Subtyping CKD Patients by Consensus Clustering: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. METHODS: We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. RESULTS: The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (n=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (n=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (n=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. CONCLUSIONS: Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.

An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Perampanel, a selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist, is capable of slowing the progression of the amyotrophic lateral sclerosis (ALS) phenotype and increasing the number of anterior horn cells in transgenic mice. Trials of perampanel in epilepsy showed a favorable tolerability profile. In this study we aimed to determine the tolerability and safety of perampanel in patients with ALS. METHODS: Enrolled subjects were started on 2 mg/day of perampanel and the dose was increased by 2 mg/day every week to a maximum dose of 8 mg/day. Our primary outcome measure was tolerability, which was evaluated by monitoring adverse events. The secondary outcome measure was clinical progression, assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and spirometry. RESULTS: Six participants were enrolled. All had adverse events, mostly behavioral. Two completed the trial and the other four withdrew due to adverse events. All participants reported resolution of these events after discontinuation of the drug. The trial was halted due to the large number of adverse events. DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerability.

Impact of AKI on Urinary Protein Excretion: Analysis of Two Prospective Cohorts.

BACKGROUND: Prior studies of adverse renal consequences of AKI have almost exclusively focused on eGFR changes. Less is known about potential effects of AKI on proteinuria, although proteinuria is perhaps the strongest risk factor for future loss of renal function. METHODS: We studied enrollees from the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) study and the subset of the Chronic Renal Insufficiency Cohort (CRIC) study enrollees recruited from Kaiser Permanente Northern California. Both prospective cohort studies included annual ascertainment of urine protein-to-creatinine ratio, eGFR, BP, and medication use. For hospitalized participants, we used inpatient serum creatinine measurements obtained as part of clinical care to define an episode of AKI (i.e., peak/nadir inpatient serum creatinine ≥1.5). We performed mixed effects regression to examine change in log-transformed urine protein-to-creatinine ratio after AKI, controlling for time-updated covariates. RESULTS: At cohort entry, median eGFR was 62.9 ml/min per 1.73 m2 (interquartile range [IQR], 46.9-84.6) among 2048 eligible participants, and median urine protein-to-creatinine ratio was 0.12 g/g (IQR, 0.07-0.25). After enrollment, 324 participants experienced at least one episode of hospitalized AKI during 9271 person-years of follow-up; 50.3% of first AKI episodes were Kidney Disease Improving Global Outcomes stage 1 in severity, 23.8% were stage 2, and 25.9% were stage 3. In multivariable analysis, an episode of hospitalized AKI was independently associated with a 9% increase in the urine protein-to-creatinine ratio. CONCLUSIONS: Our analysis of data from two prospective cohort studies found that hospitalization for an AKI episode was independently associated with subsequent worsening of proteinuria.

CKD Self-management: Phenotypes and Associations With Clinical Outcomes.

BACKGROUND: To slow chronic kidney disease (CKD) progression and its complications, patients need to engage in self-management behaviors. The objective of this study was to classify CKD self-management behaviors into phenotypes and assess the association of these phenotypes with clinical outcomes. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. 3,939 participants in the CRIC Study recruited between 2003 and 2008 served as the derivation cohort and 1,560 participants recruited between 2013 and 2015 served as the validation cohort. PREDICTORS: CKD self-management behavior phenotypes. OUTCOMES: CKD progression, atherosclerotic events, heart failure events, death from any cause. MEASUREMENTS: Latent class analysis stratified by diabetes was used to identify CKD self-management phenotypes based on measures of body mass index, diet, physical activity, blood pressure, smoking status, and hemoglobin A1c concentration (if diabetic); Cox proportional hazards models. RESULTS: 3 identified phenotypes varied according to the extent of implementation of recommended CKD self-management behaviors: phenotype I characterized study participants with the most recommended behaviors; phenotype II, participants with a mixture of recommended and not recommended behaviors; and phenotype III, participants with minimal recommended behaviors. In multivariable-adjusted models for those with and without diabetes, phenotype III was strongly associated with CKD progression (HRs of 1.82 and 1.49), death (HRs of 1.95 and 4.14), and atherosclerotic events (HRs of 2.54 and 1.90; each P < 0.05). Phenotype II was associated with atherosclerotic events and death among those with and without diabetes. LIMITATIONS: No consensus definition of CKD self-management; limited to baseline behavior data. CONCLUSIONS: There are potentially 3 CKD self-management behavior phenotypes that distinguish risk for clinical outcomes. These phenotypes may inform the development of studies and guidelines regarding optimal self-management.

No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease.

Whether higher serum phosphorus levels are associated with a higher risk for death and/or progression of chronic kidney disease (CKD) is not well established, and whether the association is confounded by access and barriers to care is unknown. To answer these questions, data of 10,672 individuals identified to have CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m(2)) from those participating in a community-based screening program were analyzed. Over a median follow-up of 2.3 years, there was no association between quartiles of serum phosphorus and all-cause mortality (adjusted hazards ratio for serum phosphorus over 3.3 to 3.7, over 3.7 to 4.1, and over 4.1 mg/dl, respectively: 1.22 (0.95-1.56), 1.00 (0.76-1.32), and 1.00 (0.75-1.33); reference, serum phosphorus of 3.3 mg/dl and below). Individuals in the highest quartile for serum phosphorus had a significantly higher risk for progression to end-stage renal disease (ESRD) (unadjusted hazards ratio, 6.72 (4.16-10.85)); however, the risk became nonsignificant on adjustment for potential confounders. There was no appreciable change in hazards ratio with inclusion of variables related to access and barriers to care. Additional analyses in subgroups based on 12 different variables yielded similar negative associations. Thus, in the largest cohort of individuals with early-stage CKD to date, we could not validate an independent association of serum phosphorus with risk for death or progression to ESRD.

Racial variation in medical outcomes among living kidney donors.

BACKGROUND: Data regarding health outcomes among living kidney donors are lacking, especially among nonwhite persons. METHODS: We linked identifiers from the Organ Procurement and Transplantation Network (OPTN) with administrative data of a private U.S. health insurer and performed a retrospective study of 4650 persons who had been living kidney donors from October 1987 through July 2007 and who had post-donation nephrectomy benefits with this insurer at some point from 2000 through 2007. We ascertained post-nephrectomy medical diagnoses and conditions requiring medical treatment from billing claims. Cox regression analyses with left and right censoring to account for observed periods of insurance benefits were used to estimate absolute prevalence and prevalence ratios for diagnoses after nephrectomy. We then compared prevalence patterns with those in the 2005-2006 National Health and Nutrition Examination Survey (NHANES) for the general population. RESULTS: Among the donors, 76.3% were white, 13.1% black, 8.2% Hispanic, and 2.4% another race or ethnic group. The median time from donation to the end of insurance benefits was 7.7 years. After kidney donation, black donors, as compared with white donors, had an increased risk of hypertension (adjusted hazard ratio, 1.52; 95% confidence interval [CI], 1.23 to 1.88), diabetes mellitus requiring drug therapy (adjusted hazard ratio, 2.31; 95% CI, 1.33 to 3.98), and chronic kidney disease (adjusted hazard ratio, 2.32; 95% CI, 1.48 to 3.62); findings were similar for Hispanic donors. The absolute prevalence of diabetes among all donors did not exceed that in the general population, but the prevalence of hypertension exceeded NHANES estimates in some subgroups. End-stage renal disease was identified in less than 1% of donors but was more common among black donors than among white donors. CONCLUSIONS: As in the general U.S. population, racial disparities in medical conditions occur among living kidney donors. Increased attention to health outcomes among demographically diverse kidney donors is needed. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Association between lack of health insurance and risk of death and ESRD: results from the Kidney Early Evaluation Program (KEEP).

BACKGROUND: Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000-2011 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) to examine this association. METHODS: The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables. RESULTS: Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2) or urine albumin-creatinine ratio ≥ 30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56-2.12; P < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33-2.22; P < 0.001). The association between insurance and outcomes varied by CKD stage. CONCLUSIONS: Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.

Prognostic importance of serum alkaline phosphatase in CKD stages 3-4 in a clinical population.

BACKGROUND: Elevated total serum alkaline phosphatase (ALP) levels have been associated with mortality in the general population and in dialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 28,678 patients with chronic kidney disease (CKD) stages 3 and 4 (estimated glomerular filtration rate, 15-59 mL/min/1.73 m(2)) were identified using the Cleveland Clinic CKD Registry. CKD was defined as 2 estimated glomerular filtration rate values <60 mL/min/1.73 m(2) drawn more than 90 days apart using the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation. PREDICTOR: ALP levels measured using the calorimetric assay were examined as quartiles (quartile [Q]1, <66 U/L; Q2, 66-81 U/L; Q3, 82-101 U/L; and Q4, ≥102 U/L) and as a continuous measure. OUTCOMES & MEASUREMENTS: All-cause mortality and end-stage renal disease (ESRD) were ascertained using the Social Security Death Index and US Renal Data System. RESULTS: After a median follow-up of 2.2 years, 588 patients progressed to ESRD and 4,755 died. There was a graded increase in risk of mortality with higher ALP quartiles (Q2, Q3, and Q4) compared to the reference quartile (Q1) after adjusting for demographics, comorbid conditions, use of relevant medications, and liver function test results. The highest ALP quartile was associated with an HR for ESRD of 1.38 (95% CI, 1.09-1.76). Each 1-SD (42.7 U/L) higher ALP level was associated with 15% (95% CI, 1.09-1.22) and 16% (95% CI, 1.14-1.18) increased risk of ESRD and mortality, respectively. LIMITATIONS: Single-center observational study; lack of complete data, including parathyroid hormone level, for all study participants, and attrition bias. CONCLUSIONS: Higher serum ALP levels in patients with CKD stages 3-4 were associated independently with all-cause mortality and ESRD.

Association of physician care with mortality in Kidney Early Evaluation Program (KEEP) participants.

BACKGROUND: People with or at high risk of chronic kidney disease (CKD) are at increased risk of premature morbidity and mortality. We sought to examine the effect of care provided by a primary care physician (PCP) on survival for all participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) and the effect of care provided by a nephrologist on survival for KEEP participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). METHODS: Provision of care by a PCP (n = 138,331) or nephrologist (n = 10,797) was defined using self-report of seeing that provider within the past year. Survival was ascertained by linking KEEP data to the Social Security Administration Death Master File. Multivariable Cox proportional hazards models examining the relationship between primary care and nephrologist provider status adjusted for age, sex, race, smoking status, education, health insurance, diabetes, cardiovascular disease, hypertension, cancer, albuminuria, body mass index, baseline eGFR, and hemoglobin level, with nephrology models further adjusting for calcium, phosphorus, and parathyroid hormone levels. RESULTS: Of all participants, 70.9% (98,050 of 138,331) reported receiving PCP care; older age and female sex were associated with this care. During a median follow-up of 4.2 years, 4,836 deaths occurred. After multivariable adjustment, receiving PCP care and mortality were not associated (HR, 0.94; 95% CI, 0.86-1.03; P = 0.2). Of participants with eGFR <60 mL/min/1.73 m(2), 10.1% (1,095 of 10,797) reported receiving nephrology care; younger age and male sex were associated with receipt of nephrology care. During a mean follow-up of 2.2 years, 558 deaths occurred. After multivariable adjustment, nephrologist care was not associated with mortality (HR, 1.01; 95% CI, 0.75-1.36; P = 0.9). These associations were not modified by other specialist care (endocrinologist or cardiologist). CONCLUSIONS: For all KEEP participants, neither PCP nor nephrology care was associated with improved survival. These results highlight the need to explore the connection between access to health care and outcomes in persons at high risk of or with CKD.

Physician utilization, risk-factor control, and CKD progression among participants in the Kidney Early Evaluation Program (KEEP).

BACKGROUND: Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular mortality, but little is known about the association between physician utilization and cardiovascular disease risk-factor control in patients with CKD. We used 2005-2010 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) to examine this association at first and subsequent screenings. METHODS: Control of risk factors was defined as control of blood pressure, glycemia, and cholesterol levels. We used multinomial logistic regression to examine the association between participant characteristics and seeing a nephrologist after adjusting for kidney function and paired t tests or McNemar tests to compare characteristics at first and second screenings. RESULTS: Of 90,009 participants, 61.3% had a primary care physician only, 2.9% had seen a nephrologist, and 15.3% had seen another specialist. The presence of 3 risk factors (hypertension, diabetes, and hypercholesterolemia) increased from 26.8% in participants with CKD stages 1-2 to 31.9% in those with stages 4-5. Target levels of all risk factors were achieved in 7.2% of participants without a physician, 8.3% of those with a primary care physician only, 9.9% of those with a nephrologist, and 10.3% of those with another specialist. Of up to 7,025 participants who met at least one criterion for nephrology consultation at first screening, only 12.3% reported seeing a nephrologist. Insurance coverage was associated strongly with seeing a nephrologist. Of participants who met criteria for nephrology consultation, 406 (5.8%) returned for a second screening, of whom 19.7% saw a nephrologist. The percentage of participants with all risk factors controlled was higher at the second screening (20.9% vs 13.3%). CONCLUSION: Control of cardiovascular risk factors is poor in the KEEP population. The percentage of participants seeing a nephrologist is low, although better after the first screening. Identifying communication barriers between nephrologists and primary care physicians may be a new focus for KEEP.

Chronic Cognitive Impairment in AQP4+ NMOSD With Improvement in Cognition on Eculizumab: A Report of Two Cases.

Cognitive impairment may be associated with aquaporin-4 antibody positive (AQP4+) NMOSD, particularly where there is prominent cerebral, corpus callosum, or thalamic involvement. It is unclear to what extent this phenomenon may be treatable after months to years. We describe two cases of AQP4+ NMOSD with cognitive impairment persisting over more than 6 months, where cognition improved after eculizumab was initiated. In the first case, a 51-year-old woman presented with a 2-month history of cognitive decline and ataxia, and diffuse involvement of the corpus callosum on MRI. AQP4 antibody testing returned positive. Cognitive impairment persisted on therapy with mycophenolate, then rituximab. She was switched to eculizumab from rituximab 18 months after disease onset because of breakthrough optic neuritis; memory and cognitive function improved on eculizumab. In the second case, a 26-year-old woman initially presented with visual, auditory and tactile hallucinations, and impairment in activities of daily living, and was given a diagnosis of schizophrenia. Nine months later she was hospitalized for increasing confusion. MRI showed leukoencephalopathy and diffuse involvement of the corpus callosum with multiple enhancing callosal lesions. AQP4 antibody testing was positive and CSF testing for other antibodies of autoimmune encephalitis was negative. She had some improvement in cognition with high dose corticosteroids but remained significantly impaired. On follow-up, her repeat MRI showed a small new right inferomedial frontal enhancing lesion although she did not complain of any new cognitive issues, her MOCA score was 21/30, and she was started on eculizumab. Two months after eculizumab initiation she and her family reported cognitive improvement and MOCA score was 25/30. Common features of these two cases included extensive callosal involvement and an element of ongoing gadolinium enhancement on MRI. Our experience suggests the possibility that cognitive impairment may be amenable to immunotherapy in certain cases of NMOSD.

Antibody-Positive Neuromyelitis Optica Spectrum Disorder After Second COVID-19 Vaccination: a Case Report.

In the era of the COVID-19 pandemic declared in March 2020, widespread vaccination protocols were initiated to mitigate the severity and spread of COVID-19. Although COVID-19 vaccines have been generally considered safe, adverse events post-vaccination have been reported, including the development of demyelinating disease. We report a rare case of de novo aquaporin-4-positive neuromyelitis optica spectrum disorder (NMOSD) in an 80-year-old man following BNT162b SARS-CoV-2 vaccination to raise the awareness of this possible severe adverse event in an older adult. An 80-year-old South Asian man presented 2 days following his second dose of the Pfizer-BioNTech COVID-19 mRNA BNT162b2 vaccine with progressive left-sided leg weakness and numbness resulting in falls. MRI of the spine revealed a longitudinally extensive transverse myelitis from T3-T4 to T9-T10. Serum antibody testing revealed positive aquaporin-4 (AQP4) antibodies. He was diagnosed with AQP4-positive NMOSD and was treated with high-dose intravenous methylprednisolone and plasma exchange with some improvement. He was subsequently treated with mycophenolate mofetil and a slow steroid wean. This case report adds to the existing literature and suggests that COVID-19 vaccinations may trigger de novo NMOSD or NMOSD relapses in some individuals. Although rare, our patient presented with new-onset NMOSD in his 80 s following COVID-19 vaccination. As such, it is relevant to consider AQP4 testing in those presenting with a post-vaccination myelitis, regardless of age. Ongoing vaccine surveillance and research are needed to understand the risk of NMOSD post-COVID-19 vaccinations further.

Association of NEDA-4 With No Long-term Disability Progression in Multiple Sclerosis and Comparison With NEDA-3: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression. METHODS: English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression. RESULTS: Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I2 = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses. DISCUSSION: In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

Association of serum phosphorus with left ventricular mass in men and women with stable cardiovascular disease: data from the Heart and Soul Study.

BACKGROUND: Higher serum phosphorus levels are associated with cardiovascular disease (CVD) events in the general population, an association that may be stronger in men. Estradiol has phosphaturic properties. Whether higher serum phosphorus levels are associated with left ventricular (LV) mass in persons without end-stage renal disease and whether the association is modified by sex is unknown. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: 978 outpatients with stable CVD. PREDICTOR: The primary predictor variable was serum phosphorus level. Sex was evaluated as an effect modifier. OUTCOME & MEASUREMENTS: LV mass using transthoracic echocardiography. RESULTS: The association of serum phosphorus level with LV mass differed by sex (interaction P=0.04). In models adjusted for age, race, kidney function, smoking, diabetes, blood pressure, cholesterol level, C-reactive protein level, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, each 1-mg/dL higher serum phosphorus level was associated with 4.52-g/m2 greater LV mass (95% CI, 1.04-8.01; P=0.01) in men. Conversely, in women, no statistically significant association was found between serum phosphorus level and LV mass. LIMITATIONS: Older adult population with stable CVD; 19% were women. CONCLUSIONS: In outpatients with stable CVD, higher serum phosphorus levels are associated with greater LV mass in men, but not women. Whether sex hormones may account for these differences requires future study.

The pathogenesis of vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature.

Considerable scientific progress in the pathogenesis of vascular calcification that has accrued in recent years is reviewed in this article. Factors regulating mesenchymal cell differentiation and their role in the neointimal calcification of atherosclerosis and the vascular media calcification observed in chronic kidney disease and diabetes are discussed, as is the role of bone regulatory proteins in bone mineralization and vascular calcification. This includes recent studies related to fetuin-A, and the discovery of a new circulating hormone involved in regulating phosphate homeostasis and sensing skeletal hydroxyapatite precipitation. Finally, the relationship between skeletal mineralization and vascular mineralization is discussed in terms of their links, especially through serum phosphate concentrations.

Gadolinium-containing magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a case-control study.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a newly described disorder occurring in persons with renal failure. Gadolinium-based contrast used in magnetic resonance imaging (MRI) has been suggested as a cause. A cluster of patients with NSF was investigated to identify risk factors. Limited preliminary findings from this investigation were presented in the Morbidity and Mortality Weekly Report. STUDY DESIGN: Matched case-control. SETTING & PARTICIPANTS: Dialysis patients with and without a diagnosis of NSF treated at an academic medical center. PREDICTOR: Exposure to gadolinium-based contrast. OUTCOMES & MEASUREMENTS: Laboratory and clinical characteristics of NSF. RESULTS: 19 of 28 cases identified at the hospital from December 2002 to August 2006 met inclusion criteria and were matched to 57 controls. In univariate analysis, receipt of gadolinium-containing MRI contrast in the preceding year (odds ratio [OR], 7.99; 95% confidence interval, 2.22 to 28.8) was associated with NSF; the measure of association increased as cumulative dose increased. Gadodiamide exposure (OR, 9.83; 95% confidence interval, 2.09 to 46.2) was associated more strongly with NSF than gadoversetamide (OR, 1.82; 95% confidence interval, 0.33 to 10.2). Although not statistically significant, cases were more likely than controls to have undergone primarily peritoneal dialysis in the preceding 6 months. There was no significant difference in receipt of high-dose recombinant erythropoietin between cases and controls. In multivariable analysis, gadolinium contrast exposure (OR, 8.97; 95% confidence interval, 1.28 to 63.0) remained significantly associated with NSF. LIMITATIONS: Retrospective design, small sample size, inability to completely evaluate erythropoietin. CONCLUSIONS: Receipt of gadolinium-containing MRI contrast is associated with NSF in a dose-dependent manner. The risk associated with gadolinium may differ by contrast agent and dialysis modality. Use of gadolinium-based contrast agents should be avoided when possible in patients with renal failure.

Nephrogenic systemic fibrosis--implications for nephrologists.

Nephrogenic systemic fibrosis (NSF) is a debilitating disorder seen in-patient with advanced chronic kidney disease (CKD). Recent evidence suggests a link between NSF and the administration of gadolinium-based contrast agents (Gd-CA). In addition, other risk factors have also been suggested to facilitate the development of NSF in this population after Gd-CA. These include metabolic acidosis, high-dose erythropoietin therapy, and the altered mineral metabolism of CKD. While it is possible that these factors may increase the risk of NSF after Gd-CA exposure, they may also simply reflect conditions that increase the risk of getting exposed to Gd-CA, particularly at high doses. Furthermore, given the risk of NSF in CKD, physicians must weigh the risks of NSF versus the risk of contrast-induced nephropathy (CIN) with iodinated agents in this population. In this review, we will provide a nephrologist's perspective on these issues and the nephrologist's role in the prevention of NSF.

Bone morphogenetic proteins in vascular calcification.

Vascular calcification is a common problem among the elderly and those with chronic kidney disease (CKD) and diabetes. The process of tunica media vascular calcification in CKD appears to involve a phenotypic change in the vascular smooth muscle cell (VSMC) resulting in cell-mediated mineralization of the extracellular matrix. The bone morphogenetic proteins (BMPs) are important regulators in orthotopic bone formation, and their localization at sites of vascular calcification raises the question of their role. In this review, we will discuss the actions of the BMPs in vascular calcification. Although the role of BMP-2 in vascular calcification is not proven, it has been the most studied member of the BMP family in this disease process. The role of BMP-2 may be through inducing osteoblastic differentiation of VSMCs through induction of MSX-2, or by inducing apoptosis of VSMCs, a process thought critical in the initiation of vascular calcification. Additionally, BMP-2 may be related to loss of regulation of the matrix Gla protein. A second BMP, BMP-7, less studied than BMP-2 may have opposing actions in vascular calcification. In postnatal life, BMP-7 is expressed primarily in the kidney, and expression is diminished by renal injury. BMP-7 is an important regulator of skeletal remodeling and the VSMC phenotype. BMP-7 restores skeletal anabolic balance in animal models of CKD with disordered skeletal modeling, also reducing serum phosphate in the process. BMP-7 also reverses vascular calcification in CKD, and reduction in vascular calcification is due, in part, to reduced serum phosphate, an important inducer of VSMC-mediated vascular mineralization and in part to direct actions on the VSMC.