Cystinuria: current concepts and future directions.

Cystinuria, an autosomic recessive genetic disorder is an uncommon cause of nephrolithiasis characterized by an impairment of transport of cystine, ornithine, lysine, and arginine (COLA). Of these, only cystine is insoluble enough to cause stone formation. Although a classification exists that categorizes the disease depending on chromosomal mutation, this does not currently alter management which consists of increased fluid intake, urine alkalinization, reduced sodium intake and, if warranted, cystine-binding thiol drugs. Cystine stones are relatively resistant to fragmentation. Intrinsic characteristics on imaging may help in planning surgical treatment. Finally, advances in crystal growth inhibition are encouraging as they may provide a new tool to treat this condition which although uncommon, is treatable and has been associated with lower quality of life and renal function compared to other stone formers.

Multidisciplinary CKD care enhances outcomes at dialysis initiation.

In 2003, the Nephrology Section at Dartmouth-Hitchcock Medical Center embraced a new concept for providing care that included a continuing care manager and a nephrologist working together with the patient to introduce stage-based education and clinical interventions. This study compares the outcomes of patients initiating hemodialysis or peritoneal dialysis who received CKD care using a multidisciplinary care model (n = 89) with those who received traditional nephrology care (n = 82). Overall, the findings in this study support the use of the multidisciplinary clinic as a method for improving care of the patient with CKD initiating dialysis, and reducing hospital admissions and costs. The care coordination provided in the multidisciplinary setting improved the number of fistulas placed (60.7% vs. 21%, p < 0.001), the number of fistulas used for dialysis initiation (40.4% vs. 12.3, p < 0.001), and the management of anemia with higher hemoglobin levels prior to dialysis initiation (10.9 g/dL vs. 10.0 g/dL, p = 0.003). Patients receiving multidisciplinary care were 42% less likely to be admitted to the hospital for dialysis initiation, had significantly fewer days hospitalized (p = 0.001), fewer admissions (p = 0.005), and reduced charges for a 90-day period (p = 0.003) after dialysis initiation.

A health policy model of CKD: 2. The cost-effectiveness of microalbuminuria screening.

BACKGROUND: Microalbuminuria screening may detect chronic kidney disease in its early stages, allowing for treatment that delays or prevents disease progression. The cost-effectiveness of microalbuminuria screening has not been determined. STUDY DESIGN: A cost-effectiveness model simulating disease progression and costs. SETTING & POPULATION: US patients. MODEL, PERSPECTIVE, AND TIMEFRAME: The microsimulation model follows up disease progression and costs in a cohort of simulated patients from age 50 to 90 years or death. Costs are evaluated from the health care system perspective. INTERVENTION: Microalbuminuria screening at 1-, 2-, 5-, or 10-year intervals followed by treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We considered universal screening, as well as screening targeted at persons with diabetes, persons with hypertension but no diabetes, and persons with neither diabetes nor hypertension. OUTCOMES: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS: For the full model population, universal screening increases costs and increases QALYs. Universal annual screening starting at age 50 years has a cost-effectiveness ratio of $73,000/QALY relative to no screening and $145,000/QALY relative to usual care. Cost-effectiveness ratios improved with longer screening intervals. Relative to no screening, targeted annual screening has cost-effectiveness ratios of $21,000/QALY, $55,000/QALY, and $155,000/QALY for persons with diabetes, those with hypertension, and those with neither current diabetes nor current hypertension, respectively. LIMITATIONS: Results necessarily are based on a microsimulation model because of the long time horizon appropriate for chronic kidney disease. The model includes only health care costs. CONCLUSIONS: Microalbuminuria screening is cost-effective for patients with diabetes or hypertension, but is not cost-effective for patients with neither diabetes nor hypertension unless screening is conducted at longer intervals or as part of existing physician visits.

A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences.

BACKGROUND: A cost-effectiveness model that accurately represents disease progression, outcomes, and associated costs is necessary to evaluate the cost-effectiveness of interventions for chronic kidney disease (CKD). STUDY DESIGN: We developed a microsimulation model of the incidence, progression, and treatment of CKD. The model was validated by comparing its predictions with survey and epidemiologic data sources. SETTING & POPULATION: US patients. MODEL, PERSPECTIVE, & TIMEFRAME: The model follows up disease progression in a cohort of simulated patients aged 30 until age 90 years or death. The model consists of 7 mutually exclusive states representing no CKD, 5 stages of CKD, and death. Progression through the stages is governed by a person's glomerular filtration rate and albuminuria status. Diabetes, hypertension, and other risk factors influence CKD and the development of CKD complications in the model. Costs are evaluated from the health care system perspective. INTERVENTION: Usual care, including incidental screening for persons with diabetes or hypertension. OUTCOMES: Progression to CKD stages, complications, and mortality. RESULTS: The model provides reasonably accurate estimates of CKD prevalence by stage. The model predicts that 47.1% of 30-year-olds will develop CKD during their lifetime, with 1.7%, 6.9%, 27.3%, 6.9%, and 4.4% ending at stages 1-5, respectively. Approximately 11% of persons who reach stage 3 will eventually progress to stage 5. The model also predicts that 3.7% of persons will develop end-stage renal disease compared with an estimate of 3.0% based on current end-stage renal disease lifetime incidence. LIMITATIONS: The model synthesizes data from multiple sources rather than a single source and relies on explicit assumptions about progression. The model does not include acute kidney failure. CONCLUSION: The model is well validated and can be used to evaluate the cost-effectiveness of CKD interventions. The model also can be updated as better data for CKD progression become available.

Comprehensive public health strategies for preventing the development, progression, and complications of CKD: report of an expert panel convened by the Centers for Disease Control and Prevention.

Chronic kidney disease (CKD) is a public health threat in the United States, with increasing prevalence, high costs, and poor outcomes. More widespread effort at the prevention, early detection, evaluation, and management of CKD and antecedent conditions could prevent complications of decreased kidney function, slow the progression of kidney disease to kidney failure, and reduce cardiovascular disease risk. In 2006, the Centers for Disease Control and Prevention (CDC) launched an initiative on CKD. As part of this initiative, the CDC convened an expert panel to outline recommendations for a comprehensive public health strategy to prevent the development, progression, and complications of CKD in the United States. The panel adapted strategies for primary, secondary, and tertiary prevention for chronic diseases to the conceptual model for the development, progression, and complications of CKD; reviewed epidemiological data from US federal agencies; and discussed ways of integrating public health efforts from various agencies and organizations. The panel recommended a 10-point plan to the CDC to improve surveillance, screening, education, and awareness directed at 3 target populations: people with CKD or at increased risk of developing CKD; providers, hospitals, and clinical laboratories; and the general public. Cooperation among federal, state, and local governmental and private organizations will be necessary to carry out these recommendations.

Transient and persistent renal dysfunction are predictors of survival after percutaneous coronary intervention: insights from the Dartmouth Dynamic Registry.

OBJECTIVES: We sought to determine if transient and persistent elevations in creatinine following percutaneous coronary intervention (PCI) resulted in poor survival. BACKGROUND: Limited survival data exist that defines the natural survival history of transient and persistent renal dysfunction following interventional PCI cases. METHODS: Data were collected prospectively on 7,856 consecutive patients undergoing PCI from January 1, 2000 to July 31, 2006. Ninety-three patients were excluded due to pre-PCI dialysis. Patients were stratified into three categories of renal dysfunction: no renal dysfunction from baseline (<0.5 mg/dL increase in creatinine within 48 hr of the procedure), transient renal dysfunction (> or =0.5 mg/dL increase in creatinine within 48 hr with return to normal within 2 weeks), and persistent renal dysfunction (> or =0.5 mg/dL increase in creatinine without returning to normal within 2 weeks of the procedure). Mortality was determined by comparing with the Social Security Death Master File. RESULTS: Median survival was 3.2 years (mean 3.4). Renal dysfunction occurred in 250 patients (0.5 mg/dL increase in creatinine). Survival was significantly different between patients at 1, 3.2, and 7.5 years (P-value < 0.001): no renal dysfunction (95%, 88%, 75%), with transient (61%, 42%, 0%), and with persistent (58%, 44%, 36%) renal dysfunction. Patients with transient or persistent renal dysfunction had a twofold-threefold increased risk of 7.5-year mortality compared with patients with no renal dysfunction. CONCLUSIONS: Both transient and persistent postprocedural renal dysfunction are prognostically significant for mortality during extended follow-up. Renal dysfunction should be closely monitored before and after PCI.

Obesity is associated with family history of ESRD in incident dialysis patients.

BACKGROUND: Obesity is an established risk factor for chronic kidney disease and aggregates in families. The objective of this study is to examine the relationship between obesity and family history of end-stage renal disease (ESRD). METHODS: Data were collected from 25,883 incident patients with ESRD in US ESRD Network 6 (Georgia, North Carolina, and South Carolina) dialysis clinics between 1995 and 2003. Family history is defined as a first- or second-degree relative with ESRD. Body mass index (BMI) at dialysis therapy initiation was classified as underweight (BMI < 18.5 kg/m2), normal (BMI, 18.5 to <25 kg/m2), overweight (BMI, 25 to < 30 kg/m2), obese (BMI, 30 to <35 kg/m2), or morbidly obese (BMI > or = 35 kg/m2). RESULTS: Twenty-three percent of patients reported a family history of ESRD. Of patients reporting a family history of ESRD, 5.5% were underweight, 32.5% had normal BMI, 28.0% were overweight, 17.3% were obese, and 16.7% were morbidly obese. After controlling for age, race, sex, primary cause of ESRD, history of diabetes, history of hypertension, and estimated glomerular filtration rate at dialysis therapy initiation, reported family history of ESRD was associated with being overweight (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.08 to 1.26), obese (OR, 1.25; 95% CI, 1.14 to 1.37), and morbidly obese (OR, 1.40; 95% CI, 1.27 to 1.55). CONCLUSION: Obesity at dialysis therapy initiation was associated independently with reported family history of ESRD. This finding suggests that behavioral factors, adiposity-related genes, and gene-by-BMI interaction may contribute to familial risk for ESRD. This finding also suggests that management of obesity may be even more important for patients with a family history of ESRD than for the general population.

Chronic kidney disease: a public health problem that needs a public health action plan.

For a health problem or condition to be considered a public health issue, four criteria must be met: 1) the health condition must place a large burden on society, a burden that is getting larger despite existing control efforts; 2) the burden must be distributed unfairly (i.e., certain segments of the population are unequally affected); 3) there must be evidence that upstream preventive strategies could substantially reduce the burden of the condition; and 4) such preventive strategies are not yet in place. Chronic kidney disease meets these criteria for a public health issue. Therefore, as a complement to clinical approaches to controlling it, a broad and coordinated public health approach will be necessary to meet the burgeoning health, economic, and societal challenges of chronic kidney disease.

A public health action plan is needed for chronic kidney disease.

In 2005, chronic kidney disease (CKD) meets all criteria for classification as a public health problem in the United States. It imposes a large burden on society that is increasing despite ongoing efforts to control the disease. The burden is unevenly distributed by race and economic status, whereas evidence suggests that preventive strategies could substantially reduce the burden. Finally, there are indications that such strategies are not yet in place. A broad and coordinated public health approach to the burgeoning health, economic, and societal challenges of CKD is needed to complement present clinical approaches, increase awareness, promote early detection, and facilitate prevention and treatment.

Chronic kidney disease: issues and establishing programs and clinics for improved patient outcomes.

The spectrum of chronic kidney disease (CKD) extends from the point at which there is slight kidney damage, but normal function, to the point at which patients require either a renal transplant or renal replacement therapy to survive. Epidemiological studies suggest there are approximately 20,000,000 patients with various stages of CKD. These patients have many comorbidities, including cardiovascular disease, hypertension, diabetes, anemia, nutritional and metabolic derangements, and fluid overload. Unfortunately, evidence shows that current CKD care in the United States is suboptimal, and late referral to a nephrologist is often the rule and not the exception. Roles of primary care physicians (PCPs) and nephrologists in the care of patients with CKD remain undefined. Several studies have suggested that care provided by multidisciplinary nephrology teams can improve patient outcomes. Currently, there are published evidence-based clinical practice guidelines for anemia management, nutritional therapy, and vascular access placement, with other CKD guidelines under development. The intent of this review includes providing compelling evidence for earlier screening, identification, and management of patients with CKD; showing that current CKD care is suboptimal; encouraging the development of multidisciplinary teams that provide collaborative care to patients with CKD, suggesting roles for PCPs and nephrologists in the care of these patients; describing CKD initiatives from national organizations; and providing a comprehensive checklist that can guide the development of CKD clinics and programs.

The role of the renin-angiotensin system in cholesterol and puromycin mediated renal injury.

BACKGROUND: Puromycin aminonucleoside (PAN) nephropathy is a widely studied model of glomerular sclerosis (GS) in the rat, and cholesterol feeding exacerbates the injury induced by PAN. The importance of the interaction of angiotensin II (Ang II) with the AT2 receptor is unclear. We investigated the role of the renin-angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in PAN and cholesterol-mediated GS. METHODS: Sprague-Dawley rats were given a 4% cholesterol diet (group II), subcutaneous PAN (group III), or a 4% cholesterol diet and PAN (group IV) and compared with a control group given PAN vehicle (group I). After 16 weeks, kidneys were harvested and tissue Ang II concentration, angiotensin-converting enzyme (ACE) activity, and ACE, AT1, and AT2 mRNA levels were determined. RESULTS: Compared with control rats, proteinuria was significantly higher in groups II to IV. Kidney ACE activity and ACE mRNA levels in groups III and IV were 2- and 3-fold higher than in groups I and II, respectively. Kidney Ang II concentration also was increased in the experimental groups. Whereas kidney AT1 mRNA was significantly lower in groups III and IV, kidney AT2 mRNA was significantly increased in groups II to IV. CONCLUSION: In these experimental models of GS, there is significant activation of the tissue-based renin-angiotensin system. Puromycin with and without cholesterol decreased the AT1 receptor mRNA and increased the AT2 receptor mRNA. Up-regulation of AT2 receptors may be important in ameliorating the proliferative effects of Ang II, which presumably occur through the AT1 receptor.

Does safe dosing of iodinated contrast prevent contrast-induced acute kidney injury?

BACKGROUND: Previous work on contrast-induced acute kidney injury (CI-AKI) has identified contrast volume as a risk factor and suggested that there is a maximum allowable contrast dose (MACD) above which the risk of CI-AKI is markedly increased. We hypothesized that there is a relationship between contrast volume and CI-AKI and that there might be reason to track incremental contrast volumes above and below the MACD limit. METHODS AND RESULTS: Consecutive patients undergoing percutaneous coronary intervention (PCI) were prospectively enrolled from 2000 to 2008 (n=10 065). Patients on dialysis before PCI were excluded (n=155). MACD was defined as (5 mL x body weight [kg])/baseline serum creatinine [mg/dL]) and divided into categories in which 1.0 reflects the MACD limit: < or =MACD ratios (<0.5, 0.5 to 0.75, and 0.75 to 1.0) and >MACD (1.0 to 1.5, 1.5 to 2.0, and >2.0). CI-AKI was defined as a > or =0.3 (mg/dL) or > or =50% increase in serum creatinine from baseline or new dialysis. Multivariable regression was conducted to evaluate the effect of exceeding the MACD on CI-AKI. Twenty percent of patients exceeded the MACD. Risk-adjusted CI-AKI increased by an average of 45% for each category exceeding the MACD (odds ratio, 1.45; 95% confidence interval, 1.29 to 1.62) Adjusted odds ratios for each category exceeding the MACD were 1.60 (95% confidence interval, 1.29 to 1.97), 2.02 (95% confidence interval, 1.45 to 2.81), and 2.94 (95% confidence interval, 1.93 to 4.48). CI-AKI for contrast dose

Sodium bicarbonate plus N-acetylcysteine prophylaxis: a meta-analysis.

OBJECTIVES: We sought to conduct a meta-analysis to compare N-acetylcysteine (NAC) in combination with sodium bicarbonate (NaHCO(3)) for the prevention of contrast-induced acute kidney injury (AKI). BACKGROUND: Contrast-induced AKI is a serious consequence of cardiac catheterizations and percutaneous coronary interventions (PCI). Despite recent supporting evidence for combination therapy, not enough has been done to prevent the occurrence of contrast-induced AKI prophylactically. METHODS: Published randomized controlled trial data were collected from OVID/PubMed, Web of Science, and conference abstracts. The outcome of interest was contrast-induced AKI, defined as a >or=25% or >or=0.5 mg/dl increase in serum creatinine from baseline. Secondary outcome was renal failure requiring dialysis. RESULTS: Ten randomized controlled trials met our criteria. Combination treatment of NAC with intravenous NaHCO(3) reduced contrast-induced AKI by 35% (relative risk: 0.65; 95% confidence interval: 0.40 to 1.05). However, the combination of N-acetylcysteine plus NaHCO(3) did not significantly reduce renal failure requiring dialysis (relative risk: 0.47; 95% confidence interval: 0.16 to 1.41). CONCLUSIONS: Combination prophylaxis with NAC and NaHCO(3) substantially reduced the occurrence of contrast-induced AKI overall but not dialysis-dependent renal failure. Combination prophylaxis should be incorporated for all high-risk patients (emergent cases or patients with chronic kidney disease) and should be strongly considered for all interventional radio-contrast procedures.

The epidemiology and outcome of acute renal failure and the impact on chronic kidney disease.

Acute renal failure (ARF) is a common condition, especially among the critically ill, and confers a high mortality. Recent publications have highlighted changes in the epidemiology and improvement in mortality that was long thought to be static despite improvements in clinical care. The incidence of ARF is increasing. Efforts, such as the Acute Dialysis Quality Initiative, are being undertaken to establish a consensus definition of ARF, and to distinguish between varying degrees of acute kidney injury. Data are emerging to allow comparison of the epidemiology of ARF across institutions internationally. There is ongoing recognition of the important interaction between ARF and chronic kidney disease. Two brief case reports are offered to help frame the context and clinical impact of this disorder, followed by a review of some of the recent literature that addresses these points.

Electrolyte disturbances in the intensive care unit.

The development of many electrolyte disturbances in the ICU can be prevented by attention to the use of intravenous fluids and nutrition. Hyponatremia is a relative contraindication to the use of hypotonic intravenous fluids and hypernatremia calls for the administration of water. Formulae have been devised to guide the therapy of severe hyponatremia and hypernatremia. All formulae regard the patient as a closed system, and none takes into account ongoing fluid losses that are highly variable between patients. Thus, therapy of severe hyponatremia and hypernatremia must be closely monitored with serial electrolyte measurements. The significance of hypocalcemia in the critically ill is controversial. Hypokalemia, hypophosphatemia, and hypomagnesemia should be corrected.

Acid-base disturbances in the intensive care unit: metabolic acidosis.

This article will discuss metabolic acidosis and, to a lesser extent, metabolic alkalosis in the ICU setting. A classification and clinical approach will be the focus.

Part 1. Uric acid and losartan.

PURPOSE OF REVIEW: To characterize the mechanism and clinical impact of the angiotensin-receptor blocker losartan on both renal uric acid handling and thereby serum uric acid. RECENT FINDINGS: Losartan effect on serum uric acid has been demonstrated at various stages of renal failure including most recently observations obtained in end-stage renal disease patients. Other angiotensin-receptor blockers do not alter renal handling of uric acid. The uricosuria, which accompanies losartan administration, has not been associated with adverse renal consequences, in part, because of the increase in urinary pH that follows its administration. SUMMARY: Hyperuricemia is closely linked to both hypertension and cardiovascular disease. The development of hyperuricemia and its persistence are clearly renal processes. Likewise, the correction of hyperuricemia is often accomplished by increasing its renal excretion. A number of medications, by way of varying mechanisms, can alter renal urate handling and thereby influence serum uric acid values. Most recently, the angiotensin-receptor blocker losartan has been shown to reduce serum uric acid. The mechanism of this process relates to losartan alone and does not involve the E-3174 metabolite of this compound. This probenecid-like effect of losartan occurs shortly after drug administration, and is both transient and dose-dependent. This property of losartan, touted by some as a meaningful pharmacological distinction among the angiotensin-receptor blockers, remains to be proved, since, to date, the hypothesis that a reduction in serum uric acid alters the natural history of cardiovascular disease has not been formally tested.

PPARgamma ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase.

BACKGROUND: Mesangial proliferation is a key feature in the pathogenesis of a number of renal diseases and can be experimentally induced by the mitogen platelet-derived growth factor (PDGF). Mitogen-activated protein kinase (MAPK) signaling plays a key role in mesangial cell proliferation. In the present study we examined whether peroxisome proliferator-activated receptor gamma (PPARgamma) activators/ligands, thiazolidinediones such as ciglitazone, troglitazone, and rosiglitazone, can inhibit cell proliferation by modulating individual steps in the MAPK pathway. METHODS: Mouse mesangial cells were made quiescent and proliferation was measured following the application of PDGF. Using ciglitazone as the model compound, the mechanism of the antiproliferative effect of PPARgamma activators on MAPK and specific cell cycle regulatory proteins were examined by Western blot analysis and transfection studies. RESULTS: Ciglitazone inhibited PDGF-induced mesangial cell proliferation in a dose-dependent manner (1 to 20 micromol/L). The inhibitory effect was blocked by a peroxisome proliferator-activated receptor element (PPRE) decoy oligonucleotide, indicating that the observed effect of ciglitazone was via PPARgamma activation. Ciglitazone (1 to 20 micromol/L) did not affect extracellular signal-regulated protein kinase (ERK) activation but inhibited the activation of serum response element (SRE) by 85 +/- 6% (P < 0.01). This effect was associated with a reduction in c-fos expression (80 +/- 9%, P < 0.01). Ciglitazone (1, 10, and 20 micromol/L) also inhibited cyclin D1 expression by 37 +/- 8%, 79 +/- 15%, and 87 +/- 12%, respectively (P < 0.001 to 0.001), and p21 expression by 45 +/- 6% (P < 0.01), 61 +/- 10% (P < 0.001), and 72 +/- 8% (P < 0.001), respectively. Ciglitazone inhibited PDGF-mediated up-regulation of p27. In addition, the antiproliferative effect of ciglitazone was potentiated by PD98059, a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor that acts at a step upstream from ERK. CONCLUSION: These data indicate that PPARgamma activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.