Direction- and Angle-Assisted Buttonhole Cannulation of Arteriovenous Fistula in Hemodialysis Patients: A Multicenter Randomized Controlled Trial

Rationale & objective: Arteriovenous fistula cannulation with the buttonhole technique is often preferred by patients but has been associated with an increased infection risk. Guidelines disagree on whether it should be abandoned, thus we assessed a technologically simple method to facilitate gentler arteriovenous fistula cannulation with potentially less discomfort and damage to the epithelial lining of the buttonhole tract. Study design: 8-week, prospective, open-label, randomized controlled trial. Setting & participants: Patients with buttonhole tracts receiving hemodialysis at 7 dialysis centers in Norway were randomized to the intervention group (43 patients, 658 cannulations) or control group (40 patients, 611 cannulations). Intervention: Direction and angle of the established buttonhole tract were marked on the forearm skin in the intervention group, whereas the control group had no structured cannulation information system. Outcomes: The primary outcome was successful cannulation, defined as correct placement of both blunt needles at the first attempt without needing to change needles, perform extra perforations, or reposition the needle. The secondary outcomes were patient-reported difficulty of cannulation (verbal rating scale: 1 = very easy, 6 = impossible) and intensity of pain (numeric rating scale: 0 = no pain, 10 = unbearable pain). Results: After a 2-week run-in period, successful cannulation was achieved in 73.9% and 74.8% of the patients in the intervention and control groups, respectively (relative risk [RR], 0.99; 95% CI, 0.87-1.12; P = 0.85). However, the probability of a difficult arterial cannulation (verbal rating scale, 3-6) was significantly lower in the intervention group (RR, 0.69; 95% CI, 0.55-0.85; P = 0.001). There were no improvements for venous cannulations. Furthermore, the probability of a painful cannulation (numeric rating scale, 3-10) was lower in the intervention group (RR, 0.72; 95% CI, 0.51-1.02; P = 0.06). Limitations: Unable to evaluate hard end points such as infections and thrombosis owing to the small sample size. Conclusions: Marking direction and angle of cannulation did not improve cannulation success rates; however, patients more often reported an unproblematic procedure and less pain. Funding: None. Trial registration: ClinicalTrials.gov (NCT01536548).publishedVersio

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics

Background Hypertensive nephrosclerosis is the presumed underlying cause in many end‐stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods We included adults from the population‐based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve‐based methods of optimal cut‐offs were used to improve clinical nephrosclerosis criteria. Results Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney‐related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy‐verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false‐positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk‐tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.publishedVersio

Clinical triage of patients on kidney replacement therapy presenting with COVID-19:an ERACODA registry analysis

Background. Patients on kidney replacement therapy (KRT) are at very high risk of coronavirus disease 2019 (COVID-19). The triage pathway for KRT patients presenting to hospitals with varying severity of COVID-19 illness remains ill-defined. We studied the clinical characteristics of patients at initial and subsequent hospital presentations and the impact on patient outcomes.Methods. The European Renal Association COVID-19 Database (ERACODA) was analysed for clinical and laboratory features of 1423 KRT patients with COVID-19 either hospitalized or nonhospitalized at initial triage and those re-presenting a second time. Predictors of outcomes (hospitalization, 28-day mortality) were then determined for all those not hospitalized at initial triage.Results. Among 1423 KRT patients with COVID-19 [haemodialysis (HD), n = 1017; transplant, n = 406), 25% (n = 355) were not hospitalized at first presentation due to mild illness (30% HD, 13% transplant). Of the non-hospitalized patients, only 10% (n = 36) re-presented a second time, with a 5-day median interval between the two presentations (interquartile range 2-7 days). Patients who re-presented had worsening respiratory symptoms, a decrease in oxygen saturation (97% versus 90%) and an increase in C-reactive protein (26 versus 73 mg/L) and were older (72 vs 63 years) compared with those who did not return a second time. The 28-day mortality between early admission (at first presentation) and deferred admission (at second presentation) was not significantly different (29% versus 25%; P = 0.6). Older age, prior smoking history, higher clinical frailty score and self-reported shortness of breath at first presentation were identified as risk predictors of mortality when representing after discharge at initial triage.Conclusions. This study provides evidence that KRT patients with COVID-19 and mild illness can be managed effectively with supported outpatient care and with vigilance of respiratory symptoms, especially in those with risk factors for poor outcomes. Our findings support a risk-stratified clinical approach to admissions and discharges of KRT patients presenting with COVID-19 to aid clinical triage and optimize resource utilization during the ongoing pandemic

A translational medicine approach to hypertensive nephropathy: Prevalence, diagnosis, and pathophysiology

NORSK SAMMENDRAG Translasjonsmedisinske studier av hypertensiv nefropati: Prevalens, diagnose og patofysiologi Kronisk nyresjukdom defineres som nedsatt nyrefunksjon (estimert glomerulær filtrasjonsrate (eGFR) <60 mL/min/1,73m2), og/eller avvik i urinfunn (proteinuri, hematuri) eller bildediagnostikk av nyrene, som varer i mer enn 3 måneder. Kronisk nyresjukdom finnes hos rundt én av ti voksne i industrialiserte land. Tilstanden utgjør en byrde på samfunn og helsevesen, spesielt på grunn av den økte risikoen for hjerte-/karsjukdom og slag som følger med kronisk nyresjukdom. Tidlig diagnose og behandling, med vekt på blant annet blodtrykk, proteinlekkasje i urin og kolesterol, bremser forverringa av nyrefunksjonen. Dagens diagnoseverktøy med blod- og urinprøver gir utslag først når nyrefunksjonen er moderat redusert, og nyresjukdommen er etablert. Vi trenger bedre diagnoseredskaper for å finne de som har tidlig nyresjukdom, og skille ut de som gradvis forverres til endestadium nyresvikt. Vi trenger også mer kunnskap om hvilke sjukdomsmekanismer som er viktigst i utviklinga av nyresvikt, for å kunne finne nye behandlinger. Den vanligste årsaken til endestadium nyresvikt i Norge er nyresjukdom på grunn av høgt blodtrykk, såkalt hypertensiv nefropati. Etter sukkersyke er det den vanligste årsaken til endestadium nyresvikt i industrialiserte land. Sjøl om tilstanden er godt kjent, er det paradoksalt nok debatt rundt både definisjonen, utbredelsen, årsakene og de grunnleggende sjukdomsmekanismene bak sjukdommen. Hypertensiv nefropati har ofte vært antatt årsak til kronisk nyresjukdom hos individer med langvarig høgt blodtrykk, kun sparsomme urinfunn (lite blod eller protein i urinen), og som ikke har tegn til andre sjukdommer som kan gi nyreskade (for eksempel sukkersyke, cystenyrer eller kronisk nyrebetennelse/glomerulonefritt). Hos disse har man tidligere ofte antatt diagnosen hypertensiv nefropati uten å ta vevsprøve fra nyrene (nyrebiopsi) for bekreftelse. Det har vært omdiskutert hvor presise disse kliniske kriteriene er. Dette har vært undersøkt hos afrikansk-amerikanere og i enkelte andre etniske grupper, men ikke så godt hos hvite europeere. I artikkel 2 gjennomgikk vi 4920 nyrebiopserte pasienter fra Norsk nyreregister, hvorav 918 hadde biopsi-bekreftet hypertensiv nefropati. Blant de 918 hadde mange urinfunn, hvorav 34 % hadde blod i urinen og 57 % hadde protein i urinen. Vi fant at de tradisjonelle kliniske diagnosekriteriene var relativt upresise (sensitivitet 0,12, spesifisitet 0,96), og at mens fravær av disse kriteriene utelukket diagnosen relativt presist (negativ prediktiv verdi 0,83), klarte ikke disse kriteriene, de gangene de var tilstede, å forutsi diagnosen presist (positiv prediktiv verdi 0,41). Kriteriene som var sterkest assosiert med biopsi-bekreftet hypertensive nefropati var høg alder, høgt diastolisk blodtrykk, lav proteinuri, fravær av blod i urin, hankjønn og fravær av sukkersyke. Vi fant at de kliniske kriteriene var mest presise hvis man brukte alder >50 år, proteinuri 90 mmHg, og ingen blod i urinen. I artikkel 1 beskreiv vi forekomsten av kronisk nyresjukdom i Norge på to tidspunkter med ti års mellomrom ved hjelp av tall fra tverrsnittsundersøkelsene HUNT2 i 1995-97 og HUNT3 i 2006-08. Hovedfunnet var at forekomsten av kronisk nyresjukdom holdt seg stabil på rundt 11 %. I denne perioden fant det sted en klar reduksjon av høgt blodtrykk, noe reduksjon av kolesterol og økt fysisk aktivitet, samt moderate økninger i både sukkersyke og overvekt. Vi tror at blodtrykksreduksjonen har bidratt til at nyresjukdom-tallene har holdt seg stabile, på tross av økt sukkersyke og overvekt. I artikkel 3 undersøkte vi proteiner og peptider i urinen hos pasienter med langtkommen nyresjukdom av forskjellige typer, og fant at et sett av 273 forskjellige urin-proteiner og peptider skiller mellom nyresjuke og –friske. Urin-proteinene som var mest forskjellige, peker i retning mot forstyrrelser i bindevev- og arrvevsproduksjonen hos de nyresjuke. I artikkel 4 viste kombinerte gen- og urin-analyser at individer med hypertensiv nefropati har endringer innen flere områder av metabolismen eller stoffomsetninga, med spesielt redusert utskillelse i urin av flere typer aminosyrer sammenliknet med friske. Disse forskjellene peker mot forstyrrelser av blodtrykksregulering, åreforkalkning, arrdannelse/fibrose og oksidativt stress, som er kjente mekanismer i dannelsen av hypertensiv nefropati og nyresjukdom generelt

Urinary proteomics in chronic kidney disease: diagnosis and risk of progression beyond albuminuria

Background: The contrast between a high prevalence of chronic kidney disease (CKD) and the low incidence of end-stage renal disease highlights the need for new biomarkers of progression beyond albuminuria testing. Urinary proteomics is a promising method, but more studies focusing on progression rate and patients with hypertensive nephropathy are needed. Results: We analyzed urine samples with capillary electrophoresis coupled to a mass-spectrometer from 18 well characterized patients with CKD stage 4–5 (of whom six with hypertensive nephropathy) and 17 healthy controls. Classification scores based on a previously developed panel of 273 urinary peptides were calculated and compared to urine albumin dipstick results. Urinary proteomics classified CKD with a sensitivity of 0.95 and specificity of 1.00. Overall diagnostic accuracy (area under ROC curve) was 0.98, which was better than for albuminuria (0.85, p = 0.02). Results for hypertensive nephropathy were similar to other CKD diagnoses. Adding the proteomic score to an albuminuria model improved detection of rapid kidney function decline (>4 ml/min/1.73 m2 per year) substantially: area under ROC curve increased from 0.762 to 0.909 (p = 0.042), and 38% of rapid progressors were correctly reclassified to a higher risk and 55% of slow progressors were correctly reclassified to a lower risk category. Reduced excretion of collagen types I–III, uromodulin, and other indicators of interstitial inflammation, fibrosis and tubular dysfunction were associated with CKD diagnosis and rapid progression. Patients with hypertensive nephropathy displayed the same findings as other types of CKD. Conclusions: Urinary proteomic analyses had a high diagnostic accuracy for CKD, including hypertensive nephropathy, and strongly improved identification of patients with rapid kidney function decline beyond albuminuria testing

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics

Background Hypertensive nephrosclerosis is the presumed underlying cause in many end‐stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods We included adults from the population‐based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve‐based methods of optimal cut‐offs were used to improve clinical nephrosclerosis criteria. Results Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney‐related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy‐verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false‐positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk‐tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics

Background. Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective. To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods. We included adults from the populationbased HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria. Results. Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (<0.75 g d 1 ), systolic blood pressure (>155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion. Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment

Clinical phenotypes and long-term prognosis in white patients with biopsy-verified hypertensive nephrosclerosis

Introduction Hypertensive nephrosclerosis is considered the second most common cause of end-stage renal disease (ESRD), but it is still an insufficiently studied and controversial disease entity. More information on the phenotype and prognosis is needed to improve clinical diagnostics and treatment. Methods We included all Norwegian patients with chronic kidney disease (CKD) referred for kidney biopsy between 1988 and 2012 whose clinical presentation was consistent with, but not primarily suspicious for, hypertensive nephrosclerosis (n = 4920); follow-up continued until 2013. Results A total of 918 patients (19%) had biopsy-verified hypertensive nephrosclerosis (i.e., arterionephrosclerosis). Their most common biopsy indications were proteinuria (57%), low estimated glomerular filtration rate (eGFR) (44%), hematuria (34%), or combinations of these indications. Multivariable logistic regression analysis revealed that arterionephrosclerosis was significantly associated with higher age, male sex, not having diabetes, higher blood pressure, lower proteinuria, and not having hematuria (P 0.05 for all). The most common biopsy-verified diagnoses in patients fulfilling the clinical criteria for hypertensive nephrosclerosis were arterionephrosclerosis (40%), glomerulonephritis (22%), and interstitial nephritis (14%), reflecting that the criteria had low sensitivity (0.17) and high specificity (0.94). ESRD and mortality risks did not differ in patients with arterionephrosclerosis compared to patients with glomerulonephritis, interstitial nephritis, or other relevant diagnoses (P > 0.1 for both), whereas patients with diabetic kidney disease had a 2-fold higher risk (P < 0.001 for both). Conclusion Arterionephrosclerosis is a high-risk disease, often with an atypical phenotype with proteinuria and hematuria contributing to low accuracy for current clinical criteria for hypertensive nephrosclerosis

Clinical phenotypes and long-term prognosis in white patients with biopsy-verified hypertensive nephrosclerosis

Introduction Hypertensive nephrosclerosis is considered the second most common cause of end-stage renal disease (ESRD), but it is still an insufficiently studied and controversial disease entity. More information on the phenotype and prognosis is needed to improve clinical diagnostics and treatment. Methods We included all Norwegian patients with chronic kidney disease (CKD) referred for kidney biopsy between 1988 and 2012 whose clinical presentation was consistent with, but not primarily suspicious for, hypertensive nephrosclerosis (n = 4920); follow-up continued until 2013. Results A total of 918 patients (19%) had biopsy-verified hypertensive nephrosclerosis (i.e., arterionephrosclerosis). Their most common biopsy indications were proteinuria (57%), low estimated glomerular filtration rate (eGFR) (44%), hematuria (34%), or combinations of these indications. Multivariable logistic regression analysis revealed that arterionephrosclerosis was significantly associated with higher age, male sex, not having diabetes, higher blood pressure, lower proteinuria, and not having hematuria (P 0.05 for all). The most common biopsy-verified diagnoses in patients fulfilling the clinical criteria for hypertensive nephrosclerosis were arterionephrosclerosis (40%), glomerulonephritis (22%), and interstitial nephritis (14%), reflecting that the criteria had low sensitivity (0.17) and high specificity (0.94). ESRD and mortality risks did not differ in patients with arterionephrosclerosis compared to patients with glomerulonephritis, interstitial nephritis, or other relevant diagnoses (P > 0.1 for both), whereas patients with diabetic kidney disease had a 2-fold higher risk (P < 0.001 for both). Conclusion Arterionephrosclerosis is a high-risk disease, often with an atypical phenotype with proteinuria and hematuria contributing to low accuracy for current clinical criteria for hypertensive nephrosclerosis

Gene expression studies and targeted metabolomics reveal disturbed serine, methionine, and tyrosine metabolism in early hypertensive nephrosclerosis

Introduction Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. Methods We analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls. Results Amino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin. Conclusion Early hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis