Chemokines and their receptors in human renal allotransplantation.

BACKGROUND: Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. Therefore, we evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. METHODS: Renal biopsies were grouped as postreperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathologic assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in preprocurement biopsies from live donor kidneys (n=15). RESULTS: Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10, and CXCL11) and chemokine receptors (CCR5, CCR7, and CXCR3) were significantly increased in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a T-helper 1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with nonrejection causes of renal dysfunction. Biopsies from patients with stable function without histologic evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared with rejecting allografts. CONCLUSIONS: This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention.

Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. STUDY DESIGN: We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. RESULTS: Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. CONCLUSIONS: These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion.

T-cell depletion facilitates reduced immunosuppression following organ transplantation and has been suggested to be pro-tolerant. However, the characteristics of post-depletional T cells have not been evaluated as they relate to tolerance induction. We therefore studied patients undergoing profound T-cell depletion with alemtuzumab or rabbit anti-thymocyte globulin following renal transplantation, evaluating the phenotype and functional characteristics of their residual cells. Naive T cells and T cells with potential regulatory function (CD4+CD25+) were not prevalent following aggressive depletion. Rather, post-depletion T cells were of a single phenotype (CD3+CD4+CD45RA-CD62L-CCR7-) consistent with depletion-resistant effector memory T cells that expanded in the first month and were uniquely prevalent at the time of rejection. These cells were resistant to steroids, deoxyspergualin or sirolimus in vitro, but were calcineurin-inhibitor sensitive. These data demonstrate that therapeutic depletion begets a limited population of functional memory-like T cells that are easily suppressed with certain immunosuppressants, but cannot be considered uniquely pro-tolerant.

Functionally significant renal allograft rejection is defined by transcriptional criteria.

Renal allograft acute cellular rejection (ACR) is a T-cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T-cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub-clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT-PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up-regulated during effector T(H)1 T-cell activation, most significantly the transcription factor T-bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Solid organ transplantation at the National Institutes of Health: development of a research-based transplantation practice.

The National Institutes of Health has established a clinical transplant research program focusing on translational research in kidney transplantation. The program has been developed with a multidisciplinary approach under a common administrative structure that integrates transplant physicians and surgeons with clinical laboratory and data analysis support personnel. The program has achieved excellent clinical outcomes despite focusing exclusively on investigational methods and serving a diverse and medically complex patient population. Novel approaches toward consenting, computer integration, and tissue acquisition have been layered over interventional and observational studies to serve the scientific mission while delivering quality transplant care.

Strategies for minimizing immunosuppression in kidney transplantation.

Immunosuppression remains the cause of most morbidity following organ transplantation. However, its use is also responsible for the outstanding graft and patient survival rates commonplace in modern transplantation. Thus, the predominant challenge for transplant clinicians is to provide a level of immunosuppression that prevents graft rejection while preserving immunocompetence against environmental pathogens. This review will outline several strategies for minimizing or tailoring the use of immunosuppressive drugs. The arguments for various strategies will be based on clinical trial data rather than animal studies. A distinction will be made between conventional immunosuppressive drug reduction based on over-immunosuppression, and newer induction methods specifically designed to lessen the need for chronic immunosuppression. Based on the available data we suggest that most patients can be transplanted with less immunosuppression than is currently standard.

The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials.

Organ transplantation has become a standard life-saving therapy for many causes of end stage organ failure. Although valuable, it remains hampered by the requirement for, and complications of, immunosuppression to prevent immune rejection of the transplanted organ. It is now clear that rejection can be avoided in some experimental systems without a requirement of immunosuppressive medication, and these experimental concepts are now making their way into the clinic in the form of early transplantation tolerance trials. This manuscript will discuss the most promising techniques for tolerance induction, namely, costimulation blockade, lymphocyte depletion, and mixed chimerism. Seminal preclinical studies will be cited and the results of initial clinical trials will be reviewed. The data to date indicate that while tolerance remains elusive, immunosuppression minimization is a feasible near-term alternative.

Late urinary tract infection after renal transplantation in the United States.

BACKGROUND: Although urinary tract infection (UTI) occurring late after renal transplantation has been considered "benign," this has not been confirmed in a national population of renal transplant recipients. METHODS: We conducted a retrospective cohort study of 28,942 Medicare primary renal transplant recipients in the United States Renal Data System (USRDS) database from January 1, 1996, through July 31, 2000, assessing Medicare claims for UTI occurring later than 6 months after transplantation based on International Classification of Diseases, 9th Revision (ICD-9), codes and using Cox regression to calculate adjusted hazard ratios (AHRs) for time to death and graft loss (censored for death), respectively. RESULTS: The cumulative incidence of UTI during the first 6 months after renal transplantation was 17% (equivalent for both men and women), and at 3 years was 60% for women and 47% for men (P < 0.001 in Cox regression analysis). Late UTI was significantly associated with an increased risk of subsequent death in Cox regression analysis (P < 0.001; AHR, 2.93; 95% confidence interval [CI], 2.22, 3.85); and AHR for graft loss was 1.85 (95% CI, 1.29, 2.64). The association of UTI with death persisted after adjusting for cardiac and other infectious complications, and regardless of whether UTI was assessed as a composite of outpatient/inpatient claims, primary hospitalized UTI, or solely outpatient UTI. CONCLUSION: Whether due to a direct effect or as a marker for serious underlying illness, UTI occurring late after renal transplantation, as coded by clinicians in the United States, does not portend a benign outcome.

Induction sirolimus and delayed graft function after deceased donor kidney transplantation in the United States.

BACKGROUND/AIMS: Previous studies have reported a link between the use of induction sirolimus (INDSRL) and delayed graft function (DGF) after kidney transplantation. However, none have had sufficient power to adjust for all factors known to be associated with DGF. METHODS: We conducted a retrospective cohort study of US deceased donor kidney transplantation recipients in the United States Renal Data System (USRDS) from January 1, 2000 to May 31, 2001. Logistic regression analysis was used to model adjusted odds ratios (AOR) for the development of DGF, adjusted for other factors previously reported to be associated with DGF. RESULTS: Among 8,319 patients meeting inclusion criteria, 361 patients received INDSRL, of whom 98 (27.1%) had DGF, compared to 22.5% among patients who did not receive INDSRL. In multivariate analysis, INDSRL was associated with an increased risk of DGF, with an adjusted odds ratio of 1.42 (95% CI: 1.07-1.90). Other factors associated with DGF were similar to those previously reported. INDSRL was not significantly associated with graft loss at 1 year in Cox regression. CONCLUSIONS: INDSRL was independently associated with DGF in US deceased donor kidney transplantation recipients, adjusted for all other factors previously shown to be associated with DGF.

Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression.

Before the era of highly active antiretroviral therapy, kidney transplant recipients infected with HIV had increased risk of death compared with HIV-uninfected recipients. More recent single-center reports have indicated improved results, but this has not been assessed in a national population. Therefore, a retrospective cohort study of US adult deceased donor kidney transplant recipients from January 1, 1996, to May 31, 2001 was conducted; patients were followed until October 31, 2001. A total of 27,851 patients had valid recipient HIV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Centers for Medicare and Medicaid Studies Form 2728. Factors independently associated with HIV infection were also assessed by logistic regression analysis. Only 12.8% of HIV-infected recipients were black, compared with 27.6% in the entire study cohort. HIV-infected kidney transplant recipients were significantly less likely to be black in logistic regression analysis (adjusted OR, 0.29; 95% CI, 0.08 to 0.99; P = 0.049), which was the only factor independently associated with HIV infection. It was found that HIV-infected recipients had improved survival compared with HIV-uninfected recipients, although this was not statistically significant in adjusted analysis (adjusted HR, 0.36; 95% CI, 0.05 to 2.53; P = 0.31). Kidney transplantation in HIV-infected patients is plausible and ongoing, but HIV-infected candidates who underwent kidney transplantation in the United States during the course of the study were demographically unrepresentative of HIV-infected candidates generally.

Hepatitis C and renal transplantation in the era of modern immunosuppression.

Kidneys from donors who are positive for hepatitis C virus (DHCV+) have recently been identified as an independent risk factor for mortality after renal transplantation. However, it has not been determined whether risk persists after adjustment for baseline cardiac comorbidity or applies in the era of modern immunosuppression. Therefore, a historical cohort study was conducted of US adult cadaveric renal transplant recipients from January 1, 1996, to May 31, 2001; followed until October 31, 2001. A total of 36,956 patients had valid donor and recipient HCV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Center for Medicare and Medicaid Studies Form 2728 and previous dialysis access-related complications. It was found that DHCV+ was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P < 0.001), primarily as a result of infection. Mycophenolate mofetil was associated with improved survival in DHCV+ patients, primarily related to fewer infectious deaths. Adjusted analyses limited to recipients who were HCV+, HCV negative, or age 65 and over, or by use of mycophenolate mofetil confirmed that DHCV+ was independently associated with mortality in each subgroup. It is concluded that DHCV+ is independently associated with an increased risk of mortality after renal transplantation adjusted for baseline comorbid conditions in all subgroups. Recipients of DHCV+ organs should be considered at high risk for excessive immunosuppression.

Objective, real-time, intraoperative assessment of renal perfusion using infrared imaging.

Allograft ischemia induces delayed graft function and is correlated with increasing rates of rejection. There is not currently a way to objectively measure the effects of ischemia in real-time, nor to relate therapies combating reperfusion injury with their intended effects. An infrared (IR) method utilizing a focal plane array detector camera was developed for real-time intraoperative IR imaging of renal allografts, and evaluated in a pilot trial to quantify perfusion in recipients of live (n = 8) and cadaveric donor (n = 5) allografts. Digital images were taken for 3-8 min postreperfusion. Image data were compared to ischemic time and allograft function to assess potential clinical relevance. Cold ischemic time ranged from 0.5 to 29 h and was bimodally distributed between living and cadaveric donors. Renal rewarming time (RT) as determined by IR imaging correlated with cold ischemic time (p < 0.001, R 2 = 0.81), and predicted the subsequent return of renal function with RT negatively correlated to the regression slopes of creatinine (p = 0.02, R 2 = 0.38) and BUN (p = 0.07, R 2 = 0.26). Intraoperative IR imaging noninvasively provides clinically relevant real-time whole kidney assessment of reperfusion. This technology may aide in the objective assessment of therapies designed to limit reperfusion injury, and allow for quantitative assessment of allograft ischemic damage.

Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).

BACKGROUND: Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion. METHODS: Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis. RESULTS: Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels. CONCLUSIONS: T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.

Renal cell carcinoma as a cause of end-stage renal disease in the United States: patient characteristics and survival.

BACKGROUND: The patient characteristics and mortality associated with renal cell carcinoma (RCC) as a cause of end-stage renal disease (ESRD) have not been characterized for a national population. METHODS: An historical cohort study of renal cell carcinoma (RCC) was conducted from April 1, 1995, to December 31, 1999. Included were 360,651 patients in the United States Renal Data System (USRDS) who were initiated on ESRD therapy with valid causes of ESRD. RESULTS: Of the study population, 1646 patients (0.5%) had RCC. The mean age of patients with RCC was 66.8 +/- 14.6 years versus 61.3 +/- 16.4 years for patients with other causes of ESRD (P < 0.01 by Student t test). The unadjusted 3-year survival (censored at the date of renal transplantation) of patients with RCC during the study period was 23% versus 36% in all other patients [adjusted hazard ratio (AHR), 1.10, 95% confidence interval (CI) 1.02-1.19, P = 0.019 by Cox regression]. However, patients with RCC who underwent nephrectomy (bilateral or unilateral) had significantly better survival compared to RCC patients who did not (AHR, 0.73, 95% CI, 0.63-0.85, P < 0.01), and their survival was not significantly different in comparison with nondiabetic ESRD patients. Bilateral nephrectomy (vs. unilateral) was not associated with any difference in adjusted mortality. CONCLUSION: Among patients with ESRD, the demographics of those with RCC were similar to those of patients with RCC in the general population. Overall, patients with RCC had decreased survival compared to patients with other causes of ESRD; those who underwent nephrectomy had significantly better survival than those who did not, with survival comparable to patients with nondiabetic ESRD.

Hospitalized nephrolithiasis after renal transplantation in the United States.

The national incidence of and risk factors for hospitalized nephrolithiasis (NEP) in renal transplant (RT) recipients has not been reported. We conducted a historical cohort study of 42 096 RT recipients in the United States Renal Data System between 1 July 1994 and 30 June 1998. The 1-year incidence of NEP (ICD-9 codes 592.x) after RT in 1997 was compared to the rate of NEP in the general population using the National Hospital Discharge Survey. Associations with time to hospitalizations for a primary diagnosis of nephrolithiasis were assessed by Cox Regression. NEP was uncommon after RT (104 cases per 100 000 person years in 1997). However, females, but not males, had a statistically significant increased risk of NEP compared to the general population (rate ratio for females, 2.84, 95% confidence interval, 2.35-3.58). Kidney stones were more common than ureteral stones, and percutaneous procedures were more common than ureteroscopy or extracorporeal shock wave lithotripsy (ESWL). The only risk factor identified for NEP was renal failure due to stone disease (only one case). NEP was uncommon after RT, but was still more common than in the general population. We identified differences in the presentation and management of NEP after RT in comparison to the general population.