single kidneys from younger donors. Dual transplantation is the use of both adult donor kidneys into a single adult recipient. DESIGN: Donor and recipient variables were entered into a database. Analysis was performed in a retrospective fashion. The unpaired t test and chi2 test were used as appropriate. SETTING: A university teaching hospital. PATIENTS: All adult recipients of cadaveric kidney-only transplants from adult donors between November 1991 and January 1999. Patients were grouped based on whether they received a dual or single transplant and whether the donor was an ECD. The control group of patients received non-ECD cadaveric kidneys. RESULTS: Donors for recipients of dual kidneys were older and had a lower creatinine clearance on hospital admission than recipients of single control kidneys. Recipients of dual transplants were older, had fewer rejections, and had similar 3-month and 1-year serum creatinine levels vs controls. Predictors of an elevated serum creatinine level or graft loss at 3 months in recipients of ECD dual and single transplants included kidneys from donors with unstable preprocurement renal function, and recipients who developed delayed graft function. CONCLUSION: Recipients of dual kidney transplants from ECDs have excellent outcomes similar to recipients of single control kidneys.

The influence of combined trophic factors on the success of fetal pancreas grafts.

BACKGROUND: Fetal pancreas (FP) has the capacity for abundant proliferation and beta cell differentiation. Insulin-like growth factor-1 (IGF-1) promotes FP engraftment in the i.m. site and reversal of diabetes in a rodent model. However, reversal of diabetes by an FP transplant in rats under the influence of IGF-1 is still an inefficient process requiring multiple FP grafts and a prolonged latent period. Numerous other growth and differentiation factors, which include platelet derived growth factor (PDGF), vascular endothelial growth factor, endothelial cell growth factor-alpha and pancreatic islet neogenesis-associated protein, have been implicated in beta cell neogenesis and proliferation. We have analyzed the in vivo role of these growth factors in FP engraftment and reversal of streptozotocin-induced diabetes in rats. METHODS: IGF-1 alone or in combination with other trophic factors was locally administered to eight FP isografts in the thigh muscle of diabetic rats. RESULTS: Diabetes was reversed in a mean of 60+/-26 days in 11 of 11 animals treated with IGF-1. PDGF alone did not promote reversal of diabetes; however, PDGF + IGF-1 resulted in euglycemia in 6 of 6, with a mean of 36+/-14 days (P<0.05). Islet neogenesis-associated protein +IGF-1 resulted in reversal of diabetes in 6 of 6 rats with a mean interval of 50+/-10 days. Vascular endothelial growth factor or endothelial cell growth factor-alpha + IGF-1 provided no advantage compared with IGF-1 alone. CONCLUSIONS: These results demonstrate that IGF-1 is a potent trophic factor for transplanted FP and that PDGF acts synergistically with IGF-1 to promote reversal of diabetes by transplanting FP.

PAH extraction and estimation of plasma flow in human postischemic acute renal failure.

We determined the effect of postischemic injury to the human renal allograft on p-aminohippurate (PAH) extraction (E(PAH)) and renal blood flow. We evaluated renal function in 44 allograft recipients on two occasions: 1-3 h after reperfusion (day 0) and again on postoperative day 7. On day 0 subsets underwent intraoperative determination of renal blood flow (n = 35) by Doppler flow meter and E(PAH) (n = 25) by renal venous assay. Blood flow was also determined in another subset of 16 recipients on postoperative day 7 by phase contrast-cine-magnetic resonance imaging, and E(PAH) was computed from the simultaneous PAH clearance. Glomerular filtration rate (GFR) on day 7 was used to divide subjects into recovering (n = 23) and sustained (n = 21) acute renal failure (ARF) groups, respectively. Despite profound depression of GFR in the sustained ARF group, renal plasma flow was only slightly depressed, averaging 296 +/- 162 ml. min(-1). 1.73 m(-2) on day 0 and 202 +/- 72 ml. min(-1). 1.73 m(-2) on day 7, respectively. These values did not differ from corresponding values in the recovering ARF group: 252 +/- 133 and 280 +/- 109 ml. min(-1). 1.73 m(-2), respectively. E(PAH) was profoundly depressed on day 0, averaging 18 +/- 14 and 10 +/- 7% in recovering and sustained ARF groups, respectively, vs. 86 +/- 6% in normal controls (P < 0.001). Corresponding values on day 7 remained significantly depressed at 65 +/- 20 and 11 +/- 22%, respectively. We conclude that postischemic injury to the renal allograft results in profound impairment of E(PAH) that persists for at least 7 days, even after the onset of recovery. An ensuing reduction in urinary PAH clearance results in a gross underestimate of renal plasma flow, which is close to the normal range in the initiation, maintenance, and recovery stages of this injury.

Dual kidney transplantation: older donors for older recipients.

BACKGROUND: Dual kidney transplantation, the transplantation of both donor kidneys into a single recipient, allows increased use of expanded criteria donors (eg, older donors with a history of hypertension) to alleviate the disparity between available donors and potential recipients. We evaluated outcomes in our dual kidney transplant program that started in 1995. STUDY DESIGN: A retrospective comparison of donor and recipient data between recipients of dual (n = 41) versus single (n = 199) cadaveric renal transplants from February 1, 1995, to March 22, 1998, was performed. Dual kidney transplantation was selectively performed when the calculated donor admission creatinine clearance was less than 90 mL/min and the donor age was greater than 60 years, or if the donor had an elevated terminal serum creatinine. Every attempt was made to age- and size-match the donor and recipients. RESULTS: Recipients of dual kidneys had donors who were older than single kidney donors (59 +/- 12 versus 42 +/- 17 years respectively, p < 0.0001) and had more hypertension (51% versus 29%, p = 0.024). Average urine output was lower in the dual versus single kidney group (252 +/- 157 versus 191 +/- 70 mL/hr, p = 0.036). Donors for dual kidney recipients had a lower donor admission creatinine clearance of 82 +/- 28 mL/min versus 105 +/- 45 mL/min in the single kidney group (p = 0.005). Recipients of dual versus single kidneys were older (58 +/- 11 versus 47 +/- 12 years, p > 0.0001). Dual versus single kidney recipients had similar serum creatinines up to 2 years posttransplant (1.6 +/- 0.3 versus 1.6 +/- 0.7 mg/dL at 2 years, p = NS) and a comparable incidence of delayed graft function (24% versus 33%, p = NS) and 3-month posttransplant creatinine clearance (54 +/- 23 versus 57 +/- 25 mL/min, p = NS). One-year patient and graft survival for single kidney transplantation was 97% and 90%, respectively, and 98% and 89% for dual kidney transplantation (p = NS). CONCLUSIONS: Dual kidney donors were significantly older, had more hypertension, lower urine outputs, and lower donor admission creatinine clearance. Despite these differences, dual kidney recipients had comparable postoperative function, outcomes, and survival versus single kidney recipients. We believe selective use of dual kidney transplantation can provide excellent outcomes to recipients of kidneys from older donors with reduced renal function.

Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.

BACKGROUND: A loss of proximal tubule cell polarity is thought to activate tubuloglomerular feedback, thereby contributing to glomerular filtration rate depression in postischemic acute renal failure (ARF). METHODS: We used immunomicroscopy to evaluate the segmental distribution of Na+/K+-ATPase in tubules of recipients of cadaveric renal allografts. Fractional excretion (FE) of sodium and lithium was determined simultaneously. Observations were made on two occasions: one to three hours after graft reperfusion (day 0) and again on post-transplant day 7. An inulin clearance below or above 25 ml/min on day 7 was used to divide subjects into groups with sustained (N = 15) or recovering (N = 16) ARF, respectively. RESULTS: In sustained ARF, the fractional excretion of sodium (FENa) was 40 +/- 6% and 11 +/- 5%, and the fractional excretion of lithium (FELi) was 76 +/- 5% and 70 +/- 2% on days 0 and 7, respectively. Corresponding findings in recovering ARF were 28 +/- 2% and 6 +/- 2% for the FENa and 77 +/- 4% and 55 +/- 3% (P < 0.05 vs. sustained) for FELi. Na+/K+-ATPase distribution in both groups was mainly basolateral in distal straight and convoluted tubule segments and collecting ducts. However, Na+/K+-ATPase was poorly retained in the basolateral membrane of proximal convoluted and straight tubule segments in sustained and recovering ARF on both days 0 and 7. CONCLUSIONS: We conclude that loss of proximal tubule cell polarity for Na+/K+-ATPase distribution is associated with enhanced delivery of filtered Na+ to the macula densa for seven days after allograft reperfusion. Whether an ensuing activation of tubuloglomerular feedback is an important cause of glomerular filtration rate depression in this form of ARF remains to be determined.

Distribution of cell membrane-associated proteins along the human nephron.

Cytoskeletal proteins associate with specific cell adhesion complexes and membrane proteins and influence the structural and functional organization of polarized epithelial cells in the kidney. Among such proteins that have been studied in cultured cell lines and in animals are the tight junction complex (ZO-1 and occludin), the adherens cell-cell adhesion complex (alpha-, beta-catenin and plakoglobin), and Na+,K+-ATPase, with its associated membrane skeleton proteins ankyrin and fodrin. Although abnormal distribution of these proteins has been implicated in the pathogenesis of various renal diseases, the relevance of these findings to corresponding disease of the human kidney remains to be established. As a first step towards elucidating a role for such proteins in human kidney disease, we undertook a histochemical analysis of the distribution of these proteins in biopsy specimens of human kidney taken from healthy kidney transplant donors. We found each protein to have a characteristic subcellular localization and an intensity of staining that varied among different segments of the nephron in a manner that is consistent with discrete, segmental nephron function.

What is the optimal approach for the end-stage diabetic nephropathy patient considering simultaneous pancreas-kidney transplantation?

This case-based discussion regards two very different patients with end-stage diabetic nephropathy (ESDN) who are considering transplantation. What is the best approach for each individual: pancreas-kidney transplant or kidney transplant alone? Suppose a live kidney donor is available? What are the risks and benefits of each approach? In the candidate evaluation process, medical issues, such as uncorrectable coronary artery disease, are investigated and may preclude transplantation altogether or dictate the optimal approach. Similarly, a careful psychosocial profile is important to tailor the approach to the patient. The multidisciplinary transplant team has an obligation to provide informed consent, foster realistic expectations, and advise the candidate based on collective expertise. Ultimately, the decision as to the best course-pancreas-kidney, kidney transplant alone, or no transplantation-is the result of a collaborative effort between the patient and the transplant team.

Outcome in cadaveric renal transplant recipients treated with cyclosporine A and mycophenolate mofetil versus cyclosporine A and azathioprine.

BACKGROUND: Recent multicenter reports have demonstrated improved outcome in recipients of cadaveric renal transplants treated with mycophenolate mofetil (MMF) versus azathioprine (AZA) in combination with cyclosporine A (CSA) and prednisone. We compared the outcome at our center in patients treated with MMF versus AZA, CSA, and prednisone. METHODS: We retrospectively reviewed 242 adult cadaveric renal transplant recipients treated between 11/91 and 5/97. We compared 25 donor variables and 27 recipient variables and outcome parameters between patients treated with MMF versus AZA. There were 117 patients treated with CSA+AZA, 84 with CSA+MMF, and 42 who received other immunosuppressive strategies. RESULTS: There were no significant differences in any clinically important donor variables. Patients treated with MMF versus AZA and CSA had significantly fewer rejections and readmissions. There was no significant difference in 1- or 2-year patient survival. Recipients treated with MMF had a 5% higher graft survival at 2 years, although the difference did not reach statistical significance. CONCLUSIONS: Outcome is improved in adult recipients of cadaveric renal transplants treated with MMF versus AZA in combination with CSA and prednisone.

[Kidney-pancreas transplantation. Clinical results in 23 consecutive patients]. / Il trapianto di rene-pancreas. Risultati clinici su 23 pazienti consecutivi.

Immunosuppressive approaches to combined kidney-pancreas tx include quadruple therapy with either antilymphocyte globulin (ATG) or OKT3 for a short period (7-14 days) immediately after transplantation. Maintenance therapy with prednisone, azathioprine and cyclosporin is then used to ensure the long-term survival of the graft. This study reports 23 cases of combined kidney-pancreas tx under ATG induction (n = 7) and OKT3 induction (n = 16). Both groups had maintenance therapy with azathioprine, prednisone and cyclosporin. The follow-up was 12 months. Graft loss was 3 out of 7 vs 1 out of 16 (p < 0.05) for the kidney and 3 out of 7 vs 3 out of 16 for the pancreas in ATG treated vs OKT3 treated patients respectively. There were two deaths in the ATG group and one in the OKT3 group; two patients died with functioning graft, one in each group. The one year actuarial survival was 87% for graft and patient, 83% for kidney and 77% for pancreas. Combined kidney-pancreas tx with ATG or OKT3 have a similar outcome. OKT3 allows a longer period before the onset of rejection. There is a trend in survivals which suggests a better survival in OKT3 treated recipients. Infections and other complications were similar in ATG and OKT3 patients.

Dual renal grafts: expansion of the donor pool from an overlooked source.

This is a review of the emerging practice of dual renal allografting. In the setting of the expanded criteria cadaveric (and usually older) donor with inadequate function to allow single kidney transplantation, both kidneys have been transplanted into a single recipient. The recipient and donor have often been matched for age and size as dictated by the concept of nephron dosing. The reported results of dual grafting are excellent and statistically comparable to contemporaneous single cadaveric grafts. Criteria are evolving regarding when to apply single or dual grafting. Wider acceptance of dual renal grafting could have a significant impact on the cadaver kidney shortage.