Non-proteinuric Chronic Kidney Disease Research Articles

Ubiquitin-Specific Protease 18 in Chronic Kidney Disease-Another Emerging Biomarker to Consider?

Ubiquitin-specific protease 18 (USP18) is a protein recognized for its dual enzymatic and non-enzymatic nature. It is involved in many physiological processes like the cell cycle and cell signaling. It also suppresses heart muscle remodeling upon an increase in the afterload. The role of USP18 in kidney pathology remains unknown. The objective of the study was to assess the relationship between serum and urine USP18 levels, the factors contributing to cardiovascular risk, and the markers of kidney disease activity at different stages of chronic kidney disease (CKD). One hundred participants, aged between 24 and 85 years (mean 53.1 ± 17.1 years), were included. Five groups (n = 20 each) were recruited according to their renal status (healthy individuals, patients with proteinuric glomerulonephritis, patients with non-proteinuric CKD, patients who were treated with hemodialysis, and kidney transplant recipients). The measurements of serum and urine USP18 levels were performed using ELISA. The median serum USP18 level was the highest in healthy participants (1143.0 pg/mL) and kidney transplant recipients (856.6 pg/mL), whereas, in individuals with different forms of CKD, it fitted within the range of 402.1-471.9 pg/mL. Urinary USP18 reached the highest level in the group of CKD patients not yet on dialysis (303.3 pg/mL). Only in this group did it correlate with serum creatinine and urea concentrations. Our results suggest the inhibition of cardioprotective USP18 signaling when kidney function is impaired. Moreover, an increased level of urinary USP18 may indicate chronic tubular damage.

A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases.

With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).

Strategies to Prevent and Delay Chronic Kidney Disease Progression: A Pathway to Sustainability and Green Nephrology

Chronic kidney disease prevalence is increasing worldwide and is responsible for important morbidity, mortality and poor quality of life. Progression to end stage renal disease leads to major sustainability burden with high consumption of human and material resources. Hemodialysis particularly is associated with high rates of water consumption, waste production and greenhouse gas emissions. The nephrology community is gaining environmental awareness and several international societies are creating specific groups focusing on green nephrology. The first concerns are centered in the impact of hemodialysis, but it is unanimous that chronic kidney disease prevention and delayed progression are the most important measures to sustainability. New drug classes such as SGLT-2 inhibitors, selective mineralocorticoid receptors antagonists and GLP-1 analogues are revolutionizing the treatment of proteinuric and non-proteinuric chronic kidney disease. Large randomized clinical trials have proved strong and sustained benefits in renal and cardiovascular outcomes, and these drugs are now first and second-line therapy for the treatment of diabetic and non-diabetic kidney disease. In this mini-review article we explore the prevalence of chronic kidney disease, its environmental impact and resume the major strategies to prevent and delay its progression, including recent evidence on pharmacotherapy. Implementing prevention strategies and adopting environmentally-friendly practices, is the key to a better patient care and a greener nephrology.

Machine-learning enhancement of urine dipstick tests for chronic kidney disease detection.

Screening for chronic kidney disease (CKD) requires an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) from a blood sample and a proteinuria level from a urinalysis. We developed machine-learning models to detect CKD without blood collection, predicting an eGFR less than 60 (eGFR60 model) or 45 (eGFR45 model) using a urine dipstick test. The electronic health record data (n = 220018) obtained from university hospitals were used for XGBoost-derived model construction. The model variables were age, sex, and 10 measurements from the urine dipstick test. The models were validated using health checkup center data (n = 74380) and nationwide public data (KNHANES data, n = 62945) for the general population in Korea. The models comprised 7 features, including age, sex, and 5 urine dipstick measurements (protein, blood, glucose, pH, and specific gravity). The internal and external areas under the curve (AUCs) of the eGFR60 model were 0.90 or higher, and a higher AUC for the eGFR45 model was obtained. For the eGFR60 model on KNHANES data, the sensitivity was 0.93 or 0.80, and the specificity was 0.86 or 0.85 in ages less than 65 with proteinuria (nondiabetes or diabetes, respectively). Nonproteinuric CKD could be detected in nondiabetic patients under the age of 65 with a sensitivity of 0.88 and specificity of 0.71. The model performance differed across subgroups by age, proteinuria, and diabetes. The CKD progression risk can be assessed with the eGFR models using the levels of eGFR decrease and proteinuria. The machine-learning-enhanced urine-dipstick test can become a point-of-care test to promote public health by screening CKD and ranking its risk of progression.

Serum concentrations of leptin and adiponectin in dogs with chronic kidney disease.

BackgroundAn imbalance in adipokines is associated with the progression of chronic kidney disease (CKD) in humans. However, alterations in adipokines in dogs with CKD remain unclear.ObjectivesTo examine whether adipokine concentrations in serum differ between healthy dogs and dogs with CKD and to determine the correlation between serum adipokine concentrations and CKD severity in dogs.AnimalsTwenty dogs with CKD and 10 healthy dogs.MethodsIn this cross‐sectional study, serum concentrations of leptin, adiponectin, interleukin (IL)‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF)‐α were measured in healthy dogs and dogs with CKD, which were classified according to the International Renal Interest Society guidelines.ResultsSerum leptin concentrations were positively correlated with systolic arterial blood pressure (r = .41), creatinine concentrations (r = .39), and symmetric dimethylarginine concentrations (r = .73). Serum adiponectin concentrations (median [range]) in CKD dogs with borderline or non‐proteinuric (20.25 [14.9‐45.8] ng/mL) were significantly higher than those in proteinuric CKD dogs (13.95 [6.4‐22.1] ng/mL; P = .01). Serum IL‐6 (median [range]; 43.27 [24.30‐537.30] vs 25.63 [6.83‐61.03] pg/mL; P = .02), IL‐18 (median [range]; 25.98 [11.52‐280.55] vs 10.77 [3.53‐38.45] pg/mL; P = .01), and TNF‐α (median [range]) concentrations (11.44 [8.54‐38.45] vs 6.105 [3.97‐30.68] pg/mL; P = .02) were significantly different between proteinuric and borderline or non‐proteinuric CKD dogs.Conclusions and Clinical Importanceleptin and adiponectin concentrations in serum might be associated with severity of CKD and proteinuria in dogs with CKD, respectively.

Elevated Intrarenal Resistive Index Predicted Faster Renal Function Decline and Long-Term Mortality in Non-Proteinuric Chronic Kidney Disease.

Background. Intrarenal resistive index (RI) ≥ 0.80 predicts renal outcomes in proteinuric chronic kidney disease (CKD). However, this evidence in non-proteinuric patients with CKD of unknown etiology is lacking. In this study, we assessed the effect of intrarenal RI on renal function and all-cause mortality in non-proteinuric patients with CKD of unknown etiology despite an extensive diagnostic work-up. Methods. Non-proteinuric CKD patients were evaluated in a retrospective longitudinal study. Progression of renal disease was investigated by checking serum creatinine levels at 1, 3, and 5 years and defined by a creatinine level increase of at least 0.5 mg/dL. The discrimination performance of intrarenal RI in predicting the 5-year progression of renal disease was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Results. One-hundred-thirty-one patients (76 ± 9 years, 56% males) were included. The median follow-up was 7.5 years (interquartile range 4.3–10.5) with a cumulative mortality of 53%, and 5-year renal disease progression occurred in 25%. Patients with intrarenal RI ≥ 0.80 had a faster increase of serum creatinine levels compared to those with RI < 0.80 (+0.06 mg/dL each year, 95% CI 0.02–0.10, p < 0.010). Each 0.1-unit increment of intrarenal RI was an independent determinant of 5-year renal disease progression (odds ratio 4.13, 95% CI 1.45–12.9, p = 0.010) and predictor of mortality (hazards ratio 1.80, 95% CI 1.05–3.09, p = 0.034). AUROCs of intrarenal RI for predicting 5-year renal disease progression and mortality were 0.66 (95% CI 0.57–0.76) and 0.67 (95% CI 0.58–0.74), respectively. Conclusions. In non-proteinuric patients with CKD of unknown etiology, increased intrarenal RI predicted both a faster decline in renal function and higher long-term mortality, but as a single marker, it showed poor discrimination performance.

MO419: Many Faces of Non-Proteinuric CKD—A Cluster-Analysis-Based Observation

Abstract BACKGROUND AND AIMS With a global expansion of the elderly population, physicians encounter a growing number of chronic kidney disease (CKD) patients who have no or only a minimal amount of proteinuria. However, those patients are not clinically uniform; some quickly develop into a progressive loss of kidney function while others stay in their CKD stages for years or even over a few decades. The purpose of this study is to distinguish high-risk non-proteinuric CKD patients whose estimated glomerular filtration rate (eGFR) decline is faster than others. METHOD A hospital-wide study with all the laboratory data for a period of 4 years and 2 months was performed. Non-dialysis CKD patients (median eGFR &amp;lt; 60 mL/min/1.73m2) with ≥18 years in whom the eGFR slope was obtained over 731 days or more were retrieved, then the patients with a median of dipstick proteinuria of less than 1+, i.e. (−) or (±), were included for analysis. An eGFR slope/patient was calculated by at least three eGFR measurements over time. Medians were used for each laboratory datum, including dipstick proteinuria and haematuria (both changed to numeric variables, e.g. 1 + into 1.0), blood cell count and serum chemistry. Cluster analyses, hierarchical and k-means, were performed. Statistical analysis was done with R 3.6.0 on Ubuntu. Missing values were imputed by an R package {mice}. RESULTS A total of 905 patients [Male: Female = 395:510, age 75.7 ± 10.4 (34–101, median 76 years)] were analysed whose median eGFR was 49.6 ± 9.34 (14.4–59.9, median 52.6) mL/min/1.73m2. A hierarchical cluster analysis was initially performed so a group count of 5 was suggested to be appropriate. Then performed was a k-means cluster analysis which identified 5 clusters; Cluster 1 was a group of patients with the least progressive CKD, whereas Cluster 5 had the fastest decline in eGFR. Cluster 5 had background features such as higher blood leukocyte count, higher blood urea nitrogen, higher red cell distribution width and less serum albumin, compared with other clusters. Cluster 2 also had modestly higher blood leukocyte count, Cluster 3 had lower haemoglobin, and Cluster 4 had higher serum uric acid; Cluster 3 had a variable speed of decline in eGFR. CONCLUSION Non-proteinuric CKD patients are not uniform but are variable in the clinical background as well as in the speed of CKD progression. They are better be treated according to the estimated risks for each patient.

Precision medicine in diabetic nephropathy and chronic kidney disease

Progressive chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, CKD leading to uremia can be seen as a systemic disease with a critical impact on virtually all organ systems. Thus it is of particular importance to identify patients with incipient CKD and ongoing CKD progression, but the individual course of CKD is challenging to predict. Patterns of progression in persons with CKD include linear and nonlinear trajectories of glomerular filtration rate (GFR) loss. Kidney function can also remain stable for years, especially in the elderly. In particular, one-fifth of individuals show a substantial GFR decline in the absence of high albuminuria (nonproteinuric CKD), rendering albuminuria less suitable for predicting the progression in such individuals.

HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES MELLITUS AND PROTEINURIC PHENOTYPE OF CHRONIC KIDNEY DISEASE ARE CHARACTERIZED BY WORSE PARAMETERS OF 24-H CENTRAL AORTIC BLOOD PRESSURE

Objective: The aim of the study was to evaluate the 24-h profile of peripheral and central blood pressure (BP) in hypertensive patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) according to the presence of proteinuria. Design and method: The study included 90 patients with HTN, T2DM and CKD with eGFR 30-&lt;60 ml/min/1.73 m2 and urine albumin–creatinine ratio (UACR) &lt;300 mg/g (66% females, median age 60 years, median duration of DM–7.5 years, median duration of HTN 18 years). All received antihypertensive therapy and antidiabetic drugs (insulin in 58%). The analysis was performed according to CKD phenotype: proteinuric (UACR 30-&lt;300 mg/g) and non-proteinuric (UACR &lt; 30 mg/g). Office BP was measured with a validated oscillometric device. Clinical central BP and 24-hour ABPM of brachial and central aortic BP were performed with BPLab Vasotens. All results are presented as median values. p &lt; 0.05 was considered significant. Results: Office brachial BP was 156/83 mmHg, aortic – 139/90 mmHg, median UACR was 26.5 mg/g. Proteinuric phenotype was found in 78% and compared to non-proteinuric phenotype was characterized by higher rate of dyslipidemia (85% vs 45%, p = 0.0004), more frequent history of coronary artery disease (53% vs 10%, p = 0.001), longer duration of HTN and DM (19.5 vs 7.5 years and 8 vs 3 years respectively, p &lt; 0.01), lower HDL-C (1.2 vs 1.9, p = 0.02) and higher office brachial DBP (83 vs 80 mmHg, p = 0.04) and central SBP (147 vs 137 mmHg, p = 0.007). Proteinuric phenotype compared to non-proteinuric was associated with worse 24-h profile of central SBP (daytime 147 vs 138 mmHg, p = 0.008; night-time 143 vs 130 mmHg, p = 0.04). HTN phenotypes according to diurnal index for proteinuric and non-proteinuric CKD were as follows: dippers 0 vs 10%, non-dippers 6 vs 5%, night-peakers 82 vs 70% over-dippers 12 vs 15% (all differences were non-significant). Presence of proteinuric phenotype positively correlated with daytime and night-time aortic SBP (r = 0.28 and 0.21 respectively, p &lt; 0.05). Conclusions: Proteinuric phenotype of CKD in patients with HTN and T2DM is associated with worse 24-h profile of central BP. The publication was prepared with the of the RUDN University Program 5-100

Proteinuric and nonproteinuric chronic kidney disease among patients with sickle cell anaemia (HbSS) attending a tertiary hospital in north-eastern Nigeria

Objective/BackgroundIndividuals with sickle cell anaemia (SCA) may manifest various forms of renal abnormalities. Proteinuria is an early marker of renal dysfunction and a strong risk factor for chronic kidney disease (CKD) progression in both patients with SCA and non-SCA population. Currently, the degree of attention given to proteinuric CKD far exceeds that of nonproteinuric CKD, and risk factors that might trigger a progressive decline of the glomerular filtration rate (GFR) in the absence of proteinuria have not been well evaluated in SCA. The aim of this study was to compare the clinical and laboratory parameters among SCA patients with proteinuric and nonproteinuric CKD. MethodsThis was a cross-sectional study conducted at the University of Maiduguri Teaching Hospital in north-eastern Nigeria between January 2013 and April 2018. Clinical variables including age of diagnosis of SCA, frequency of vaso-occlusive crises, number of hospitalizations per annum and transfusion therapy were collected. Laboratory data including haematological profile and renal function test were obtained from routine blood sampling. ResultsA total of 257 patients with SCA (HbSS) were enrolled during the study period of which 42 had proteinuric CKD, and 48 had nonproteinuric CKD. The two groups were matched for the number of hospital admission (p = .063) and blood transfusion per year (p = .450), frequency of painful crisis (p = .210), systolic blood pressure (p = .084) and diastolic blood pressure (p = .400). In the proteinuric CKD group, the mean serum creatinine was higher (332.17 µmol/L, p = .001) and the estimated GFR was lower (31.88 mL/min, p = .046). The serum alkaline phosphatase was higher in the nonproteinuric CKD group (81.81 IU/L, p = .012). ConclusionNonproteinuric CKD was more frequent than proteinuric CKD in our study population; however, the proteinuric group presented with more advanced disease.

Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis

BackgroundKaryomegalic interstitial nephritis (KIN) is a rare hereditary cause of chronic kidney disease. It typically causes progressive renal impairment with haemoproteinuria requiring renal replacement therapy before 50 years of age. It has been associated with mutations in the Fanconi anaemia-associated nuclease 1 (FAN1) gene and has an autosomal recessive pattern of inheritance. Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is the third most common cause of amyloid nephropathy presenting with chronic kidney disease and variable proteinuria. We report a novel mutation in the FAN1 gene causing KIN and to our knowledge, the first case of concurrent KIN and ALECT.Case presentationWe describe the case of 44 year old Pakistani woman, presenting with stage four non-proteinuric chronic kidney disease, and a brother on dialysis. Renal biopsy demonstrated KIN and concurrent ALECT2. Genetic sequencing identified a novel FAN1 mutation as the cause of her KIN and she is being managed conservatively for chronic kidney disease. Her brother also had KIN with no evidence of amyloidosis and is being worked up for kidney transplantation.ConclusionThis case highlights two rare causes of chronic kidney disease considered underdiagnosed in the wider population due to their lack of proteinuria, and may contribute to the cohort of patients reaching end stage renal disease without a renal biopsy. We report a novel mutation of the FAN1 gene causing KIN, and report the first case of concurrent KIN and ALECT2. This case highlights the importance of renal biopsy in chronic kidney disease of unclear aetiology which has resulted in a diagnosis with implications for kidney transplantation and family planning.

Proteomics analysis of blood plasma in HIV-infected patients with chronic kidney disease

BackgroundPatients treated for human immunodeficiency virus (HIV) infection are prone to developing chronic kidney disease (CKD). Current methods used in assessing kidney function suffer inaccuracy in HIV-infected patients. This study aims to identify biomarkers that could complement existing methods of kidney assessment among HIV-infected subjects. MethodsPlasma protein profiling was performed for HIV patients with CKD presented with negative/trace proteinuria (non-proteinuric) (n = 8) and their matched non-CKD controls, using two-dimensional gel electrophoresis (2DE); selected protein candidates were identified using mass spectrometry. Subsequently, altered plasma abundance of protein candidates were verified using Western blotting in HIV-infected subjects with non-proteinuric CKD (n = 8), proteinuric CKD (n = 5), and their matched non-CKD controls, as well as in HIV-uninfected subjects with impaired kidney function (n = 3) and their matched controls. ResultsAnalysis of 2DE found significantly altered abundance of five protein candidates between HIV-infected patients with non-proteinuric CKD and without CKD: alpha-1-microglobulin (A1M), serum albumin (ALB), zinc-alpha-2-glycoprotein (AZGP1), haptoglobin (HP), and retinol binding protein (RBP4). Western blotting showed an increased abundance of A1M and HP in HIV-infected patients with non-proteinuric CKD compared to their non-CKD controls, whereas A1M, AZGP1, and RBP4 were significantly increased in HIV-infected patients with proteinuric CKD compared to their non-CKD controls. Such pattern was not found in HIV-uninfected subjects with impaired kidney function. ConclusionThe data suggests four proteins that may be used as biomarkers of CKD in HIV-infected patients. Further validation in a larger cohort of HIV-infected patients is necessary for assessing the clinical use of these proposed biomarkers for CKD.

SAT-187 EPIDEMIOLOGY 0F CHRONIC TUBULO-INTERSTITIAL NEPHRITIS IN A NEPHROLOGY SERVICE IN SRI LANKA- ARE THESE CKDu ALL?

Epidemic chronic kidney disease (CKD) from agricultural communities in many regions of the world has been termed CKD of unknown cause (CKDu) and has been widely recognized as an idiopathic chronic tubulo-interstitial nephritis (iCTIN). This unique CKD which affects people of a similar social stratum and environment, appeared from agricultural communities in these regions around the same period of time, and has very similar clinical and biochemical features. Attempted case definitions of CKDu from Sri Lanka and Central America only narrow it down to a non-proteinuric CKD. CTIN from any cause would fit into these case definitions. In all renal biopsy registries in the world there have been iCTIN, ranging from 11-30%, even before the emergent epidemic of CKDu. In one case series from Texas in 1990, 25% of CTIN were idiopathic and in another series published in 2001, the incidence of iCTIN among Indo-Asians in a London hospital was seven times that of white Caucasians. Obviously, all these cannot be termed CKDu. A retrospective study was conducted in those who underwent renal biopsies at Sri Jayewardenepura General Hospital, Sri Lanka, situated in the non-endemic region for CKDu, but gets many referrals from the endemic area. All case records of patients who underwent renal biopsies during the period March 2016-March 2018 were analyzed. 1218 patients with CKD were treated during this period. 297 underwent a renal biopsy. 77/297 (26%) had primary CTIN. 13/77 (17%) had identifiable causes of CTIN, while the rest-64/77(83%) - were idiopathic. 24/64 (38%) were from known endemic agricultural areas. 14 of 40 from non-endemic areas (35%) were from areas with high agricultural activity. Hence, 26 of the cohort of 64 iCTIN (40%) were from urban or semi-urban areas with neither significant agricultural activity nor occupational exposure to heat stress. Idiopathic CTIN of unknown cause was a recognized biopsy diagnosis even before the CKDu epidemic. The epidemic CKDu which appeared from agricultural communities in Sri Lanka, Central America and India are likely to have similar, if not the same etiology due to the simultaneity of their emergence, and the similar demographic, clinical, biochemical and pathological features. The name CKDu confusingly mixes up all patients with undiagnosed CTIN hence the name CINAC (chronic interstitial nephritis of agricultural communities) is more appropriate to identify the global epidemic CKD identified since the 1990s.

248-OR: Empagliflozin and Cardiorenal Outcomes in Patients with Nonproteinuric Kidney Disease in the EMPA-REG OUTCOME Trial

Proteinuria in chronic kidney disease (CKD) is a strong risk predictor for adverse cardiorenal outcomes. However, non-proteinuric CKD in type 2 diabetes (T2D) is rarely studied in clinical trials despite epidemiological evidence indicating a recent shift towards this phenotype. We explored the effect of empagliflozin (EMPA) on cardiorenal outcomes in a subgroup of patients from EMPA-REG OUTCOME with non-proteinuric CKD at baseline. 7020 patients with T2D and prior CV disease were treated with EMPA 25mg, 10mg or placebo (PBO) (median follow-up of 3.1 years). Post hoc, Cox regression assessed effects of EMPA vs. PBO on the composite outcome of CV death/HHF, CV death, HHF, a composite kidney outcome of incident/worsening nephropathy and all-cause mortality. Non-proteinuric CKD was defined as low eGFR and absence of overt albuminuria (eGFR &amp;lt;60 ml/min/1.73m2 and UACR &amp;lt;300 mg/g). Overall, 1290 (18.4%) met this criterion. In this exploratory analysis, beneficial effects of EMPA vs. PBO on cardiorenal outcomes were consistent in patients with T2D and non-proteinuric CKD as compared to all other patients. This result suggests that absence of overt proteinuria may not alter the cardiorenal treatment response to EMPA. The ongoing EMPA-KIDNEY study investigates effects of EMPA on cardiorenal outcomes in a broad CKD population with and w/o diabetes including patients with lower proteinuria levels. Disclosure S.E. Inzucchi: Consultant; Self; vTv Therapeutics, Zafgen, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. J. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Mattheus: Employee; Self; Boehringer Ingelheim Pharma GmbH&amp;Co.KG. M. von Eynatten: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. S. Hauske: Employee; Self; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim; Eli Lilly and Company

Improving CKD Diagnosis and Blood Pressure Control in Primary Care: A Tailored Multifaceted Quality Improvement Programme

Background: Chronic kidney disease (CKD) is a worldwide public health issue. From 2009 to 2014, the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care Greater Manchester (NIHR CLAHRC GM) in England ran 4 phased, 12-month quality improvement (QI) projects with 49 primary care practices in GM. Two measureable aims were set – halve undiagnosed CKD in participating practices using modelled estimates of prevalence; and optimise blood pressure (BP) control (<140/90 mm Hg in CKD patients without proteinuria; <130/80 mm Hg in CKD patients with proteinuria) for 75% of recorded cases of CKD. The 4 projects ran as follows: P1 = Project 1 with 19 practices (September 2009 to September 2010), P2 = Project 2 with 11 practices (March 2011 to March 2012), P3 = Project 3 with 12 practices (September 2012 to October 2013), and P4 = Project 4 with 7 practices (April 2013 to March 2014). Methods: Multifaceted intervention approaches were tailored based on a contextual analysis of practice support needs. Data were collected from practices by facilitators at baseline and again at project close, with self-reported data regularly requested from practices throughout the projects. Results: Halving undiagnosed CKD as per aim was exceeded in 3 of the 4 projects. The optimising BP aim was met in 2 projects. Total CKD cases after the programme increased by 2,347 (27%) from baseline to 10,968 in a total adult population (aged ≥18 years) of 231,568. The percentage of patients who managed to appropriate BP targets increased from 34 to 74% (P1), from 60 to 83% (P2), from 68 to 71% (P3), and from 63 to 76% (P4). In nonproteinuric CKD patients, 88, 90, 89, and 91%, respectively, achieved a target BP of <140/90 mm Hg. In proteinuric CKD patients, 69, 46, 48, and 45%, respectively, achieved a tighter target of <130/80 mm Hg. Analysis of national data over similar timeframes indicated that practices participating in the programme achieved higher CKD detection rates. Conclusions: Participating practices identified large numbers of “missing” CKD patients with comparator data showing they outperformed non-QI practices locally and nationally over similar timeframes. Improved BP control also occurred through this intervention, but overall achievement of the tighter BP target in proteinuric patients was notably less.

Use of ACE inhibition and blood pressure management in deferring dialysis initiation.

Elevated blood pressure is one of the most significant risk factor for the development of chronic kidney disease (CKD); its treatment is a milestone in CKD management. While it is accepted that a stricter blood pressure control is indicated in patients with proteinuria or microalbuminuria, the exact degree of blood pressure reduction to be obtained in CKD patients is still under debate. Following more recent interpretation of old trials, a BP target for <140/90 mmHg is suggested for non-proteinuric CKD patients. In those with microalbuminuria/proteinuria, the ideal blood pressure target should be ≤130/80 mmHg. Recently, the SPRINT trial put new emphasis on a stricter blood pressure control, mainly from the cardiovascular point of view. The blockers of the renin-angiotensin system (RAS) are recommended as first line treatment in all CKD hypertensive patients with micro or macroalbuminuria either diabetics or not. However, their nephroprotective efficacy is less relevant in non-proteinuric patients. The dual RAS blockade was proposed as an additional option. Despite a greater antiproteinuric effect, some large trials in patients at high cardiovascular risk did not demonstrate significant advantage on hard endpoint. Its use is now contraindicated in diabetic CKD patients. Given that RAS blockers can cause acute derangements in kidney function and hyperkalemia, caution is needed with their use, especially in frail and old patients with cardiovascular disease or in the presence of advanced CKD.

PP.21.20

Objective: A 76 years old man accessed the Emergency Department for general discomfort associated with hypertensive urgency (systolic BP > 200 mm Hg). In anamnesis: treated but poorly controlled hypertension and severe, non-proteinuric chronic kidney disease (last creatinine: 2.32 mg/dl). Patient also suffered from exudative macular degeneration with neovascularization (AMD) treated with repeated intravitreal injections of anti-VEGF agents: first Bevacizumab, then Aflibercept, a soluble decoy receptor fusion protein, named VEGF-Trap, created by fusing domain 1 of human VEGF receptor 1 to domain 3 of human VEGF receptor 2, both than fused to the constant region of human IgG1. Aflibercept has high binding affinities to all isoforms of VEGF as well as to the PLGF and it was administered two days before the ED access. Design and method: The study revealed primary hyperaldosteronism with low potassium despite marked reduction of the renal function (creatinine: 3.8 mg/dl, eGFR: 15 ml/min/1.73 mq), and proteinuria (1.5 g/24 hours). LV concentric hypertrophy, grade 1diastolic dysfunction, ectasia of the ascending aorta. ABPM results: 24 hour average BP: 144/84 mmHg despite multiple drugs. Results: After suspension of Aflibercept administration and after anti-hypertensive therapy adjustment, based on kidney function, we obtained a prompt reduction of blood pressure (24 hour average BP on a repeated ABPM: 117/67 mmHg) with disappearance of proteinuria. Conclusions: Anti-VEGF agents represent a cornerstone in the treatment of various solid tumors (intravenous administration) and AMD (intravitreal). When administered systemically they represent a well established cause of hypertension and proteinuria. Although the incidence of systemic adverse events by intraocular administration of anti-VEGF is low, in the context of an elderly patient with aldosteron-dependent hypertension and impaired renal function, intravitreal administration of Aflibercept caused hypertensive urgency with acute kidney injury and proteinuria. To confirm this, his suspension led to resolution of proteinuria and return to the basal values of eGFR. A limitation of this case, reported to the Italian Medicines Agency (AIFA report N. 242934) as the first of its kind, to the best of our knowledge, is the fact that nephrologists did not consider appropriate to perform a renal biopsy.

The Role of Systemic Blood Pressure in the Progression of Chronic Kidney Disease

Chronic kidney disease (CKD) regardless of etiology tends to progress. Substantial evidence indicates that even modest coexistent hypertension (HTN) plays a major role in such progression due to an increased transmission of systemic HTN to the renal microvasculature in CKD states. This is due to preglomerular vasodilation and an impairment of the renal autoregulatory responses that normally protect against such transmission. Accordingly, effective BP control that also includes renin-angiotensin system (RAS) blockade is recommended as a primary management strategy for slowing CKD progression. It is widely believed that RAS blockade provides additional renoprotection beyond BP lowering. While the BP-independence of such renoprotective effects remains a matter of some controversy, there is nevertheless other compelling rationale for the use of RAS blockade in CKD patients. Hypertension in CKD states is usually volume dependent and requires effective diuretic therapy for adequate and sustained BP control. Not only is RAS blockade a very effective antihypertensive regimen in adequately diuresed patients, it counteracts the negative effects of diuretics on potassium and magnesium balance. Although definitive clinical trial evidence in favor of lower BP goals in proteinuric CKD is not yet available, some guidelines also recommend a lower systolic BP target of <130 mmHg for proteinuric CKD vs. <140 mmHg that is recommended for most individuals including those with non-proteinuric CKD. Finally, given that ambulatory blood pressure monitoring (ABPM) has shown that masked and nocturnal HTN may be both more frequent and more difficult to control in CKD patients, it may be as important to focus on achieving 24-h BP control as on the clinic BP targets.

Underestimating chronic kidney disease by urine dipstick without serum creatinine as a screening tool in the general Japanese population.

It is not known if urine dipstick alone can identify chronic kidney disease (CKD) in the general Japanese population. We designed a cross-sectional study using data obtained in 2008 from a nationwide community-based health examination program for adults aged 40-74. The data consisted of blood tests, urine tests and questionnaire related to metabolic disorders. Those who had both serum creatinine measured and urine dipstick tested were analyzed. Data were obtained from 538,846 people with a mean age of 62.8 years, consisting of 41.6 % males. Our study showed that 14.4 % had an eGFR below 60 mL/min/1.73 m(2), 5.2 % had proteinuria and 18.1 % had CKD. Within the population with CKD, non-proteinuric CKD accounted for 71.4 %. The proportion of non-proteinuric CKD was highest in stage G3a (91.8 %) followed by G3b (77.0 %) disease, and was greater in the more elderly and in females. The proportion of non-proteinuric CKD was 47.9 % in diabetes mellitus, 69.3 % in dyslipidemia, 66.8 % in hypertension and 57.1 % in metabolic syndrome. Furthermore, non-proteinuric CKD accounted for 78.1 % of the population without these lifestyle diseases, suggesting that even in the population without apparent risk, CKD is still prevalent and can be missed when urine dipstick is the only screening method used. This study showed that a considerable population of CKD might be overlooked when only dipstick proteinuria is assessed for CKD screening. Hence, we strongly recommend that both urinalysis and serum creatinine measurement should be a part of the nationwide CKD screening system.

Renin–angiotensin system blockade in older adults with chronic kidney disease: a review of the literature

We have reviewed the literature examining the benefits and harms of renin-angiotensin system (RAS) blockade in older adults, using studies which included patients with chronic kidney disease (CKD) as well as those which included a broader patient population. We review the results of key trials which evaluate the impact of RAS blockade on renal outcomes, and those which address the impact of RAS blockade on more global outcomes (cardiovascular events and mortality). Many trials examining renal outcomes of RAS blockade excluded older patients or did not present age-stratified results, whereas trials which examined global outcomes often excluded patients with CKD. Most older patients with CKD have nonproteinuric nondiabetic CKD, thus differing from participants in trials which examined renal outcomes, which often included only patients with diabetes or proteinuria. Most studies did not address alternate outcomes which may carry greatest import for older patients, such as worsening comorbid illness or changes in functional status. The role of RAS inhibition for older patients with CKD remains unclear. Information on age-specific effects of RAS blockade on a range of different outcomes among older patients with CKD would improve our ability to assess the benefits and harms of RAS inhibition in this population.