Acute kidney injury and long-term renal effects of alectinib in anaplastic lymphoma kinase-positive non-small cell lung carcinoma: a case report.

BACKGROUND: Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib. CASE PRESENTATION: A 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months. CONCLUSIONS: Our data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient.

Discontinuation of Antihypertensive Medications on the Outcome of Hospitalized Patients With Severe Acute Respiratory Syndrome-Coronavirus 2.

[Figure: see text].

Role of Risk Factors in Developing Osmotic Demyelination Syndrome During Correction of Hyponatremia: A Case Study.

This case report describes a 57-year-old man who presented first with lethargy and dysarthria due to hyponatremia resulting from poor intake and diuretics. One week after discharge, he returned with confusion, ataxia and dysphagia, and he ultimately turned out to have developed an osmotic demyelination syndrome (ODS). In his first hospital admission, his serum sodium was corrected without new neurological symptoms occurring. In retrospect, he had several risk factors for the development of ODS during the correction of hyponatremia. The serum sodium correction rate only briefly exceeded the recommended limits. This case underlines that (1) extra awareness of the serum sodium correction rate is warranted in patients with risk factors, (2) factors other than sodium can play an important role in the development of ODS and (3) that the manifestations of ODS can be delayed substantially after an incident of osmotic stress.

Effects of crizotinib on creatinine clearance and renal hemodynamics.

OBJECTIVES: The tyrosine kinase inhibitor crizotinib may affect renal function. The mechanism of this effect is not understood. We aimed to get more insight by measuring renal hemodynamics in patients treated with crizotinib. MATERIALS AND METHODS: Renal hemodynamics (i.e. glomerular filtration rate and effective renal plasma flow) were measured with radioactive tracers in three patients with stage IV non small-cell lung cancer during treatment with crizotinib. The results were compared with simultaneous creatinine based renal function measurements in the same patients. RESULTS: Patients had been treated with crizotinib between 155 and 320 days at the first measurement. In one patient the measurement was repeated after a total of one year and two months of treatment. All patients had been treated with chemotherapy containing cisplatin before. In these patients true glomerular filtration rate was 64-83% higher than estimated by creatinine based measurements. Filtration fraction, a measure of glomerular pressure, was increased in all three patients. The glomerular pressure was even further increased in a follow-up measurement. CONCLUSION: Creatinine-based estimates of GFR on crizotinib may underestimate the true GFR. However, evidence of increased glomerular pressure may increase risk of long term true nephrotoxicity.

Effects of Vitamin D Receptor Activation and Dietary Sodium Restriction on Residual Albuminuria in CKD: The ViRTUE-CKD Trial.

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 µg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet. We analyzed the treatment effect by linear mixed effect models for repeated measurements. In the intention-to-treat analysis, albuminuria (geometric mean) was 1060 (95% confidence interval, 778 to 1443) mg/24 h during RS + PLAC and 990 (95% confidence interval, 755 to 1299) mg/24 h during RS + PARI (P=0.20 versus RS + PLAC). LS + PLAC reduced albuminuria to 717 (95% confidence interval, 512 to 1005) mg/24 h (P<0.001 versus RS + PLAC), and LS + PARI reduced albuminuria to 683 (95% confidence interval, 502 to 929) mg/24 h (P<0.001 versus RS + PLAC). The reduction by PARI beyond the effect of LS was nonsignificant (P=0.60). In the per-protocol analysis restricted to participants with ≥95% compliance with study medication, PARI did provide further albuminuria reduction (P=0.04 LS + PARI versus LS + PLAC). Dietary adherence was good as reflected by urinary excretion of 174±64 mmol Na+ per day in the combined RS groups and 108±61 mmol Na+ per day in the LS groups (P<0.001). In conclusion, moderate dietary sodium restriction substantially reduced residual albuminuria during fixed dose angiotensin-converting enzyme inhibition. The additional effect of PARI was small and nonsignificant.

Purulent lupus panniculitis unmasked by FDG-PET/CT scan: A case report.

RATIONALE: Lupus panniculitis (LP) is a unique variant of cutaneous lupus erythematosus. Clinical manifestations are typically mild and include erythema, nodules, and small ulcers. In certain cases, diagnosing LP may be challenging. Skin overlying the typical subcutaneous inflammation may appear normal, and bacterial superinfections of the skin sometimes mask the underlying LP. It has been suggested that a computed tomography (CT) scan may help to identify obscure LP lesions. Here, we report a case of a 54-year-old woman with an unusually severe form of LP, in which the full disease extent was only revealed by a fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan. PATIENT CONCERNS/DIAGNOSES/INTERVENTIONS/OUTCOMES: Our patient initially presented with a bacterial infection of the skin. After initial improvement with antibiotic treatment, new erythematous lesions and sterile subcutaneous pus collections developed. An FDG-PET/CT scan revealed extensive subcutaneous inflammation at sites that had appeared normal during physical examination and on CT scan. As the subcutaneous lesions showed a remarkably linear pattern on FDG-PET/CT scan, the patient was suspected of having LP. After confirmation of this diagnosis by a deep-skin biopsy, our patient was treated with systemic glucocorticoids. Eventually, our patient succumbed to complications of LP and its treatment. LESSONS: Our case demonstrates that clinical manifestations of LP are not always mild and that timely diagnosis is needed. Furthermore, we show that obscure LP lesions are more readily identified on an FDG-PET/CT scan than CT scan.

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial.

OBJECTIVE: To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. DESIGN: Multicentre crossover randomised controlled trial. SETTING: Outpatient clinics in the Netherlands. PARTICIPANTS: 52 patients with non-diabetic nephropathy. INTERVENTIONS: All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. MAIN OUTCOME MEASURES: The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. RESULTS: Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition. CONCLUSIONS: Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675.

Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria.

BACKGROUND: Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). METHODS AND RESULTS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51+/-12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8+/-1.0 mmol/L, mean systolic/diastolic blood pressure was 130+/-18/76+/-10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank). CONCLUSIONS: In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.

Corticosteroid use and its association with microalbuminuria in the adult population.

BACKGROUND: Corticosteroids exhibit a wide range of adverse effects, among which are a number of cardiovascular effects. Microalbuminuria shows a strong correlation with these cardiovascular effects and is an indicator for cardiovascular risk. We now investigate whether use of corticosteroids, either systemic or nonsystemic, is associated with microalbuminuria. METHODS: We used the data of 7010 subjects of an on-going population based study, focussed on the impact of microalbuminuria (PREVEND). Microalbuminuria was defined as urinary albumin excretion of 30-300 mg/24 h, measured as the mean of two 24-h urine collections. Corticosteroid use was measured in the year preceding the albumin measurement using community pharmacy data. RESULTS: After adjusting for age and sex, the odds ratio (OR) for having microalbuminuria was slightly elevated (1.21; 95% CI 1.03-1.41; N=1798) for corticosteroid users. The ORs were lower for subjects using only systemic corticosteroids (1.07; 95% CI 0.67-1.72; N=146), or only local corticosteroids (1.11; 95% CI 0.93-1.32; N=1442). However, the OR for subjects using both systemic and local corticosteroids was raised (1.99; 95% CI 1.42-2.77; N=210). CONCLUSION: Corticosteroid use, and especially use of both systemic and local corticosteroids is associated with microalbuminuria. Based on this investigation we cannot say if this is due to adverse effects of corticosteroids themselves, or effects of the underlying disease.

Role of the endothelin-1 gene locus for renal impairment in the general nondiabetic population.

A decreased GFR in the range of mild renal insufficiency and an increased urinary albumin excretion (UAE) rate in the range of microalbuminuria are important cardiovascular risk factors. Endothelin-1 (ET-1) has been suggested to be a major disease promoting factor in renal disease. The role of the ET-1 gene locus (EDN1) for renal function in the general nondiabetic population was evaluated. To explore the overall relevance of EDN1, two suitable single-nucleotide polymorphisms, EDN1 K198N and EDN1 T-1370G, were selected, and haplotype analysis was performed. Determined were genotypes in 7291 nondiabetic subjects from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Genetic analysis was related to UAE and GFR as continuous variables and to microalbuminuria and diminished filtration as dichotomous traits. In a logistic regression analysis, no significant higher risk for increased UAE, microalbuminuria, decreased GFR, or diminished filtration could be observed for either single-nucleotide polymorphism separately. Haplotype analysis revealed that individuals with the homozygous G-N haplotype (compound EDN1 -1370GG/198NN genotype) have a lower GFR than the remaining subjects (P < 0.05) and exhibit a significant higher risk for the presence of a diminished filtration (relative risk, 2.4; 95% confidence interval, 1.07 to 5.33; P < 0.05). Further analysis demonstrated no association between this haplotype and UAE or plasma ET-1 levels. Although a functional relevance of the EDN1 G-N haplotype itself remains unclear, the data demonstrate that genetic variation at the EDN1 locus has a significant effect on glomerular filtration but not on UAE in the general nondiabetic population.

A central body fat distribution is related to renal function impairment, even in lean subjects.

BACKGROUND: Overweight and obesity are believed to be associated with renal damage. Whether this depends on fat distribution is not known. We hypothesize that in addition to overweight, fat distribution may be associated with renal function abnormalities. METHODS: We studied the relation between body weight and fat distribution and microalbuminuria and elevated or diminished filtration in 7,676 subjects without diabetes. Microalbuminuria is defined as urinary albumin excretion (UAE) of 30 to 300 mg/24 h. Elevated and diminished filtration are defined as filtration plus or minus 2 SDs of a nondiabetic lean group with a peripheral fat distribution and UAE of 0 to 15 mg/24 h, corrected for age and sex. The total population was divided into six groups according to body weight (overweight is defined as body mass index [BMI] > 25 and < or = 30 kg/m2; obesity, as BMI > 30 kg/m2) and fat distribution. RESULTS: In logistic regression analysis, obese subjects with central fat distribution had a greater risk for microalbuminuria (relative risk, 1.7; 95% confidence interval, 1.19 to 2.35). Obese subjects with either peripheral or central fat distribution had a greater risk for elevated filtration (relative risk, 3.2; 95% confidence interval, 1.19 to 8.47; relative risk, 2.6; 95% confidence interval, 1.59 to 4.28, respectively). Furthermore, subjects with central fat distribution, either lean, overweight, or obese, had a greater risk for diminished filtration (relative risk, 1.9; 95% confidence interval, 1.19 to 3.12; relative risk, 2.0; 95% confidence interval, 1.19 to 3.19; and relative risk, 2.7; 95% confidence interval, 1.46 to 4.85, respectively). Finally, by dividing waist-hip ratio (WHR) into quartiles, greater WHR was associated with a greater risk for diminished filtration, even when corrected for BMI. CONCLUSION: Not only overweight and obese subjects, but also lean subjects with central fat distribution are at risk for diminished filtration. Therefore, a central pattern of fat distribution, not overweight or obesity by itself, seems to be important for renal impairment.

Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.

BACKGROUND: For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. METHODS AND RESULTS: In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P=0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. CONCLUSIONS: Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.

Pharmacy data in epidemiological studies: an easy to obtain and reliable tool.

PURPOSE: The agreement between drug use measured in computerized pharmacy records and patient interviews or questionnaires is generally good. However, most investigations on this subject studied selected populations or subsets. We studied the coverage of Dutch pharmacy data for our study cohort, and the agreement between the different sources. METHODS: We used the data from 8592 subjects of an on-going population-based study, focused on the impact of microalbuminuria (PREVEND). Data on drug use was collected in a questionnaire and at community pharmacies. Drug use was measured in the year preceding the questionnaire. Agreement between the sources was measured using kappa-values, sensitivity and positive predictive value. RESULTS: Pharmacy data could be collected for 7568 (88%) of the study cohort. Pharmacy data and questionnaires showed good agreement for antihypertensives, lipid lowering drugs, oral antidiabetics and oral contraceptives, but poor agreement for nitrates, hormone replacement therapy and painkillers. CONCLUSIONS: Pharmacy data could be collected for a large proportion of our cohort. For chronically used drugs pharmacy data generally agrees well with questionnaires. However, for drugs used for shorter periods, as needed, or also available over-the-counter, the agreement is not so good. Pharmacy data can be a valuable source of drug information in epidemiological studies.

The impact of antihypertensive drug groups on urinary albumin excretion in a non-diabetic population.

AIMS: Microalbuminuria (30-300 mg 24 h-1) is recognized to be independently associated with renal and cardiovascular risk. Antihypertensives may lower microalbuminuria. We questioned whether the use of different antihypertensive drug classes in general practice influences microalbuminuria as related to blood pressure in nondiabetic subjects. METHODS: To study this, we used the data from 6836 subjects of an on-going population based study, focused on the meaning of microalbuminuria (PREVEND). Odds ratios, adjusted for age, sex, blood pressure, cholesterol level, smoking and the use of other antihypertensive or cardiovascular drugs, were calculated to determine the association of drug groups with microalbuminuria. Influence of antihypertensives on the relation between blood pressure and (log) urinary albumin excretion was determined by comparing linear regression lines. RESULTS: Microalbuminuria was significantly associated with the use of dihydropyridine calcium channel blockers (odds ratio: 1.76 [1.22-2.54]), but not with other antihypertensive drug groups. The linear regression line of the relation between blood pressure and (log) urinary albumin excretion was significantly steeper (P = 0.0047) for users of calcium channel blockers, but not for other antihypertensives, compared with subjects using no antihypertensive. Users of a combination of renin-angiotensin system inhibitors and diuretics however, had a less steep regression line (P = 0.037). CONCLUSIONS: This study suggests a disadvantageous effect of dihydropyridine calcium channel blockers on microalbuminuria compared with other antihypertensive drug groups. Thus, if microalbuminuria is causally related to an increased risk for cardiovascular morbidity and mortality, dihydropyridines do not seem to be agents of choice to lower blood pressure. Furthermore, the combination of renin-angiotensin system inhibition and diuretics seems to act synergistically.

Urinary albumin excretion is associated with renal functional abnormalities in a nondiabetic population.

Microalbuminuria (MA) is an important early sign of diabetic nephropathy. Hyperfiltration and impaired filtration in relation to albuminuria has been well investigated in diabetic subjects. This study tested the hypothesis that an increased urinary albumin excretion (UAE) is associated with renal functional abnormalities also in nondiabetic subjects. The relation between UAE and creatinine clearances (Ccr) in 7728 nondiabetic subjects was studied. Subjects were divided in four groups according to UAE (mg/24 h): 0 to 15 (control), 15 to 30 (high-normal albuminuria [HNA]), 30 to 300 (MA), >300 (macroalbuminuria). An elevated filtration and a diminished filtration were defined as a Ccr exceeding or below 2x the SD of the control group corrected for age and gender. Ccr followed a parabolic trend, with a higher Ccr in the HNA as compared with control and a lower Ccr in the MA and macroalbuminuria group as compared with HNA. With each increasing UAE level, male sex, age, body mass index, minimal waist circumference, systolic and diastolic BP, plasma glucose, and a positive family history for diabetes all followed a significant linear increasing trend (P < 0.001). After adjustment for age, gender, body mass index, plasma glucose, a positive family history for diabetes, systolic and diastolic BP, antihypertensive medication, and smoking in a multivariate analysis, HNA and MA were independently associated with an elevated filtration (RR 1.8 [95% confidence interval, 1.30 to 2.51] and 1.7 [1.17 to 2. 45]). Macroalbuminuria was independently associated with a diminished filtration (4.3 [range, 1.97 to 9.36]). In conclusion, an elevated UAE might be an important and early sign for progressive renal function loss in a nondiabetic population.