Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10- to 12-wk-old male noncystic Pkd1(+/-) and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploin-sufficient mice, a process that apparently depends on a relative deficiency of p2l activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

Predictive models for diagnosis of pleural effusions secondary to tuberculosis or cancer

Background and objective: Tuberculosis (TB) and cancer are two of the main causes of pleural effusions which frequently share similar clinical features and pleural fluid profiles. This study aimed to identify diagnostic models based on clinical and laboratory variables to differentiate tuberculous from malignant pleural effusions. Methods: A retrospective study of 403 patients (200 with TB; 203 with cancer) was undertaken. Univariate analysis was used to select the clinical variables relevant to the models composition. Variables beta coefficients were used to define a numerical score which presented a practical use. The performances of the most efficient models were tested in a sample of pleural exudates (64 new cases). Results: Two models are proposed for the diagnosis of effusions associated with each disease. For TB: (i) adenosine deaminase (ADA), globulins and the absence of malignant cells in the pleural fluid; and (ii) ADA, globulins and fluid appearance. For cancer: (i) patient age, fluid appearance, macrophage percentage and presence of atypical cells in the pleural fluid; and (ii) as for (i) excluding atypical cells. Application of the models to the 64 pleural effusions showed accuracy higher than 85% for all models. Conclusions: The proposed models were effective in suggesting pleural tuberculosis or cancer.

Active tuberculosis and Mycobacterium tuberculosis latent infection in patients with HIV/AIDS

Objectives Tuberculosis (TB) remains an important disease associated with HIV infection and AIDS in Brazil, even in a setting of free access to antiretroviral therapy (ART) and TB treatment. In previous studies, isoniazid therapy (IT) for latent infection with Mycobacterium tuberculosis (LIMTb) was found to reduce the risk of TB by 62% in patients with a tuberculin test (TT)> 5 mm. The objectives of this study were to investigate the occurrence of TB, the prevalence of LIMTb and the coverage of the TT and IT, and to estimate the number of missed opportunities to prevent TB in patients with HIV/AIDS. Methods A random sample of patients with HIV/AIDS was selected; data from the medical files were obtained, and a TT was performed in consenting subjects. Results In the 203 subjects included in the study, TB occurrence was 13.3%, LIMTb prevalence was 20% and the coverage of the TT and IT was 59.2 and 55%, respectively. Patients with TB had a lower nadir CD4 cell count, but their CD4 recovery was comparable to that of non-TB patients. Patients with LIMTb always had a higher CD4 cell count. Conclusions By expanding the coverage of the TT and IT to nearly 100%, we could more than double the number of prevented cases of TB. TB prevention programmes must be reinforced to reduce the number of missed opportunities for diagnosis, and IT must be improved to reduce TB among patients with HIV/AIDS. Empowering patients with knowledge about TB, the preventive role of IT and the need for an annual TT may be the best way of lowing rates of TB in patients with HIV/AIDS.

Pulmonary involvement in pleural tuberculosis: How often does it mean disease activity?

Objective: To evaluate in chest X-rays and high-resolution computed tomographies of patients with pleural tuberculosis, the incidence of parenchymal and mediastinal lung lesions suggestive of active disease. Methods: Prospective study (2008-2009) evaluating the radiographic and tomographic abnormalities of 88 HIV-negative patients with pleural tuberculosis (unilateral effusion). The images were reviewed by 3 independent specialists, and the observed changes were classified according to previously established criteria: presence or absence of signs suggestive of disease activity, and nonspecific findings. Results: Abnormal changes were observed in chest X-rays of 22 (25%) patients and in the computed tomography of 55 (63%). Images compatible with active pulmonary tuberculosis were detected by radiography in 9 (10%) patients and by tomography in 38 (43%). Only 4 (4.5%) patients had tomography images suggestive of residual disease. Conclusion: The present study demonstrates that pulmonary involvement is quite common in pleural tuberculosis. This finding is mainly observed in high-resolution computed tomography and has important epidemiological implications, since patients with pleural tuberculosis are significant sources of infection and disease dissemination. (C) 2011 Elsevier Ltd. All rights reserved.

Polymerase chain reaction compared to other laboratory findings and to clinical evaluation in the diagnosis of cutaneous tuberculosis and atypical mycobacteria skin infection

Cutaneous tuberculosis has re-emerged in the last 15 years together with the higher incidence of pulmonary tuberculosis and multidrug resistance. The choice for a single diagnostic tool among the many available today is a challenge. Our objective was to compare polymerase chain reaction (PCR) with other exams in the diagnosis of cutaneous tuberculosis and atypical mycobacteria skin infection. PCR and a set of five different exams were performed in 32 patients (34 samples of paraffin-embedded tissue) evaluated for 3 years in a university hospital, considering the response to mycobacterial infection treatment as a positive case. PCR was the most sensitive (88%) and specific (83%) exam. Culture, immunohistochemistry and acid-fast bacilli were not in agreement with clinical response to treatment. Although PCR is a useful tool, careful clinical exam is still the gold standard for the evaluation and treatment of cutaneous tuberculosis and mycobacteria skin infection.

Radical Retropubic Prostatectomy for Localized Prostate Cancer in Renal Transplant Patients

OBJECTIVE To investigate the feasibility of radical retropubic prostatectomy (RRP) in renal transplant recipients with clinically localized prostate cancer. METHODS A prospective protocol was established between August 2004 and November 2007. In that period, 8 patients diagnosed with localized prostate cancer were submitted to RRP, and their clinicopathologic data were reviewed. RESULTS The mean age (standard deviation) at surgery was 59.6 +/- 6.7 years (range, 49-67 years). All patients had TIC tumors, except for 1 with a T2A tumor. The mean preoperative prostate-specific antigen value was 4.5 +/- 1.8 ng/mL (range, 1.6-7.0 ng/mL). The mean interval between renal transplantation and RRP was 89.9 +/- 65.1 months (range, 40-209 months). The procedure was well tolerated without major complications, and all patients were discharged on the fifth postoperative day. There was no impairment to bladder descent caused by the presence of the allograft or the ureteroneocystostomy. Urethrovesical anastomosis was easily performed in all cases in the standard manner. Blood transfusion was needed in 2 patients (1 received 2 U and another 5 U of blood). The mean operative duration was 183 +/- 29.7minutes (range, 150-240 minutes), the mean estimated blood loss was 656 +/- 576 mL (range, 100-2000 mL), and no deterioration of graft function was observed. All patients were followed, and the mean follow-up was 10.5 months (range, 2-30 months). Prostate-specific antigen was undetectable in all cases during this time frame. CONCLUSIONS Radical retropubic prostatectomy in renal transplant patients is safe, effective, and can be easily performed in the same manner as described by Walsh, regardless of the presence of the allograft. The only necessary technical modification is the avoidance of ipsilateral lymphadenectomy to prevent damage to the transplanted organ. UROLOGY 72: 1362-1365, 2008. (C) 2008 Elsevier Inc.

Percutaneous ultrasound-guided renal biopsy in children - safety, efficacy, indications and renal pathology findings: 14-year Brazilian university hospital

Introduction: Pediatric percutaneous renal biopsy (Bx) is a routine procedure in pediatric nephrology to obtain renal tissues for histological study. We evaluated the safety, efficacy, indications and renal findings of this procedure at a tertiary care pediatric university hospital and compared our findings with the literature. Methods: Retrospective study based on medical records from January 1993 to June 2006. Results: In the study period, 305 Bx were performed in 262 patients, 127 (48.5%) male, aged 9.8 +/- 4.2 years. A 16-gauge needle was utilized in 56/305 Bx, an 18-gauge needle in 252/305 Bx (82.6%). 56.1% Bx were performed under sedation plus local anesthesia, 43.9% under general anesthesia. The number of punctures per Bx was 3.1 +/- 1.3. Minor complications occurred in 8.6% procedures. The 16-gauge needle caused a higher frequency of renal hematomas (p = 0.05). The number of glomeruli per puncture was >= 5 in 96.7% and >= 7 in 92%. Glomeruli number per puncture and frequency of complications were not different according to the type of anesthesia used. A renal pathology diagnosis was achieved in 93.1% Bx. The main indications of Bx were nephrotic syndrome (NS), lupus nephritis (LN) and hematuria (HE). The diagnosis of minimal change disease (MCD) (61.3%), class V (35.6%) and IgA nephropathy (26.3%) predominated in NS, LN and HE patients, respectively. Conclusion: Pediatric real-time ultrasound-guided percutaneous renal biopsy was safe and effective. The main clinical indications for Bx were NS and LN, the predominant renal pathology diagnoses were MCD and class V LN.

Protective Effect of N-acetylcysteine on Early Outcomes of Deceased Renal Transplantation

We investigated the effects of the antioxidant N-acetylcysteine (NAC) on early outcomes of deceased donor renal transplantation. Between April 2005 and June 2008, adult primary graft recipients of deceased renal donors were assigned to treatment (n = 38) or control (n = 36) groups and evaluated for 90 days and one year after renal transplantation. The treatment group received NAC orally (600 mg twice daily) from day 0 to 7 postoperatively. Renal function was determined by serum creatinine, MDRD and Cockcroft-Gault estimated GFR (eGFR), delayed graft function (DGF) and dialysis free Kaplan-Meier estimate curve. Serum levels of thiobarbituric acid reactive substances (TBARS), were employed as markers of oxidative stress. The NAC group displayed a lower mean serum creatinine during the first 90 days (P = .026) and at 1 year after transplantation (P = .005). Furthermore, the NAC group showed a higher mean eGFR throughout the first 90 days and at 1 year. DGF was lower among the NAC group (P = .017) and these recipients required fewer days of dialysis (P = .012). Oxidative stress was significantly attenuated with NAC (P < .001). Our results suggested that NAC enhanced early outcomes of deceased donor renal transplantation by attenuating oxidative stress.

Comparison of renal transplantation outcomes in children with and without bladder dysfunction. A customized approach equals the difference

Purpose: We examined the development of urological abnormalities in a group of pediatric renal transplant recipients. Materials and Methods: We reviewed 211 patients younger than 19 years who underwent 226 renal transplants. Three groups of patients were studied-136 children with end stage renal disease due to a nonurological cause (group 1), 56 children with a urological disorder but with an adequate bladder (group 2a) and 19 children with lower urinary tract dysfunction and/or inadequate bladder drainage (group 2b). A total of 15 children in group 2b underwent bladder augmentation (ureterocystoplasty in 6, enterocystoplasty in 9), 2 underwent continent urinary diversion, 1 underwent autoaugmentation and 1 underwent a Mitrofanoff procedure at the bladder for easier drainage. Kidney transplantation was performed in the classic manner by extraperitoneal access, and whenever possible the ureter was reimplanted using an antireflux procedure. Results: At a mean followup of 75 months 13 children had died, 59 grafts were lost and 15 children had received a second transplant. Two patients in group 2a required a complementary urological procedure to preserve renal function (1 enterocystoplasty, 1 vesicostomy). A total of 12 major surgical complications occurred in 226 kidney transplants (5.3%), with a similar incidence in all groups. The overall graft survival at 5 years was 75%, 74% and 84%, respectively, in groups 1, 2a and 2b. Conclusions: With individualized treatment children with severely inferior lower urinary tract function may undergo renal transplantation with a safe and adequate outcome.

Evaluation of renal function in leprosy: a study of 59 consecutive patients

Background. Renal abnormalities in leprosy have been largely described in medical literature, but there are few studies evaluating renal function in these patients. Methods. This is a cross-sectional study in 59 consecutive paucibacillary (PB) and multibacillary (MB) leprosy patients. Glomerular filtration rate (GFR) was estimated by simplified-MDRD formula. Microalbuminuria was determined by 24 h urine collection. Urinary acidification capacity was measured after water deprivation and acid-loading with CaCl2. Urinary concentration capacity was evaluated after desmopressin acetate administration, using the urinary to plasma osmolality (U/P-osm) ratio. All parameters except microalbuminuria were measured in a control group of 18 healthy volunteers. Results. Age and gender were similar between leprosy (MB or PB) and control groups. GFR <= 80 ml/min/1.73 m(2) was observed in 50% of the leprosy patients. GFR and U/P-osm in leprosy patients were significantly lower than in controls (P < 0.001). Urinary acidification defect was found in 32% of PB and in 29% of MB patients and urinary concentrating ability was abnormal in 83% of PB and 85% of MB patients. Microalbuminuria was found in 4 patients (8.5%), leukocyturia was found in 13 (22%) and haematuria was present in 16 patients (27%). Plasma creatinine (P-cr) > 1.2 mg/dl was observed in 17.9% of MB patients and in none of the controls (P = 0.020). A negative correlation was observed between GFR and time of treatment (r = -0.339; P = 0.002). Age and time of treatment were independent risk factors for GFR <= 80 ml/min/1.73 m(2) in multivariate analysis. Conclusions. Asymptomatic GFR changes and renal tubular dysfunction, including urine concentration defect and impaired acidifying mechanisms, can be caused by leprosy on specific treatment and without any reaction episodes.

Non-Human Leukocyte Antigen Antibodies Reactive with Endothelial Cells Could Be Involved in Early Loss of Renal Allografts

Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies.

Programmed hypertension in rats treated with a NF-kappa B inhibitor during nephrogenesis: renal mechanisms

Suppression of the renin-angiotensin system (RAS) during murine lactation causes progressive renal injury, indicating a physiological action of angiotensin II on nephrogenesis. The nuclear factor NF-kappa B system is one of the main intracellular mediators of angiotensin II. We investigated whether inhibition of this system with pyrrolidine dithiocarbamate (PDTC) during rat nephrogenesis would lead to similar hypertension and renal injury as observed with RAS suppressors. Immediately after delivery, 32 Munich-Wistar dams, each nursing 6 male pups, were divided into 2 groups: C, untreated, and PDTC, receiving PDTC, 280 mg kg(-1) day(-1) orally, during 21 days. After weaning, the offspring were followed until 10 months of age without treatment. Adult rats that received neonatal PDTC exhibited stable hypertension and myocardial injury, without albuminuria. To gain additional insight into this process, the renal expression of RAS components and sodium transporters were determined by quantitative real-time PCR (qRT-PCR) at 3 and 10 months of life. Renal renin and angiotensinogen were upregulated at 3 and downregulated at 10 months of age, suggesting a role for early local RAS activation. Likewise, there was early upregulation of the proximal sodium/glucose and sodium/bicarbonate transporters, which abated later in life, suggesting that additional factors sustained hypertension in the long run. The conclusions drawn from the findings were as follows: (1) an intact NF-jB system during nephrogenesis may be essential to normal renal and cardiovascular function in adult life; (2) neonatal PDTC represents a new model of hypertension, lacking overt structural injury or functional impairment of the kidneys; and (3) hypertension in this model seems associated with early temporary activation of renal RAS and sodium transporters. Hypertension Research (2011) 34, 693-700; doi: 10.1038/hr. 2011.4; published online 17 February 2011

Enhancement of diagnostic efficiency by a gamma interferon release assay for pulmonary tuberculosis

This study was designed to examine the use of the QuantiFERON-TB Gold assay as an aid in the diagnosis of active pulmonary tuberculosis (TB) in Brazilian patients. Using the receiver operating characteristic curve, the cutoff was adjusted to >= 0.20 IU/ml. The sensitivity increased to 86%, with 100% specificity. All TB patients with negative sputum smear microscopy and negative culture results were positive using this test.

Using BCG, MPT-51 and Ag85 as antigens in an indirect ELISA for the diagnosis of bovine tuberculosis

This study evaluated the Mycobacterium tuberculosis protein antigen MPT-51, the trimeric antigen 85 (Ag85) complex, and Bacillus Calmette-Guerin (BCG) in an indirect ELISA to diagnose bovine tuberculosis (TB) from serum samples. Serum was collected from 208 intra-dermal tuberculin test (ITT)-positive and 54 ITT-negative animals from a region where bovine TB is endemic. Using the Ag85 and BCG antigens, the indirect ELISA was able to discriminate ITT-positive from ITT-negative animals. This level of discrimination was not achieved when using the MPT-51 antigen. The highest sensitivity (Se) and specificity (Sp) of the test was found when BCG was used (Se, 82%; Sp, 91%). Further work in different epidemiological settings and with larger numbers of animals will be required to validate these findings. (C) 2009 Elsevier Ltd. All rights reserved.

A subunit vaccine based on biodegradable microspheres carrying rHsp65 protein and KLK protects BALB/c mice against tuberculosis infection

Of the hundreds of new tuberculosis ( TB) vaccine candidates some have therapeutic value in addition to their prophylactic properties. This is the case for the DNA vaccine encoding heat-shock protein 65 (DNAhsp65) from Mycobacterium leprae. However, there are concerns about the use of DNA vaccines in certain populations such as newborns and pregnant women. Thus, the optimization of vaccination strategies that circumvent this limitation is a priority. This study evaluated the efficacy of a single dose subunit vaccine based on recombinant Hsp65 protein against infection with M. tuberculosis H37Rv. The Hsp65 protein in this study was either associated or not with immunostimulants, and was encapsulated in biodegradable PLGA microspheres. Our results demonstrate that the protein was entrapped in microspheres of adequate diameter to be engulfed by phagocytes. Mice vaccinated with a single dose of Hsp65-microspheres or Hsp65 + CpG-microspheres developed both humoral and cellular-specific immune responses. However, they did not protect mice against challenge with M. tuberculosis. By contrast, Hsp65+KLK-microspheres induced specific immune responses that reduced bacilli loads and minimized lung parenchyma damage. These data suggest that a subunit vaccine based on recombinant protein Hsp65 is feasible.