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.     

Hyperparathyroidism and dialysis vintage

BACKGROUND: Secondary hyperparathyroidism and its effects on bone and viscera are among the most important complications of end-stage renal disease. Despite its ubiquity, little is known about the treated natural history of the disorder. METHODS: We assembled a cohort of 310 patients with endstage renal disease on hemodialysis who were participants in one of four clinical trials of the phosphate binder sevelamer. Baseline parathyroid hormone levels were collected, and the relation between dialysis vintage and other clinical variables with parathyroid hormone were described. RESULTS: There was a direct relation between dialysis vintage and the severity of hyperparathyroidism. Other variables that were significantly associated with PTH on univariate analysis included age, African American race, Kt/V, and the serum concentrations of calcium, phosphate, and bicarbonate. Multivariable linear regression analysis yielded three significant predictors of PTH: calcium, phosphorus, and vintage (5.8% (4.0-7.5%) expected increase in PTH per year of vintage). The model R2 was 0.22. CONCLUSION: Dialysis vintage is a key determinant of the severity of secondary hyperparathyroidism. Vintage and certain laboratory variables should be considered in the evaluation of therapies aimed at modifying the treated natural history of this disorder.     

Predicting acute renal failure after coronary bypass surgery: cross-validation of two risk-stratification algorithms

BACKGROUND: Acute renal failure (ARF) requiring dialysis after coronary artery bypass grafting (CABG) occurs in 1 to 5% of patients and is independently associated with postoperative mortality, even after case-mix adjustment. A risk-stratification algorithm that could reliably identify patients at increased risk of ARF could help improve outcomes. METHODS: To assess the validity and generalizability of a previously published preoperative renal risk-stratification algorithm, we analyzed data from the Quality Measurement and Management Initiative (QMMI)1 patient cohort. The QMMI includes all adult patients (N = 9498) who underwent CABG at 1 of 12 academic tertiary care hospitals from August 1993 to October 1995. ARF requiring dialysis was the outcome of interest. Cross-validation of a recursive partitioning algorithm developed from the VA Continuous Improvement in Cardiac Surgery Program (CICSP) was performed on the QMMI. An additive severity score derived from logistic regression was also cross-validated on the QMMI. RESULTS: The CICSP recursive partitioning algorithm discriminated well (ARF vs. no ARF) in QMMI patients, even though the QMMI cohort was more diverse. Rates of ARF were similar among risk subgroups in the CICSP tree, as was the overall ranking of subgroups by risk. Using logistic regression, independent predictors of ARF in the QMMI cohort were similar to those found in the CICSP. The CICSP additive severity score performed well in the QMMI cohort, successfully stratifying patients into low-, medium-, high-, and very high-risk groups. CONCLUSIONS: The CICSP preoperative renal-risk algorithms are valid and generalizable across diverse populations.     

预防造影剂肾病回到基础

在本期杂志，Merten及其同事^1向我们提供了造影剂肾病的重要资料，该病正在成为急性肾脏病的研究热点。作者在119例基线血清肌酐至少1．1mg／dL的患者比较了0．9％氯化钠溶液与等渗碳酸氢钠溶液对造影剂肾病的预防作用。两者均于造影术前1小时开始以每小时3mL／kg的速度给药，并于造影后以每小时1mL／kg的速度继续给药6小时。碳酸氢钠组只有不足2％患者出现造影剂肾病（其定义为造影后血清肌酐上升≥25％），而生理盐水组发生率则高达14％。碳酸氢钠组造影剂肾病2％的发生率也在随后进行的开放性随访登记（open-label follow-up registry）观察中得到证实。作者认为碳酸氢钠对尿液pH值的影响可使氧自由基生成减少，从而减轻造影剂肾损伤。     

Specificity of cytotoxic effector cells directed against trinitrobenzene sulfonate-modified syngeneic cells. Failure to recognize cell surface- bound trinitrophenyl dextran

Mouse splenic lymphocytes and lymphoid tumor cells were modified with the trinitrophenyl (TNP) group either by treatment with trinitrobenzene sulfonate (TNBS) (which covalently modifies cell surface proteins) or with TNP stearoyl dextran (TSD) (which binds to the cell by noncovalent forces). These cell preparations were compared for their ability to: (a) sensitive syngeneic splenic lymphocytes leading to the generation of cytotoxic effector cells; (b) serve as lysable targets in a 4-h(51)Cr- release assay for effector cells generated in (a); and (c) act as blocking cells in the lysis of TNBS-medified targets lysed by TNP self effector cells generated in (a). In none of these three experimental systems did TSD-medified syngeneic spleen or H-2-matched tumor cells act either as a sensitizing immunogen or as a target antigen, despite the demonstration that quantitatively equivalent mounts of TNP were exposed on the cell surface in the TNBS- and TSD-modified cells. In contrast, TNBS-modified spleen cells sensitized syngeneic lymphocytes to generate effectors against TNBS-modified syageneic targets. Furthermore, TNBS- modified, H-2-matched cells served as specific lysable targets and as inhibiting cells for such effectors. These results indicate that the manner in which TNP is associated with the cell surface is important in the immunogenicity and antigenicity of hapten-modified syngeneic stimulating cells in generating H-2-associated cell-mediated lympholysis (CML) reactions. These findings raise the possibility that a covalent or at least a stable linkage with cell surface proteins (possibly H-2- controlled products) is important for immunological function. Furthermore, these observations do not favor the dual receptor model for H-2-restricted syngeneic CML if it is assumed in such a model that one receptor is specific for the TNP moiety and the second for unmodified self major histocompatibility products.     

Mixed lymphocyte reactivity and cell-mediated lympholysis to trinitrophenyl-modified autologous lymphocytes in C57BL/10 congenic and B10.A recombinant mouse strains

Cell-mediated lympholysis (CML) to trinitrophenyl (TNP)-modified autologous splenic lymphocytes has been recently reported in the mouse (1). Both the sensitization and effector phases of this phenomenon were shown to be T-cell mediated. Effector cell specificity studies indicated that modification of the target cells is a necessary but insufficient requirement for cytolysis, and suggested that altered cell surface components controlled by genes mapping in the mouse major histocompatibility H-2 complex (MHC) are important in the specificity of the cytotoxic reaction (1). In allogeneic models the generation of cytotoxic effector cells has been shown to be preceded or accompanied by immunogen- induced proliferation of responding lymphocytes, i.e. a mixed lymphocyte reaction (MLR) (2-5), although the generation of effectors may not necessarily always be the consequence of extensive cell proliferation (5). If the induction of cytotoxic effector lymphocytes by modified syngeneic spleen cells is characteristic of sensitization with cellular alloantigens, one would expect to find that sensitization with TNP-modified autologous cells would also induce thymidine incorporation by the responding cells in the culture. The present report demonstrates that both stimulation of thymidine incorporation and generation of cytotoxic effector cells are part of the in vitro response to TNP-modified autologous lymphocytes. However, the MLR to TNP- modified autologous cells consistently appeared to be less pronounced when compared with an allogeneic MLR, whereas the cytotoxic activity of the effector cells generated by sensitization against TNP-modified autologous cells was frequently as high as that detected against H-2 alloantigens. These two components of reactivity to “modified self” are verified in several C57BL/10 congenic and B10.A recombinant mouse strains.     

Detection of platelet-directed immunoglobin G in sera using the peroxidase-anti-peroxidase (PAP) slide technique

An immunohistochemical procedure for the detection of immunoglobulin G adherent to platelets is described. The peroxidase anti-peroxidase method is used to detect antibody activity directed against platelets from normal donors in the sera from 305 individuals. These subjects were divided into three groups: group 1, patients referred for tissue typing; group 2, healthy normal females; group 3, healthy normal males. In group 1, 28% of the sera were found to be positive; in most of these a history of prior transfusions was obtained. In group 2, 7.4% were found to be positive, most having previous pregnancies. Only 1% were found to be positive in group 3, and no reason for presensitization was found. Results from the indirect immunofluorescence technique served as a control and as a means to compare the sensitivity. Under the conditions chosen, the peroxidase anti-peroxidase test was two to eight times more sensitive than the immunofluorescence technique. Specificity of the peroxidase anti-peroxidase technique was demonstrated using a monospecific anti-PLA1 antiserum. It is concluded that the peroxidase anti-peroxidase slide technique may be a useful tool in the study of platelet-related immunophenomena.     

Elevated NAD(P) glycohydrolase activity: a possible enzymatic marker for malignancy in Burkitt's lymphoma cells

A comparative analysis of enzymatic activities has been performed on 47 human continuous lymphoid lines: 22 tumors derived from Burkitt's lymphoma lines, 6 other lymphomatous long-term cultures, and 19 nonmalignant ties determined on the cell extracts. 4 showed no significant differences between the various lines. They included adenosine diphosphoribose incorporation, glucose-6-phosphate dehydrogenase, cyclic-AMP phosphodiesterase, and glutathione reductase. However, striking differences of activity were found for the enzyme, NAD(P) glycohydrolase (EC 3.2.2.6). Activity levels were, as a mean, four times higher in Burkitt's lymphoma-derived cell lines than in nonmalignant control lines, and the difference was highly significant (p less than 0.02). All Burkitt cell lines containing translocations of chromosome 8 with either chromosomes 2, 14 or 22 showed an increased activity. The specificity and significance of this possible enzymatic marker of Burkitt's lymphoma cells is discussed.     

The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial

Background and objectives

The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.

Design, setting, participants, & measurements

Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.

Results

Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.

Conclusions

In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.