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.

Outcome of acute myeloid leukemia patients with hyperleukocytosis in Brazil

Acute myeloid leukemia (AML) with a high white blood cell (WBC) count at presentation has been associated with an increased early mortality rate, usually secondary to leukostasis. However, the value of the WBC count at which there is a high risk of early death (ED) and the efficiency of supportive treatments remain unclear. In this report, a series of 187 consecutive adult patients with AML in our institution was reviewed. The outcome of 40 patients with WBC above 50 x 10(9) L(-1) (hyperleukocytosis) was compared to 147 patients with a leukocyte count lower than 50 x 10(9) L(-1). The group with hyperleukocytosis showed a significantly shorter OS (P < 0.0001) and a higher rate of ED (P = 0.0008). Even when the data from ED patients were removed from analysis, we still detected a shorter OS in patients with hyperleukocytosis (P = 0.0049), which suggests that high WBC number influences long-term survival, and not only ED. We also observed higher lactic dehydrogenase (LDH) and serum creatinine levels in the group of patients with hyperleukocytosis (P = 0.0003 and 0.0406, respectively). Besides considering all the patients with ED, we could observe higher levels of lactic dehydrogenase, a serum creatinine and nitrogen urea (P = 0.0056, P = 0.0008 and P < 0.0001, respectively). Pulmonary involvement was more frequent in patients with ED (P = 0.0277). In conclusion, hyperleukocytosis confers a poorer prognosis in patients with AML.

Effect of the Absence of Interleukin-12 on Mesangial Proliferative Glomerulonephritis Induced by Habu Snake Venom

Background. Interleukin-12 (IL12) participates in the pathophysiology of various experimental types of progressive glomerulonephritis, but its role in acute mesangial glomerulonephritis (AMG) induced by habu snake venom (HSV) has not been determined. This study aims to evaluate the effect of the absence of IL12 on AMG induced by HSV. Methods. AMG was induced in IL12 knockout (IL12-/-) and C57B1/6 (IL12+/+) mice by a single i.v. administration of HSV. Vehicle was used in control animals. Mice were studied after 3, 7, and 14 days (D3, D7, and D14). Results. After treatment with HSV, IL12+/+ and -/-mice developed focal glomerular lesions, but groups of both lineages showed no statistical difference concerning albuminuria, serum creatinine, histopathology, number of cells by glomerular tuft, and glomerular tuft area. Compared to IL12+/+ mice, IL12-/-mice showed lower scores of glomerular desmin expression on D7 [1.55 (1.32; 1.65) vs. 1.12 (1.07; 1.22); p < 0.01] and D14 [1.60 (1.55; 1.75) vs. 1.20 (1.15; 1.20); p < 0.001], respectively, and lower scores of glomerular alpha-SMA expression on D14 [0.30 (0.21; 0.38) vs. 0.16 (0.26; 0.36); p < 0.001], respectively. Conclusion. The absence of IL12 reduced the activity of mesangial cells, but did not modify the course of HSV-induced AMG in mice.

Effect of stem cells seeded onto biomaterial on the progression of experimental chronic kidney disease

Different routes for the administration of bone marrow-derived cells (BMDC) have been proposed to treat the progression of chronic renal failure (CRF). We investigated whether (1) the use of bovine pericardium (BP) as a scaffold for cell therapy would retard the progression of CAF and (2) the efficacy of cell therapy differently impacts distinct degrees of CRF. We used 2/3 and 5/6 models of renal mass reduction to simulate different stages of chronicity. Treatments consisted of BP seeded with either mesenchymal or mononuclear cells implanted in the parenchyma of remnant kidney. Renal function and proteinuria were measured at days 45 and 90 after cell implantation. BMDC treatment reduced glomerulosclerosis, interstitial fibrosis and lymphocytic infiltration. Immunohistochemistry showed decreased macrophage accumulation, proliferative activity and the expression of fibronectin and alpha-smooth muscle-actin. Our results demonstrate: (1) biomaterial combined with BMDC did retard the progression of experimental CRF; (2) cellular therapy stabilized serum creatinine (sCr), improved creatinine clearance and 1/sCr slope when administered during the less severe stages of CRF; (3) treatment with combined therapy decreased glomerulosclerosis, fibrosis and the expression of fibrogenic molecules; and (4) biomaterials seeded with BMDC can be an alternative route of cellular therapy.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation

Background. A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. Methods. A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. Results. Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs nonrejecters (P = 0.04). The average median concentration (+/- SD) in the biopsy-proven rejecter group was 5.09 +/-1.16 ng/ml, compared to 9.20 +/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57 +/-1.47 ng/rnl, compared with 9.20 +/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. Conclusion. A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients

The aim of this study was to determine the pharmacokinetic profile of the normal recommended dose of ceftriaxone in critically ill patients and to establish whether the current daily dosing recommendation maintains plasma concentrations adequate for antibacterial efficacy. Ceftriaxone at a recommended dose of 2 g iv was administered od to 12 critically ill patients with severe sepsis and normal serum creatinine concentrations. Blood samples were taken at predetermined intervals over the first 24 h and on day 3 for measurement of ceftriaxone concentrations. There was wide variability in drug disposition, explained by the presence of variable renal function and identified by the measurement of creatinine clearance. In nine patients with normal renal function, there was a high level of creatinine clearance(mean +/- S.D., 41 +/- 12 mL/min) and volume of distribution (20 +/- 3.3 L), which resulted in an elimination half-life of 6.4 +/- 1.1 h. In comparison with normal subjects, ceftriaxone clearance was increased 100%, volume of distribution increased 90% and the elimination half-life was similar. Three patients had substantially suboptimal plasma ceftriaxone concentrations. We confirm previous findings that ceftriaxone clearance in critically ill patients correlates with renal clearance by glomerular filtration. The elimination half-life is prolonged (21.4 +/- 9.8 h) in critically ill patients with renal failure when compared with previously published data in non-critically ill patients with renal failure. We conclude that in critically ill patients with normal renal function, inadequate plasma concentrations may result following od bolus dosing of ceftriaxone. Drug accumulation may occur in critically ill patients with renal failure.

NEPHROTOXICITY ATTRIBUTED TO MEGLUMINE ANTIMONIATE (GLUCANTIME) IN THE TREATMENT OF GENERALIZED CUTANEOUS LEISHMANIASIS

Background: Pentavalent antimonials have became of basic importance for the treatment of leishmaniasis. Their most severe side effects have been reported to be increased hepatic enzyme levels and electrocardiographic abnormalities. Nephrotoxicity has been rarely related. Observations: We report a case of generalized cutaneous leishmaniasis involving a 50-year old male patient who was submitted to treatment with meglumine antimoniate (Glucantime). He developed acute renal failure (ARF) due to acute tubular necrosis (ATN), followed by death after receiving a total of 53 ampoules of Glucantime. Conclusions: The treatment with Glucantime was responsible by ARF diagnosed in this patient. The previous urine osmolarity and serum creatinine levels were normal and the autopsy showed ATN. It should be pointed out if ARF may also be explained by massive deposits of immunocomplexes by leishmania antibodies and antigens due to the antigenic break by the antimonial compound, since our patient presented countless lesions covering the entire tegument, similar to the Hexheimer phenomenon, but at the autopsy no glomerular alterations were seen.

Evaluation of hemostasis disorders and anticardiolipin antibody in patients with severe leptospirosis

A prospective study was designed to evaluate disorders of hemostasis and levels of anticardiolipin antibodies (ACL) in 30 patients with severe leptospirosis and acute renal failure (ARF) (ARF was defined as serum creatinine > or = 1.5 mg/dL). The patients had been admitted to the Walter Cantídio University Hospital, São José Infectious Diseases Hospital and General Hospital of Fortaleza, Ceará, from August 1999 to July 2001. They all were male, with a mean age of 32 ± 14 years and with clinical and laboratory diagnoses of ARF leptospirosis. The time elapsed between onset of symptoms and the first hemorrhagic manifestation was 9 ± 4 days. Bleeding was observed in 86% of the patients. Laboratory tests showed significantly high levels of urea (181 ±95 mg/dl), fibrinogen, (515 ± 220 mg/dl), prothrombin time (13.3 ± 0.9 seconds) and low platelet counts (69 ± 65x10³/mm³) on admission. There was no elevation in activated partial thromboplastin time or thrombin time. Levels of IgM and IgG ACL concentrations were significantly increased (p < 0.05) in leptospirosis patients when compared to control patients (28.5 ± 32.4 vs. 11.5 ± 7.9MPL U/ml and 36.7 ± 36.1 vs. 6.5 ± 2.5 GPL U/ml), respectively. Vasculitis, thrombocytopenia and uremia should be considered important factors for the pathogenesis of hemorrhagic disturbances and the main cause of death in severe leptospirosis.

Comparative study of the in-hospital case-fatality rate of leptospirosis between pediatric and adult patients of different age groups

The main objective was to compare the in-hospital case-fatality rate of leptospirosis between pediatric (< 19 years) and adult (>19 years) patients, taking into account gender, renal function, duration of symptoms and jaundice. Medical records of 1016 patients were reviewed. Comparative analysis was restricted to 840 patients (100 pediatric, 740 adults) with recorded information on the variables included in the analysis. Among these patients 81.7% were male and 91.5% were icteric. The case-fatality rate of leptospirosis was 14.4%. The odds of death adjusted for gender, jaundice, duration of symptoms, serum urea and serum creatinine were almost four times higher for the adult than for the pediatric group (odds ratio (OR) = 3.94; 95% confidence interval = 1.19-13.03, p = 0.029). Among adults, increased age was also significantly and independently associated with increased risk of death (p < 0.01). Older patients were also more often treated by dialysis. In conclusion, the data suggest that the in-hospital case fatality rate of leptospirosis is higher for adults than for children and adolescents, even after taking into account the effects of several potential risk factors of death. Among adults, older age was also strongly and independently associated with higher risk of death.

Renal involvement in human rabies: clinical manifestations and autopsy findings of nine cases from northeast of Brazil

A retrospective study was conducted in nine patients with rabies admitted to a hospital of Fortaleza, Brazil. Autopsy was performed in all cases. The ages ranged from three to 81 years and six were males. They all were bitten by dogs. The time between the accident and the hospital admission ranged from 20 to 120 days (mean 45 ± 34 days). The time until death ranged from one to nine days (mean 3.3 ± 5.5 days). The signs and symptoms presented were fever, hydrophobia, aerophobia, agitation, disorientation, dyspnea, sialorrhea, vomiting, oliguria, sore throat, pain and hypoesthesia in the site of the bite, headache, syncope, cough, hematemesis, mydriasis, hematuria, constipation, cervical pain and priapism. In three out of six patients, there was evidence of acute renal failure, defined as serum creatinine > 1.4 mg/dL. The post-mortem findings in the kidneys were mild to moderate glomerular congestion and mild to intense peritubular capillary congestion. Acute tubular necrosis was seen in only two cases. This study shows some evidence of renal involvement in rabies. Histopathologic findings are nonspecific, so hemodynamic instability, caused by autonomic dysfunction, hydrophobia and dehydration must be responsible for acute renal failure in rabies.

Terapêutica Endovascular de Pseudoaneurisma e Fístula Arteriovenosa em Enxerto Renal

A 31 year old male Caucasian received a renal cadaveric allograft. Reconstruction of an inferior polar artery was corrected pre-implantation. Delayed graft function occurred leading to dialysis support for one month. Graft biopsies(days 7, 15) showed acute tubular necrosis(ATN) and no rejection. Serial ultrasound (US), performed on average weekly, were compatible with ATN. On day 31, Doppler US and a CAT scan suggested for the first time a pseudoaneurysm adjacent to the implantation of the graft artery on the external iliac artery. For clinical and technical reasons, arteriography was only performed on day 67, when serum creatinine was 3.3 mg/dl. It showed a large pseudoaneurysm with an arteriovenous fistula to the right common iliac vein. Compression of the right external iliac artery was clear. In an attempt to close the arteriovenous fistula, the communication with the pseudoaneurysm was embolised with gelfoam and metallic coils with partial success. One week later, by right femoral approach a covered wallstent was placed immediately below the origin of the graft artery.Subsequent Doppler US and arteriography con-firmed closure of the communication with thepseudoaneurysm and of the arteriovenous fistula. The calibre of the right external iliac artery was then normal. By month 18, serum creatinine is stable at 2.1 mg/dl. We can only speculate on the origin of thepseudoaneurysm and of the AV fistula, whichwere not evident until one month post-transplantation. Backtable surgery was performed on thepolar not the main graft artery. Invasive angiography was irreplaceable in this unusual clinical situation.

Impact of Renal Dysfunction on Liver Transplantation: a Retrospective Study in 708 Orthotopic Liver Transplant Recipients

Renal dysfunction often complicates the course of orthotopic liver transplant recipients and is associated with increased morbid -mortality. The aims of this study were to determine the incidence of chronic renal disease and its impact on patient survival. Clinical data included age, gender and weight,aetiology of hepatic failure, presence of diabetes,hypertension, hepatitis B and C infection, renal dysfunction pretransplant and immunosuppression. Laboratory data included serum creatinine at days 1, 7, 21, month 6, 12 and yearly. The glomerular filtration rate was determined by Cockcroft-Gault equation. We studied retrospectively from September 1992 to March 2007 708 orthotopic liver transplant recipients. Mean age 44±12.6 years, 64% males, 17% diabetic, 18.8% hypertensive, 19.9% with hepatitis C and 3.8% hepatitis B. Renal dysfunction pretransplant was known in 21.6%. Mean follow-up was 3.6 years. Mean transplant survival 75% at 12 months. 154 patients died. Univariate and multivariate analyses were performed and a p<0.05 was considered significant. Acute kidney injury occurred in 33.2%. Chronic kidney disease stage 3 was observed in 34.3%,stage 4 in 6.2% and stage 5 in 5.1%. At the time of this study, 46.4% were on Cyclosporine A, 44.7% on tacrolimus and 8.9% on sirolimus. Using multivariate analysis, renal dysfunction was correlated with renal dysfunction pre -orthotopic liver transplant (p<0.001), acute kidney injury (p<0.001), haemodialysis development (p<0.001), and inversely correlated with the use of mycophenolate mophetil (p<0.001); mortality was positively correlated with renal dysfunction pretransplant (p=0.03),chronic kidney disease stage 4 (p=0.001), chronic kidney disease stage 5 (p<0.001) and inversely correlated with the use of tacrolimus (p=0.006). In conclusion orthotopic liver transplant recipients are disposed to renal complications that have a negative impact on survival of these patients.

Transplantation in Highly Sensitised Patients Treated with Intravenous Immunoglobulin and Rituximab

Renal transplant in highly sensitised patients is associated with increased morbidity. The aim of this retrospective study was to evaluate the clinical evolution of 30 highly sensitised deceased donor kidney transplants and the influence of different timing of B cell directed treatment and its importance in the outcome of these patients. All recipients had negative complement dependent lymphocytotoxicity cytotoxic T cell crossmatch and no identified anti human leucocyte antigen class I donor specific antibodies. T cell flow crossmatch was performed within 24h of transplantation with serum obtained pretransplant (historic, recent or baseline). Posttransplant flow crossmatch were performed prospectively starting on the 3rd posttransplantation day. The immunosuppressive regime included thymoglobulin, tacrolimus, mycofenolate mofetil and steroids. Positive flow crossmatch occurred in 20/29 patients by the 3rd posttransplantation day, and in 17/27 patients after the 3rd posttransplantation day. All patients were started on intravenous immunoglobulin before transplantation: in nine patients (group A) at 400mg/kg/day for five days; in the remaining 21 patients (group B), as a continued infusion of 2g/kg during 48h. In group A, Rituximab was added only in the presence of antibody mediated rejection; in group B, introduced on the 3rd posttransplantation day whenever a positive flow crossmatch (with serum obtained pre or posttransplant) was reported. Antibody mediated rejection was observed in 44.4% of patients in group A, and 19% of those in group B. Mean follow-up was 12.2±5.5 months. Overall allograft survival was 76.6%, 81% in group B, and 66.6% in group A. At last follow up, mean serum creatinine was 1.3±0.6 mg/dl. Renal transplantation with pretransplant positive flow crossmatch is highly associated with antibody mediated rejection, despite introduction of intravenous immunoglobulin pretransplantation. However high dose intravenous immunoglobulin for 48h plus Rituximab by the 3rd posttransplantation day reduce the incidence of antibody mediated rejection by more than 50% and allowed for allograft survival of 81% at one year, with an excellent renal function.

Magnesium – association with inflammation and renal disease in systemic lupus erythematosus

Introduction: Recent studies suggest that magnesium deficiency may play a role in inflammation. In diabetes and cardio-vascular diseases, conditions with a component of chronic inflammation, C–reactive protein levels are higher and associated with low serum magnesium. The objective of this study is to evaluate serum magnesium levels in patients with systemic lupus erythematosus and its potential association with inflammation and renal manifestations. Methods: All patients with systemic lupus erythematosus followed in a Systemic Immune Diseases Unit, from January 2012 until January 2014, were included in this cross sectional analysis. Patients with infection, neoplasia, liver failure and chronic kidney disease (stage > 3) were excluded. Clinical information and laboratory results (serum magnesium, C-reactive protein, erythrocyte sedimentation rate, serum creatinine and spot urine test) were collected. A multivariate analysis was performed to explore possible predictive factors for hypomagnesaemia. Results: One hundred and two patients were included (94.1% female, 21-86 years). 33.4% had hypertension, 8.8% had diabetes and 20.6% had hypomagnesaemia (< 1.8mg/dL). There were no significant differences between the inflammatory parameters of patients with hypomagnesaemia or normomagnesaemia. Serum magnesium was significantly lower with increasing comorbidities (p = 0.01). Leukocyturia was significantly higher in the hypomagnesaemia group (p = 0.03) and haematuria had a negative correlation with serum magnesium (-0.23, p < 0.05). Multivariate analysis showed that patients with hypertension and diabetes had higher risk of hypomagnesaemia: OR 42.29 (95% CI, 1.43-1249.31). Leukocyturia was also individually and independently associated with hypomagnesaemia: OR 8.37 (95% CI, 1.40-49.97). Conclusion: The presence of hypomagnesaemia in our patients with systemic lupus erythematosus was high. There was no association between the levels of serum magnesium and the inflammatory parameters. Increasing comorbidities and leukocyturia were independent predictors of lower serum magnesium. Finally, the association of leukocyturia and haematuria with lower serum magnesium may suggest a relationship with a higher disease activity.