Showing papers in "Clinical Journal of The American Society of Nephrology in 2007"

Septic Acute Kidney Injury in Critically Ill Patients: Clinical Characteristics and Outcomes

Abstract: Sepsis is the most common cause of acute kidney injury (AKI) in critical illness, but there is limited information on septic AKI. A prospective, observational study of critically ill patients with septic and nonseptic AKI was performed from September 2000 to December 2001 at 54 hospitals in 23 countries. A total of 1753 patients were enrolled. Sepsis was considered the cause in 833 (47.5%); the predominant sources of sepsis were chest and abdominal (54.3%). Septic AKI was associated with greater aberrations in hemodynamics and laboratory parameters, greater severity of illness, and higher need for mechanical ventilation and vasoactive therapy. There was no difference in enrollment kidney function or in the proportion who received renal replacement therapy (RRT; 72 versus 71%; P = 0.83). Oliguria was more common in septic AKI (67 versus 57%; P < 0.001). Septic AKI had a higher in-hospital case-fatality rate compared with nonseptic AKI (70.2 versus 51.8%; P < 0.001). After adjustment for covariates, septic AKI remained associated with higher odds for death (1.48; 95% confidence interval 1.17 to 1.89; P = 0.001). Median (IQR) duration of hospital stay for survivors (37 [19 to 59] versus 21 [12 to 42] d; P < 0.0001) was longer for septic AKI. There was a trend to lower serum creatinine (106 [73 to 158] versus 121 [88 to 184] mumol/L; P = 0.01) and RRT dependence (9 versus 14%; P = 0.052) at hospital discharge for septic AKI. Patients with septic AKI were sicker and had a higher burden of illness and greater abnormalities in acute physiology. Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT.

Obesity and Obesity-Initiated Metabolic Syndrome: Mechanistic Links to Chronic Kidney Disease

Abstract: There is an epidemic of obesity and the metabolic syndrome in the United States and across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular disease. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD). Several recent epidemiologic studies have shown that obesity and the metabolic syndrome are independent predictors of CKD. In addition to diabetes and hypertension, several other mechanisms have been postulated to initiate and maintain kidney injury in patients with obesity and the metabolic syndrome. This article reviews the recent epidemiologic data linking obesity and the metabolic syndrome to CKD and summarizes the potential mechanisms of renal injury in this setting, with a focus on the role of inflammation, lipotoxicity, and hemodynamic factors. Potential preventive and therapeutic modalities based on the limited evidence available are discussed.

Adult Minimal-Change Disease: Clinical Characteristics, Treatment, and Outcomes

Abstract: Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and alternate-day-treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD.

Microalbuminuria and Cardiovascular Disease

Abstract: To reduce the burden of cardiovascular disease (CVD), management strategies are increasingly focusing on preventive measures following early detection of markers of atherosclerosis. This review focuses on microalbuminuria, which is gaining recognition as a simple marker of an atherogenic milieu. Prospective and epidemiologic studies have found that microalbuminuria is predictive, independently of traditional risk factors, of all-cause and cardiovascular mortality and CVD events within groups of patients with diabetes or hypertension, and in the general population. The pathophysiologic mechanism underlying the association between albumin excretion and CVD is not fully defined. One hypothesis is that microalbuminuria may be a marker of CVD risk because it reflects subclinical vascular damage in the kidneys and other vascular beds. It may also signify systemic endothelial dysfunction that predisposes to future cardiovascular events. Based on this theory, periodic screening for microalbuminuria could allow early identification of vascular disease and help stratify overall cardiovascular risk, especially in patients with risk factors such as hypertension or diabetes. A positive test for urinary albumin excretion could signify the need for an intensive multifactorial intervention strategy, including behavior modification and targeted pharmacotherapy, aimed at preventing further renal deterioration and improving the overall CVD risk factor profile. Data from intervention studies suggest that treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, statins, and/or strict glycemic control (in diabetics) offer significant reductions in cardiovascular and/or renal morbidity in patients with albuminuria. Use of this (old) marker may allow improved use of medications and strategies for secondary prevention.

Hypomagnesemia in Patients with Type 2 Diabetes

Abstract: Hypomagnesemia has been reported to occur at an increased frequency among patients with type 2 diabetes compared with their counterparts without diabetes. Despite numerous reports linking hypomagnesemia to chronic diabetic complications, attention to this issue is poor among clinicians. This article reviews the literature on the metabolism of magnesium, incidence of hypomagnesemia in patients with type 2 diabetes, implicated contributing factors, and associated complications. Hypomagnesemia occurs at an incidence of 13.5 to 47.7% among patients with type 2 diabetes. Poor dietary intake, autonomic dysfunction, altered insulin metabolism, glomerular hyperfiltration, osmotic diuresis, recurrent metabolic acidosis, hypophosphatemia, and hypokalemia may be contributory. Hypomagnesemia has been linked to poor glycemic control, coronary artery diseases, hypertension, diabetic retinopathy, nephropathy, neuropathy, and foot ulcerations. The increased incidence of hypomagnesemia among patients with type 2 diabetes presumably is multifactorial. Because current data suggest adverse outcomes in association with hypomagnesemia, it is prudent to monitor magnesium routinely in this patient population and treat the condition whenever possible.

Serum and Dialysate Potassium Concentrations and Survival in Hemodialysis Patients

Abstract: Background and objectives: Controlling serum potassium is an important goal in maintenance hemodialysis patients. We examined the achievement of potassium balance through hemodialysis treatments and the associated fluctuations in serum potassium. Design, setting, participants, & measurements: A 3-yr (July 2001 to June 2004) cohort of 81,013 maintenance hemodialysis patients from all DaVita dialysis clinics across the United States were studied. Nine quarterly-averaged serum potassium groups ( Results: Serum potassium correlated with nutritional markers. Serum potassium between 4.6 and 5.3 mEq/L was associated with the greatest survival, whereas potassium Conclusions: A predialysis serum potassium of 4.6 to 5.3 mEq/L is associated with the greatest survival in maintenance hemodialysis patients. Hyperkalemic patients who undergo maintenance hemodialysis against lower dialysate bath may have better survival. Limitations of observational studies including confounding by indication should be considered when interpreting these results.

Progressive Vascular Calcification over 2 Years Is Associated with Arterial Stiffening and Increased Mortality in Patients with Stages 4 and 5 Chronic Kidney Disease

Abstract: Background and objectives: Vascular calcification is increasingly recognized as an important component of cardiovascular disease in chronic kidney disease. The objective of this study was to investigate prospectively the determinants, cardiovascular functional consequences, and survival associated with vascular calcification over 24 mo. Design, setting, participants, & measurements: A total of 134 patients (60 on hemodialysis, 28 on peritoneal dialysis, and 46 with stage 4 chronic kidney disease) were studied. Vascular calcification of the superficial femoral artery was assessed using multislice spiral computed tomography; pulse wave velocity; all medications and time-averaged biochemical parameters were recorded at baseline and 12 and 24 mo. Results: A total of 101 patients remained at 24 mo. Progressive calcification was seen in 58 of 101 patients. Most (31 of 46) patients with an initial calcification score of zero did not develop calcification. The hemodialysis group demonstrated a greater degree of progression than patients who were on peritoneal dialysis or had stage 4 chronic kidney disease. Progressive calcification was associated with age, male gender, serum alkaline phosphatase, β blockers, and lipid-lowering agents. Increases in vascular calcification correlated with increased arterial stiffness. Vascular calcification was present in 20 of 21 patients who died. Cox proportional hazard analysis identified change in calcification score, calcium intake from phosphate binders, and low albumin as risk factors for death. Conclusions: Patients with stages 4 and 5 chronic kidney disease and preexisting vascular calcification exhibit significantly increased calcification over 24 mo. Rapid progression of calcification is associated with arterial stiffness and mortality.

Fistula first initiative: advantages and pitfalls

Abstract: ### Vascular Access Care before 1997 The arteriovenous fistula (AVF) was first described and used as a reliable form of hemodialysis (HD) vascular access (VA) by Brescia et al. (1) in 1966. Improvements in dialysis technology and the expansion of dialysis eligibility ( e.g. , inclusion of patients with diabetes) resulted in a rapid growth of the ESRD population. Many of these patients benefited from the development of prosthetic grafts when autogenous AVF were not feasible (2–5). In the mid-1980s, permanent catheters (central venous catheters [CVC]) in the internal jugular vein became a means of prolonging temporary access (6–8) and dramatically increased in use. The cumulative effect was a reduction in AVF use and an increase in graft and CVC use in the 1990s. This was associated with increased patient care costs; for example, up to 73% of patients were hospitalized to initiate dialysis and almost invariably had a temporary CVC inserted. VA was a major cause of morbidity and mortality (9), with HD access failure accounting for the most frequent cause of hospitalizations (10) and complications accounting for 14% of all ESRD expenses ($1 billion annually) (9). ### 1997 to 2003: Critical Events That Affected VA Care In an effort to improve VA outcomes, the National Kidney Foundation published the Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Vascular Access in 1997. The goal was to optimize management of VA through a set of evidence- and opinion-based based guidelines (10). In the following year, Centers for Medicare and Medicaid Services (CMS; the government-reimbursement agency for Medicare-insured patients) developed ESRD clinical performance measures (CPM) based on the K/DOQI VA guidelines, in response to the Balanced Budget Act of 1997 (11). VA-related CPM include ( 1 ) the proportion of HD patients with AVF, ( 2 ) the proportion of HD patients with a CVC, and ( 3 ) monitoring arteriovenous grafts for stenosis. The overriding goal …

Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study

Abstract: Background and objectives: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. Design, setting, participants, & measurements: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of Results: Mean estimated GFR at baseline was 65.6 ± 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 ± 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 ± 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 ± 0.14 ml/min per 1.73 m2 with 80 mg (P Conclusions: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.

Depression and anxiety in urban hemodialysis patients.

Abstract: Depression is well established as a prevalent mental health problem for people with ESRD and is associated with morbidity and mortality. However, depression in this population remains difficult to assess and is undertreated. Current estimates suggest a 20 to 30% prevalence of depression that meets diagnostic criteria in this population. The extent of other psychopathology in patients with ESRD is largely unknown. The aim of this study was to expand the research on psychiatric complications of ESRD and examine the prevalence of a broad range of psychopathology in an urban hemodialysis center and their impact on quality of life. With the use of a clinician-administered semistructured interview in this randomly selected sample of 70 predominately black patients, >70% were found to have a psychiatric diagnosis. Twenty-nine percent had a current depressive disorder: 20% had major depression, and 9% had a diagnosis of dysthymia or depression not otherwise specified. Twenty-seven percent had a current major anxiety disorder. A current substance abuse diagnosis was found in 19%, and 10% had a psychotic disorder. The mean Beck Depression Inventory score was 12.1 +/- 9.8. Only 13% reported being in current treatment by a mental health provider, and only 5% reported being prescribed psychiatric medication by their physician. A total of 7.1% had compound depression or depression coexistent with another psychiatric disorder. The construct of depression was also disentangled from the somatic effects of poor medical health by demonstrating a unique relationship between depressive affect and depression diagnosis, independent of health status. This study also suggests the utility of cognitive variables as a meaningful way of understanding the differences between patients who have ESRD with clinical depression or other diagnoses and those who have no psychiatric comorbidity. The findings of both concurrent and isolated anxiety suggest that the prevalence of psychopathology in patients with ESRD might be higher than previously expected, and the disorders may need to be treated independently. In addition, the data suggest that cognitive behavioral therapeutic techniques may be especially advantageous in this population of patients who are treated with many medications.

North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): Targeting the Problem with the RIFLE Criteria

Abstract: Acute kidney injury (AKI) in the intensive care unit (ICU) is associated with an enhanced mortality. The Acute Dialysis Quality Initiative group has proposed the RIFLE (Risk–Injury–Failure–Loss–ESRD) classification to standardize the approach to AKI. This study was performed to estimate the AKI incidence in ICU patients in northeastern Italy and describe clinical characteristics and outcomes of patients with AKI on the basis of their RIFLE class. A prospective multicenter observational study was performed of patients who fulfilled AKI criteria in 19 ICU in northeastern Italy. Data were analyzed using multivariate logistic regression and survival curve analysis. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%; 95% confidence interval 9.5 to 12.1%) developed AKI; 19% were classified as risk (R), 35% as injury (I), and 46% as failure (F). Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/d, respectively. ICU mortality was 49.5% in class F, 29.3% in I, and 20% in R. Independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine, and urine output were associated with lower mortality risk. In this study, AKI incidence in the ICU was between 9 and 12%, with 3.3% of ICU patients requiring renal replacement therapy. Sepsis was a significant contributing factor. Overall mortality was between 30 and 42%, and was highest among those in RIFLE class F.

Pathophysiology of the Clinical Manifestations of Preeclampsia

Abstract: Five to 7% of all pregnancies are complicated by preeclampsia. Proteinuria and hypertension dominate the clinical picture, because the chief target organ is the kidney (glomerular endotheliosis). The pathogenesis of preeclampsia is complex; numerous genetic, immunologic, and environmental factors interact. It has been suggested that preeclampsia is a two-stage disease (1). The first stage is asymptomatic, characterized by abnormal placental development during the first trimester resulting in placental insufficiency and the release of excessive amounts of placental materials into the maternal circulation. This in turn leads to the second, symptomatic stage, wherein the pregnant woman develops characteristic hypertension, renal impairment, and proteinuria and is at risk for the HELLP syndrome (hemolysis, elevated liver function enzymes and low platelets), eclampsia, and other end-organ damage. This review focuses on the pathophysiology of stages 1 and 2 and then considers the potential that changes in soluble angiogenic factors may underlie much of the disease process. On the basis of the observation that the only definitive cure for preeclampsia is delivery of the placenta and that women who experience a molar pregnancy, in which a placenta develops without a fetus, frequently develop severe preeclampsia, it is reasonable to assume that the placenta plays a central role in the pathogenesis of the disease. Pathologic examination of placentas from preeclamptic pregnancies generally reveals placental infarcts and sclerotic narrowing of arteries and arterioles, with characteristic diminished endovascular invasion by cytotrophoblasts and inadequate remodeling of the uterine spiral arterioles (2). Although gross pathologic changes are not always seen in the placentas of women with preeclampsia, placental profiles including abnormal uterine artery Doppler and placental morphology have been used to identify a subset from a cohort of high-risk women who go on to develop the syndrome (3). Uterine artery Doppler studies that assess the pulsatility index (PI) reveal increased …

Renal Provider Recognition of Symptoms in Patients on Maintenance Hemodialysis

Abstract: Background and Objectives: Although several studies have found that the burden of symptoms in patients who are on maintenance hemodialysis is substantial, little is known about renal providers’ awareness of these symptoms. The aim of this study was to assess renal provider recognition of symptoms and their severity in hemodialysis patients. Design, Setting, Participants, & Measurements: The Dialysis Symptom Index, a 30-item measure of symptoms and their severity, was administered to patients during a routine hemodialysis session. Immediately after surveying patients, the renal provider who evaluated the patient completed the Dialysis Symptom Index to report the symptoms that he or she believed were present in that patient. Sensitivity, specificity, and positive and negative predictive values of provider reports of symptoms were calculated using patient reports as the reference standard. Patient–provider agreement on the presence and severity of symptoms was assessed using the κ statistic. Results: Surveys were completed by 75 patients and 18 providers. For 27 of 30 symptoms, the sensitivity of provider responses was Conclusions: Renal providers are largely unaware of the presence and severity of symptoms in patients who are on maintenance hemodialysis. Implementation of a standardized symptom assessment process may improve provider recognition of symptoms and promote use of symptom-alleviating treatments.

Pharmacologic treatment of acute kidney injury: why drugs haven't worked and what is on the horizon.

Abstract: Current strategies to limit the extent of injury in acute renal failure are based on extensive studies that identified cellular and molecular mechanisms of acute kidney injury. Despite successes in various animal models, translation to human studies has failed or studies are inconclusive. This review describes past failures and barriers to successful clinical trials. It also focuses on promising preclinical studies using novel compounds that currently are in or close to human investigation. Implementation of previous or novel compounds in well-designed clinical trials provides hope for the successful treatment of this devastating disorder.

Current Management of Vascular Access

Abstract: Optimizing vascular access outcomes remains an ongoing challenge for clinical nephrologists. All other things being equal, fistulas are preferred over grafts, and grafts are preferred over catheters. Mature fistulas have better longevity and require fewer interventions, as compared with mature grafts. The major hurdle to increasing fistula use is the high rate of failure to mature of newly created fistulas. There is a desperate need for enhanced understanding of the mechanisms of failure to mature and the optimal type and timing of interventions to promote maturity. Grafts are prone to frequent stenosis and thrombosis. Surveillance for graft stenosis with preemptive angioplasty may reduce graft thrombosis, but recent randomized clinical trials have questioned the efficacy of this approach. Graft stenosis results from aggressive neointimal hyperplasia, and pharmacologic approaches to slowing this process are being investigated in clinical trials. Catheters are prone to frequent thrombosis and infection. The optimal management of catheter-related bacteremia is a subject of ongoing debate. Prophylaxis of catheter-related bacteremia continues to generate important clinical research. Close collaboration among nephrologists, surgeons, radiologists, and the dialysis staff is required to optimize vascular access outcomes and can be expedited by having a dedicated access coordinator to streamline the process. The goal of this review is to provide an update on the current status of vascular access management.

Low urine pH: a novel feature of the metabolic syndrome.

Abstract: Background and Objectives: The metabolic syndrome is associated with alterations in renal function. An overly acidic urine has been described as a renal manifestation of the metabolic syndrome in patients with kidney stone disease. This study examined the association between the metabolic syndrome and urine pH in individuals without a history of nephrolithiasis. Design, Setting, Participants, & Measurements: A total of 148 adults who were free of kidney stones were evaluated in this outpatient cross-sectional study. Height, weight, BP, fasting blood, and 24-h urine chemistries were obtained. Urine pH was measured by pH electrode. The following features of the metabolic syndrome were evaluated: BP; body mass index; and serum triglyceride, glucose, and HDL cholesterol concentrations. The degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance. Results: Participants with the metabolic syndrome had a significantly lower 24-h urine pH compared with participants without the metabolic syndrome. Mean 24-h urine pH, adjusted for age, gender, creatinine clearance, and 24-h urine sulfate, decreased from 6.15, 6.10, 5.99, 5.85, to 5.69 with increasing number of metabolic syndrome abnormalities. An association was observed between 24-h urine pH and each metabolic feature. After adjustment for age, gender, creatinine clearance, urine sulfate, and body mass index, a significant inverse relationship was noted between 24-h urine pH and the degree of insulin resistance. Conclusions: An unduly acidic urine is a feature of the metabolic syndrome and is associated with the degree of insulin resistance.

Nephrogenic Systemic Fibrosis: A Population Study Examining the Relationship of Disease Development to Gadolinium Exposure

Abstract: Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant ( P ≤ 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised.

Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry.

Abstract: Background: This article reports demographic characteristics and intensive care unit survival for 344 patients from the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry, a voluntary multicenter observational network. Design, setting, participants, and measurements: Ages were newborn to 25 yr, 58% were male, and weights were 1.3 to 160 kg. Patients spent a median of 2 d in the intensive care unit before CRRT (range 0 to 135). At CRRT initiation, 48% received diuretics and 66% received vasoactive drugs. Mean blood flow was 97.9 ml/min (range 10 to 350 ml/min; median 100 ml/min); mean blood flow per body weight was 5 ml/min per kg (range 0.6 to 53.6 ml/min per kg; median 4.1 ml/min per kg). Days on CRRT were Results: Overall survival was 58%; survival differed across participating centers. Survival was lowest (51%) when CRRT was started for combined fluid overload and electrolyte imbalance. There was better survival in patients with principal diagnoses of drug intoxication (100%), renal disease (84%), tumor lysis syndrome (83%), and inborn errors of metabolism (73%); survival was lowest in liver disease/transplant (31%), pulmonary disease/transplant (45%), and bone marrow transplant (45%). Overall survival was better for children who weighed >10 kg (63 versus 43%; P = 0.001) and for those who were older than 1 yr (62 versus 44%; P = 0.007). Conclusions: CRRT can be used successfully for a wide range of critically ill children. Survival is best for those who have acute, specific abnormalities and lack multiple organ involvement; sicker patients with selected diagnoses may have lower survival. Center differences might suggest opportunities to define best practices with future study.

A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.

Abstract: A spectrum of proteinuric glomerular diseases results from podocyte abnormalities. The understanding of these podocytopathies has greatly expanded in recent years, particularly with the discovery of more than a dozen genetic mutations that are associated with loss of podocyte functional integrity. It is apparent that classification of the podocytopathies on the basis of morphology alone is inadequate to capture fully the complexity of these disorders. Herein is proposed a taxonomy for the podocytopathies that classifies along two dimensions: Histopathology, including podocyte phenotype and glomerular morphology (minimal-change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy), and etiology (idiopathic, genetic, and reactive forms). A more complete understanding of the similarities and differences among podocyte diseases will help the renal pathologist and the nephrologist communicate more effectively about the diagnosis; this in turn will help the nephrologist provide more accurate prognostic information and select the optimal therapy for these often problematic diseases. It is proposed that final diagnosis of the podocytopathies should result from close collaboration between renal pathologists and nephrologists and should whenever possible include three elements: Morphologic entity, etiologic form, and specific pathogenic mechanism or association.

BK Virus Nephropathy and Kidney Transplantation

Abstract: Nephropathy from BK virus (BKV) infection is an evolving challenge in kidney transplant recipients. It is the consequence of modern potent immunosuppression aimed at reducing acute rejection and improving allograft survival. Untreated BKV infections lead to kidney allograft dysfunction or loss. Decreased immunosuppression is the principle treatment but predisposes to acute and chronic rejection. Screening protocols for early detection and prevention of symptomatic BKV nephropathy have improved outcomes. Although no approved antiviral drug is available, leflunomide, cidofovir, quinolones, and intravenous Ig have been used. Retransplantation after BKV nephropathy has been successful.

Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist

Abstract: The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing.

Home Blood Pressures Are of Greater Prognostic Value than Hemodialysis Unit Recordings

Abstract: Background and objectives: Although ambulatory BP recordings are found to be superior to dialysis unit recordings in predicting outcomes, ambulatory BP are difficult to obtain in the day-to-day treatment of hemodialysis patients. Home BP agree well with ambulatory BP, but the prognostic significance of home BP recordings is unknown in hemodialysis patients. This study ascertained the role of home BP in predicting all-cause and cardiovascular mortality. Design, setting, participants, & measurements: A prospective cohort study was conducted in 150 patients who were on chronic hemodialysis dialyzing at four university-affiliated units. BP was self-measured at home for 1 wk, for an interdialytic interval by ambulatory recording, and by “routine” and standardized methods in the dialysis unit for 2 wk. Patients were followed for a median of 24 mo to assess the end points of all-cause and cardiovascular mortality. Results: Cardiovascular death occurred in 26 (17%) patients and death in 46 (31%) patients. A 1-SD increase in systolic BP increased the risk for death by 1.35 (95% CI 0.99 to 1.84) and in diastolic BP by 1.40 (95% CI 1.03 to 1.93) for home BP and between 0.97 to 1.19 (P > 0.20) for all-cause mortality for dialysis unit BP recording. A dose–response relationship between increasing quartiles of home BP and all-cause mortality and cardiovascular mortality was seen. Conclusions: Self-measured systolic BP of 125 to 145 mmHg and of 115 to 125 mmHg by ambulatory BP is associated with the best prognosis in hemodialysis patients.

Screening, Diagnosis, and Treatment of Depression in Patients with End-Stage Renal Disease

Abstract: Depression is common in patients with end-stage renal disease and has been linked to increased mortality. Screening for depression in the general medical population remains controversial; however, given the high prevalence of depression and its significant impact on morbidity and mortality, a strong case for depression screening in patients with end-stage renal disease can be made. Several studies have been performed to validate the more common depression screening measures in patients with chronic kidney disease. The Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Nine-Question Patient Health Questionnaire, and the Center for Epidemiologic Studies Depression Scale are some of the measures that have been used to screen for depression in patients with end-stage renal disease. Data suggest a higher Beck Depression Inventory cutoff score, of >14 to 16, will have increased positive predictive value at diagnosing depression in patients with end-stage renal disease. There are limited data on the treatment of depression in this patient population. Pharmacotherapy, including selective serotonin reuptake inhibitors, can be used if deemed clinically indicated, and no active contraindication exists. There are even fewer data to support the role of cognitive behavioral therapy, social support group interventions, and electroconvulsive therapy for treatment of depression in patients with chronic kidney disease. Larger randomized, controlled clinical trials aimed at the treatment of depression in patients with end-stage renal disease are desperately needed.

Genetic Factors in Diabetic Nephropathy

Abstract: Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.

High Sirolimus Levels May Induce Focal Segmental Glomerulosclerosis De Novo

Abstract: Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.

Pirfenidone Slows Renal Function Decline in Patients with Focal Segmental Glomerulosclerosis

Abstract: Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis. Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m2, was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment. Results: The monthly change in GFR improved from a median of −0.61 ml/min per 1.73 m2 (interquartile range −1.31 to −0.41) during the baseline period to −0.45 ml/min per 1.73 m2 (interquartile range −0.78 to −0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.

Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview

Abstract: Background and Objectives: The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes. Design, Setting, Participants, & Measurements: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation). Results: The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr. Conclusions: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients.

Hypertonic saline for hyponatremia: risk of inadvertent overcorrection.

Abstract: Background and objectives: Data regarding dosage–response relationships for using hypertonic saline in treatment of hyponatremia are extremely limited. Objectives of this study were to assess adherence to previously published guidelines (limiting correction to Design, setting, participants & measurements: A retrospective review was conducted of all 62 adult, hyponatremic patients who were treated with hypertonic saline during 5 yr at a 528-bed, acute care, teaching hospital. Results: Median infusion rate was 0.38 ml/kg per h, increasing serum sodium concentration by 0.47 ± 0.05 mEq/L per h, 7.1 ± 0.6 mEq/L per 24 h, and 11.3 ± 0.7 mEq/L per 48 h. In 11.3% of cases, the increase was >12 mEq/L per 24 h and in 9.7% was >18 mEq/L per 48 h. No patient9s rate was corrected by >25 mEq/L per 48 h. Among patients with serum sodium Conclusions: The Adrogue-Madias formula underestimates increase in sodium concentration after hypertonic saline therapy. Unrecognized hypovolemia and other reversible causes of water retention pose a risk for inadvertent overcorrection. Hypertonic saline should be infused at rates lower than those predicted by formulas with close monitoring of serum sodium and urine output.

Plasma Pentraxin 3 in Patients with Chronic Kidney Disease: Associations with Renal Function, Protein-Energy Wasting, Cardiovascular Disease, and Mortality

Abstract: Background and Objectives: Plasma protein pentraxin 3 concentrations are elevated in a wide range of diseased states. However, no study has evaluated protein pentraxin 3 in patients with chronic kidney disease. Design, Setting, Participants, & Measurements: Plasma protein pentraxin 3 concentrations were analyzed in relation to GFR, inflammation, cardiovascular disease, and protein-energy wasting in 71 patients with stages 3 to 4 chronic kidney disease, 276 patients with stage 5 chronic kidney disease, and 61 control subjects. Survival (5 yr) in patients with stage 5 chronic kidney disease was analyzed in relation to protein pentraxin 3 levels. Results: Both patient groups with chronic kidney disease had higher protein pentraxin 3 concentrations than control subjects, with the highest concentration in patients with stage 5 chronic kidney disease. In all patients with chronic kidney disease, protein pentraxin 3 correlated negatively with GFR and positively with inflammatory markers. Patients with protein-energy wasting, inflammation, and cardiovascular disease had higher concentrations of protein pentraxin 3 than their counterparts. Patients with high protein pentraxin 3 levels had higher all-cause and cardiovascular mortality. After adjustment for age, gender, C-reactive protein, and cardiovascular disease, all-cause mortality was still significantly higher in patients with high protein pentraxin 3. Finally, protein pentraxin 3 showed a predictive value of mortality similar to that of IL-6 and better than C-reactive protein. Conclusion: Plasma protein pentraxin 3 increases as GFR declines and is associated with the presence of cardiovascular disease and protein-energy wasting. Furthermore, in patients with chronic kidney disease, elevated protein pentraxin 3 predicted all-cause mortality.

Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy.

Abstract: Background and Objectives: Rituximab, given in four weekly doses, is a promising treatment for idiopathic membranous nephropathy and other immune-mediated diseases and lymphoproliferative disorders. This multidose regimen, however, may cause hypersensitivity reactions and is extremely expensive. This study was aimed at evaluating whether titrating rituximab to circulating CD20 B cells may improve safety and limit costs of treatment. Design, Setting, Participants, & Measurements: In a matched-cohort, single-center, controlled study, the outcome of 12 new incident patients who had idiopathic membranous nephropathy and nephrotic syndrome and received a B cell–driven treatment was compared with that of 24 historical reference patients who were given the standard protocol of four weekly doses of 375 mg/m2. Results: Only one patient needed a second dose to achieve full CD20 cell depletion. At 1 yr, time course of the components of nephrotic syndrome and the proportion of patients who achieved disease remission (25%) was identical in both groups. Persistent CD20 cell depletion was achieved in all patients. Costs for rituximab treatment and hospitalizations totalled €3770.90 ($4902.20) and €13,977.60 ($18,170.80) with the B cell–driven and the four-dose protocol, respectively. One patient on standard protocol had a severe adverse reaction at second rituximab dose. Thus, B cell titrated as effectively as standard rituximab treatment achieves B cell depletion and idiopathic membranous nephropathy remission but is fourfold less expensive, allowing for more than €10,000, approximately $13,000 in savings per patient. Conclusions: Avoiding unnecessary reexposure to rituximab is extremely cost-saving and may limit the production of antichimeric antibodies that may increase the risk for adverse reactions and prevent re-treatment of disease recurrences.