Daniel A. Shoskes

Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection

BACKGROUND In cadaveric renal transplantation, delayed graft function (DGF) correlates with poor long-term graft survival; however, whether its effects are independent of acute rejection is controversial. We wished to study the effect of DGF on graft survival, controlling for acute rejection, discharge creatinine, and human leukocyte antigen match. METHODS We analyzed 27,096 first cadaveric donor renal transplants reported to the UNOS Scientific Renal Transplant Registry between January 1994 and November 1997. DGF was defined as dialysis need in the first week. Acute rejection was recorded for initial hospitalization and within 6 months. Kaplan Meier survival curves were analyzed with the log rank test. RESULTS DGF increased the incidence of acute rejection before discharge (8% without DGF; 25% with DGF, P<0.01) and any acute rejections by 6 months (25% without DGF, 42% with DGF, P<0.01). Without early rejection, DGF reduced 1-year graft survival from 91 to 75% (P<0.0001) and graft half-life from 12.9 to 8.0 years. In kidneys with acute rejection within 6 months, DGF decreased 3-year graft survival from 77 to 60% and graft half-life from 9.4 to 6.2 years (P<0.001). With a discharge creatinine of less than 2.5 mg/dl, the difference in graft half-life between no DGF and no rejection (13.4 years) and DGF with rejection (9.8 years) was significant (P<0.001). Increased donor age and cold ischemia time additionally decreased graft survival, whereas a good human leukocyte antigen match could not overcome the deleterious effects of DGF or acute rejection. CONCLUSIONS DGF is an important independent predictor of poor graft survival. Newer immunosuppressive strategies must minimize nonimmune and immune renal injury if long-term graft survival is to improve.

Indirect presentation of MHC antigens in transplantation

T cells can recognise foreign major histocompatibility complex (MHC) antigens by two distinct routes, either directly as intact molecules or indirectly as peptides after antigen processing. Danny Shoskes and Kathryn Wood review the evidence that indirect presentation of allopeptides may play a significant role in the events leading to the rejection or acceptance of allo- and xenografts.

Delayed Graft Function in Renal Transplantation: Etiology, Management and Long-term Significance

PURPOSE In cadaveric renal transplantation a period of delayed graft function postoperatively is not uncommon and often associated with a poor outcome. We reviewed the biology of reperfusion injury and delayed graft function in renal transplantation, as well as its prevention, management and long-term effects. MATERIALS AND METHODS The medical literature covering acute tubular necrosis, delayed graft function in renal transplantation and immunology of ischemia reperfusion injury was reviewed. RESULTS Delayed graft function is clearly associated with poor allograft survival, and is caused by an interaction of ischemic and immunological factors. Technical and pharmacological maneuvers can improve early function rates. The response to ischemic injury is complex, and may increase graft immunogenicity and promote the chronic proliferative changes seen in chronic allograft nephropathy. CONCLUSIONS Improvement in early renal function should be a primary goal in renal transplantation to enhance early and long-term results. Basic research into the injury response may yield insights into renal pathophysiology.

QUERCETIN IN MEN WITH CATEGORY III CHRONIC PROSTATITIS: A PRELIMINARY PROSPECTIVE, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

OBJECTIVES The National Institutes of Health (NIH) category III chronic prostatitis syndromes (nonbacterial chronic prostatitis and prostatodynia) are common disorders with few effective therapies. Bioflavonoids have recently been shown in an open-label study to improve the symptoms of these disorders in a significant proportion of men. The aim of this study was to confirm these findings in a prospective randomized, double-blind, placebo-controlled trial. METHODS Thirty men with category IIIa and IIIb chronic pelvic pain syndrome were randomized in a double-blind fashion to receive either placebo or the bioflavonoid quercetin 500 mg twice daily for 1 month. The NIH chronic prostatitis symptom score was used to grade symptoms and the quality-of-life impact at the start and conclusion of the study. In a follow-up unblind, open-label study, 17 additional men received 1 month of a supplement containing quercetin, as well as bromelain and papain (Prosta-O), which enhance bioflavonoid absorption. RESULTS Two patients in the placebo group refused to complete the study because of worsening symptoms, leaving 13 placebo and 15 bioflavonoid patients for evaluation in the blind study. Both the quercetin and placebo groups were similar in age, symptom duration, and initial symptom score. Patients taking placebo had a mean improvement in NIH symptom score from 20.2 to 18.8 (not significant), while those taking the bioflavonoid had a mean improvement from 21.0 to 13.1 (P = 0.003). Twenty percent of patients taking placebo and 67% of patients taking the bioflavonoid had an improvement of symptoms of at least 25%. In the 17 patients who received Prosta-Q in the open-label study, 82% had at least a 25% improvement in symptom score. CONCLUSIONS Therapy with the bioflavonoid quercetin is well tolerated and provides significant symptomatic improvement in most men with chronic pelvic pain syndrome.

Urological Complications in 1,000 Consecutive Renal Transplant Recipients

The urological complications in the first consecutive 1,000 renal transplants at our transplant center are reported with a minimum followup of 12 months. The kidney was implanted in the iliac fossa in all cases and in all but 3 the ureter was inserted into the bladder with a Politano-Leadbetter technique. Overall, there were 71 primary complications in 68 patients (7.1%), which included 36 ureteral obstructions, 25 ureteral or bladder leaks (including ureteral necrosis), 7 bladder outflow obstructions, 2 ureteral stones and 1 case of symptomatic vesicoureteral reflux. The use of high dose steroids in the early years was associated with a 10% urological complication rate, which decreased to 4% in patients receiving low dose steroids thereafter combined with azathioprine or cyclosporine. The urological complication was corrected after 1 procedure in 65 cases and after 2 procedures in 4. No grafts were lost due to urological complications. Two patients died, 1 of sepsis following transurethral resection of the prostate and subsequent ureteral necrosis, and 1 of hemorrhage following nephrostomy tube insertion. Most ureteral complications were treated by an open operation, although in recent years endoscopic techniques have become more common. Meticulous retrieval technique, low dose steroid protocols and rapid diagnosis are the crucial factors associated with a minimal incidence of urological complications after renal transplantation.

Increased major histocompatibility complex antigen expression in unilateral ischemic acute tubular necrosis in the mouse.

In many studies of renal transplant recipients, acute tubular necrosis has been shown to predispose to a higher rate of graft loss, apparently due to rejection, but the mechanism of this effect is unknown. One possibility is an increased immunogenicity of the graft. To study this possibility, we examined the expression of major histocompatibility complex antigens in kidneys damaged by ischemia, using a mouse model of ischemic ATN. ATN was produced in the left kidney of male CBA mice by temporary clamping of the vascular pedicle for up to 60 min. Class I and II MHC expression was quantified by the extent of binding of monoclonals in radioimmunoassay, after 1 to 35 days in both kidneys. MHC induction was localized by indirect immunoperoxidase staining. Specific steady state mRNA for beta 2 microglobulin and class II were quantified by northern blotting using 32P-labeled probes. Changes in MHC expression were assessed by comparing the ischemically injured left kidney to the control right kidney. By day 1, ATN was evident by histology but there was no change in MHC expression. By day 3, class I was increased in the left kidney by 3-6-fold over the right. In tissue sections, the class I increase was localized to tubular epithelial cells. Starting on day 7 and persisting to day 35, class II was increased by 1.5 to 3 times for the ischemic kidney over the control, primarily in interstitial cells but also in tubular cells. This increase in class II was associated with the appearance of Thy 1.2-positive cells in the interstitial areas. Increased antigen expression was preceded by increased steady state mRNA. Thus unilateral ischemic ATN causes increased MHC expression in tubular cells and the accumulation of an inflammatory infiltrate, both of which may contribute to the increased rate of rejection and graft loss in ischemically injured kidneys.

Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial

Context Although the cause of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is unknown, physicians sometimes try to treat it with antibiotics or -receptor blockers. Contribution In this multicenter, double-blind factorial trial, 196 men with moderately severe CP/CPPS were randomly assigned to 6 weeks of treatment with ciprofloxacin, tamsulosin, both drugs, or placebo. Neither ciprofloxacin nor tamsulosin substantively reduced symptoms. Implications Ciprofloxacin and tamsulosin were not effective treatments for CP/CPPS. Cautions Patients had long-standing, refractory CP/CPPS and received trial treatments for only 6 weeks. Patients with new diagnoses who are given longer courses of the trial treatments might respond differently. The Editors Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder and accounts for approximately 2 million visits to physicians annually in the United States (1). The substantial impact of CP/CPPS includes bothersome lower urinary tract symptoms, sexual dysfunction, reduced quality of life (2-5), and increased health care expenditures (6). The syndrome is diagnosed only on the basis of symptoms, principally pain or discomfort in the pelvic region. No objective measures can help define the disease. Although bacteria can infect the prostate, most men with prostatitis have a negative midstream urine culture, indicating that bacteria may not be the cause of their symptoms (2). Such men are classified as having National Institutes of Health (NIH) category III prostatitis, the most common of the clinically defined prostatitis syndromes (7). It is by no means clear that the disease is characterized by inflammation of the prostate or that the prostate is responsible for symptoms in a substantial proportion of patients. Because of this uncertainty, the term CP/CPPS is used. Chronic prostatitis/chronic pelvic pain syndrome is commonly seen by primary care practitioners, internists, and urologists. In the Olmsted County Study of Urinary Symptoms and Health Status Among Men (8), a population-based study in Olmstead County, Minnesota, the overall prevalence rate of a physician-assigned diagnosis of prostatitis was 9%. Population-based surveys of symptoms have estimated that the prevalence of the syndrome ranges from 9% to 12% among men (9, 10). It is difficult to estimate the proportion of patients with symptoms lasting longer than 3 months whose disorder remains refractory to empirical therapy. These patients are commonly seen by urologists, but whether they represent a minor subpopulation of the overall symptomatic group or make up the majority of patients is unknown. We chose to study these patients because they present with a troubling, long-standing problem and are usually treated with agents of unclear benefit. Even if a relatively large number of men whose symptoms last 3 months or more are cured by standard empirical therapy and the clinical scenario we describe is uncommon, men with refractory symptoms still present a substantial problem to internists and urologists who have little information to guide therapy. Because the cause of CP/CPPS is unknown, affected men receive many empirical therapies. The 2 most common treatments prescribed by physicians are antimicrobial agents and -adrenergic receptor antagonists (2), although there is little objective evidence to support their use (11). Quinolones, such as ciprofloxacin, are commonly used to treat CP/CPPS because of their excellent penetration into the prostate and broad spectrum of coverage for uropathogens and other organisms traditionally believed to be associated with the syndrome (12). Tamsulosin, an -blocker, is an effective treatment for lower urinary tract symptoms in men with benign prostatic hyperplasia, and it has been hypothesized that tamsulosin may improve these symptoms in men with CP/CPPS. This randomized clinical trial was designed to evaluate whether ciprofloxacin or tamsulosin reduces symptoms of long-standing CP/CPPS of at least moderate severity, typical of the 488 men in our Chronic Prostatitis Cohort Study (2). The primary purpose of the trial was to test the most common prescription treatments given to men with CP/CPPS, who are commonly seen in our referral-based urologic practices. Methods Organization The Chronic Prostatitis Collaborative Research Network, a consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), conducted the trial. Urologists and their clinical associates recruited patients at 10 sites in the United States and 1 site in Canada. The NIDDK established an independent data and safety monitoring board to review the progress, safety, and final analysis of the trial. The individual institutional review boards at each of the 10 participating clinical centers approved the study, and all men gave written informed consent. Participants The design of this trial has been described in detail previously (13). Participating urologists recruited both newly referred patients and patients with established CP/CPPS from their referral-based clinical practices at 10 tertiary medical centers in North America. Trial referrals came from primary care providers, internists, and other urologists. The primary diagnostic criterion was pain or discomfort in the pelvic region for at least 3 months in the previous 6 months. Severity of symptoms was assessed by using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (14, 15). This instrument is a validated questionnaire, completed by the patient, consisting of 4 questions about pain, 3 about voiding symptoms, and 2 about quality of life. The scores in these 3 individual domains (pain, voiding, and quality of life) are combined without weighting to yield the NIH-CPSI total score. Eligible men were required to have at least moderate symptoms, defined as an NIH-CPSI score of at least 15 of 43 possible points, at the time of randomization. We excluded men who had a documented urinary tract infection (midstream urine culture > 100000 colonies/mL) within the past 3 months, a history of active genital herpes within the previous year, a history of genitourinary cancer, inflammatory bowel disease, active urethral stricture, prostate or bladder surgery, or neurologic disease affecting the bladder. We used ligase chain reaction to screen for Chlamydia in urethral urine samples and excluded men whose tests yielded positive results. Previous treatment with antimicrobial agents or -adrenergic receptor blockers, including the study drugs, had to be completed at least 4 weeks before eligibility screening. Additional details of the eligibility criteria are available elsewhere (13). Study Design and Interventions Men were randomly assigned in equal proportions within a 2 2 factorial design to receive placebo; ciprofloxacin alone, 500 mg twice daily; tamsulosin alone, 0.4 mg once daily; or a combination of both drugs (Table 1). Patients were treated for 6 weeks, at which time the primary end point was assessed. Symptoms at 9 and 12 weeks after randomization (6 weeks after completion of treatment) were also assessed to evaluate longer-term treatment response. The 2 baseline screening contacts and the primary end point contact at 6 weeks were clinic visits; interim contacts at 3, 9, and 12 weeks were conducted by telephone. Table 1. Study Design Each patient was randomly assigned by computer. A permuted block randomization schedule with varying block sizes was used, stratified by clinical site. The research pharmacist at each site provided the blinded study drugs in 2 tamper-evident bottles. All clinical investigators, research nurses, and patients were blinded to treatment assignments until all patients had completed follow-up. Outcomes The primary outcome was the change in the NIH-CPSI total score from baseline to 6 weeks. The NIH-CPSI was administered at each of the 2 baseline screening visits, 1 to 3 weeks apart, and every 3 weeks thereafter until 12 weeks. The average of the 2 scores before randomization was used as the baseline score. Evaluation of the responsiveness of the NIH-CPSI indicates that a 4-point change on a scale of 0 to 43 points represents a difference detectable by the patient. Secondary outcomes included changes in the pain, voiding, and quality-of-life subscales of the NIH-CPSI; physical and mental summary scores on the Medical Outcomes Study 12-Item Short-Form Health Survey (16); and a 7-point patient-reported global response assessment. Responders for the global response assessment were defined as men reporting that they were markedly improved or moderately improved at 6 weeks compared with baseline. Men for whom the global response assessment was missing were considered nonresponders and were included in the denominator for the assessment of response rates. Adverse events were monitored throughout the study and graded according to the National Cancer Institute Common Toxicity Criteria (ctep.cancer.gov/reporting/ctc.html). Patients were asked at each contact to report any adverse events that had occurred since the previous contact. The questions were open-ended, and researchers did not ask about any specific categories of adverse events. All events, regardless of whether they were expected reactions to the study drugs, were recorded. Attribution to treatment was also assessed. However, because it was difficult to determine whether certain adverse events, such as pain, were related to treatment or to CP/CPPS, all events were analyzed. Statistical Analysis For each of the 2 primary treatment comparisons, the recruitment goal of 184 patients provided 80% power, at a 2-sided significance level of 5%, to detect a 4-point treatment difference in the NIH-CPSI total score between baseline and 6 weeks. We recognized that although patients could detect this difference, most might not perceive it as a major improvement. However, we did not want to miss even a minor change in

Effect of bioflavonoids quercetin and curcumin on ischemic renal injury : A new class of renoprotective agents

BACKGROUND Nonimmune renal injury plays an important role in acute and chronic rejection by triggering an injury response through cytokine and chemokine release. Bioflavonoids are agents with potential immunosuppressive and renoprotective properties. We studied the effects of quercetin and curcumin, two bioflavonoids, on ischemia-reperfusion in the rat. METHODS Rats underwent 30 min of left renal pedicle occlusion with simultaneous right nephrectomy and were pretreated with quercetin or curcumin. Serial serum creatinine was measured, and renal expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), and allograft inflammatory factor (AIF) was quantified by polymerase chain reaction. RESULTS Pretreatment with quercetin or curcumin resulted in preservation of histological integrity, with a decrease in tubular damage and interstitial inflammation. On day 2 after ischemia-reperfusion, quercetin pretreatment decreased the mean serum creatinine level from 6.5+/-1.4 to 3.3+/-0.5 mg/dl (P=0.06). On day 7, the creatinine level for control animals was 7.5+/-1.5 mg/dl, which was significantly decreased by pretreatment with quercetin, curcumin, or both together (creatinine levels: 1.6+/-1.3, 1.8+/-0.2, and 2.0+/-0.4 mg/dl, respectively; all P<0.05 vs. untreated). By semiquantitative polymerase chain reaction, RANTES, MCP-1, and AIF were detected at high levels in kidneys on day 2 but not in normal kidneys. Pretreatment with quercetin or curcumin strongly attenuated this expression. CONCLUSION Quercetin and curcumin reduce ischemia-reperfusion injury and its inflammatory sequelae. The bioflavonoids hold promise as agents that can reduce immune and nonimmune renal injury, the key risk factors in chronic graft loss.

LEUKOCYTE AND BACTERIAL COUNTS DO NOT CORRELATE WITH SEVERITY OF SYMPTOMS IN MEN WITH CHRONIC PROSTATITIS: THE NATIONAL INSTITUTES OF HEALTH CHRONIC PROSTATITIS COHORT STUDY

PURPOSE We examine whether leukocytes and bacteria correlate with symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS All 488 men screened into the National Institutes of Health Chronic Prostatitis Cohort Study before close of recruitment on August 22, 2001 were selected for analysis. The National Institutes of Health Chronic Prostatitis Symptom Index, including subscores, were used to measure symptoms. Urethral inflammation was defined as white blood cell (WBC) counts of 1 or more (1+) in the first voided urine. Participants were classified as category IIIa based on WBC counts of 5 or more, or 10 or more (5+, 10+) in the expressed prostatic secretion, or 1+ or 5+ either in the post-expressed prostatic secretion urine (voided urine 3) or semen. Uropathogens were classified as localizing if the designated bacterial species were absent in voided urine 1 and voided urine 2 but present in expressed prostatic secretion, voided urine 3 or semen, or present in expressed prostatic secretion, voided urine 3 or semen at 2 log concentrations higher than at voided urine 1 or 2. Associations between symptoms, and inflammation and infection were investigated using generalized Mantel-Haenszel methods. RESULTS Of all participants 50% had urethral leukocytes and of 397 with expressed prostatic secretion samples 194 (49%) and 122 (31%) had 5+ or 10+ WBCs in expressed prostatic secretion, respectively. The prevalence of category IIIa ranged from 90% to 54%, depending on the composite set of cut points. None of the index measures were statistically different (p >0.10) for selected leukocytosis subgroups. Based on prostate and semen cultures, 37 of 488 men (8%) had at least 1 localizing uropathogen. None of the index measures were statistically different (p >0.10) for selected bacterial culture subgroups. CONCLUSIONS Although men with chronic prostatitis routinely receive anti-inflammatory and antimicrobial therapy, we found that leukocytes and bacterial counts as we defined them do not correlate with severity of symptoms. These findings suggest that factors other than leukocytes and bacteria also contribute to symptoms associated with chronic pelvic pain syndrome.

Emphysematous cystitis: a review of 135 cases

To review recently published data on emphysematous cystitis (EC), a potentially life‐threatening condition characterized by air within the bladder wall, and that most typically affects middle‐aged diabetic women.