Peter J. Conlon

The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery

BACKGROUND Acute renal injury is a common serious complication of cardiac surgery. Moderate hemodilution is thought to reduce the risk of kidney injury but the current practice of extreme hemodilution (target hematocrit 22% to 24%) during cardiopulmonary bypass (CPB) has been linked to adverse outcomes after cardiac surgery. Therefore we tested the hypothesis that lowest hematocrit during CPB is independently associated with acute renal injury after cardiac surgery. METHODS Demographic, perioperative, and laboratory data were gathered for 1,404 primary elective coronary bypass surgery patients. Preoperative and daily postoperative creatinine values were measured until hospital discharge per institutional protocol. Stepwise multivariable linear regression analysis was performed to determine whether lowest hematocrit during CPB was independently associated with peak fractional change in creatinine (defined as the difference between the preoperative and peak postoperative creatinine represented as a percentage of the preoperative value). A p value of less than 0.05 was considered significant. RESULTS Multivariable analyses including preoperative hematocrit and other perioperative variables revealed that lowest hematocrit during CPB demonstrated a significant interaction with body weight and was highly associated with peak fractional change in serum creatinine (parameter estimate [PE] = 4.5; p = 0.008) and also with highest postoperative creatinine value (PE = 0.06; p = 0.004). Although other renal risk factors were significant covariates in both models, TM50 (an index of hypotension during CPB) was notably absent. CONCLUSIONS These results add to concerns that current CPB management guidelines accepting extreme hemodilution may contribute to postoperative acute renal and other organ injury after cardiac surgery.

Silastic cuffed catheters for hemodialysis vascular access: thrombolytic and mechanical correction of malfunction.

Silastic cuffed catheters are assuming a greater role in providing long-term vascular access for hemodialysis patients. However, catheter thrombosis, fibrin sheath formation, and catheter malposition are recurrent problems that reduce extracorporeal flow rates and shorten catheter life. We reviewed 163 consecutive episodes of catheter malfunction that occurred in 121 catheters in 88 patients over a 3.5-year period. Intraluminal instillation of urokinase was successful in reestablishing an extracorporeal flow rate of > or = 300 mL/min in 74% of episodes. The 42 remaining episodes (26%) were radiologically evaluated. Two catheters required replacement for catheter kinking or insufficient catheter length. Two additional catheters were malpositioned; both were successfully repositioned with percutaneous techniques. A fibrin sheath was detected encasing the catheter in 38 instances. The fibrin sheath was successfully stripped from the distal portion of the catheter in 36 of the 38 instances. Using endoluminal thrombolytic therapy and percutaneous mechanical techniques, we have extended the mean survival for catheters intended for permanent vascular access to 12.7 months and have allowed 95% of the catheters inserted for temporary use to reach their use goal. Tunnel tract infection and catheter-mediated bacteremia were the primary reasons for catheter removal.

Bacterial endocarditis in hemodialysis patients

Infective endocarditis (IE) is one of the most serious complications of bacteremia. Hemodialysis patients with prosthetic vascular access devices such as dual-lumen cuffed venous catheters and polytetrafluoroethylene (PTFE) grafts are at increased risk for bacteremia compared with patients with primary arteriovenous fistulae (PAVF). We present 20 cases of IE in hemodialysis patients seen at our institution over a 7-year period. Eight patients had PTFE grafts, 11 had dual-lumen cuffed catheters, and one had a PAVF. All patients underwent transthoracic echocardiography (TTE) and 16 patients also received transesophageal echocardiography (TEE). The Duke Criteria were used to characterize patients as definite or possible IE. Organisms were Staphylococcus aureus (55%), Staphylococcus epidermidis (25%), and Enterococcus sp (10%). The mitral valve (50%) was the most commonly affected valve, followed by aortic (30%) and right-sided IE (25%). Valve replacement was performed in five patients, of whom three survived hospitalization. The overall mortality rate for the series was 30%. All the dual-lumen cuffed catheters were removed, while only two of the eight PTFE grafts were removed. Four of the six patients who died had PTFE grafts, of which one was judged to be infected and removed. Echocardiography was essential to the diagnosis of IE. Vegetations were found in 50% by TTE and 81% by TEE. Six patients with no vegetations on TTE were found to have vegetations on TEE.

Preliminary report on the Association of Apolipoprotein E Polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients

Background Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery. Methods The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989–1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values. Results The &egr;4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the &egr;2 and &egr;3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. &egr;3, P = 0.038 vs. &egr;2). There was no difference in baseline creatinine among allele groups. Conclusions Inheritance of the apolipoprotein &egr;4 allele is associated with reduced postoperative increase in serum creatinine after cardiac surgery, compared with the &egr;3 or &egr;2 allele. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.

Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Clinical and Pathologic Features of Familial Focal Segmental Glomerulosclerosis

The occurrence of focal segmental glomerulosclerosis (FSGS) in a familial pattern has been rarely reported previously. Over the last 10 years we have treated 31 patients among eight families with familial FSGS. The diagnosis was confirmed by renal biopsy in 18 cases, and each family had at least two members in whom the diagnosis was confirmed histologically. Both males and females were affected, as were both blacks and whites. The mean age at presentation was 28 years, with a range of 8 to 56 years. The mean serum creatinine at presentation was 3.7 mg/dL. Twenty-five of the 31 patients progressed to end-stage renal disease; and treatment with prednisone did not appear to retard the progression to end-stage renal disease. Seven patients received a cadaveric renal transplant and none of them showed evidence of recurrence of disease in the graft. The pattern of inheritance in two families appeared to be autosomal dominant; in the other families the pattern of inheritance was less clear and may have been autosomal recessive, although a familial exposure to an unidentified environmental toxin cannot be excluded. Histologic examination of the renal tissue revealed a variety of changes previously described as occurring in FSGS. We conclude that FSGS may occur in a familial pattern that carries a poor prognosis. Further studies of these families may shed light on the pathogenesis of sporadic FSGS.

Predictors of prognosis and risk of acute renal failure in patients with Rocky Mountain spotted fever

BACKGROUND Acute renal failure has long been associated with severe Rocky Mountain spotted fever (RMSF). Despite many descriptions of the protean manifestations of this disease, relatively little is known concerning the risk factors for acute renal failure. Only a few studies have examined the outcome of patients infected with Rickettsia rickettsii who develop renal insufficiency, and these studies had methodological problems. OBJECTIVE To study the incidence, risk factors, and outcomes of acute renal failure in a large group of hospitalized patients with definite or probable RMSF. METHODS The clinical records of 114 patients with definite or probable RMSF were retrospectively reviewed to identify clinical and biochemical abnormalities at the time of admission that were associated with the development of acute renal failure and subsequent mortality. Renal failure was defined as a serum creatinine (Cr) above 2 mg/dL. Logistic regression was used to study the association between these variables and the outcomes during hospitalization: death and the development of acute renal failure. RESULTS The mortality rate in this series was 14%; 19% of the patients developed acute renal failure. The development of acute renal failure increased the odds ratio (OR) of dying by a factor of 17 (P = 0.001). Factors at the time of hospitalization that were associated at a univariate level with subsequent mortality included elevated serum Cr, increased age, increased level of AST, increased level of bilirubin, decreased serum sodium and platelet count, the presence of neurological involvement, and being male. Both the presence of neurological involvement and an elevated serum Cr at presentation were independently associated with increased mortality by multivariate analysis. Three patients developed acute renal failure that required hemodialysis, and only 1 of these 3 patients survived; he was ultimately discharged with a normal serum Cr. Factors at presentation that were associated with the development of acute renal failure included increased bilirubin, increasing age, thrombocytopenia, and the presence of neurological involvement. Both age and decreased platelet count at presentation were independently associated with the development of acute renal failure by multivariate analysis. CONCLUSION Acute renal failure was a frequent complication of RMSF in this series of patients from a tertiary referral medical center. The presence of acute renal failure was strongly associated with death. Clinical and biochemical variables are useful in predicting which patients will develop acute renal failure.

Linkage of a Gene Causing Familial Membranoproliferative Glomerulonephritis Type III to Chromosome 1

Membranoproliferative glomerulonephritis (MPGN) type III is a chronic progressive renal disease of unknown cause. The diagnosis is based on renal pathologic features (specifically immunofluorescence staining patterns and ultrastructural appearance). Mesangial cell proliferation and subendothelial and subepithelial deposits characterize the renal disease. Although the actual prevalence of this disease is not known, the disease is rare and usually sporadic. The clinical features of MPGN include the nephrotic syndrome and hematuria, with renal dysfunction occurring in approximately 50% of patients. Progression to end-stage renal disease is variable, and some patients exhibit stabilization or even improvement. Here is presented an Irish family in which there are eight affected members in four generations, suggesting autosomal dominant inheritance. This is the only reported family with an inherited form of MPGN type III. To evaluate the disease in this family, a genome-wide scan was performed with a panel of 402 polymorphic microsatellite markers, defining a grid with an average resolution of 10 cM (centimorgans). Significant evidence for linkage was observed on chromosome 1q31-32, with a maximal logarithm of the odds score of 3.86 at theta = 0.00 for microsatellite marker GATA135F02. Recombination events among affected individuals, as detected by haplotype analysis, established a 22-cM minimal candidate region flanked by markers D1S3470 and GATA124F08. The data provide evidence for a gene for familial MPGN on chromosome 1q.

Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure.

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30 ± 3% to 42 ± 3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the “Normal hematocrit Study”. Methods Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42 ± 3% and patients in Group B were maintained with a hematocrit of 30 ± 3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.Results The mean hematocrit increased in Group A from 29.1 ± 2.4% to 40.8 ± 5.2% after 30 weeks. The hematocrit in Group B remained stable at 30 ± 3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.Conclusion It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30 ± 3% to 42 ± 3% is not associated with increased blood pressure.

NORMALIZATION OF HEMATOCRIT IN HEMODIALYSIS PATIENTS DOES NOT AFFECT SILENT ISCHEMIA

Transient ST-segment depression measured on ambulatory ECG monitors has been described as representing silent ischemia. Patients who demonstrate silent ischemia have been reported to show increased mortality compared to patients without silent ischemia. We undertook this study to determine if the correction of anemia in End Stage Renal Disease (ESRD) patients from(± = standard deviation) 30 ± 3 to 42 ± 3 with the use of Epoetin alfa would result in decreased silent ischemia in patients with clinically evident ischemic heart disease or congestive heart failure. Methods: Thirty one ESRD patients with congestive heart failure or patients with clinically-evident ischemic heart disease were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42 ± 3% and patients in Group B were maintained with a hematocrit of 30 ± 3% throughout the course of the study. All patients had a 24 hour Holter monitor recording at baseline and at 28 weeks after randomization (when they had reached their target hematocrit). Significant silent ischemia was considered to be present if patients demonstrated at least 60 seconds of ≥ 1 mm ST segment depression. Results: Fifteen patients were randomized to Group A and 16 patients were randomized to Group B. The mean hematocrit increased in group A from 29.1 ± 2.4% to 40.8 ± 5.2% after 30 weeks. The mean hematocrit in Group B remained stable at 30 ± 3% throughout the course of the study. Ten patients demonstrated silent ischemia at baseline. At follow up patients in group A demonstrated a mean of 1.7 ± 4.9 minutes of ischemia compared to 1.1 ± 3.4 minutes in group B. These were not significantly different. A similar number of patients in group A and Group B required adjustments in their anti-anginal medication during the course of the study. Conclusion: It is possible to increase hematocrit to near normal levels in hemodialysis with the administration of exogenous Epoetin alfa. The increase in hematocrit form 30 ± 3% to 42 ± 3% is not associated with a change in the level of silent ischemia these patients demonstrate.