Contribution of CD4+ T cells to the early mechanisms of ischemia- reperfusion injury in a mouse model of acute renal failure

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 µ, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of ßC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-g and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.

Hypomagnesemia is a risk factor for nonrecovery of renal function and mortality in AIDS patients with acute kidney injury

The objective of the present study was to determine the prevalence of electrolyte disturbances in AIDS patients developing acute kidney injury in the hospital setting, as well as to determine whether such disturbances constitute a risk factor for nephrotoxic and ischemic injury. A prospective, observational cohort study was carried out. Hospitalized AIDS patients were evaluated for age; gender; coinfection with hepatitis; diabetes mellitus; hypertension; time since HIV seroconversion; CD4 count; HIV viral load; proteinuria; serum levels of creatinine, urea, sodium, potassium and magnesium; antiretroviral use; nephrotoxic drug use; sepsis; intensive care unit (ICU) admission, and the need for dialysis. Each of these characteristics was correlated with the development of acute kidney injury, with recovery of renal function and with survival. Fifty-four patients developed acute kidney injury: 72% were males, 59% had been HIV-infected for >5 years, 72% had CD4 counts <200 cells/mm³, 87% developed electrolyte disturbances, 33% recovered renal function, and 56% survived. ICU admission, dialysis, sepsis and hypomagnesemia were all significantly associated with nonrecovery of renal function and with mortality. Nonrecovery of renal function was significantly associated with hypomagnesemia, as was mortality in the multivariate analysis. The risks for nonrecovery of renal function and for death were 6.94 and 6.92 times greater, respectively, for patients with hypomagnesemia. In hospitalized AIDS patients, hypomagnesemia is a risk factor for nonrecovery of renal function and for in-hospital mortality. To determine whether hypomagnesemia is a determinant or simply a marker of critical illness, further studies involving magnesium supplementation in AIDS patients are warranted.

Acute liver failure in children: observations in Vitória, Espírito Santo State, Brazil

In this communication we report 46 cases of acute liver failure in children diagnosed at the Hospital Infantil Nossa Senhora da Glória in Vitória, E Santo. Serology for IgM anti-HAV, IgM anti-HBc, HbsAg, anti-HCV and biochemical tests were performed in all cases in a routine laboratory. The M/F ratio was 1.1:1 and the mean age was 4.7±3.2 years, without gender difference. Anti-HAV IgM+ in 38 (82.6%) cases, anti-HbcIgM+ in two (4.3 %) cases and 6 (13.1%) cases were negative for all viral markers investigated. Anti- HCV+ in one anti-HAV IgM+ case. HbsAg+ in two anti-HbcIgM+ and in two HAVIgM+ cases. Among the six A, B and C negative cases, four (8.6%) did not have the suspected exogenous intoxication. Mortality was 50%, without gender or age differences. These results demonstrate that HAV infection is the main etiology of acute liver failure in children in Brazil, confirming that, although it is a self limited, relatively mild illness, it can cause serious and even fatal disease. The observation of four cases without A, B and C viral markers and no history of exogenous intoxication, agree with the observation of non A-E acute sporadic hepatitis in Northeastern Brazil.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.

BIOPSY PROVEN ACUTE TUBULAR NECROSIS DUE TO RHABDOMYOLYSIS IN A DENGUE FEVER PATIENT: A CASE REPORT AND REVIEW OF LITERATURE

Renal histology results are very scarce in dengue-associated rhabdomyolysis patients developing acute kidney injury (AKI). We report a case of dengue fever-induced AKI associated to rhabdomyolysis with a renal biopsy showing acute tubular necrosis (ATN) and renal deposition of myoglobin. A 28-year-old patient who presented dengue fever (DF) complicated by severe AKI and rhabdomyolysis is described. The patient required hemodialysis for three weeks. A renal biopsy revealed ATN with positive staining for myoglobin in the renal tubuli. The patient was discharged with recovered renal function. In conclusion, this case report described a biopsy proven ATN associated to DF-induced rhabdomyolysis, in which renal deposition of myoglobin was demonstrated. We suggest that serum creatine phosphokinase should be monitored in DF patients to allow for an early diagnosis of rhabdomyolysis and the institution of renal protective measures.

Effect of dietary linoleic acid on the progression of chronic renal failure in rats

The role of linoleic acid in chronic renal failure (CRF) is controversial. In the present study 21 male Wistar rats submitted to 5/6 renal mass reduction (R) and 16 normal controls (C) were fed a supplement (S) or normal (N) linoleic acid diet for 60 days starting 10 days after CRF. As expected, serum creatinine, cholesterol and triglycerides (mean ± SEM) were higher in the CRF groups compared to the C groups (P<0.05). The RS group presented lower cholesterol (84 ± 4 vs 126 ± 13 mg%) and triglyceride (88 ± 9 vs 132 ± 19 mg%) levels compared to the RN group. Proteinuria and kidney weight did not differ between CRF groups. Glomerular area increased 78% in RS and 100% in RN compared to control rats. Glomerular sclerosis index tended to be lower in RS (27%) compared to RN (38%), tubulointerstitial damage was similar between CRF groups (RS = 1.91 ± 0.2 and RN = 2.14 ± 0.3), and mesangial fractional volume increased to the same extent in both CRF groups. The data suggest that a linoleic acid-enriched diet did not protect against the progression of CRF after 60 days.

Use of intravascular ultrasonography for the characterization of coronary artery disease in patients with chronic kidney disease

INTRODUCTION: Chronic kidney disease patients present a very high cardiovascular mortality. Nevertheless, a comparative description of lesion characteristics, using intravascular ultrasound in dialysis patients, has not yet been reported. The objective of the present study was to analyze the plaque morphology through intravascular ultrasound in comparison to their counterparts with normal renal function. METHODS: Patients were screened for coronary artery disease, and the coronary angiography was performed when indicated. Plaque morphology was evaluated by ultrasound, and findings were compared to a group of patients with coronary artery disease, who presented normal renal function, it carefully matched for all Framingham risk factors and lesion location at the coronary artery tree. RESULTS: One hundred and thirty-nine patients from a single center of hemodialysis were screened for the study. Patients with coronary lesions confirmed at the angiography presented lower hemoglobin (10.8 ± 1.5 versus 12.0 ± 19; p < 0.046) levels and higher levels of low-density lipoprotein (110.6 ± 25.8 versus 75.5 ± 43.1; p < 0.004), when compared to the ones without coronary artery disease. The ultrasound revealed greater proximal reference diameter (4.1 ± 0.6 versus 3.7 ± 0.5; p < 0.007), smaller crossed sectional area (4.2±1.6 versus 5.2 ± 1.8; p < 0.02), and the calcification was located in a deeper arterial layer (69 versus 9%; p < 0.004) in patients with chronic kidney disease when compared to the Control Group. CONCLUSION: Lesions of the patients with chronic kidney disease presented a larger proximal diameter and intense calcification in the deeper layer of the vessel, which suggest a greater positive remodeling effect in response to a more aggressive atherosclerotic process in the medial section of the artery.

Vitamin D and Kidney disease: what we know and what we do not know

Vitamin D deficiency is common in the chronic kidney disease (CKD) population. CKD has been recognized as a significant public health problem and CKD patients are at increased risk of total and cardiovascular morbidity and mortality. There are increasing epidemiological data suggesting that vitamin D deficiency may play a role in overall morbidity and mortality associated with CKD. The vitamin D hormonal system is classically implicated in the regulation of calcium homeostasis and bone metabolism but there is ample evidence to support the claim that extra renal conversion of 25(OH)D to 1.25(OH)2 has significant biological roles beyond those traditionally ascribed to vitamin D. Based on the current state of evidence this review intends to give an update on novel biological and clinical insights with relevance to the steroid hormone vitamin D specifically in patients with kidney disease.

The quest for a better understanding of chronic kidney disease complications: an update on uremic toxins

Chronic kidney disease is characterized by a progressive reduction of glomerular filtration rate and/or the appearance of proteinuria, and subsequently the progressive retention of organic waste compounds called uremic toxins (UT). Over the last decades, a large number of such compounds have been identified and their effects on organs and tissues, especially the cardiovascular system, has been demonstrated. In this review, we present the current classification of UT, as proposed by the EUTox Group, and the effects of some of the probably most important UTs, such as phosphate, FGF-23, PTH, AGEs, indoxyl sulfate and para-cresyl sulfate. We provide an overview on therapeutic approaches aimed to increase their extracorporeal removal via convective and/or adsorptive strategies and to lower their intestinal production/ absorption via dietetic and pharmacological interventions. The recognition that multiple toxins contribute to the uremia supports the need for new therapeutic targets, with a potentially positive impact on CKD progression and survival.

Impact of social vulnerability on the outcomes of predialysis chronic kidney disease patients in an interdisciplinary center

Introduction: Numerous studies examined the associations between socio-demographic, economic and individual factors and chronic kidney disease (CKD) outcomes and observed that the associations were complex and multifactorial. Socioeconomic factors can be evaluated by a model of social vulnerability (SV). Objective: To analyze the impact of SV on the outcomes of predialysis patients. Methods: Demographic, clinical and laboratory data were collected from a cohort of patients with predialysis stage 3 to 5 who were treated by an interdisciplinary team (January 2002 and December 2009) in Minas Gerais, Brazil. Factor, cluster and discriminant analysis were performed in sequence to identify the most important variables and develop a model of SV that allowed for classification of the patients as vulnerable or non-vulnerable. Cox regression was performed to examine the impact of SV on the outcomes of mortality and need for renal replacement therapy (RRT). Results: Of the 209 patients examined, 29.4% were classified as vulnerable. No significance difference was found between the vulnerable and non-vulnerable groups regarding either mortality (log rank: 0.23) or need for RRT (log rank: 0.17). In the Cox regression model, the hazard ratios (HRs) for the unadjusted and adjusted impact of SV on mortality were found to be 1.87 (confidence interval [CI]: 0.64-5.41) and 1.47 (CI: 0.35-6.0), respectively, and the unadjusted and adjusted impact of need for RRT to be 1.85 (CI: 0.71-4.8) and 2.19 (CI: 0.50-9.6), respectively. Conclusion: These findings indicate that SV did not influence the outcomes of patients with predialysis CKD treated in an interdisciplinary center.

Is severe visceral leishmaniasis a systemic inflammatory response syndrome? A case control study

INTRODUCTION: The objective of the study is to identify the main risk factors for death by New World visceral leishmaniasis and establish a coherent pathogenic substrate of severe disease based on clinical findings. METHODS: Seventy-six deceased inpatients and 320 successfully treated inpatients with VL were studied in a case control study. RESULTS: Bacterial infection and bleeding were mutually exclusive events leading to death. Five risk factors were unique for death by bacterial infection (malnutrition, pulmonary rales, severe anemia, severe absolute neutropenia and higher neutrophil count), while another six were unique for death by bleeding (jaundice, severe relative neutropenia, severe thrombocytopenia, liver injury, kidney failure, higher bone marrow parasite load). Bacterial infection, bleeding, severe anemia, diarrhea, dyspnea, edema, jaundice and bone marrow parasite load were the main syndromes of visceral leishmaniasis among successfully treated patients. CONCLUSIONS: The data support the idea that bacterial infections are due to immune paralysis. Broad organ and system involvement is plausibly due to the high production of proinflammatory cytokines, whose actions fit well with visceral leishmaniasis. The syndromes and causative mediators are typical of a slowly developing systemic inflammatory response syndrome.

Survival and Predictive Factors of Lethality in Hemodyalisis: D/I Polymorphism of The Angiotensin I-Converting Enzyme and of the Angiotensinogen M235T Genes

Background: End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes. Objective: To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis. Methods: Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study. Results: The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34%) and infections (15%). Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038), TT angiotensinogen (p = 0.08261), and family income greater than five times the minimum wage (p = 0.03089), the latter being a protective factor. Conclusions: The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene.

Monitoring renal function: measured and estimated glomerular filtration rates - a review

Chronic kidney disease (CKD) is a world-wide public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death. This finding has led to the hypothesis that earlier recognition of kidney disease and successful intervention may improve outcome. The National Kidney Foundation, through its Kidney Disease Outcomes Quality Initiative (K/DOQI), and other National institutions recommend glomerular filtration rate (GFR) for the definition, classification, screening, and monitoring of CKD. Blood creatinine clearance, the most widely used clinical marker of kidney function, is now recognized as an unreliable measure of GFR because serum creatinine is affected by age, weight, muscle mass, race, various medications, and extra-glomerular elimination. Cystatin C concentration is a new and promising marker for kidney dysfunction in both native and transplanted kidneys. Because of its low molecular weight, cystatin C is freely filtered at the glomerulus and is almost completely reabsorbed and catabolized, but not secreted, by tubular cells. Given these characteristics, cystatin C concentration may be superior to creatinine concentration in detecting chronic kidney disease. This review aims to evaluate from recent literature the clinical efficiency and relevance of these GFR markers in terms of screening CKD.

Weight loss improves renal hemodynamics in patients with metabolic syndrome

OBJECTIVE: We investigated the impact of weight loss on urinary albumin excretion (UAE) and creatinine clearance in obese patients with metabolic syndrome. METHODS: Thirty-five obese patients undertook a 12-week calorie-restricted diet. The patients underwent a metabolic (oral glucose tolerance test, plasma lipids, and uric acid) and renal hemodynamic evaluations (creatinine clearance and urinary albumin excretion) before (phase 1), and after the 12-week diet (phase 2). RESULTS: After the dietary intervention, the subjects were divided into two groups: patients who achieved the target weight reduction (R: responders, n = 14), and patients who did not (NR: non-responders, n = 21). The patients in Group R showed an improvement in lipid profile, a decrease in UAE (median = 162.5 mg/24 hours, range: 0.8 to 292 mg/24 hours, at phase 1 versus 10.4 mg/24 hours, range: 1.6 to 22.4 mg/24 hours, at phase 2), and a significant reduction in creatinine clearance (121.4 ± 66.5 mL/min. in phase 1 to 92.9 ± 35.6 mL/min. at the end of phase 2, p = 0.001). In Group NR, no statistically significant differences were observed between phases 1 and 2. CONCLUSION: Body weight reduction has a positive impact on renal hemodynamics, decreasing urinary albumin excretion as well as glomerular hyperfiltration in obese patients with metabolic syndrome.

A case of late-onset oligomeganephronia

A 33-year old caucasian man was investigated for pain in the right flank, proteinuria, hemathuria and an elevated serum creatinine level. He also presented an abnormal ultrasonography, which revealed asymmetric kidneys. Through renal biopsy, the diagnosis of oligomeganephronia (OMN) was confirmed. OMN is a very rare form of renal hypoplasia, and late-onset in adulthood is even rarer. In the pediatric population, OMN leads to end-stage-renal-failure(ESRF) in a few years. This is the sixth case related in the literature of a late-onset OMN who have not yet developed ESRF.