Mark S. Segal

Acute Kidney Injury Is Associated With Increased Long-Term Mortality After Cardiothoracic Surgery

Background— Long-term survival after acute kidney injury (AKI) is poorly studied. We report the relationship between long-term mortality and AKI with small changes in serum creatinine during hospitalization after various cardiothoracic surgery procedures. Methods and Results— This was a retrospective study of 2973 patients with no history of chronic kidney disease who were discharged from the hospital after cardiothoracic surgery between 1992 and 2002. AKI was defined by the RIFLE classification (Risk, Injury, Failure, Loss, and End stage), which requires at least a 50% increase in serum creatinine and stratifies patients into 3 grades of AKI: Risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed with a risk-adjusted Cox proportional hazards regression model. Survival was worse among patients with AKI and was proportional to its severity, with an adjusted hazard ratio of 1.23 (95% CI 1.06 to 1.42) for the least severe RIFLE risk class and 2.14 (95% CI 1.73 to 2.66) for the RIFLE failure class compared with patients without AKI. Survival was worse among all subgroups of cardiothoracic surgery with AKI except for valve surgery. Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.28 (95% CI 1.11 to 1.48) compared with patients without AKI. Conclusions— The risk of death associated with AKI after cardiothoracic surgery remains high for 10 years regardless of other risk factors, even for those patients with complete renal recovery. Improved renal protection and closer postdischarge follow-up of renal function may be warranted.

Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?

We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.

Long-term risk of mortality and acute kidney injury during hospitalization after major surgery.

Objective:To determine the relationship between long-term mortality and acute kidney injury (AKI) during hospitalization after major surgery. Summary Background Data:AKI is associated with a risk of short-term mortality that is proportional to its severity; however the long-term survival of patients with AKI is poorly studied. Methods:This is a retrospective cohort study of 10,518 patients with no history of chronic kidney disease who were discharged after a major surgery between 1992 and 2002. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires at least a 50% increase in serum creatinine (sCr) and stratifies patients into 3 severity stages: risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed using a risk-adjusted Cox proportional hazards regression model. Results:In the risk-adjusted model, survival was worse among patients with AKI and was proportional to its severity with an adjusted hazard ratio of 1.18 (95% confidence interval [CI], 1.08–1.29) for the RIFLE-Risk class and 1.57 (95% CI, 1.40–1.75) for the RIFLE-Failure class, compared with patients without AKI (P < 0.001). Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.20 (95% CI, 1.10–1.31) compared with patients without AKI (P < 0.001). Conclusions:In a large single-center cohort of patients discharged after major surgery, AKI with even small changes in sCr level during hospitalization was associated with an independent long-term risk of death.

SDF-1 is both necessary and sufficient to promote proliferative retinopathy

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell-derived factor-1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses. Treatment of patients with triamcinolone decreases SDF-1 levels in the vitreous, with marked disease improvement. SDF-1 induces human retinal endothelial cells to increase expression of VCAM-1, a receptor for very late antigen-4 found on many hematopoietic progenitors, and reduce tight cellular junctions by reducing occludin expression. Both changes would serve to recruit hematopoietic and endothelial progenitor cells along an SDF-1 gradient. We have shown, using a murine model of proliferative adult retinopathy, that the majority of new vessels formed in response to oxygen starvation originate from hematopoietic stem cell-derived endothelial progenitor cells. We now show that the levels of SDF-1 found in patients with proliferative retinopathy induce retinopathy in our murine model. Intravitreal injection of blocking antibodies to SDF-1 prevented retinal neovascularization in our murine model, even in the presence of exogenous VEGF. Together, these data demonstrate that SDF-1 plays a major role in proliferative retinopathy and may be an ideal target for the prevention of proliferative retinopathy.

Essential Hypertension, Progressive Renal Disease, and Uric Acid: A Pathogenetic Link?

Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.

Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock

The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of diabetic retinopathy. In rats that had diabetes for 4 mo, we observed a dramatic reduction in the number of nerve terminal endings in the bone marrow. Denervation was accompanied by increased numbers of EPCs within the bone marrow but decreased numbers in circulation. Furthermore, denervation was accompanied by a loss of circadian release of EPCs and a marked reduction in clock gene expression in the retina and in EPCs themselves. This reduction in the circadian peak of EPC release led to diminished reparative capacity, resulting in the development of the hallmark feature of diabetic retinopathy, acellular retinal capillaries. Thus, for the first time, diabetic retinopathy is related to neuropathy of the bone marrow. This novel finding shows that bone marrow denervation represents a new therapeutic target for treatment of diabetic vascular complications.

The role of uric acid in the pathogenesis of human cardiovascular disease

Hyperuricaemia is common in subjects with cardiovascular disease, but is not commonly considered a true risk factor. Recent studies suggest that uric acid is biologically active and can stimulate oxidative stress, endothelial dysfunction, inflammation and vasoconstriction. Epidemiological studies have found that uric acid can independently predict the development of hypertension, as well as stroke and heart failure. Experimentally raising uric acid in animals increases blood pressure, and pilot studies suggest that lowering uric acid in humans can reduce blood pressure in hypertensive individuals. Uric acid may also have emerging roles in the pathogenesis of kidney disease, metabolic syndrome and diabetes. More studies need to be performed on the pathophysiology and clinical consequences of hyperuricaemia in cardiovascular disease.

Urinary CD80 Excretion Increases in Idiopathic Minimal-Change Disease

CD80 is expressed on all antigen-presenting cells and is present on podocytes in a number of experimental models of nephrotic syndrome. We tested whether urinary soluble CD80 increased with idiopathic minimal-change disease (MCD). We collected urine and serum samples from patients with MCD in relapse and in remission, patients with nephrotic syndrome resulting from other glomerular diseases (FSGS, membranoproliferative glomerulonephritis, IgA nephropathy, and membranous nephropathy), patients with systemic lupus erythematosus, and normal control subjects. Urinary concentrations of soluble CD80 in patients with relapsed MCD were significantly higher compared with those observed in patients with MCD in remission, other glomerular diseases, and systemic lupus erythematosus with and without proteinuria and healthy control subjects. Urinary concentrations of soluble CTLA-4, which is a negative regulator of CD80, were not statistically different in patients with relapsed MCD compared with those in remission. The urinary soluble CD80/CTLA-4 ratio was >100-fold higher in patients with relapsed MCD compared with those in remission (P < 0.008). In contrast, serum concentrations of soluble CD80 and CTLA-4 did not distinguish patients with MCD in relapse and in remission. In conclusion, urinary soluble CD80 is elevated in idiopathic MCD, which could be relevant to both diagnosis and pathogenesis.

End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end‐stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.

COST AND MORTALITY ASSOCIATED WITH POSTOPERATIVE ACUTE KIDNEY INJURY

OBJECTIVE To determine the incremental hospital cost and mortality associated with the development of postoperative acute kidney injury (AKI) and with other associated postoperative complications. BACKGROUND Each year 1.5 million patients develop a major complication after surgery. Postoperative AKI is one of the most common postoperative complications and is associated with an increase in hospital mortality and decreased survival for up to 15 years after surgery. METHODS In a single-center cohort of 50,314 adult surgical patients undergoing major inpatient surgery, we applied risk-adjusted regression models for cost and mortality using postoperative AKI and other complications as the main independent predictors. We defined AKI using consensus Risk, Injury, Failure, Loss and End-Stage Renal Disease criteria. RESULTS The prevalence of AKI was 39% among 50,314 patients with available serum creatinine. Patients with AKI were more likely to have postoperative complications and had longer lengths of stay in the intensive care unit and the hospital. The risk-adjusted average cost of care for patients undergoing surgery was