Jeffrey C. Fink

The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods

Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.

Clinical Course of Polyoma Virus Nephropathy in 67 Renal Transplant Patients

Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.

APOL1 risk variants, race, and progression of chronic kidney disease.

BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

The frequency of hyperkalemia and its significance in chronic kidney disease.

BACKGROUND Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality. METHODS This retrospective analysis of a national cohort comprised 2 103 422 records from 245 808 veterans with at least 1 hospitalization and at least 1 inpatient or outpatient serum potassium record during the fiscal year 2005. Chronic kidney disease and treatment with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers (blockers of the renin-angiotensin-aldosterone system [RAAS]) were the key predictors of hyperkalemia. Death within 1 day of a hyperkalemic event was the principal outcome. RESULTS Of the 66 259 hyperkalemic events (3.2% of records), more occurred as inpatient events (n = 34 937 [52.7%]) than as outpatient events (n = 31 322 [47.3%]). The adjusted rate of hyperkalemia was higher in patients with CKD than in those without CKD among individuals treated with RAAS blockers (7.67 vs 2.30 per 100 patient-months; P < .001) and those without RAAS blocker treatment (8.22 vs 1.77 per 100 patient-months; P < .001). The adjusted odds ratio (OR) of death with a moderate (potassium, >or=5.5 and <6.0 mEq/L [to convert to mmol/L, multiply by 1.0]) and severe (potassium, >or=6.0 mEq/L) hyperkalemic event was highest with no CKD (OR, 10.32 and 31.64, respectively) vs stage 3 (OR, 5.35 and 19.52, respectively), stage 4 (OR, 5.73 and 11.56, respectively), or stage 5 (OR, 2.31 and 8.02, respectively) CKD, with all P < .001 vs normokalemia and no CKD. CONCLUSIONS The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within 1 day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.

Chronic Renal Insufficiency Cohort (CRIC) Study: Baseline Characteristics and Associations with Kidney Function

BACKGROUND AND OBJECTIVES The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. RESULTS A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. CONCLUSIONS Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.

Risk for posttransplant diabetes mellitus with current immunosuppressive medications

With improvements in the practice of transplantation and the introduction of new immunosuppressive medications, there has been a substantial increase in 1-year allograft survival rates. Consequently, the pool of potential candidates for organ transplants continues to grow and a greater preponderance of older patients with more comorbidities are undergoing transplantation. As a result, there is interest in such medical complications as posttransplantation diabetes mellitus (PTDM) that develop after the transplantation of a successful allograft. PTDM is an undesirable consequence of transplantation because of its associated morbidity and impairment of both patient and graft survival. Although some controversy exists, it is likely that glucose intolerance after transplantation results in both macrovascular and microvascular disease, and there is an increasing risk for infectious and cardiovascular diseases, to which transplant recipients are already at increased susceptibility. Both experimental and clinical observations have shown that immunosuppressive agents currently used in transplantation account for a large degree of the increased risk for PTDM. Consequently, improved understanding of the effects of currently used immunosuppressive medicines on glycemic tolerance is of interest in clinical transplantation.

A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy.

Background. Laparoscopic donor nephrectomy (laparoNx) has the potential to increase living kidney donation rates by reducing the pain and suffering of the donor. However, renal function outcomes of a large series of recipients of laparoNx have not been studied. Methods. We retrospectively reviewed the records of 132 recipients of laparoNx done at our center between 3/96 and 11/97 and compared them to 99 recipients of kidneys procured by the open technique (openNx) done between 10/93 and 3/96. Results. Significantly more patients in the laparoNx group (25.2%) were taking tacrolimus within the first month than those in the openNx group (2.1%). Mean serum creatinine was higher in laparoNx compared with openNx at 1 week (2.860.3 and 1.860.2 mg/dl, respectively; P50.005) and at 1 month (2.060.1 and 1.660.1 mg/dl, P50.05) after transplant. However, by 3 and 6 months, the mean serum creatinine was similar in the two groups (1.760.1 versus 1.560.05 mg/dl, and 1.760.1 versus 1.760.1, respectively). By 1 year posttransplant, the mean serum creatinine for laparoNx was actually less than that for openNx (1.460.1 and 1.760.1 mg/dl, P50.03). Although patients in the laparoNx compared to the openNx group were more likely to have delayed graft function (7.6 versus 2.0%) and ureteral complications (4.5 versus 1.0%), the rate of other complications, as well as hospital length of stay, patient and graft survival rates were similar in the two groups. Conclusion. Although laparoNx allografts have slower initial function compared with openNx, there was no significant difference in longer term renal function. Kidney transplantation is considered to be the treatment of choice for end-stage renal failure. Insufficient supply of organs for donation has produced long waiting times for many patients who may benefit from transplantation (1). During this period patients accumulate the morbidity of renal failure, they must endure the lifestyle limitations of dialysis, and they often die while waiting for the organ sharing system to grant them this resource. Live donor renal transplantation represents a large potential supply of organs that may relieve much of this shortage. Additionally, recipients of live renal transplants may reap benefits of improved patient and allograft survival that have been clearly demonstrated in this population (2,3). Although unilateral nephrectomy has proven to be safe and the solitary kidney state has been found to be well tolerated in a carefully chosen candidate for donation (4,5), substantial disincentives to donation exist. These include a significant hospitalization, prolonged convalescence period with time away from jobs, intractable perioperative pain, and, for some, cosmetic concerns of the resulting

Human polyoma virus in renal allograft biopsies: Morphological findings and correlation with urine cytology

Human polyoma virus (PV) interstitial nephritis occurs in immunosuppressed patients after reactivation of latent virus in renal epithelium. Currently, there is neither general consensus about the incidence of clinically significant PV infection in renal transplants nor conclusive evidence determining its significance in the long-term graft outcome. We evaluated 601 renal transplant biopsy specimens (from 365 patients) by routine light microscopy and immunoperoxidase stains with antibody against SV40 (which cross reacts with PV). We also examined urine samples from 200 patients (100 obtained concurrently with a renal biopsy in patients presenting with acute graft dysfunction and 100 from patients with stable graft function). Electron microscopic evaluation was performed in 50 renal biopsy specimens and in 23% of all urine samples. PV was identified in 1.8% biopsy specimens (1.9% of patients). PV interstitial nephritis showed the typical viral cytopathic changes in tubular epithelial cells associated with marked tubular damage and a disproportionately mild degree of tubulitis. There was no difference in the incidence of PV in the urine of patients with acutely deteriorating versus stable renal function (18% and 19%, respectively); however, urines with large numbers of infected cells (> 10/cytospin) and inflammatory changes in the sediments corresponded invariably to patients with acute allograft dysfunction (8 of 8), and in most cases to biopsy specimens showing PV interstitial nephritis (7 of 8). Based on these findings, urine samples seem to be the most sensitive and cost-effective screening method for PV infection; only urine samples with inflamed sediments and abundant infected cells correlate with clinically significant disease. In these cases, examination of a renal biopsy is indicated. Immunohistochemical stains are useful to confirm the presence of PV but do not increase the sensitivity of diagnosis of PV if this is not already suspected on routine light microscopy. In our material, immunostains were helpful ruling out the presence of PV in a small number of biopsy specimens (2%) that showed markedly reactive tubular cells resembling PV infection. Most patients with PV interstitial nephritis responded to decreased immunosuppression; however, the decay in graft function (based on creatinine slopes) was significantly more rapid in these patients than in matched controls. Evidence of PV infection should be systematically sought in renal biopsy specimens and urine samples from renal allograft recipients.

The Use and Interpretation of Quasi-Experimental Studies in Infectious Diseases

Quasi-experimental study designs, sometimes called nonrandomized, pre-post-intervention study designs, are ubiquitous in the infectious diseases literature, particularly in the area of interventions aimed at decreasing the spread of antibiotic-resistant bacteria. Little has been written about the benefits and limitations of the quasi-experimental approach. This article outlines a hierarchy of quasi-experimental study design that is applicable to infectious diseases studies and that, if applied, may lead to sounder research and more-convincing causal links between infectious diseases interventions and outcomes.

Frequency of Hypoglycemia and Its Significance in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES This study set out to determine the incidence of hypoglycemia in patients with chronic kidney disease (CKD), with and without diabetes, and the association of hypoglycemia with mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective cohort analysis of 243,222 patients who had 2,040,206 glucose measurements and were cared for at the Veterans Health Administration. CKD was defined as an estimated GFR of <60 ml/min per 1.73 m(2). Hypoglycemia was set at <70 mg/dl. Mortality was measured 1 day after glucose measurement. RESULTS The incidence of hypoglycemia was higher in patients with CKD versus without CKD. Among patients with diabetes, the rate was 10.72 versus 5.33 per 100 patient-months and among patients without diabetes was 3.46 versus 2.23 per 100 patient-months, for CKD versus no CKD, respectively. The odds of 1-d mortality were increased at all levels of hypoglycemia but attenuated in CKD versus no CKD. Adjusted odds ratios for 1-d mortality that were associated with glucose values of <50, 50 to 59, and 60 to 69 mg/dl, respectively, versus glucose of >or=70 mg/dl were 6.09, 4.10, and 1.85 for inpatient records from patients with CKD; 9.95, 3.79, and 2.54 for inpatients records from patients without CKD; 6.84, 3.28, and 3.98 for outpatient records from patients with CKD; and 13.28, 7.36, and 4.34 for outpatient records from patients without CKD. CONCLUSIONS CKD is a risk for hypoglycemia, with or without diabetes. The excessive mortality associated with hypoglycemia makes this complication a significant threat to patient safety in CKD.