Predictive Ability of NGAL as a Marker of Renal Damage: evaluation of Multiple Clinical Settings

Introduction. Neutrophil Gelatinase-Associated Lipocalin (NGAL) belongs to the family of lipocalins and it is produced by several cell types, including renal tubular epithelium. In the kidney its production increases during acute damage and this is reflected by the increase in serum and urine levels. In animal studies and clinical trials, NGAL was found to be a sensitive and specific indicator of acute kidney injury (AKI). Purpose. The aim of this work was to investigate, in a prospective manner, whether urine NGAL can be used as a marker in preeclampsia, kidney transplantation, VLBI and diabetic nephropathy. Materials and methods. The study involved 44 consecutive patients who received renal transplantation; 18 women affected by preeclampsia (PE); a total of 55 infants weighing ≤1500 g and 80 patients with Type 1 diabetes. Results. A positive correlation was found between urinary NGAL and 24 hours proteinuria within the PE group. The detection of higher uNGAL values in case of severe PE, even in absence of statistical significance, confirms that these women suffer from an initial renal damage. In our population of VLBW infants, we found a positive correlation of uNGAL values at birth with differences in sCreat and eGFR values from birth to day 21, but no correlation was found between uNGAL values at birth and sCreat and eGFR at day 7. systolic an diastolic blood pressure decreased with increasing levels of uNGAL. The patients with uNGAL <25 ng/ml had significantly higher levels of systolic blood pressure compared with the patients with uNGAL >50 ng/ml ( p<0.005). Our results indicate the ability of NGAL to predict the delay in functional recovery of the graft. Conclusions. In acute renal pathology, urinary NGAL confirms to be a valuable predictive marker of the progress and status of acute injury.

Urinary soluble HLA-DR is a potential biomarker for acute renal transplant rejection

BACKGROUND.: Urine is a potentially rich source of biomarkers for monitoring kidney dysfunction. In this study, we have investigated the potential of soluble human leukocyte antigen (sHLA)-DR in the urine for noninvasive monitoring of renal transplant patients. METHODS.: Urinary soluble HLA-DR levels were measured by sandwich enzyme-linked immunosorbent assay in 103 patients with renal diseases or after renal transplantation. sHLA-DR in urine was characterized by Western blotting and mass spectrometry. RESULTS.: Acute graft rejection was associated with a significantly elevated level of urinary sHLA-DR (P<0.0001), compared with recipients with stable graft function or healthy individuals. A receiver operating characteristic curve analysis showed the area under the curve to be 0.88 (P<0.001). At a selected threshold, the sensitivity was 80% and specificity was 98% for detection of acute renal transplant rejection. sHLA-DR was not exosomally associated and was of lower molecular weight compared with the HLA-DR expressed as heterodimer on the plasma membrane of antigen-presenting cells. CONCLUSIONS.: sHLA-DR excreted into urine is a promising indicator of renal transplant rejection.

Gout in pediatric renal transplant recipients

Clinical gout has rarely been described after pediatric renal transplantation (RTx), although asymptomatic hyperuricemia is common in these patients. We describe three male pediatric patients who presented with gouty arthritis 7-8.5 years following RTx. Since receiving allopurinol, all patients had been free of gouty symptoms. To prevent severe bone marrow depletion, the dosage of azathioprine, an immunosupressant drug, was reduced by 50% to prevent interaction with allopurinol. Because atypical presentation of gout can occur, a high index of suspicion is needed to allow appropriate diagnosis of this disease in patients with skeletal pain after RTx.

Effect of cinacalcet cessation in renal transplant recipients with persistent hyperparathyroidism

BACKGROUND: Persistent hyperparathyroidism after renal transplantation affects bone and allografts. Cinacalcet, a calcimimetic, reduces serum calcium and PTH in renal transplant recipients with persistent hyperparathyroidism. Here, we address the question whether this effect of cinacalcet persists after withdrawal. METHODS: Therefore, cinacalcet was stopped after 12 months treatment in 10 stable renal transplant patients. Serum calcium, phosphate, PTH, creatinine and cystatin C were monitored for 3 months. RESULTS: Serum calcium, normalized in nine patients before cessation of cinacalcet (2.32 +/- 0.05mmol/l, mean +/- SEM), increased after 3 months of discontinuation by 0.17 +/- 0.04mmol/l, P < 0.05, but remained within the normal range in eight patients. Compared with the time point of cessation, PTH remained unchanged or decreased further after 3 months without therapy in six patients. Measurements of cystatin C suggested an improvement of the glomerular filtration rate after cessation in 9 out of 10 patients (1.55 +/- 0.09 vs 1.33 +/- 0.12 mg/l, P < 0.01). CONCLUSION: First, a beneficial effect of cinacalcet beyond the duration of a 12-month therapy appears to be present in some patients and second, the previously suspected influence of cinacalcet therapy on renal function is reversible. Thus, it is reasonable to consider a trial of cinacalcet cessation to identify these patients. The optimal time point for such a discontinuation is unknown. The present observations are preliminary. They clearly require a prospective randomized trial for definitive confirmation.

Scleroderma Renal Crisis: A Rare but Severe Complication of Systemic Sclerosis

Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation.

Renal resistance index in renal allograft recipients: a role for ADMA

BACKGROUND: Renal resistance index, a predictor of kidney allograft function and patient survival, seems to depend on renal and peripheral vascular compliance and resistance. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and therefore influences vascular resistance. STUDY DESIGN: We investigated the relationship between renal resistance index, ADMA, and risk factors for cardiovascular diseases and kidney function in a cross-sectional study. SETTING ; PARTICIPANTS: 200 stable renal allograft recipients (133 men and 67 women with a mean age of 52.8 years). PREDICTORS: Serum ADMA concentration, pulse pressure, estimated glomerular filtration rate and recipient age. OUTCOME: Renal resistance index. MEASUREMENTS: Renal resistance index measured by color-coded duplex ultrasound, serum ADMA concentration measured by liquid chromatography-tandem mass spectrometry, estimated glomerular filtration rate (Nankivell equation), arterial stiffness measured by digital volume pulse, Framingham and other cardiovascular risk factors, and evaluation of concomitant antihypertensive and immunosuppressive medication. RESULTS: Mean serum ADMA concentration was 0.72 +/- 0.21 (+/-SD) micromol/L and mean renal resistance index was 0.71 +/- 0.07. Multiple stepwise regression analysis showed that recipient age (P < 0.001), pulse pressure (P < 0.001), diabetes (P < 0.01) and ADMA concentration (P < 0.01) were independently associated with resistance index. ADMA concentrations were correlated with estimated glomerular filtration rate (P < 0.01). LIMITATIONS: The cross-sectional nature of this study precludes cause-effect conclusions. CONCLUSIONS: In addition to established cardiovascular risk factors, ADMA appears to be a relevant determinant of renal resistance index and allograft function and deserves consideration in prospective outcome trials in renal transplantation.

[Transition in kidney transplantation]

Transition from pediatric to adult care in renal transplantation has emerged as a critical step in the life of a young kidney recipient. During this phase, young patients are faced with the physiological and psychological changes associated with adolescence that can lead to non-compliance and potentially graft loss. To date, there is not a unique accepted model of transition, however it has been proved that the presence of a multidisciplinary team including specialists in adolescent management and in the transition from pediatric to adult transplant care is beneficial during this at-risk phase. The goal of this team is to ensure a progressive transition of the patients according to a precise plan and time line.

A single-centre experience of post-renal transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD) complicates 1 to 10% of all transplantations. Previous clinicopathological studies of PTLD have been limited by small numbers, short follow-up times, outdated data, heterogeneity of pooled solid-organ transplant results, and selective inclusion of early-onset disease. We therefore undertake here a retrospective analysis and identify all cases of PTLD that complicated renal transplantation at the Princess Alexandra Hospital between 30 June 1969 and 31 May 2001. Tumour samples were subsequently retrieved for pathological review and for Epstein-Barr virus-encoded RNA in situ hybridisation (EBER-ISH). Of 2,030 renal transplantation patients, 29 (1.4%) developed PTLD after a median period of 0.5 years (range 0.1 to 23.3 years). PTLD patients were more likely to have received cyclosporine (76% versus 62%, P

Estudo da resposta Th17 no transplante renal alogênico: contribuição do eixo quimiotático CCR6/CCL20 e dos polimorfismos gênicos em IL17A e IL17RA

Kidney transplantation is the best treatment for patients who have lost kidney function. Renal transplant patients require accurate immunosuppressive drugs to prevent rejection. In this process T helper cells of the immune system perform key role in the immune response to the graft, and recently the Th17 cells has been investigated by production of IL-17 potent proinflammatory cytokine whose role in the rejection has also been described. Increased of Th17 cell expression has an important association with the development of rejection in renal microenvironment, however the likely mechanism is not well understood. This study aimed to evaluate the Th17 response from the influence of the chemotactic axis CCR6/CCL20 and genetic variants in IL-17 and IL-17RA. We conducted a case-control study involving 148 patients transplanted at the University Hospital Onofre Lopes/UFRN in which assessed by immunohistochemistry protein expression of IL-17 and chemokines CCR6/CCL20 and by PCR-RFLP genetic variants in IL17A and IL17RA. Our results showed no influence of genetic polymorphisms on the outcome of the graft or the protein expression of IL-17. In renal graft microenvironment found several sources producing IL-17: tubular epithelial cells, glomerular cells, neutrophils and cell interstitial infiltration, in turn the expression of chemotactic axis CCR6/CCL20 was restricted to the tubular epithelium cells. There was a slight positive linear correlation between the presence of IL-17 and expression of chemotactic axis CCR6/CCL20 in the microenvironment of renal graft. Therefore, we believe that, combined with our results, further studies with increased "n" sample and greater control over the variables involved in obtaining the renal specimen, can determine more clearly the influence of chemotactic axis CCR6 / CCL20 and polymorphisms in cytokines related to Th17 profile on the control of this cell subtype response in rejection processes to renal allograft.

Prevalência da síndrome metabólica em receptores de transplante renal de acordo com o gênero e tempo pós-transplante /

Metabolic syndrome (MS) is defined as a set of cardiovascular risk factors including obesity, systemic high blood pressure (SHBP), changes in glucose metabolism and dyslipidemia. The prevalence of MS in renal transplant recipients (RTR) ranges from 15% to 65%, increasing the risk of cardiovascular disease (CVD) and reducing renal allograft survival in the long term. The objectives of this study were to determine the prevalence and frequency of MS in renal transplant patients according to gender and time of transplantation and to evaluate renal function in patients with and without MS. Patients and Methods: Crosssectional study conducted from August 2012 to September 2013 involving 153 renal transplant recipients. MS was defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). The sample was divided into two groups: patients with metabolic syndrome (WMS patients) and patients without metabolic syndrome (WoMS patients) and according to gender. The WMS patients were stratified into quartiles according to the renal transplantation period (RTP), and variables related to MS were analyzed for both sexes. Results: MS was diagnosed in 58.1% of the studied population, specifically in MS was found 58.4% of men and 41.6% of women (P ˂ 0.05). The male and female with MS were 48.8 ± 11.6 years old vs. 47.1 ± 12.7 years old and the time of post transplantation was 76.1 ± 76.5 months vs. 84.7 ± 65.4 months, respectively (P >0,05). When we compared the sexes in the WMS group, systolic blood pressure (SBP) was higher in men (137.0 ± 18.1 vs. 128.9 ± 13.6 mmHg, P= 0.029), while the other components of MS did not exhibit significant differences. With respect to renal function, when we compared the sexes in the WMS group, the serum creatinine (sCr) was higher in men (1.73 ± 0.69 vs. 1.31 ± 0.47 mg/dL, P= 0.0012), while the urinary protein/creatinine ratio was higher in women (0.48 ± 0.69 vs. 0.37 ± 0.48 mg/dL, P=0.0150). We found no significant difference in the estimated glomerular filtration rate (eGFR) between WMS and WoMS patients for women and men (50.6 ± 19.1 vs. 50.1 ± 18.3 mL/min/1.73 m², P=0.909). We found a significant positive association between eGFR and HDL-c levels (r=0.3371; P=0.0145) for WMS men. The MS components showed no significant differences in RTP for different interquartile ranges, except for diastolic blood pressure (DBP) in women, where there was a significant variation among the quartiles evaluated (P=0.0009). Conclusion: the prevalence of MS was similar in the different quartiles in both sexes, in relation to time post TX. There was no significant difference in eGFR in patients WMS and WoMS, in both sexes. Concluding that the MS did not vary in relation to time post transplant.

Índice del perfil del donante renal (KDPI) como factor pronóstico del trasplante

La enfermedad renal crónica ha aumentado a nivel mundial y nacional, mientras que el número de donantes viene en descenso, y los pacientes en lista de espera aumentan. Los donantes cadavéricos son una opción para estos pacientes, y han sido utilizados en últimos años para aumentar los órganos disponibles. La evaluación de la calidad de estos es importante para optimizar su uso. Estudio analítico tipo cohorte retrospectiva, cálculo de KDPI en donantes cadavéricos, seguimiento función renal creatinina sérica 1 mes, 3 meses, 6 meses y un año. Correlación supervivencia del injerto, función renal, KDPI y EPTS. Análisis de supervivencia y regresión logística con variables del donante, receptor y acto quirúrgico.

Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.

Long-term outcome and extraintestinal manifestations in congenital chloride diarrhea

The rare autosomal recessive disease congenital chloride diarrhea (CLD) is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene on chromosome 7q22.3-31.1. SLC26A3 encodes for an apical epithelial chloride-bicarbonate exchanger, the intestinal loss of which leads to profuse chloride-rich diarrhea, and a tendency to hypochloremic and hypokalemic metabolic alkalosis. Although untreated CLD is usually lethal in early infancy, the development of salt substitution therapy with NaCl and KCl in the late 1960s made the disease treatable. While the salt substitution allows normal childhood growth and development in CLD, data on long-term outcome have remained unclarified. One of the world s highest incidences of CLD 1:30 000 to 1:40 000 occurs in Finland, and CLD is part of the Finnish disease heritage. We utilized a unique sample of Finnish patients to characterize the long-term outcome of CLD. Another purpose of this study was to search for novel manifestations of CLD based on the extraintestinal expression of the SLC26A3 gene. This study on a sample of 36 patients (ages 10-38) shows that the long-term outcome of treated CLD is favorable. In untreated or poorly treated cases, however, chronic contraction and metabolic imbalance may lead to renal injury and even to renal transplantation. Our results demonstrate a low-level expression of SLC26A3 in the human kidney. Although SLC26A3 may play a minor role in homeostasis, post-transplant recurrence of renal changes shows the unlikelihood of direct transporter modulation in the pathogenesis of CLD-related renal injury. Options to resolve the diarrheal symptoms of CLD have been limited. Unfortunately, our pilot trial indicated the inefficacy of oral butyrate as well. This study reveals novel manifestations of CLD. These include an increased risk for hyperuricemia, inguinal hernias, and probably for intestinal inflammation. The most notable finding of this study is CLD-associated male subfertility. This involves a low concentration of poorly motile spermatozoa with abnormal morphology, high seminal plasma chloride with a low pH, and a tendency to form spermatoceles. That SLC26A3 immunoexpression appeared at multiple sites of the male reproductive tract in part together with the main interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and sodium-hydrogen exchanger 3 (NHE3) suggests novel sites for the cooperation of these proteins. As evidence of the cooperation, defects occurring in any of these transporters are associated with reduced male fertility. Together with a finding of high sweat chloride in CLD, this study provides novel data on extraintestinal actions of the SLC26A3 gene both in the male reproductive tract and in the sweat gland. These results provide the basis for future studies regarding the role of SLC26A3 in different tissues, especially in the male reproductive tract. Fortunately, normal spermatogenesis in CLD is likely to make artificial reproductive technologies to treat infertility and even make unassisted reproduction possible.