Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. METHODS: Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. RESULTS: Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CONCLUSIONS: CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy.

Fibrin Glue Injections: A Minimally Invasive and Cost-Effective Treatment for Post-Renal Transplant Lymphoceles and Lymph Fistulas.

Pelvic lymphoceles/lymph fistulas are commonly observed after kidney allotransplantation, especially when the kidney is placed in a retroperitoneal position. While the majority are <5 cm in diameter and resolve without intervention, some may continue to enlarge, and cause local or systemic symptoms or graft dysfunction. Among 1662 recipients of both living and deceased donor kidney transplants between January 2003 and July 2014, we found 46 (2.7%) patients with symptomatic lymphoceles requiring intervention. We studied the clinical outcomes and charges for three treatment modalities including open surgical drainage (22), laparoscopic surgical drainage (11), and percutaneous fibrin glue injections into the drained lymphocele cavity (13). The patient demographics and clinical characteristics were comparable for each treatment group, although maintenance immunosuppressive drugs differed by era. We found fibrin glue injections resulted in significantly lower (p = 0.04) rates of recurrence (1; 7.7%) than either laparoscopic (6; 54%) or open surgical drainage (6; 27.3%). In addition, fibrin glue injections generated significantly (p < 0.001) lower median ($4559) charges compared to either laparoscopic ($26,330) or open surgical drainage ($23,758). Fibrin glue treatment has the advantage of being an outpatient procedure, performed with the patient under local anesthesia, and does not incur the expense of an operative procedure or hospital admission associated with laparoscopic or open surgery.

Evaluation of alloreactivity in kidney transplant recipients treated with antithymocyte globulin versus IL-2 receptor blocker.

Induction therapy is used in kidney transplantation to inhibit the activation of donor-reactive T cells which are detrimental to transplant outcomes. The choice of induction therapy is decided based on perceived immunological risk rather than by direct measurement of donor T-cell reactivity. We hypothesized that immune cellular alloreactivity pretransplantation can be quantified and that blocking versus depleting therapies have differential effects on the level of donor and third-party cellular alloreactivity. We studied 31 kidney transplant recipients treated with either antithymocyte globulin (ATG) or an IL-2 receptor blocker. We tested pre- and posttransplant peripheral blood cells by flow cytometry to characterize T-cell populations and by IFN-γ ELISPOT assays to assess the level of cellular alloreactivity. CD8(+) T cells were more resistant to depletion by ATG than CD4(+) T cells. Posttransplantation, frequencies of donor-reactive T cells were markedly decreased in the ATG-treated group but not in the IL-2 receptor blocker group, whereas the frequencies of third-party alloreactivity remained nearly equivalent. In conclusion, when ATG is used, marked and prolonged donor hyporesponsiveness with minimal effects on nondonor responses is observed. In contrast, induction with the IL-2 receptor blocker is less effective at diminishing donor T-cell reactivity.

Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes.

The urologic chronic pain conditions such as chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis are syndromes whose evaluation and management are controversial. Part of the difficulty in diagnosis and therapy is the heterogeneity of etiologies and symptoms. We propose a six-domain phenotype, which can classify these patients clinically and can direct the selection of therapy in the most evidence based multimodal manner. The domains are urinary, psychosocial, organ specific, infection, neurologic and tenderness of skeletal muscles. This system is flexible and responsive to new biomarkers and therapies as their utility and efficacy are proven.

A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis).

OBJECTIVE: To determine if finasteride can reduce symptoms in men with a clinical diagnosis of chronic nonbacterial prostatitis (National Institutes of Health, NIH, category IIIA chronic pelvic pain syndrome, CPPS) compared with placebo. PATIENTS AND METHODS: Men (76) with category IIIA CPPS enrolled in four North American prostatitis research centres were randomized after a 2-week placebo run-in to finasteride or placebo for 6 months. The primary efficacy variable was a subjective overall assessment (SOA); the secondary efficacy variables included the NIH chronic prostatitis symptom index (NIH-CPSI) and safety data. Patients were assessed at screening, baseline (after the 2-week placebo run-in), 3 and 6 months. RESULTS: Sixty-four patients had at least one assessment on medication (31 placebo, 33 finasteride); 75% of the finasteride and 54% of the placebo group had at least a mild improvement (defined as > 25% improvement in SOA), and 44% and 27%, respectively, a moderate or marked improvement (>50% improvement in SOA). The trend was similar in the NIH-CPSI scores. Five patients in the finasteride and seven in the placebo group reported medication-related adverse events. CONCLUSION: This randomized placebo-controlled pilot study suggests that finasteride was of benefit for some men with category IIIA CPPS, but the results do not justify recommending finasteride as monotherapy, except for men who also have benign prostatic hyperplasia. A larger, properly powered study, possibly evaluating combination with other therapies or specifically in men with prostatitis and benign prostatic hyperplasia, is required to confirm any clinical benefit.

Correlation of beta-endorphin and prostaglandin E2 levels in prostatic fluid of patients with chronic prostatitis with diagnosis and treatment response.

PURPOSE: The chronic pelvic pain syndrome is a clinically defined symptom complex of unclear etiology. We have noted increased oxidative stress in the prostatic fluid of these patients, implying an active inflammatory response. Immune cells can produce the natural opioid beta-endorphin at the site of injury, which may modulate pain. We measured beta-endorphin and the inflammatory marker prostaglandin E2 in the expressed prostatic secretions of men with prostatitis, and correlated the results with symptoms. MATERIALS AND METHODS: Expressed prostatic secretions samples from 70 patients and 8 asymptomatic controls were collected and frozen. beta-Endorphin and prostaglandin E2 were measured by enzyme-linked immunosorbent assay. Results were stratified according to prostatitis category and compared in individuals before and after therapy. RESULTS: In symptomatic patients beta-endorphin and prostaglandin E2 were not significantly different in categories II, IIIa and IIIb expressed prostatic secretions but they were higher than in controls. The mean beta-endorphin level plus or minus standard error of mean in symptomatic patients was significantly higher (23.8 +/- 11 ng./ml. versus 8.7 +/- 4.7, p = 0.0001) and mean prostaglandin E2 was lower (6.01 +/- 2.9 ng./ml. versus 3.01 +/- 2.9, p = 0.001) after successful therapy with antibiotics or antioxidant phytotherapy, Prosta-Q (Farr Laboratories, Santa Clarita, California). CONCLUSIONS: We observed a correlation of higher prostaglandin E2 and lower beta-endorphin in symptomatic men with chronic prostatitis. Increased oxidative stress and inflammation may induce prostaglandin E2 production that would inhibit beta-endorphin release. Treatment with therapeutic agents that decrease oxidative stress, such as antibiotics and antioxidant phytotherapy, may function at least partially by increasing beta-endorphin and decreasing prostaglandin E2.

Use of antibiotics in chronic prostatitis syndromes.

Chronic prostatitis is a common condition, with an incidence estimated at between 9%-14% of men worldwide. It is a medically controversial condition with significant attendant morbidity. According to a recent consensus report from the National Institutes of Health (NIH), chronic prostatitis patients fall into one of three categories: chronic bacterial prostatitis (category II prostatitis); chronic pelvic pain syndrome (category III prostatitis); or asymptomatic inflammation (category IV prostatitis). Prostatic tissues are best penetrated by drugs with a high pKa and high lipid solubility, such as quinolones, macrolides, tetracyclines, and sulfa drugs. Ciprofloxacin has been shown to be effective in the treatment of chronic bacterial prostatitis caused by Escherichia coli. The older quinolones demonstrate superiority against chronic bacterial prostatitis caused by gram-negative pathogens; the newer quinolones may be more effective against gram-positive pathogens and anaerobes. Despite continuing controversy, antimicrobial agents are the most common therapy employed in the treatment of chronic prostatitis. While some patients with nonbacterial (category III) prostatitis do improve with antibiotics, prolonged courses in the absence of documented infection or symptomatic improvement are not warranted. Prospective, randomized, placebo-controlled trials will hopefully lead to a clearer understanding of the role of antimicrobial agents in chronic bacterial prostatitis within the next year.

Treatment of interstitial cystitis with a quercetin supplement.

PURPOSE: Interstitial cystitis (IC) is a disorder of unknown etiology with few effective therapies. Oral bioflavonoid therapy utilizing quercetin recently proved to be clinically effective in men with chronic pelvic pain syndrome, a disorder with similarities to IC. We therefore tested in an open-label trial a quercetin-based supplement in patients with clinically proven IC. MATERIALS AND METHODS: Twenty-two patients (5 men and 17 women; average age 53.1 years) with classically documented IC received one capsule of Cysta-Q complex (equivalent to 500 mg of quercetin) twice a day for 4 weeks. Symptoms were assessed before and after therapy by the IC problem and symptom indices as well as by global assessment of pain (range 0-10). RESULTS: Two patients did not complete the study. In the remaining 20 patients, improvement was seen in all three parameters tested. After 4 weeks of treatment, the mean (+/- SEM) problem index improved from 11.3 +/- 0.6 to 5.1 +/- 0.7 (p = .000001), the mean symptom index improved from 11.9 +/- 0.9 to 4.5 +/- 0.5 (p = .000001), and the mean global assessment score improved from 8.2 +/- 0.4 to 3.5 +/- 0.4 (p = .000001). None of the patients experienced any negative side effects, and all but one patient had at least some improvement in every outcome measure. CONCLUSION: Oral therapy with the quercetin supplement Cysta-Q was well tolerated and provided significant symptomatic improvement in patients with IC. Larger, randomized, placebo-controlled trials appear warranted based on these preliminary open-label results.

Effective renal plasma flow calculated from a single blood sample following Technetium-99m mercaptoacetyltriglycine renal scan can predict delayed graft function in renal transplantation.

PURPOSE: Effective renal plasma flow (ERPF) can be calculated by obtaining a single blood sample at a fixed time after injection in a patient undergoing a technetium-99m mercaptoacetyltriglycine (99mTc MAG3) renal scan. The purpose of this study was to determine whether the calculated ERPF following cadaveric renal transplantation could accurately predict the need fordialysis within the first 10 postoperative days or the serum creatinine at postoperative day 10. MATERIALS AND METHODS: Between February 1994 and September 1998, 41 patients underwent 45 99mTc MAG3 renal scans within the first 10 days following a cadaveric renal transplantation at Harbor-UCLA Medical Center. A blood sample was drawn 44 minutes after injection of 99mTc and was used to calculate ERPF. This calculated ERPF was compared to measures of early function, such as the need for dialysis and serum creatinine. RESULTS: Decreased ERPF strongly correlated with the need for dialysis within the first 10 postoperative days (p < .0001). No patient with ERPF >210 mL/min/1.7 M2 required dialysis, whereas 35% (6/17) of patients with ERPF < or =210 mL/min/1.7 M2 required dialysis within the first 10 postoperative days. For those patients who did not undergo dialysis, the calculated ERPF was significantly related to the serum creatinine on postoperative day 10 (p<.0001 ). CONCLUSIONS: ERPF can be calculated from a single blood sample when performing a 99mTc MAG3 renal scan following cadaveric renal transplantation. This calculated ERPF provides a useful clinical tool to identify patients at high risk for development of delayed graft function.

Delayed graft function. Influence on outcome and strategies for prevention.

Delayed graft function remains a prevalent problem in cadaveric renal transplantation that increases rejection, decreases graft and patient survival, increases the cost of transplantation, and complicates patient management. Although current medical and surgical strategies can reduce the incidence of DGF to 20% or less, newer therapies that focus on nonimmune and immune forms of renal injury are needed to improve outcomes further.

Diagnosis and management of acute and chronic prostatitis.

Prostatitis syndromes are some of the most poorly understood yet prevalent problems in urology. There is little controversy over acute prostatitis, a urinary tract infection with systemic symptoms and signs that typically responds to antimicrobial therapy. By contrast, the chronic prostatitis syndromes have so far eluded attempts to understand their pathophysiology and design effective therapies, resulting in great frustration among patients and health care providers. An accurate diagnosis and a multidisciplinary approach are essential to assist men with this often debilitating condition.

Oxidative stress in prostatic fluid of patients with chronic pelvic pain syndrome: correlation with gram positive bacterial growth and treatment response.

The etiology of chronic pelvic pain syndrome (CPPS)/chronic prostatitis category III remains unknown. Whereas a subset of men respond to antimicrobial therapy, gram positive bacteria isolated from expressed prostatic secretions (EPS) are often considered to be commensal rather than pathogenic. We wished to study oxidative stress as a marker of tissue injury and response in EPS of men with CPPS to determine whether infection with gram positive bacteria is associated with increased oxidative stress. A total of 300 EPS specimens from 100 men with CPPS were collected for microscopy, culture, and biochemical and molecular assays. Oxidant injury was measured by 8-isoprostane F2alpha (IsoP) levels and total antioxidant capacity as Trolox equivalents. Total RNA from EPS was used for gene expression of heme oxygenase-1 (HO-1) and granzyme B. The only bacteria found in EPS were gram positive. For our analysis, these men were classified as having chronic bacterial prostatitis (category II). IsoP levels (pg/mL) were highest in men with category II prostatitis (7315 +/- 1428) followed by nonbacterial prostatitis (category IIIa, 2043 +/- 561), prostatodynia (category IIIb, 319 +/- 81), and asymptomatic controls (298 +/- 99). IsoP levels decreased significantly after successful treatment with antibiotics or an antioxidant supplement (Prosta-Q). Antioxidant capacity was detected in 11 out of 18, 4 out of 16, and 1 out of 16 men tested with category II, IIIa, and IIIb prostatitis, respectively. No correlation was observed between IsoP levels and the number of white blood cells in EPS. HO-1 and granzyme B expression was highest in men with category II prostatitis than in men with either category III prostatitis or asymptomatic controls. On the basis of elevated oxidative stress, clinical response to antibiotics, and post-treatment reduction in oxidative stress, we conclude that gram positive bacteria in some men with CPPS may be pathogens. It is speculated that oxidative stress may be a key pathway in some men with CPPS that can be targeted with antioxidant therapy.

Detection of bacterial signal by 16S rRNA polymerase chain reaction in expressed prostatic secretions predicts response to antibiotic therapy in men with chronic pelvic pain syndrome.

PURPOSE: Some men with chronic pelvic pain syndrome (CPPS) have evidence of bacteria in their prostatic fluid (expressed prostatic secretions [EPS]) detected by 16S rRNA techniques. In this study, we correlate presence of bacterial signal with response to therapy. MATERIALS AND METHODS: EPS and first voided urine (VB1) from 47 men with CPPS were analyzed by polymerase chain reaction (PCR) for bacterial signal using universal primers specific for bacterial 16S rRNA. Signal was considered positive if found only in the EPS sample, or if at least 10x stronger in the EPS than in VB1. All patients were treated with antibiotic therapy. RESULTS: Thirty-three patients were category IIIa (nonbacterial prostatitis) and 14 were category IIIb (prostatodynia). Seventeen of the 33 category IIIa patients had positive localizing cultures for gram-positive bacteria. However, a positive bacterial signal was detected in 23 EPS samples by 16S rRNA PCR. This signal was found in 14 of 17 culture-positive patients, 7 of 16 of the remaining category IIIa patients, and 2 of 14 of category IIIb patients. No patient with negative bacterial signal improved with antibiotic therapy (negative predictive value 100%). Thirteen patients with positive bacterial signal improved with antibiotic therapy. CONCLUSIONS: In men with category III chronic prostatitis/CPPS, bacterial signal detected by PCR can help predict response to antimicrobial therapy.

Modulation of apoptotic and inflammatory genes by bioflavonoids and angiotensin II inhibition in ureteral obstruction.

OBJECTIVES: Ureteral obstruction results in an injury response that can progress to irreversible renal fibrosis and tubular atrophy by apoptosis. The molecular events leading to apoptosis from obstruction are not well understood. We investigated the effect of bioflavonoids and angiotensin II inhibition on apoptotic and inflammatory gene expression in a model of unilateral ureteral obstruction (UUO). METHODS: Complete UUO was produced in rats by ureteral ligation. The rats were treated with dimethyl sulfoxide (control), enalapril, losartan, curcumin, or quercetin. The animals were killed on day 7 and both obstructed and contralateral unobstructed kidneys were harvested. Expression of the inflammatory chemokine monocyte chemotactic protein-1, apoptosis effector genes Fas and Fas ligand, and oxidative stress gene HO-1 was evaluated by reverse transcriptase-polymerase chain reaction. RESULTS: Ureteral obstruction was associated with a 6.3-fold increase in monocyte chemotactic protein-1 expression compared with sham-operated rats (P = 0.01). Monocyte chemotactic protein-1 expression was severely attenuated in all other treatment groups (P <0.05). Similarly, Fas and Fas ligand expression were increased in control UUO kidneys compared with sham-operated ones (P <0.05). Fas gene expression was significantly inhibited by quercetin but not enalapril, losartan, or curcumin compared with the control. The induction of Fas ligand was attenuated in all treatment groups (P <0.05). HO-1 was expressed at low levels in both unobstructed and obstructed kidneys. Treatment with curcumin increased HO-1 expression fourfold (P <0.05). CONCLUSIONS: The expression of apoptotic and chemokine genes is significantly upregulated in UUO. Bioflavonoids and angiotensin inhibitors are able to attenuate the expression of these genes and thus may be beneficial in renal protection.