Does Secretory Clearance Follow Glomerular Filtration Rate in Chronic Kidney Diseases? Reconsidering the Intact Nephron Hypothesis.

Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs.

Tooth loss strongly associates with malnutrition in chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), inadequate nutritional intake, inflammation, and increased oxidative stress have been the major contributing factors in malnutrition pathogenesis. However, there is still a paucity of evidence assessing the magnitude of the effect of tooth loss on malnutrition in CKD populations. The authors hypothesize that among patients with CKD, tooth loss may affect nutritional status, using the National Health and Nutrition Examination Survey 1988 to 1994 (NHANES III). METHODS: Glomerular filtration rate (GFR) was estimated based on cystatin C levels using the relevant equation. Urinary albumin-to-creatinine ratio (albuminuria) was calculated in milligrams per gram with a cutoff point of 30 mg/g. CKD was defined based on estimated GFR <60 mL/minute/1.73m(2) and albuminuria ≥30 mg/g. The cutoff point for serum albumin was set at 3.7 g/dL. Tooth loss categories were based on the number of missing and replaced teeth. RESULTS: A total of 2,749 patients was included and stratified based on their oral health status. There was a statistically significant correlation between tooth loss and the proportion of patients with low protein and caloric intake (P = 0.02 and 0.01, respectively). Serum albumin reached a frequency peak in the fully edentulous group without dentures (group 4, 19.2%). In the same group, individuals had lower protein (30.1%) and caloric intake (30.2%) (P = 0.01 and 0.02, respectively). Furthermore, logistic regression analysis confirmed the significant role of tooth loss on serum albumin and protein and energy intake in this population even after adjusting for confounding variables. CONCLUSION: Tooth loss independently predicts low energy and protein intake, as well as serum albumin levels, biomarkers of malnutrition in CKD.

JAK2/Y343/STAT5 signaling axis is required for erythropoietin-mediated protection against ischemic injury in primary renal tubular epithelial cells.

Erythropoietin has emerged as a potential therapy for the treatment of ischemic tissue injury. In erythroid cells, the JAK2/Y343/STAT5 signaling axis has been shown to be necessary for stress but not steady-state erythropoiesis. The requirement for STAT5 activation in erythropoietin-mediated protection from ischemic injury has not been well-studied. To answer this question, we induced reproducible necrotic ischemic injury in primary mouse renal tubular epithelial cells (RTEC) in vitro. Using RTEC from erythropoietin receptor mutant mice with differential STAT5 signaling capabilities, we demonstrated first, that EPO administration either before or during injury significantly protects against mild-moderate but not severe necrotic cell death; and second, the JAK2/Y343/STAT5 signaling axis is required for protection against ischemic injury in primary mouse RTEC. In addition, we identified Pim-3, a prosurvival STAT5 target gene, as responsive to EPO in the noninjured kidney both in vitro and in vivo.

Acute kidney injury: changing lexicography, definitions, and epidemiology.

In recent years, there have been numerous advances in understanding the molecular determinants of functional kidney injury after ischemic and/or toxic exposure. However, translation of successful novel therapies designed to attenuate kidney functional injury from animal models to the clinical sphere has had modest results. This lack of translatability is at least in part due to lack of sufficient standardization in definitions and classification of cases of acute kidney injury (AKI), an incomplete understanding of the natural history of human AKI, and a limited understanding of how kidney injury interacts with other organ system failure in the context of systemic metabolic abnormalities. A concerted effort is now being made by nephrologists and intensivists to arrive at standardized terminology and classification of AKI. There have also been dramatic advances in our understanding of the epidemiology and natural history of AKI, particularly in the hospital and intensive care unit setting. Promising strategies are now being developed which may ultimately lead to improved outcomes for patients at risk for or who have developed AKI, which should be readily testable in the coming decade.

Association of intradialytic blood pressure changes with hospitalization and mortality rates in prevalent ESRD patients.

The relationship between blood pressure (BP) and clinical outcomes among hemodialysis patients is complex and incompletely understood. This study sought to assess the relationship between blood pressure changes with hemodialysis and clinical outcomes during a 6-month period. This study is a secondary analysis of the Crit-Line Intradialytic Monitoring Benefit Study, a randomized trial of 443 hemodialysis subjects, designed to determine whether blood volume monitoring reduced hospitalization. Logistic regression was used to estimate the association between BP changes with hemodialysis (Deltasystolic blood pressure=postdialysis-predialysis systoic BP (SBP) and the primary outcome of non-access-related hospitalization and death. Subjects whose systolic blood pressure fell with dialysis were younger, took fewer blood pressure medications, had higher serum creatinine, and higher dry weights. After controlling for baseline characteristics, lab variables, and treatment group, subjects whose SBP remained unchanged with hemodialysis (N=150, DeltaSBP -10 to 10 mm Hg) or whose SBP rose with hemodialysis (N=58, DeltaSBP > or =10 mm Hg) had a higher odds of hospitalization or death compared to subjects whose SBP fell with hemodialysis (N=230, DeltaSBP < or =-10 mm Hg) (odds ratio: 1.85, confidence interval: 1.15-2.98; and odds ratio: 2.17, confidence interval: 1.13-4.15). Subjects whose systolic blood pressure fell with hemodialysis had a significantly decreased risk of hospitalization or death at 6 months, suggesting that hemodynamic responses to dialysis are associated with short-term outcomes among a group of prevalent hemodialysis subjects. Further research should attempt to elucidate the mechanisms behind these findings.

Mortality after acute renal failure: models for prognostic stratification and risk adjustment.

To adjust adequately for comorbidity and severity of illness in quality improvement efforts and prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately identified. Most epidemiological studies of ARF in the critically ill have been based at single centers, or have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality). We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multi-center observational study of ARF. We determined correlates of mortality in 618 patients with ARF in intensive care units using three distinct analytic approaches. The predictive power of models using information obtained on the day of ARF diagnosis was extremely low. At the time of consultation, advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality; higher blood urea nitrogen and lower serum creatinine were also associated with mortality in logistic regression models. Models incorporating time-varying covariates enhanced predictive power by reducing misclassification and incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill patients, we developed several predictive models for prognostic stratification and risk-adjustment. By incorporating exposures over time, the discriminatory power of predictive models in ARF can be significantly improved.

Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients.

AIMS: Cardiovascular mortality has been reported to be 10- to 20-fold higher in chronic dialysis patients than in the age-matched general population. It has been suggested that increased oxidant stress and resulting vascular wall injury due to uremia and the hemodialysis procedure may be one of the mechanisms predisposing to these cardiovascular complications. Further, hemodialysis membrane bioincompatibility can contribute to increased oxidative stress and prevalence of inflammation. MATERIALS: We studied 18 chronic hemodialysis (CHD) patients (age 62.8 +/- 14.7 years, 39% male, 61% African-American, 44% insulin-dependent diabetic, 61% smokers, 61% with documented coronary artery disease) during hemodialysis with 2 membranes with different flux and complement activating properties. METHODS: We have measured free and phospholipid-bound F2-isoprostane (F2-IsoP) levels, a sensitive marker of oxidative stress, in CHD patients and compared them to levels in healthy subjects. We have also examined the acute effects of the hemodialysis procedure using both biocompatible and bioincompatible membranes on F2-IsoP levels. RESULTS: The results indicated that, compared to controls, both free (96.2 +/- 48.8 pg/ml versus 37.6 +/- 17.2 pg/ml) and bound F2-IsoP (220.4 +/- 154.8 pg/ml versus 146.8 +/- 58.4 pg/ml) levels were significantly higher (p < 0.05 for both). There was a statistically significant decrease in free F2-IsoP concentrations at 15 and 30 minutes of HD, which rebounded to baseline levels at the completion of the procedure. There were no significant differences in F2-IsoP concentrations between the 2 study dialyzers at any time point. Age, smoking status, diabetes mellitus and presence of cardiovascular disease were also not correlated with F2-IsoP levels in this patient population. There was a significant association between predialysis F2-IsoP and C-reactive protein concentrations. CONCLUSION: Using a sensitive and specific assay for the measurement of F2-IsoP, we demonstrated that CHD patients are under increased oxidative stress. During a single hemodialysis treatment, the hemodialysis membrane appears to have no discernable effect on oxidative stress status. Measurement of F2-isoprostanes may be a useful biomarker of oxidative stress status as well as in developing new therapeutic strategies to ameliorate inflammatory and oxidative injury in this patient population.

Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients.

Oxidative stress has been implicated in the cardiovascular complications that affect chronic renal failure patients on hemodialysis, though the physiologically relevant pathways mediating oxidative damage are poorly understood. It is known, however, that hemodialysis activates neutrophils, a well-characterized source of hydrogen peroxide and myeloperoxidase. The phagocyte-derived myeloperoxidase-hydrogen peroxide-chloride system generates hypochlorous acid, which reacts with tyrosine residues of proteins to form 3-chlorotyrosine. To explore the role of activated phagocytes in oxidative stress in chronic renal failure, we used 3-chlorotyrosine as a specific marker of myeloperoxidase activity. Utilizing isotope dilution gas chromatography-mass spectrometry, we compared 3-chlorotyrosine levels in plasma proteins of five patients on chronic hemodialysis therapy with those of age- and sex-matched healthy controls. The oxidized amino acid was present in the plasma proteins of 4 of the hemodialysis patients (3.5 +/- 0.8 micromol per mol tyrosine) but was undetectable in the healthy subjects. Therefore, one pathway for oxidative stress in hemodialysis patients appears to involve hypochlorous acid generated by the myeloperoxidase system of activated phagocytes. We also examined intradialytic 3-chlorotyrosine levels using membranes that activate white blood cells and the alternative pathway of complement. Hemodialysis increased plasma myeloperoxidase and the expression of CD11b/CD18 by circulating phagocytes, but failed to demonstrably increase 3-chlorotyrosine levels. 3-chlorotyrosine was detectable in 12 of 19 samples in total, with significant intrasubject variability. Our observations suggest that oxidants generated by myeloperoxidase contribute to the increased oxidative stress observed in renal-failure patients but do not damage plasma proteins during the hemodialysis procedure itself.

Citric acid ingestion: a life-threatening cause of metabolic acidosis.

We present a case that illustrates the acute (<6 hours) metabolic and hemodynamic effects of the ingestion of a massive oral citric acid load. The principal findings included metabolic acidosis accompanied by an increase in the plasma anion gap that was not caused by L -lactic acidosis, hyperkalemia, and the abrupt onset of hypotension. A unique feature was a dramatic clinical improvement when ionized calcium was infused. The case illustrates the importance of considering the properties of the conjugate base (anion) of the added acid because, in this instance, the citrate anion had a unique and life-threatening consequence (lower ionized calcium level) that was rapidly reversible.

Recombinant human growth hormone in patients with acute renal failure.

OBJECTIVE: The objective of this study is to determine the impact of recombinant human growth hormone (rhGH) on metabolic and nutritional parameters in malnourished patients with acute renal failure. DESIGN: The design is an open-labeled pilot trial examining the effects of rhGH administration in a small group of highly catabolic, malnourished patients with acute renal failure. Each patient served as his or her own control. SETTING: An intensive care unit in a tertiary care medical institution. PATIENTS: Five patients with established acute renal failure in a critical care unit. Entry criteria included clinical evidence of malnutrition: a serum albumin level of <3.2 g/dL, a prealbumin level of < or = 20 mg/dL, and an insulin-like growth factor IGF 1 level <200 ng/mL. The study consisted of 3 periods: phase I, 3 day baseline; phase II, 6 day treatment; and phase III, 3 day washout. During the entire study, blood and urine samples were obtained daily to calculate normalized protein catabolic rate, total nitrogen appearance rate (TNA), and nitrogen balance. Additional data were collected to measure metabolic and inflammatory parameters. INTERVENTION: The intervention consisted of administering 100 microg/kg/d of rhGH for 6 days. RESULTS: There were significant changes in TNA, normalized protein catabolic rate, and nitrogen balance during the 3 study phases. TNA decreased from 43.3 +/- 24.4 g/d in phase I, to 25.2 +/- 16.5 g/d during phase II (P <.001). There was a further decrease in TNA to 16.2 +/- 8.3 g/d during phase III (P <.001 v phase I). Nitrogen balance improved from - 31.8 +/- 21.4 g/d during phase I, to - 12.9 +/- 10.3 g/d during phase II (P <.001), and further improved to - 4.1 +/- 4.0 g/d in phase III (P <.001 v phase I). Significant changes were also noted in levels of blood urea nitrogen, phosphorous, serum growth hormone, IGF-1, and serum leptin levels after growth hormone administration. A statistically significant increase in serum albumin was noted in phase III (3.1 g/dL) versus phase I (2.7 +/- 0.7 g/dL). CONCLUSIONS: Administration of rhGH to critically ill patients with acute renal failure resulted in improvements in negative nitrogen balance and a significant decrease in total nitrogen appearance rate. These changes corresponded to increases in serum growth hormone, IGF-1, IGF-1 binding protein 3, and leptin levels after growth hormone administration.

Albumin is the major plasma protein target of oxidant stress in uremia.

BACKGROUND: Patients with uremia are exposed to increased oxidative stress. Examination of the oxidation of individual plasma proteins may be useful in establishing specific pathways of oxidative stress in vivo and in determining functional consequences of oxidant stress exposure. We therefore examined oxidative modification of plasma proteins by carbonyl formation using Western blot immunoassay and enzyme-linked immunosorbent assay (ELISA) techniques in patients with chronic renal failure (CRF) and on chronic hemodialysis therapy (HD). METHODS: Plasma was obtained from 25 HD, 20 CRF, and 20 healthy volunteers, derivatized with 2,4 dinitrophenylhydrazine (DNP) and electrophoresed on duplicate 4 to 12% gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels, transferred to nitrocellulose, and stained for DNP for carbonyls and amido black for protein content. Data are recorded as DNP area/protein area and are reported in densitometry units. Total plasma carbonyls were determined by ELISA. RESULTS: Plasma albumin is substantially more oxidized in HD than in healthy volunteers (1.22 +/- 0.14 densitometry units vs. 0.60 +/- 0.08, P = 0.002). There were no significant differences in oxidation of plasma transferrin, immunoglobulin, and fibrinogen in HD versus healthy volunteers. In CRF patients, plasma albumin is more oxidized compared with normal volunteers (1.36 +/- 0.20 densitometry units vs. 0.94 + 0.08, P = 0.09). There were no differences in oxidation of plasma transferrin, fibrinogen, and immunoglobulin in CRF patients versus healthy volunteers. An increased plasma protein carbonyl concentration in CRF patients compared with healthy volunteers was confirmed by ELISA (0.31 +/- 0.07 vs. 0.04 +/- 0.01 nmol/mg protein (P = 0.001). CONCLUSION: Albumin is the major plasma protein target of oxidant stress in CRF and HD patients.

Plasma protein thiol oxidation and carbonyl formation in chronic renal failure.

BACKGROUND: Myeloperoxidase-catalyzed oxidative pathways have recently been identified as an important cause of oxidant stress in uremia and hemodialysis (HD), and can lead to plasma protein oxidation. We have examined patterns of plasma protein oxidation in vitro in response to hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). We measured thiol oxidation, amine oxidation, and carbonyl concentrations in patients on chronic maintenance HD compared with patients with chronic renal failure (CRF) and normal volunteers. We have also examined the effect of the dialysis procedure on plasma protein oxidation using biocompatible and bioincompatible membranes. METHODS: Plasma proteins were assayed for the level of free thiol groups using spectrophotometry, protein-associated carbonyl groups by enzyme-linked immunosorbent assay, and oxidation of free amine groups using a fluorescent spectrophotometer. RESULTS: In vitro experiments demonstrate HOCl oxidation of thiol groups and increased carbonyl formation. In vivo, there are significant differences in plasma-free thiol groups between normal volunteers (279 +/- 12 micromol/L), CRF patients (202 +/- 20 micromol/L, P = 0.005) and HD patients (178 +/- 18 micromol/L, P = 0.0001). There are also significant differences in plasma protein carbonyl groups between normal volunteers (0.76 +/- 0.51 micromol/L), CRF patients (13.73 +/- 4.45 micromol/L, P = 0.015), and HD patients (16.95 +/- 2.62 micromol/L, P = 0.0001). There are no significant differences in amine group oxidation. HD with both biocompatible and bioincompatible membranes restored plasma protein thiol groups to normal levels, while minimally affecting plasma protein carbonyl expression. CONCLUSIONS: First, both CRF and HD patients have increased plasma protein oxidation manifested by oxidation of thiol groups and formation of carbonyl groups. Second, HD with biocompatible and bioincompatible membranes restored plasma protein thiol groups to normal levels. Third, these experiments suggest that there is a dialyzable low molecular weight toxin found in uremia that is responsible for plasma protein oxidation.

Quantitating urea removal in patients with acute renal failure: lost art or forgotten science?

A 67-year-old woman is admitted to the surgical service with a high fever, a painful and distended abdomen, jaundice, and almost complete anuria. A urinalysis revealed dark red-brown urine notable for albuminuria, erythrocytes, leukocytes, and casts. The patient was treated with antibiotics, but continued to have oligoanuria. On the eighth day of hospitalization, the following laboratory tests were obtained: serum potassium, 13.7 mEq/L; BUN, 396 mg/dl. At this time the patient was noted to be encephalopathic with deteriorating clinical condition. Renal replacement therapy was initiated. The characteristics of the initial dialysis treatment are described in Table 1. After the initial dialysis treatment, the patient went on to become nonoliguric, followed by gradual recovery of urea clearance. She survived her acute illness, left the hospital, and at 7 months posthospitalization was doing quite well.

HLA-DMA allele polymorphism: no impact on kidney allograft outcome.

The purpose of this study was to analyze the association of HLA-DMA alleles with rejection episodes and early graft loss (EGL) in renal transplant recipients. One hundred and eighty four HLA-DMA alleles were retrospectively analyzed by DNA sequence analysis in 92 kidney transplant recipients. The gene frequencies of HLA-DMA *0101, *0102, *0103 and *0104 were found to be similar in all recipients, regardless of rejection vs non rejection episodes and EGL incidence. In conclusion, HLA-DMA allele polymorphism did not impact renal allograft outcome.

Pharmacologic prevention of vascular access stenosis.

Vascular access dysfunction continues to result in substantial morbidity for chronic hemodialysis patients. Pharmacologic and molecular biologic approaches to prevention of vascular access dysfunction, if clinically successful, will be cost effective and improve quality of life for chronic dialysis patients. This review summarizes currently available information and future prospects in pharmacologic and molecular biologic approaches to preventing vascular access stenosis.

Measurement of the delivery of dialysis in acute renal failure.

BACKGROUND: Recent studies in patients with acute renal failure (ARF) have shown a relationship between the delivered dose of dialysis and patient survival. However, there is currently no consensus on the appropriate method to measure the dose of dialysis in ARF patients. In this study, the dose of dialysis was measured by blood- and dialysate-based kinetic methods in a group of ARF patients who required intermittent hemodialysis. METHODS: Treatments were performed using a Fresenius 2008E volumetric hemodialysis machine with the ability to fractionally collect the spent dialysate. Single-, double-pool, and equilibrated Kt/V were determined from the pre-, immediate post-, and 30-minute post-blood urea nitrogen (BUN) measurements. The solute reduction index was determined from the collected dialysate, as well as the single- and double-pool Kt/V. RESULTS: Forty-six treatments in 28 consecutive patients were analyzed. The mean prescribed Kt/V (1.11 +/- 0.32) was significantly greater than the delivered dose estimated by single-pool (0.96 +/- 0.33), equilibrated (0.84 +/- 0.28), and double-pool (0.84 +/- 0.30) Kt/V (compared with prescribed, each P < 0.001). There was no statistical difference between the equilibrated and double-pool Kt/V (P = NS). The solute removal index, as determined from the dialysate, corresponded to a Kt/V of 0.56 +/- 0.27 and was significantly lower than the single-pool and double-pool Kt/V (each P < 0.001). CONCLUSION: Blood-based kinetics used to estimate the dose of dialysis in ARF patients on intermittent hemodialysis provide internally consistent results. However, when compared with dialysate-side kinetics, blood-based kinetics substantially overestimated the amount of solute (urea) removal.

Increased susceptibility to erythrocyte C5b-9 deposition and complement-mediated lysis in chronic renal failure.

BACKGROUND: Decreased red blood cell survival contributes to the anemia of chronic renal failure patients. Because patients on chronic dialysis therapy are frequently exposed to excessive complement activation, we investigated the susceptibility of this patient population to erythrocyte C5b-9 deposition, complement-mediated lysis, and ghost formation. METHODS: We developed a flow cytometric assay using antibodies to both glycophorin and the C5b-9 complex to detect C5b-9 deposition on intact erythrocytes and erythrocyte ghosts. Serum C5b-9 levels and C5b-9 deposition on erythrocyte ghosts were measured by enzyme-linked immunosorbent assay. RESULTS: A significant increase in C5b-9 deposition on intact erythrocytes was demonstrated in patients with advanced chronic renal failure (2.2 +/- 0.5%) and in patients on chronic maintenance hemodialysis (2.3 +/- 0.4%) compared with normal volunteers (0.9 +/- 0.1%, P = 0.005 vs. chronic renal failure, P < 0.001 vs. chronic hemodialysis patients). There was also a significantly higher percentage of C5b-9-positive erythrocyte ghosts in patients with advanced chronic renal failure (20.6 +/- 5%) and in chronic hemodialysis patients (15.5 +/- 3.1%) compared with normal controls (2.6 +/- 0.9%, P < or = 0.001 vs. advanced chronic renal failure and chronic hemodialysis patients). Treatment of erythrocyte preparations with cobra venom factor, which activates the complement cascade, resulted in dramatic increases in the percentages of C5b-9-positive erythrocyte ghosts in patients with chronic renal failure (49.9 +/- 6.9%) and in chronic hemodialysis patients (45.0 +/- 4.2%) compared with normal volunteers (22.3 +/- 2.7%, P < 0.001 vs. chronic renal failure and chronic hemodialysis patients). Erythrocyte membrane expression of the complement regulatory proteins CD59 and CD55 did not significantly differ between normal controls and hemodialysis patients. Plasma C5b-9 levels after cobra venom factor stimulation were higher in chronic renal failure patients (538 micrograms/ml) compared with normal controls (345 micrograms/ml, P < 0.001). CONCLUSIONS: Patients with chronic renal failure and on hemodialysis therapy are susceptible to erythrocyte C5b-9 deposition with subsequent lysis and ghost formation. Susceptibility to complement-mediated erythrocyte injury may contribute to the anemia of chronic renal disease.