Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform.

We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n = 25), subclinical acute rejection (subAR, n = 23), and clinical acute rejection (cAR, n = 21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.

New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Investigator Assessment of the Utility of the TruGraf Molecular Diagnostic Test in Clinical Practice.

BACKGROUND: TruGraf v1 is a well-validated DNA microarray-based test that analyzes blood gene expression profiles as an indicator of immune status in kidney transplant recipients with stable renal function. METHODS: In this study, investigators assessed clinical utility of the TruGraf test in patient management. In a retrospective study, simultaneous blood tests and clinical assessments were performed in 192 patients at 7 transplant centers, and in a prospective observational study they were performed in 45 subjects at 5 transplant centers. RESULTS: When queried regarding whether or not the TruGraf test result impacted their decision regarding patient management, in 168 of 192 (87.5%) cases the investigator responded affirmatively. The prospective study indicated that TruGraf results supported physicians' decisions on patient management 87% (39/45) of the time, and in 93% of cases physicians indicated that they would use serial TruGraf testing in future patient management. A total of 21 of 39 (54%) reported results confirmed their decision that no intervention was needed, and 17 of 39 (44%) reported that results specifically informed them that a decision not to perform a surveillance biopsy was correct. CONCLUSIONS: TruGraf is the first and only noninvasive test to be evaluated for clinical utility in determining rejection status of patients with stable renal function and shows promise of providing support for clinical decisions to avoid unnecessary surveillance biopsies with a high degree of confidence. TruGraf is an invaluable addition to the transplant physician's tool kit for managing patient health by avoiding painful and invasive biopsies, reducing health care costs, and enabling frequent assessment of patients with stable renal function to confirm immune quiescence.

Application of TruGraf v1: A Novel Molecular Biomarker for Managing Kidney Transplant Recipients With Stable Renal Function.

TruGraf v1 is a laboratory-developed DNA microarray-based gene expression blood test to enable proactive noninvasive serial assessment of kidney transplant recipients with stable renal function. It has been previously validated in patients identified as Transplant eXcellence (TX: stable serum creatinine, normal biopsy results, indicative of immune quiescence), and not-TX (renal dysfunction and/or rejection on biopsy results). TruGraf v1 is intended for use in subjects with stable renal function to measure the immune status as an alternative to invasive, expensive, and risky surveillance biopsies. MATERIALS AND METHODS: In this study, simultaneous blood tests and clinical assessments were performed in 192 patients from 7 transplant centers to evaluate TruGraf v1. The molecular testing laboratory was blinded to renal function and biopsy results. RESULTS: Overall, TruGraf v1 accuracy (concordance between TruGraf v1 result and clinical and/or histologic assessment) was 74% (142/192), and a result of TX was accurate in 116 of 125 (93%). The negative predictive value for TruGraf v1 was 90%, with a sensitivity 74% and specificity of 73%. Results did not significantly differ in patients with a biopsy-confirmed diagnosis vs those without a biopsy. CONCLUSIONS: TruGraf v1 can potentially support a clinical decision enabling unnecessary surveillance biopsies with high confidence, making it an invaluable addition to the transplant physician's tool kit for managing patients. TruGraf v1 testing can potentially avoid painful and risky invasive biopsies, reduce health care costs, and enable frequent assessment of patients with stable renal function to confirm the presence of immune quiescence in the peripheral blood.

Physiochemical properties of generic formulations of tacrolimus in Mexico.

Tacrolimus is an important immunosuppressive agent used to prevent allograft rejection after transplantation. Tacrolimus has a narrow therapeutic index; therefore, it is essential that the physicochemical properties of generic formulations be identical to the brand-name formulation, Prograf. In this study, the physicochemical properties of generic tacrolimus formulations were compared with Prograf. The drug dissolution profiles of generic formulations of tacrolimus were different from that of Prograf. Tacrobell and T-Inmun exhibited faster dissolution than Prograf, and Tenacrine, Framebin, and Talgraf showed slower and incomplete drug dissolution, releasing 24% to 51% of tacrolimus within 2 hours. Generic formulations of tacrolimus demonstrated decreased solubility compared with Prograf. The solubility of Prograf was 35.7 microg/mL at 2 hours and 29.5 microg/mL at 24 hours. The solubility of Tenacrine, Framebin, and Talgraf at 2 hours was 5.5, 12.6, and 7.8 microg/mL, respectively, and the solubility decreased to 0.5, 2.3, and 2.1 microg/mL, respectively, at 24 hours. Whereas Prograf demonstrated content uniformity, the content of the generic tacrolimus formulations varied widely. The standard deviation of content for Tenacrine, Tacrobell, and T-Inmun were high at 29.3, 6.9, and 5.6, respectively. Furthermore, the mean percentage of labeled amount of T-Inmun was 84.2% with a relative standard deviation of 6.7% (minimum value; 72.7%; maximum value; 100.7%). These results indicate that generic formulations of tacrolimus tested in this study are not bioequivalent to Prograf, which suggests that their use may be of potential risk to transplant patients.

Circulating immune complexes after renal transplantation. Correlation of increased 125I-Clq binding activity with acute rejection characterized by fibrin deposition in the kidney.

To assess the role of circulating immune complexes in the pathogenesis of acute rejection, sera were measured for such complexes by the (125)I-C1(q) binding assay in 45 normal subjects, 24 allografted patients undergoing acute rejection, and in 11 allografted patients in a quiescent phase. Increased C1(q)-binding activity (C1(q)-BA) was detected in 14 patients with acute rejection, 9 of whom had renal biopsies showing fibrin deposition in the vasculature together with cellular infiltrates in the tubulo-interstitial structures; renal histology was not available in the other 5 patients. The other 10 patients with acute rejection, whose biopsies showed only cellular infiltrates, and the 11 patients in a quiescent phase posttransplantation did not have increased levels of serum C1(q)-BA. Of the group with increased serum C1(q)-BA, serial studies in eight patients showed a correlation between increased serum C1(q)-BA and the occurrence of rejection; with reversal by therapy, serum C1(q)-BA returned to within normal levels. Complexes from six patients were analyzed by sucrose density gradient ultracentrifugation to have sedimentation coefficients ranging from 15S to 18.4S. After acid dissociation and analysis by double-diffusion techniques, C1(q)-reactive complexes were shown to contain IgG. Immunofluorescent studies done in five renal biopsies from this group revealed granular deposits of immunoglobulin, and (or) less frequently, of complement in the glomeruli or the tubular basement membranes. The findings suggest that circulating immune complexes may mediate the type of acute rejection characterized by fibrin deposition in the kidney. The role of circulating immune complexes arising from the recipient's original kidney disease could be excluded in 10 patients with humoral rejection, inasmuch as the underlying renal pathology was of a "nonimmunologic" nature; this was corroborated by sequential studies in six patients in whom circulating immune complexes could not be demonstrated before rejection. The participation of administered antilymphocyte globulin (ALG) as an antigen also appears to be excluded in four patients, two who were not given ALG, and in two of whom episodes of rejection occurred unrelated temporally to ALG administration.

Posttransplant lymphoproliferative disorder: significance of central nervous system involvement.

BACKGROUND: Few data exist regarding central nervous system (CNS) involvement in patients with posttransplant lymphoproliferative disorder (PTLD). The purpose of this study was to review the Israel Penn International Transplant Tumor Registry (IPITTR) experience with CNS involvement by PTLD. METHODS: Nine hundred ten PTLD cases from the United States were reported to the IPITTR and reviewed for CNS involvement. RESULTS: One hundred thirty-six transplant recipients with PTLD (15%) had CNS involvement. The highest incidence of CNS involvement occurred in pancreas (3 of 11; 27%) and kidney transplant recipients (76 of 429; 18%). Fifteen cases occurred in children and 121 cases in adults. For both children and adults, isolated CNS disease was associated with better survival when compared with multiple-site involvement (children: 29% vs 0%; adults: 12% vs 6%; P < .05). Three-year survival in PTLD patients with CNS involvement was 9.4% and without CNS involvement was 49.4% (P < .01). Radiation therapy alone appeared to provide the best survival rates (25%). CONCLUSIONS: CNS involvement in transplant recipients with PTLD carries an ominous prognosis; however, isolated CNS involvement has a better prognosis than CNS plus extracranial involvement. Radiation therapy alone provides the best results, but this may be a reflection of isolated CNS disease.

Chemotherapy for posttransplant lymphoproliferative disorder: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Very little published data exist regarding the results of chemotherapy treatment of posttransplant lymphoproliferative disorder (PTLD). The purpose of the study was to review the Israel Penn International Transplant Tumor Registry experience with PTLD treated with chemotherapy. METHODS: Patients with PTLD who received chemotherapy were identified and data collected regarding demographics, tumor characteristics, recurrence rates, and survival. RESULTS: One hundred ninety three solid organ transplant recipients with PTLD who received chemotherapy were identified. Most patients were male (142:51) and Caucasian (148; 16 AA, 29 unspecified). Most PTLD were B-cell predominant (81%), monoclonal (71), and CD 20+ (60% of patients tested). Organ transplanted included: kidney, 92 (48%); heart, 54 (28%); liver, 30 (16%); pancreas, 8 (4%); and lung, 9 (5%). Median time to presentation posttransplant was 24.5 months (range 0.8 to 226.5 months). Ninety patients received CHOP, 12 ProMACE, 65 other multidrug regimens, and 23 patients received single-agent chemotherapy. Five-year survival for these four regimens were: 24%, 25%, 32%, and 5%. PTLD-specific death rates were 34%, 34%, 40%, and 48%. CONCLUSIONS: Single-agent chemotherapy appears to be inferior to other chemotherapy regimens for PTLD as it is associated with lower survival.

Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience.

INTRODUCTION: Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. METHODS: Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. RESULTS: Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 +/- 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). CONCLUSIONS: In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

Donor kidneys with small renal cell cancers: can they be transplanted?

INTRODUCTION: The purpose of this study was to determine whether incidentally discovered, small renal cell cancers (RCC) in donor kidneys can be excised and safely transplanted. METHODS: The Israel Penn International Transplant Tumor Registry database was searched and all small RCC that were identified and resected prior to transplantation of deceased and living donor kidneys were reviewed. Patient demographics, tumor characteristics, recurrence, and survival were examined. RESULTS: Fourteen kidneys were identified in which small RCC were noted at the time of procurement and where the tumors were excised ex vivo and then transplanted. Eleven kidneys were obtained from living related donors and three were from deceased donors. Median tumor size was 2 cm (range 0.5 to 4 cm). All 14 tumors were of histological Furhman grade II/VI (n = 8) or Furhman grade I/VI (n = 6). All kidneys had pathologically confirmed negative margins. The mean age of the recipients was 40.8 +/- 9.2 years, with the majority being men (11 men; 3 women). Median follow-up for this group was 69 months (range 14 to 200 months). There have been no recurrences of tumor in these recipients and the 1-, 3-, and 5-year patient and graft survivals are 100%, 100%, and 93%. CONCLUSIONS: These data represent the only data available (to our knowledge) on this issue. This experience indicates that donor kidneys with small, incidental RCC and low histological grade (Furhman grade I and II/IV) can be managed with excision and transplantation, with a low risk of tumor recurrence in the recipient.

Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen.

UNLABELLED: Modified release (MR) tacrolimus is an extended release formulation administered once daily (qD). The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable kidney transplant recipients converted from Prograf twice a day to MR tacrolimus qD. METHODS: This was an open-label, multicenter study with a crossover design. Eligible patients were 18 to 65 years of age, more than 6 months posttransplant with stable renal function, and received stable Prograf doses more than 2 weeks prior to enrollment. Patients received Prograf twice a day through day 7; 24-hour PK profiles were obtained on days 1 and 7. Patients were converted to the same milligram-for-milligram daily dose of MR tacrolimus qD in the morning on day 8; 24-hour PK profiles were obtained for MR tacrolimus on days 8, 14, and 21. Laboratory and safety parameters were also evaluated. RESULTS: Most patients (67 of 70) completed all 5 PK profiles. The 90% confidence intervals (CI) for the MR tacrolimus vs Prograf comparison at steady state (days 14 and 21 vs days 1 and 7) were 90.7 and 99.4 for AUC0-24 and 82.7 and 91.9 for Cmin. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 1, r = 0.80; day 7, r = 0.84) and MR tacrolimus (day 14, r = 0.92; day 21, r = 0.86). Renal function remained stable after conversion to MR tacrolimus. CONCLUSION: The steady state PK of MR tacrolimus are equivalent to Prograf after a milligram-for-milligram conversion in stable kidney transplant recipients. The results provide evidence to support a safe 1:1 conversion from Prograf twice a day to MR tacrolimus.

Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen.

INTRODUCTION: Modified release (MR) tacrolimus is an extended release formulation administered once daily. The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable liver transplant recipients converted from Prograf twice a day to MR tacrolimus once daily. METHODS: This was an open-label, multicenter study with a single sequence, four-period crossover design. Eligible patients were 18 to 65 years of age, >6 months posttransplant with stable renal and hepatic function and receiving stable doses of Prograf twice a day for >2 weeks prior to enrollment. Patients received Prograf twice a day on days 1 to 14 and 29 to 42. Patients were converted to the same milligram-for-milligram daily dose of MR once daily on days 15 to 28 and 43 to 56. Twenty-four-hour PK profiles were obtained on days 14, 28, 42, and 56. Laboratory and safety parameters were also evaluated. RESULTS: Of 70 patients, 62 completed all four PK profiles. The AUC0-24 of tacrolimus was comparable for Prograf twice a day (days 14 and 42) and MR tacrolimus once daily (days 28 and 56). The 90% confidence intervals for MR tacrolimus versus Prograf at steady state (days 28 and 56 vs days 14 and 42) was 0.85 to 0.92 for AUC0-24. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 14, r = .93; Day 42, r = .89) and for MR tacrolimus (day 28, r = .93; day 56, r = .92). Renal and liver function remained stable. One patient experienced acute rejection. CONCLUSION: The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.

African American renal transplant recipients benefit from early corticosteroid withdrawal under modern immunosuppression.

African Americans have historically been considered high-risk renal transplant recipients due to increased rejection rates and reduced long-term graft survival. Modern immunosuppression has reduced rejections and improved graft survival in African Americans and may allow successful corticosteroid withdrawal. Outcomes in 56 African Americans were compared to 56 non-African Americans enrolled in early withdrawal protocols. Results are reported as African American versus non-African American. Acute rejection at 1 year was 23% and 18% (P = NS), while patient and graft survival was 96% versus 98% and 91% versus 91% (P = NS), respectively. In conclusion, early withdrawal in African Americans is associated with acceptable rejection rates and excellent patient and graft survival, indicating that the risks and benefits of early withdrawal are similar between African Americans and non-African Americans. Additional followup is needed to determine long-term renal function, graft survival, and cardiovascular risk in African Americans with early steroid withdrawal.

Revaccination of renal transplant and hemodialysis recipients with pneumococcal vaccine.

Two years after pneumococcal vaccine was given to patients on a university renal transplant and hemodialysis service, vaccine failures began to occur. Serologic studies showed a threefold decrease in antibody levels during this period, from 913 ng of antibody nitrogen per milliliter to 315 ng/mL. The decrease was greater in patients undergoing hemodialysis than in renal transplant recipients (879 to 215 ng/mL vs 932 to 385 ng/mL). The lowest antibody levels were to types 4, 6A, and 19F. Patients were revaccinated, without serious reactions, and pneumococcal infections decreased as they had after the original vaccination program. After revaccination, there was a twofold increase in antibody levels (315 to 602 ng/mL), but the levels did not reach those seen after primary vaccination. The increase was greater in hemodialysis than in renal transplant recipients (215 to 757 ng/mL vs 385 to 536 ng/mL). This experience indicates that pneumococcal vaccines may be effective in patients undergoing hemodialysis and in asplenic renal transplant recipients, but these groups will require revaccination sooner than normal subjects to maintain immunity.

Response to pneumococcal vaccine in renal transplant and hemodialysis patients.

Because of the risk of serious pneumococcal infections in patients receiving a renal transplant, a study was undertaken to determine if pneumococcal vaccine could be administered before or after transplantation. Vaccine was given to recipients of transplants and to patients who were undergoing dialysis. Both groups responded to the vaccine, and although the mean antibody levels were lower than those reported for normal populations, the levels were in the range thought to be protective for most pneumococcal types. Antibody levels, both before and after vaccination, were substantially lower in patients with recent transplants than in patients who were undergoing hemodialysis. Patients who are awaiting renal transplantation can be immunized while they are undergoing hemodialysis. Further study is needed to determine how long antibody levels will persist after vaccination in both patients undergoing hemodialysis and those receiving a transplant.

Late onset of fatal cytomegalovirus infection after renal transplantation. Primary or reactivation infection?

Cytomegaloviurs (CMV) infections are a recognized problem in the first six months after renal transplantation. Studies have suggested that primary infections produce symptomatic disease, whereas reactivation infections are usually asymptomatic. Two patients are described who developed fatal CMV infections in the second year after transplantation. Both patients had typical CMV disease with fever, pneumonitis, and hepatitis. Results of serologic studies in one patient were characteristic of primary infection, with seroconversion at the time of disease and appearance of specific IgM antibodies. The other patient had a similar antibody response at the time of his illness, but serial antibody tests showed that he had had a transient seroconversion earlier, in the second month after transplanation, that was not associated with clinical symptoms. These patients indicate that CMV infection must be considered in the differential diagnosis of serious febrile illnesses even in the late posttransplantation period and may occur either as the result of primary or reactivation infection. Serologic studies at the time of illness may not allow distinction between the types of infection.

Utility of bronchoalveolar lavage in assessing pneumonia in immunosuppressed renal transplant recipients.

PURPOSE: To determine if initial results obtained from diagnostic bronchoalveolar lavage (BAL) in immunosuppressed renal transplant patients with pulmonary infiltrates, fever, or hypoxemia can affect therapeutic decisions, morbidity, and mortality. DESIGN: A retrospective study of all BAL specimens obtained from renal transplant patients from January 1985 through June 1991. Initial results of Gram stain, cytology, cell differential count, and semi-quantitative bacterial cultures, all available within 24 hours of bronchoscopy, were compared with clinical outcomes and final diagnoses. SETTING: University hospital nephrology-transplant/pulmonary service. PATIENTS: Seventy renal transplant patients with a suspected pneumonia were stratified into 3 groups. A total of 48 patients underwent 58 bronchoscopies. Group 1 was comprised of 32 BALs that yielded 1 or more infectious organisms and was considered diagnostic. Group 2 (n = 26) were those BALs in which no organism was isolated and were thus nondiagnostic. Twenty-two additional immunosuppressed renal transplant recipients with pneumonia were considered by the admitting transplant nephrologist to have an uncomplicated community-acquired lung infection and thus were empirically treated and did not undergo BAL (Group 3). METHODS: BAL fluid analysis included cell differential count, cytopathologic examination, and culture for mycobacteria, legionella, fungi, viruses, and bacteria using a semi-quantitative technique. Etiologic diagnosis and the time of onset of the infectious processes were recorded. Therapeutic outcome and mortality were determined for each group. RESULTS: Thirty-nine etiologic organisms were found in 32 patients, with 6 patients having more than 1 infection. Twenty-two patients had 26 negative BALs, and 8 of these patients were clinically believed to have a volume overload state. Eight of 13 (61%) patients with bacterial pneumonia had BAL neutrophil counts greater than 20%, whereas 11 of 13 (84%) patients without bacterial pneumonia had neutrophil counts less than 20% (p < 0.05). Those patients with an infectious etiology remained in the hospital longer than patients without a specific etiologic organism identified (p < 0.02). Therapeutic decisions leading to the institution of specific antibiotics were more frequently made in patients with a diagnostic BAL (p < 0.0001). An overall 3-month mortality (16%) was low compared with the historical rate (30%). CONCLUSION: BAL is a useful procedure in the diagnosis of an infectious process in immunosuppressed renal transplant patients where initial results can alter therapy in more than 70% of cases.

Herpesvirus hominis type 2 meningoencephalitis following renal transplantation.

Herpesvirus hominis (HVH) type 2 meningoencephalitis, confirmed by isolation of the virus from cerebrospinal fluid and brain biopsy specimens, is described in a 44 year old man following renal transplantation. An HVH type 2 genital infection developed two weeks after renal transplantation, which was followed by meningoencephalitis 10 days later. Subsequently an intracerebral hemorrhage developed with evidence of diffuse vasculitis on arteriography. In a second transplant patient a similar clinical syndrome also developed after an HVH type 2 genital infection, but viral studies were not made to confirm the etiology of the meningoencephalitis. HVH has been recognized as a cause ot mucocutaneous diseases in recipients of renal transplants, but involvement of the central nervous system has not been reported.

Acute interstitial nephritis. A clinical and pathologic study based on renal biopsies.

To define interstitial nephritis without preselection bias, 25 consecutive renal biopsy specimens from patients with tubular damage, interstitial damage and interstitial inflammation were analyzed in detail. In four patients (all with acute renal failure), tubulitis, and interstitial eosinophil and lymphocyte infiltration were found, but no glomerular abnormalities. In four others, the findings were similar but some glomerular abnormalities were noted. Two patients had probable healed interstitial nephritis. The clinical presentation varied from transient renal insufficincy to oliguric renal failure. Three of the patients with glomerular abnormalities had significant proteinuria. When the 10 patients with interstitial nephritis were compared with the other 15 serving as controls, striking features in the former group were skin rash, eosinophilia, the absence of hypertension and the frequency of administration of penicillin and its analogs. Serum immunoglobulin E (IgE) levels were elevated in three of the patients. The striking eosinophilia, interstitial eosinophil infiltration and increased IgE levels suggest that allergen-reaginic complexes may be involved in the pathogenesis of the lesion.

Strategies to minimize immunological and nonimmunological risk factors in the renal transplant population.

To improve long-term outcome after renal transplantation, attention should be placed on the tailored use of immunosuppressive regimens that have a more favorable impact on the immunological and nonimmunological risk profiles of an individual recipient. Tacrolimus is widely used for maintenance and rejection immunosuppression in solid organ transplantation, and compared with cyclosporine, its use in renal transplantation is associated with a reduced incidence and severity of acute rejection and a more positive effect on known cardiovascular risk factors. Recent experience with tacrolimus-based therapy has demonstrated an improved lipid profile and lower arterial blood pressure, with less requirement for lipid-lowering and antihypertensive medication compared with cyclosporine, without significantly increasing the risk of long-term insulin-dependent posttransplant diabetes mellitus. The advantageous effects of tacrolimus on both immunological and nonimmunological risk factors offer potential benefits for long-term graft function and survival.