Fernando Liaño

Long-term functional evolution after an acute kidney injury: a 10-year study

BACKGROUND Data on long-term effects of acute kidney injury (AKI) on renal function (RF) are scarce and factors implicated in the functional outcome are not established. Our aim was to investigate these aspects. METHODS At hospital discharge and annually for 10 years, we retrospectively reviewed RF of 187 patients surviving AKI. Glomerular filtration rates estimated with MDRD equation (eGFR) and KDOQI stages were used to evaluate RF. Only 34.8% of patients had pre-existing renal dysfunction (KDOQI-3). Variables determining long-term RF were collected during AKI and at discharge and analysed with a regression model. RESULTS At discharge no patient necessitated dialysis, but eGFR was lower than baseline (47.5 +/- 23.3 ml/min/ 1.73 m(2) versus 75.8 +/- 25.4 ml/min/1.73 m(2)); 38.4% of survivors had recovered basal RF: 26% of those with previous normal RF and 61% of those in KDOQI-3, respectively. At 1 year, eGFR increased to 61.9 +/- 24.4 ml/min/1.73 m(2) and remained stable later. During an 8-year median follow-up (P25:2; P75:10), 31% improved RF, 50% remained stable and 19% deteriorated. In total only 46% (n = 82) definitively recovered RF. Finally, at the end of the study period 61.6% presented some degree of renal dysfunction: 40% of those with previous normal RF developed moderate-severe renal dysfunction and 37% KDOQI-3 progressed into more severe renal failure. Only two patients needed dialysis. Regression model identified age, co-morbidities, discharge eGFR and follow-up time as independent predictors of long-term RF. CONCLUSIONS AKI carries implication for long-term RF even in patients without pre-existing renal dysfunction. Ageing, co-morbidities and RF at discharge are determinants of the long-term functional outcome.

Easy and Early Prognosis in Acute Tubular Necrosis: A Forward Analysis of 228 Cases

Multiple factors still influence the high rate of mortality in acute tubular necrosis. Trying to analyze the influence of each risk factor present in an individual patient and the possible interdependence between these factors, as well as to obtain an early prognosis, we have applied a forward analysis to demographic data, acute renal failure origin, need of dialysis, diuresis and clinical conditions in 228 patients, using a multiple linear regression model contained in a computer package. Based on this approach we have found that three variables: deep neurological coma, persistent blood hypotension and assisted respiration have significant influence on mortality. Also, a regression equation was obtained which could be applied as a discriminant score to patient prognosis. This score, calculated with the three aforementioned variables and oliguria when the nephrologist sees the patient for the first time, allows an easy and early prognosis in each patient with acute tubular necrosis.

Hypoxia Inducible Factor 1-Alpha (HIF-1 Alpha) Is Induced during Reperfusion after Renal Ischemia and Is Critical for Proximal Tubule Cell Survival

Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant.

Veno-Occlusive Hepatic Disease of the Liver in Renal Transplantation: Is Azathioprine the Cause?

Five male patients with veno-occlusive disease of the liver (VOD) were observed in 200 consecutive renal transplants (RT) treated with azathioprine and prednisone. Mild liver enzymatic increases not justified by other reasons were detected between 2 and 9 months after RT. All 5 patients developed portal hypertension and died between 18 and 79 months following RT. Diagnosis of VOD was histological; in 3 cases diagnosis was made while the patients were still alive. In our patients, 9 previous viral hepatotropic infections (5 during hemodialysis and 4 after TR) were demonstrated. Due to the reported low incidence of VOD in RT patients, when many of them have been treated with azathioprine, the etiological role of this drug must be questioned. However, the possible association of a previous hepatotropic viral infection and the use of an immunosuppressive agent should be considered as a probable cause of VOD in kidney grafts.

Prognosis of Children with Acute Renal Failure: A Study of 138 Cases

Acute renal failure (ARF) in children has a poor prognosis in spite of modern therapeutic techniques. For this reason, it would be useful to have prognostic indicators early in the course of the disease, in order to identify those patients that could benefit most from aggressive treatment. In an attempt to establish valid prognostic factors, we prospectively studied 138 cases of ARF in children. We examined age, sex, etiology of ARF, previous surgery, prerenal origin, clinical situation of the patient when first seen by the nephrologist and complications. All these variables were statistically analyzed individually by univariate tests and, except for sex and complications, also by multiple regression analysis. Median age of the patients was 26 months. The etiology of ARF was nephropathy in 16, tumor in 14, cardiopathy in 85 and other causes in 23 cases. For analysis, patients were divided into patients with and without prerenal ARF. In the prerenal group, mortality-related factors were hypotension, need for ventilatory support, age less than 1 month and serum values of creatinine. In the nonprerenal ARF group, the need for assisted ventilation and the need for dialysis correlate positively with the mortality, while an exclusive nephrological etiology was associated with less probability of death.

A Pilot Study Identifying a Set of microRNAs As Precise Diagnostic Biomarkers of Acute Kidney Injury

In the last decade, Acute Kidney Injury (AKI) diagnosis and therapy have not notably improved probably due to delay in the diagnosis, among other issues. Precocity and accuracy should be critical parameters in novel AKI biomarker discovery. microRNAs are key regulators of cell responses to many stimuli and they can be secreted to the extracellular environment. Therefore, they can be detected in body fluids and are emerging as novel disease biomarkers. We aimed to identify and validate serum miRNAs useful for AKI diagnosis and management. Using qRT-PCR arrays in serum samples, we determined miRNAs differentially expressed between AKI patients and healthy controls. Statistical and target prediction analysis allowed us to identify a panel of 10 serum miRNAs. This set was further validated, by qRT-PCR, in two independent cohorts of patients with relevant morbi-mortality related to AKI: Intensive Care Units (ICU) and Cardiac Surgery (CS). Statistical correlations with patient clinical parameter were performed. Our results demonstrated that the 10 selected miRNAs (miR-101-3p, miR-127-3p, miR-210-3p, miR-126-3p, miR-26b-5p, miR-29a-3p, miR-146a-5p, miR-27a-3p, miR-93-3p and miR-10a-5p) were diagnostic biomarkers of AKI in ICU patients, exhibiting areas under the curve close to 1 in ROC analysis. Outstandingly, serum miRNAs estimated before CS predicted AKI development later on, thus becoming biomarkers to predict AKI predisposition. Moreover, after surgery, the expression of the miRNAs was modulated days before serum creatinine increased, demonstrating early diagnostic value. In summary, we have identified a set of serum miRNAs as AKI biomarkers useful in clinical practice, since they demonstrate early detection and high diagnostic value and they recognize patients at risk.

HEMODYNAMIC CHANGES IN HEMODIALYZED PATIENTS DURING TREATMENT WITH RECOMBINANT HUMAN ERYTHROPOIETIN

Evolution of cardiac index in 12 patients with severe renal anemia on regular hemodialysis (hematocrit 19.9 +/- 2.8%) was studied during the first 4 months of treatment with recombinant human erythropoietin (rhEPO). At the end of the study period, hematocrit rose to 31.1 +/- 3.5% (p less than 0.001) and cardiac index significantly decreased (5.34 +/- 1.25 vs. 3.81 +/- 0.84 liters/min/m2, p less than 0.001). Cardiac index fell mainly because of reduction of stroke volume (108 +/- 27 vs. 81 +/- 25 ml, p less than 0.001), while heart rate did not change during the study period. Before starting rhEPO cardiac index was elevated in 11 out of the 12 patients, whereas after 4 months of treatment this was only maintained in 4 of them. We conclude that substitution with rhEPO in hemodialysis patients significantly decreases cardiac index, confirming anemia as the main factor for hyperdynamic circulatory state in these patients. Whether this reduction in cardiac index will ameliorate cardiac morbidity or not and hematocrit levels for achieving the major benefits require further studies.

Differential resolution of inflammation and recovery after renal ischemia–reperfusion injury in Brown Norway compared with Sprague Dawley rats

To investigate mechanisms conferring susceptibility or resistance to renal ischemia, we used two rat strains known to exhibit different responses to ischemia-reperfusion. We exposed proximal tubule cells isolated from Sprague Dawley or Brown Norway rats, to a protocol of hypoxia, followed by reoxygenation in vitro. The cells isolated from both rat strains exhibited comparable responses in the disruption of intercellular adhesions and cytoskeletal damage. In vivo, after 24 h of reperfusion, both strains showed similar degrees of injury. However, after 7 days of reperfusion, renal function and tubular structure almost completely recovered and inflammation resolved, but only in Brown Norway rats. Hypoxia-inducible factor-dependent gene expression, ERK1/2, and Akt activation were different in the two strains. Inflammatory mediators MCP-1, IL-10, INF-gamma, IL-1beta, and TNF-alpha were similarly induced at 24 h in both strains but were downregulated earlier in Brown Norway rats, which correlated with shorter NFkappaB activation in the kidney. Moreover, VLA-4 expression in peripheral blood lymphocytes and VCAM-1 expression in kidney tissues were initially similar at 24 h but reached basal levels earlier in Brown Norway rats. The faster resolution of inflammation in Brown Norway rats suggests that this strain might be a useful experimental model to determine the mechanisms that promote repair of renal ischemia-reperfusion injury.

Acute kidney injury as a risk factor for chronic kidney diseases in disadvantaged populations

Acute kidney injury (AKI) is considered to be a potential cause for developing chronic kidney disease (CKD); on the other hand, CKD predisposes to AKI. The lack of adequate epidemiological data makes it difficult to determine if AKI induces CKD in less developed countries. The etiology of AKI in rich populations, in whom sophisticated surgery, interventional radiology and oncology treatments are usually the cause of AKI, is very different from that of disadvantaged populations, where the origin of AKI is associated with endemic infections, obstetric problems, poisons, toxins and natural disasters. Any conclusions extrapolated from these two settings should be treated with caution. Moreover, people living in disadvantaged conditions are usually much younger than those in rich areas and this age factor could facilitate total recovery of renal function after AKI if treatment based on an adequate supply of water, rehydration and anti-infectious measures were provided. In the small segment of the population of less developed countries having an income per capita similar to that observed in the developed countries, the long-term outcome of AKI should also be expected to be similar. New data coming from two single centers analyzing only the long-term outcome of acute tubular necrosis (ATN) patients, with a normal or near normal renal function prior to the AKI episode, coincide in reporting a requirement for chronic dialysis among the surviving patients of 2%. If these data are confirmed, the importance of AKI as cause of CKD should be reconsidered, both in developed and less developed countries.

Necrotizing Myositis Secondary to Serratia marcescens in a Renal Allograft Recipient

We describe a fatal case of spontaneous necrotizing myositis due to a highly resistant strain of Serratia marcescens in a renal transplant recipient. Though Staphylococcus aureus and Clostridium are the usual agents which cause either pyomyositis or necrotizing myositis, gram-negative bacteria are a dangerous and rarely suspected possibility. Such an aggressive disease should be promptly recognized because immunosuppression in susceptible hosts makes conservative management unsuccessful. The prognosis for myositis in immunodepressed hosts is poor and wide excision of all the necrotic muscles, leaving the wound open, and intensive antibiotic therapy are required.