Alessandro Gasparini

Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality

Current guidelines for chronic kidney disease (CKD) recommend using albuminuria as well as estimated glomerular filtration rate (eGFR) to stage CKD. However, CKD progression is solely defined by change in eGFR with little regard to the risk implications of change in albuminuria. This is an observational study from the Stockholm CREAtinine Measurements (SCREAM) project, a health care utilization cohort from Stockholm, Sweden, with laboratory measures from 2006-2011 and follow-up through December 2012. Included were 31,732 individuals with two or more ambulatory urine albumin to creatinine ratio (ACR) tests. We assessed the association between change in ACR during a baseline period of 1, 2, or 3 years and end-stage renal disease (ESRD) or death. Using a 2-year baseline period, there were 378 ESRD events and 1712 deaths during a median of 3 years of follow-up. Compared to stable ACR, a 4-fold increase in ACR was associated with a 3.08-times (95% confidence interval 2.59 to 3.67) higher risk of ESRD while a 4-fold decrease in ACR was associated with a 0.34-times (0.26 to 0.45) lower risk of ESRD. Similar associations were found in people with and without diabetes mellitus, with and without hypertension, and also when adjusted for the change in eGFR during the same period. The association between change in ACR and mortality was weaker: ACR increase was associated with mortality, but the relationship was largely flat for ACR decline. Results were consistent for 1-, 2-, and 3-year ACR changes. Thus, changes in albuminuria are strongly and consistently associated with the risk of ESRD and death.

Time in Therapeutic Range and Outcomes After Warfarin Initiation in Newly Diagnosed Atrial Fibrillation Patients With Renal Dysfunction

Background It is unknown whether renal dysfunction conveys poor anticoagulation control in warfarin‐treated patients with atrial fibrillation and whether poor anticoagulation control associates with the risk of adverse outcomes in these patients. Methods and Results This was an observational study from the Stockholm CREatinine Measurements (SCREAM) cohort including all newly diagnosed atrial fibrillation patients initiating treatment with warfarin (n=7738) in Stockholm, Sweden, between 2006 and 2011. Estimated glomerular filtration rate (eGFR; mL/min per 1.73 m2) was calculated from serum creatinine. Time‐in‐therapeutic range (TTR) was assessed from international normalized ratio (INR) measurements up to warfarin cessation, adverse event, or end of follow‐up (2 years). Adverse events considered a composite of intracranial hemorrhage, ischemic stroke, myocardial infarction, or death. During median 254 days, TTR was 83%, based on median 21 INR measurements per patient. TTR was 70% among patients with eGFR <30, around 10% lower than in those with normal renal function. During observation, adverse events occurred in 4.0% of patients, and those with TTR ≤75% were at higher adverse event risk. This was independent of patient characteristics, comorbidities, number of INR tests, days exposed to warfarin, and, notably, independent of eGFR: adjusted odds ratio (OR) 1.84 (95% CI, 1.41–2.40) for TTR 75% to 60% and adjusted OR 2.09 (1.59–2.74) for TTR <60%. No interaction was observed between eGFR and TTR in association to adverse events (P=0.2). Conclusion Severe chronic kidney disease (eGFR <30) patients with atrial fibrillation have worse INR control while on warfarin. An optimal TTR (>75%) is associated with lower risk of adverse events, independently of underlying renal function.

The Stockholm CREAtinine Measurements (SCREAM) project: protocol overview and regional representativeness

Background We here describe the construction of the Stockholm CREAtinine Measurement (SCREAM) cohort and assess its coverage/representativeness of the Stockholm county in Sweden. SCREAM has the principal aims to estimate the burden and consequences of chronic kidney disease (CKD) and to identify inappropriate drug use (prescription of nephrotoxic, contraindicated or ill-dosed drugs). Methods SCREAM is a repository of laboratory data of individuals, residing or accessing healthcare in the region of Stockholm, who underwent creatinine assessments between 2006–11. Laboratory tests were linked to administrative databases with complete information on socioeconomic status, demographic data, healthcare utilization, diagnoses, vital status and dispensed prescription medicines. Results SCREAM identified 1 118 507 adult Stockholm citizens with available creatinine tests between 2006–11. This corresponded to 66% of the complete population in the region. Geographical coverage was uniform, ranging between 62 and 72% throughout its 26 municipalities. Population coverage was higher across older age strata (50% coverage for age range 18–44 years, >75% for 45–64 years and >90% coverage for ≥65 years). Of note, 97 and 98% of all individuals with a diagnosis of diabetes mellitus or cardiovascular disease, respectively, were captured by SCREAM. Further, 89% of all deaths registered in the period occurred in individuals with a creatinine test undertaken. Conclusion SCREAM represents the largest cohort to estimate the burden and healthcare implications of CKD in Sweden. The coverage and representativeness of the region of Stockholm was high and in accordance to both the commonness of creatinine assessment, and the medical indications for creatinine testing. The inclusion of individuals who sought medical care and had a creatinine test undertaken resulted in a slight over-representation of elderly and comorbid patients.

Hyperkalemia after initiating renin-angiotensin system blockade : The Stockholm creatinine measurements (SCREAM) project

Background Concerns about hyperkalemia limit the use of angiotensin‐converting enzyme inhibitors (ACE‐I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium‐monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE‐I/ARB initiation and developed and validated a hyperkalemia susceptibility score. Methods and Results We evaluated 69 426 new users of ACE‐I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow‐up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity‐matched new ACE‐I/ARB users to 20 186 new β‐blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β‐blocker and ACE‐I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m2 were risks higher among ACE‐I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium‐sparing diuretics in new ACE‐I/ARB users; this score accurately predicted 1‐year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840–0.869) and in a validation cohort from the US‐based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794–0.841), with good calibration. Conclusions Hyperkalemia within the first year of ACE‐I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m2, but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.

Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system

BACKGROUND Hypo- and hyperkalemia in clinical settings are insufficiently characterized and large-scale data from Europe lacking. We studied incidence and determinants of these abnormalities in a large Swedish healthcare system. METHODS Observational study from the Stockholm CREAtinine Measurements project, including adult individuals from Stockholm accessing healthcare in 2009 (n=364,955). Over 3-years, we estimated the incidence of hypokalemia, defined as potassium<3.5mmol/L, hyperkalemia, defined as potassium>5mmol/L, and moderate/severe hyperkalemia, defined as potassium>5.5mmol/L. Kidney function was assessed by estimated glomerular filtration rate (eGFR). RESULTS Of 364,955 participants, 69.4% had 1-2 potassium tests, 16.7% had 3-4 tests and the remaining 13.9% had >4potassiumtests/year. Hypokalemia occurred in 49,662 (13.6%) individuals, with 33% recurrence. Hyperkalemia occurred in 25,461 (7%) individuals, with 35.7% recurrence. Moderate/severe hyperkalemia occurred in 9059 (2.5%) with 28% recurrence. The frequency of potassium testing was an important determinant of dyskalemia risk. The incidence proportion of hyperkalemia was higher in the presence of diabetes, lower eGFR, myocardial infarction, heart failure (HF), or use of renin angiotensin-aldosterone system inhibitors (RAASi). In adjusted analyses, women and use of loop/thiazide diuretics were associated with lower hyperkalemia risk. Older age, lower eGFR, diabetes, HF and use of RAASi were associated with higher hyperkalemia risk. On the other hand, women, younger age, higher eGFR and baseline use of diuretics were associated with higher hypokalemia risk. CONCLUSION Hypo- and hyperkalemia are common in healthcare. Optimal RAASi and diuretics use and careful potassium monitoring in the presence of certain comorbidities, especially lower eGFR, is advocated.

eGFR and the Risk of Community-Acquired Infections

BACKGROUND AND OBJECTIVES Community-acquired infections are common, contributing to adverse outcomes and increased health care costs. We hypothesized that, with lower eGFR, the incidence of community-acquired infections increases, whereas the pattern of site-specific infections varies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Among 1,139,470 health care users (mean age =52±18 years old, 53% women) from the Stockholm CREAtinine Measurements Project, we quantified the associations of eGFR with the risk of infections, overall and major types, over 12 months. RESULTS A total of 106,807 counts of infections were recorded throughout 1,128,313 person-years. The incidence rate of all infections increased with lower eGFR from 74/1000 person-years for individuals with eGFR=90-104 ml/min per 1.73 m2 to 419/1000 person-years for individuals with eGFR<30 ml/min per 1.73 m2. Compared with eGFR of 90-104 ml/min per 1.73 m2, the adjusted incidence rate ratios of community-acquired infections were 1.08 (95% confidence interval, 1.01 to 1.14) for eGFR of 30-59 ml/min per 1.73 m2 and 1.53 (95% confidence interval, 1.39 to 1.69) for eGFR<30 ml/min per 1.73 m2. The relative proportions of lower respiratory tract infection, urinary tract infection, and sepsis became increasingly higher along with lower eGFR strata (e.g., low respiratory tract infection accounting for 25% versus 15% of community-acquired infections in eGFR<30 versus 90-104 ml/min per 1.73 m2, respectively). Differences in incidence associated with eGFR were in general consistent for most infection types, except for nervous system and upper respiratory tract infections, for which no association was observed. CONCLUSIONS This region-representative health care study finds an excess community-acquired infections incidence in individuals with mild to severe CKD. Lower respiratory tract infection, urinary tract infection, and sepsis are major infections in CKD.

Routinely measured iohexol glomerular filtration rate versus creatinine-based estimated glomerular filtration rate as predictors of mortality in patients with advanced chronic kidney disease: a Swedish Chronic Kidney Disease Registry cohort study

Background. Estimated glomerular filtration rate (eGFR) becomes less reliable in patients with advanced chronic kidney disease (CKD). Methods. Using the Swedish CKD Registry (2005‐11), linked to the national inpatient, dialysis and death registers, we compared the performance of plasma‐iohexol measured GFR (mGFR) and urinary clearance measures versus eGFR to predict death in adults with CKD stages 4/5. Performance was assessed using survival and prognostic models. Results. Of the 2705 patients, 1517 had mGFR performed, with the remainder providing 24‐h urine clearances. Median eGFR (CKD‐EPIcreatinine) was 20 mL/min/1.73 m2 [interquartile range (IQR) 14‐26], mGFR 18 mL/min/1.73 m2 (IQR 13‐23) and creatinine clearance 23 mL/min (IQR 15‐31). Median follow‐up was 45 months (IQR 26‐59), registering 968 deaths (36%). In fully adjusted Cox models, a rise in mGFR of 1 mL/min/1.73 m2 was associated with a 5.3% fall in all‐cause mortality compared with a 1.7% corresponding fall for eGFR [adjusted hazard ratio (aHR) 0.947 (95% CI, 0.930‐0.964) versus aHR 0.983 (95% CI, 0.970‐0.996)]. mGFR was also statistically superior in prognostic models (discrimination using logistic regression and integrated discrimination improvement). Urinary clearance measures showed a stronger aetiological relationship with death than eGFR, but were not statistically superior in the prognostic models. Conclusions. The performance of mGFR was superior to eGFR, in both aetiological and prognostic models, in predicting mortality in adults with CKD stage 4/5, demonstrating the importance of GFR per se versus non‐GFR determinants of outcome. However, the relatively modest enhancement suggests that eGFR may be sufficient to use in everyday clinical practice while mGFR adds important prognostic information for those where eGFR is believed to be biased.

Cinacalcet use and the risk of cardiovascular events, fractures and mortality in chronic kidney disease patients with secondary hyperparathyroidism

With the aim to expand the randomized controlled trial evidence of cinacalcet treatment to the unselected, general chronic kidney disease (CKD) population we analysed a large inception cohort of CKD patients in the region of Stockholm, Sweden 2006–2012 (both non-dialysis, dialysis and transplanted) with evidence of secondary hyperparathyroidism (SHPT). We used marginal structural models to account for both confounding by indication and time-dependent confounding. Over 37 months, 435/3,526 (12%) initiated cinacalcet de novo. Before cinacalcet initiation, parathyroid hormone (PTH) had increased progressively to a median of 636ng/L. After cinacalcet initiation, PTH declined, as did serum calcium and phosphate. In total, 42% of patients experienced a fatal/non-fatal cardiovascular event, 32% died and 9% had a new fracture. The unadjusted cardiovascular odds ratio (OR) associated with cinacalcet treatment was 1.01 (95% confidence interval: 0.83, 1.22). In the fully weighted model, the cardiovascular odds was lower in cinacalcet treated patients (OR 0.67: 0.48, 0.93). The adjusted ORs for all-cause mortality and for fractures were 0.79 (0.56, 1.11) and 1.08 (0.59, 1.98) respectively. Our study suggests cinacalcet treatment improves biochemical abnormalities in the wider CKD population, and adds real-world support that treating SHPT with cinacalcet may have beneficial effects on cardiovascular outcomes.

Lower serum calcium is independently associated with CKD progression

Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3–5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006–2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was −0.82 (−0.90; −0.74) mL/min/1.73 m2/year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was −0.10 (−0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (−0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m2/year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.

Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project

Abstract Background Small-scale studies suggest that hyperkalaemia is a less threatening condition in chronic kidney disease (CKD), arguing adaptation/tolerance to potassium (K+) retention. This study formally evaluates this hypothesis by estimating the distribution of plasma K+ and its association with mortality across CKD stages. Methods This observational study included all patients undergoing plasma K+ testing in Stockholm during 2006–11. We randomly selected one K+ measurement per patient and constructed a cross-sectional cohort with mortality follow-up. Covariates included demographics, comorbidities, medications and estimated glomerular filtration rate (eGFR). We estimated K+ distribution and defined K+ ranges associated with 90-, 180- and 365-day mortality. Results Included were 831 760 participants, of which 70 403 (8.5%) had CKD G3 (eGFR <60–30 mL/min) and 8594 (1.1%) had CKD G4–G5 (eGFR <30 mL/min). About 66 317 deaths occurred within a year. Adjusted plasma K+ increased across worse CKD stages: from median 3.98 (95% confidence interval 3.49–4.59) for eGFR >90 to 4.43 (3.22–5.65) mmol/L for eGFR ≤15 mL/min/1.73 m2. The association between K+ and mortality was U-shaped, but it flattened at lower eGFR strata and shifted upwards. For instance, the range where the 90-day mortality risk increased by no more than 100% was 3.45–4.94 mmol/L in eGFR >60 mL/min, but was 3.36–5.18  in G3 and 3.26–5.53 mmol/L in G4–G5. In conclusion, CKD stage modifies K+ distribution and the ranges that predict mortality in the community. Conclusion Although this study supports the view that hyperkalaemia is better tolerated with worse CKD, it challenges the current use of a single optimal K+ range for all patients.