Azidose-Experte
KRANKHEITEN
 19.04.2022

Nierensteine, Gicht und Hyperurikämie

Gicht im Fuß

Demoskopische Analysen aus Deutschland (D) und England (UK) zeigen, dass das Praxis-Management einer klinisch relevanten Hyperurikämie häufig suboptimal ist. Zwar erhalten insgesamt 63 Prozent der betroffenen Patienten eine Therapie (93 % (D) und 89 % (UK) davon Allopurinol), aber nur bei 9-14 Prozent dieser Patientengruppe wird in 3,5- bis 5-jährigen Follow-up-Perioden eine Zielwert-Kontrolle durchgeführt [1] – obwohl Daten aus den USA zeigen, dass weniger als die Hälfte betroffener Patienten unter einer harnsäuresenkenden Therapie (ULT) die Zielvorgaben erreicht [2].

Eine Indikation zur Einleitung einer harnsäuresenkenden medikamentösen Therapie liegt dann vor, wenn mindestens ein gesicherter Gichtanfall aufgetreten ist, bei Tophi, Nierensteinen, Urat-Arthropathien und wenn generell Urat-Kristalle diagnostiziert werden [3]. Bislang galt die Empfehlung, mit der ULT erst nach dem vollständigen Abklingen eines akuten Gichtanfalls zu beginnen. Im Gegensatz zur gängigen Praxis konnte eine kontrollierte Studie zeigen, dass der Beginn aber auch während eines akuten Anfalles möglich ist [4].

Nephro- vs. Neuroprotektion

Hohe Serum-Harnsäure-Konzentrationen (≥ 6.8 mg/dl (408 µmol/l)) erhöhen das Risiko für chronisches Nierenversagen (CKD) [5]. Dennoch ist eine exzessive medikamentöse Senkung zu vermeiden, da Harnsäure mit der Intelligenz korreliert [6], ein neuroprotektiver Faktor für Dopamin-Neuronen ist und das Risiko für Morbus Parkinson [7] u.a. neurodegenerative Erkrankungen senken kann [3]. Im Praxis-Management der ULT ist daher ein regelmäßiges Follow-up mit Zielwert-Kontrolle unerlässlich, um die nicht immer einfache Gratwanderung, Nephroprotektion auf der einen Seite und Neuroprotektion auf der anderen, zu bewältigen.

Darüber hinaus ist unklar, ob die Gabe von Allopurinol die Nieren schützen kann. So dokumentiert eine Metaanalyse [8], eine „substantielle Heterogenität“ bezüglich einer nephroprotektiven Wirkung von Allopurinol: Fünf Studien zeigten keinen Effekt auf die glomeruläre Filtrationsrate (GFR), während bei drei klinischen Studien die Zunahme der Kreatinin-Konzentrationen verlangsamt werden konnte.

Harnsäure-senkende Medikamente kritisch betrachten

Die Hinweise, dass bestimmten Subpopulationen unter einer medikamentösen Harnsäure-senkenden Therapie (ULT) geschadet wird, führte zu der Empfehlung, eine asymptomatische Hyperurikämie – auch bei begleitender Nierenschwäche – zunächst nicht mit harnsäuresenkenden Medikamenten zu behandeln. Zur Sicherheit sollte bei diesen Patienten alle sechs Monate Kreatinin als Nierenfunktionswert kontrolliert werden. Treten allerdings Urat-Kristalle im Urin-Sediment auf oder werden auffällige Alterationen im muskulo-skelettalen Ultraschall beobachtet, ändert sich die therapeutische Situation und eine ULT sollte rasch eingeleitet werden, um u.a. Nierenschäden zu vermeiden [6].

Bikarbonat schließt therapeutische Lücke

Aus praktischer Sicht liegt mit magensaftresistentem [9] Natriumbikarbonat eine medikamentöse Option vor, die diese therapeutische Lücke schließen kann. Neben einer sicheren Nephroprotektion [10] wirkt Natriumbikarbonat direkt auf die Urat-Kristall-Bildung [11] und könnte als vorgeschobene Monotherapie eine ULT vermeiden oder hinauszögern. Durch eine Urin-Alkalisierung auf pH 8 können bereits vorhandene Urat-Kristalle aufgelöst und eine weitere Bildung in den Nierentubuli gehemmt werden. Eine Urin-Alkalisierung wird mit 325-2.000 mg Natriumbikarbonat per os, 1-4x/d, erreicht [6].

Fazit: Harnsäuresenkende Medikamente sollten für Hoch-Risiko-Patienten reserviert bleiben. Ein unkritischer und unkontrollierter Einsatz könnte neuroprotektive Faktoren reduzieren und entfernt die Harnsäure-Messung als Marker für eine chronische Niereninsuffizienz aus dem diagnostischen Repertoire. Um bei Hyperurikämie Urat-Kristall-Ausfällungen und Nierenschäden zu vermeiden, ist sowohl eine Monotherapie wie auch eine zur ULT adjuvante Urin-Alkalisierung mit oralem Natriumbikarbonat therapeutisch sinnvoll.

 

Literatur

Abstract: Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005

Objective: To investigate and compare the prevalence, comorbidities and management of gout in practice in the UK and Germany.

Methods: A retrospective analysis of patients with gout, identified through the records of 2.5 million patients in UK general practices and 2.4 million patients attending GPs or internists in Germany, using the IMS Disease Analyzer.

Results: The prevalence of gout was 1.4% in the UK and Germany. Obesity was the most common comorbidity in the UK (27.7%), but in Germany the most common comorbidity was diabetes (25.9%). The prevalence of comorbidities tended to increase with serum uric acid (sUA) levels. There was a positive correlation between sUA level and the frequency of gout flares. Compared with those in whom sUA was <360 micromol/l (<6 mg/dl), odds ratios for a gout flare were 1.33 and 1.37 at sUA 360-420 micromol/l (6-7 mg/dl), and 2.15 and 2.48 at sUA >530 micromol/l ( >9 mg/dl) in the UK and Germany, respectively (p<0.01).

Conclusions: The prevalence of gout in practice in the UK and Germany in the years 2000-5 was 1.4%, consistent with previous UK data for 1990-9. Chronic comorbidities were common among patients with gout and included conditions associated with an increased risk for cardiovascular disease, such as obesity, diabetes and hypertension. The importance of regular monitoring of sUA in order to tailor gout treatment was highlighted by data from this study showing that patients with sUA levels >or=360 micromol/l (>or=6 mg/dl) had an increased risk of gout flares.

Published by BMJ Journals | DOI: 10.1136/ard.2007.076232


zur Originalarbeit nach oben  

Abstract: Gout, urate lowering therapy and uric acid levels among adults in the United States

Objective: Evidence strongly suggests that delivery of gout care is suboptimal. The 2012 American College of Rheumatology (ACR) guidelines emphasize a serum uric acid (SUA) target of <6 mg/dl when utilizing urate-lowering therapy (ULT). However, the proportion and characteristics of Americans with gout receiving ULT, or with a ULT indication, who are achieving this target is unknown.

Methods: We identified US adults with gout receiving ULT, and those with an indication for ULT, using the National Health and Nutrition Examination Surveys from 2007-2010. Using the ACR guidelines, a ULT indication comprised chronic kidney disease (CKD) stage 2-5, a history of nephrolithiasis, or current ULT use. Demographic and clinical factors associated with an SUA ≥6 mg/dl were determined using Poisson regression.

Results: In 2007-2010, an estimated 4.5 million US adults with gout had an indication for ULT; two-thirds had an SUA ≥6 mg/dl. In adjusted analyses among those with gout and CKD or nephrolithiasis, those age ≥70 years were less likely (prevalence ratio [PR] 0.77, 95% confidence interval [95% CI] 0.61-0.97) to have an SUA ≥6 mg/dl. Regarding those taking ULT, hypertension was related to a reduced prevalence (PR 0.51, 95% CI 0.30-0.87), whereas diabetes mellitus (PR 1.42, 95% CI 1.06-1.90) and obesity (PR 1.74, 95% CI 1.19-2.56) were each associated with a higher prevalence of an SUA value ≥6 mg/dl.

Conclusions: Half of all Americans with gout receiving ULT, and two-thirds with an indication for ULT, have an SUA above target. This study furnishes a meaningful baseline for assessing the effectiveness of the ACR guidelines in future years

Keywords: Cost-of-illness, Demographic change, Germany, Healthcare planning, Markov model, Osteoporosis attributable fractures

Published by American College of Rheumatology. | DOI: 10.1002/acr.22469


zur Originalarbeit nach oben  

Abstract: 2016 updated EULAR evidence-based recommendations for the management of gout

Background: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations.

Methods: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach.

Results: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended.

Conclusions: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

Keywords: Gout; Multidisciplinary team-care; Treatment.

Published by BMJ Publishing Group Limited | DOI: 10.1136/annrheumdis-2016-209707


zur Originalarbeit nach oben  

Abstract: Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial

Objective: Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack.

Methods: A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30.

Results: On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point.

Conclusions: Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers.

Published by Elsevier | DOI: 10.1016/j.amjmed.2012.05.025


zum Abstract nach oben  

Abstract: Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: a systematic review and meta-analysis based on observational cohort studies

Background: Hyperuricemia has been reported to be associated with chronic kidney disease (CKD). However whether an elevated serum uric acid level is an independent risk factor for new-onset CKD remained controversial.

Methods: A systematic review and meta-analysis using a literature search of online databases including PubMed, Embase, Ovid and ISI Web/Web of Science was conducted. Summary adjusted odds ratios with corresponding 95% confidence intervals (95% CI) were calculated to evaluate the risk estimates of hyperuricemia for new-onset CKD.

Results: Thirteen studies containing 190,718 participants were included. A significant positive association was found between elevated serum uric acid levels and new-onset CKD at follow-up (summary OR, 1.15; 95% CI, 1.05-1.25). Hyperuricemia was found be an independent predictor for the development of newly diagnosed CKD in non-CKD patients (summary OR, 2.35; 95% CI, 1.59-3.46). This association increased with increasing length of follow-up. No significant differences were found for risk estimates of the associations between elevated serum uric acid levels and developing CKD between males and females.

Conclusions: With long-term follow-up of non-CKD individuals, elevated serum uric acid levels showed an increased risk for the development of chronic renal dysfunction.

Published by BioMed Central Ltd | DOI: 10.1186/1471-2369-15-122


zur Originalarbeit nach oben  

Abstract: Urate-Lowering Agents in Asymptomatic Hyperuricemia: Role of Urine Sediment Analysis and Musculoskeletal Ultrasound

Current urate-lowering therapy (ULT) includes three direct acting drugs (allopurinol, febuxostat, Rasburicase) and at least four 'indirect' drugs with other important targets (canagliflozin, losartan, fenofibrate and sevelamer). Moreover, the alcalinization of urines using bicarbonate can be used to dissolve urate crystals and the clinician may discontinue several drugs are known to increase serum levels of uric acid, such as diuretics, aspirin, cyclosporine, theophylline, mycophenolate and ACE inhibitors. While there is a consensus to start ULT in cases of symptomatic hyperuricemia (gout, urate-nephrolithiasis), the very frequent conditions of asymptomatic hyperuricemia remains a major conundrum. The effect of asymptomatic hyperuricemia on kidney function has had fluctuating positions over decades. The conflicting results might indicate: (i) the presence of counterbalancing positive and negative effects on kidney function of both serum uric acid and urate-lowering agents, (ii) the presence of a subpopulation of patients, as yet unidentified, which could truly benefit from a urate-lowering therapy. Therefore, today the treatment of asymptomatic hyperuricemia is not recommended nor excluded by current guidelines. Here we suggest that a possible guide for the treatment of asymptomatic hyperuricemia might be the presence of urate crystals in the urine sediment and/or signs of asymptomatic articular damage by urates, identified by musculo-skeletal ultrasound. Moreover, a watchful analysis of the trend in creatinine/eGFR, proteinuria or urate levels might also guide the clinician. Initiation of ULT and follow-up in cases of asymptomatic hyperuricemia should consider urine sediment analysis, musculoskeletal ultrasound and trends in creatinine, proteinuria and serum urate levels.

Keywords: Canagliflozin; Chronic kidney disease; Rasburicase; Urate nephropathy; Uric acid.

Published by S. Karger AG, Basel | DOI: 10.1159/000489145


zur Originalarbeit nach oben  

Abstract: Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration.

Urate is the end product of purine metabolism in humans, owing to the evolutionary disruption of the gene encoding urate oxidase (UOx). Elevated urate can cause gout and urolithiasis and is associated with cardiovascular and other diseases. However, urate also possesses antioxidant and neuroprotective properties. Recent convergence of epidemiological and clinical data has identified urate as a predictor of both reduced risk and favorable progression of Parkinson's disease (PD). In rodents, functional UOx catalyzes urate oxidation to allantoin. We found that UOx KO mice with a constitutive mutation of the gene have increased concentrations of brain urate. By contrast, UOx transgenic (Tg) mice overexpressing the enzyme have reduced brain urate concentrations. Effects of the complementary UOx manipulations were assessed in a mouse intrastriatal 6-hydroxydopamine (6-OHDA) model of hemiparkinsonism. UOx KO mice exhibit attenuated toxic effects of 6-OHDA on nigral dopaminergic cell counts, striatal dopamine content, and rotational behavior. Conversely, Tg overexpression of UOx exacerbates these morphological, neurochemical, and functional lesions of the dopaminergic nigrostriatal pathway. Together our data support a neuroprotective role of endogenous urate in dopaminergic neurons and strengthen the rationale for developing urate-elevating strategies as potential disease-modifying therapy for PD.

Keywords: men, osteoporosis, vertebral fractures, population based, elderly

Published by Proceedings of the National Academy of Sciences (PNAS) | DOI: 10.1073/pnas.1217296110


zur Originalarbeit nach oben  

Abstract: Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis

Background: Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes.

Results: Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events.

Conclusions: Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.

Keywords: chronic kidney disease; clinical trial; kidney function test; renal dialysis; uric acid.

Published by Oxford Academic | DOI: 10.1093/ndt/gft378


zur Originalarbeit nach oben  

Abstract: Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule?

Sodium bicarbonate (sodium hydrogen carbonate) is used as an oral medication in disorders such as mild metabolic acidosis and chronic kidney disease. The two commercial products on the German market, bicaNorm and Nephrotrans, and also newly developed multiple-unit pellet formulations, have been characterized in these investigations by in-vitro methods like disintegration and dissolution testing. Both marketed products containing sodium bicarbonate are of sufficient pharmaceutical quality according to the European Pharmacopoeia. However, they and the novel pellet preparations showed different drug release at moderately elevated pH values. Early drug release may cause dose dumping in the stomach and adverse drug effects from the developed carbon dioxide. The soft capsule preparation (Nephrotrans) released the smallest amount of sodium bicarbonate at pH 1 and 4.5 of all formulations tested. It appeared that oral dosage formulations of sodium bicarbonate were an exception to the rule: the monolithic soft capsule seemed to be superior to an enteric-coated tablet as well as to multiple-unit pellet formulations from the biopharmaceutical point of view. Our results correspond with individual reports on adverse effects from patients treated with the sodium bicarbonate products.

Published by Royal Pharmaceutical Society | DOI: 10.1211/jpp.59.1.0008


zur Originalarbeit nach oben  

Abstract: Management of the Metabolic Acidosis of Chronic Kidney Disease.

Subjects with CKD and reduced glomerular filtration rate are at risk for chronic metabolic acidosis, and CKD is its most common cause. Untreated metabolic acidosis, even in its mildest forms, is associated with increased mortality and morbidity and should therefore be treated. If reduced glomerular filtration rate or the tubule abnormality causing chronic metabolic acidosis cannot be corrected, it is typically treated with dietary acid (H+) reduction using Na+-based alkali, usually NaHCO3. Dietary H+ reduction can also be accomplished with the addition of base-producing foods such as fruits and vegetables and limiting intake of H+-producing foods like animal-sourced protein. The optimal dose of Na+-based alkali that prevents the untoward effects of metabolic acidosis while minimizing adverse effects and the appropriate combination of this traditional therapy with dietary strategies remain to be determined by ongoing studies. Recent emerging evidence supports a phenomenon of H+ retention, which precedes the development of metabolic acidosis by plasma acid-base parameters, but further studies will be needed to determine how best to identify patients with this phenomenon and whether they too should be treated with dietary H+ reduction.

Keywords: Acid; Alkali; Bicarbonate; Chronic kidney disease; Diet.

Published by Elsevier | DOI: 10.1053/j.ackd.2017.06.006


zum Abstract nach oben  

Abstract: Urate nephropathy following chronic ileostomy acidosis.

Normal renal function and normal urinalysis results in an 81-year-old man deteriorated over a 6-month period following an ileostomy, associated with metabolic acidosis, persistent aciduria, proteinuria, and a urinary sediment that showed numerous red blood cells, granular casts, and 'reactive' epithelial cells with intracellular uric acid (UA) crystals. These also formed extensive UA casts. Oral sodium bicarbonate therapy completely reversed all of the abnormalities. Renal biopsy, while it failed to demonstrate significant tubular obstruction, showed evidence of extensive epithelial cell injury. It is suggested that intestinal losses of bicarbonate resulted in persistent excretion of an acidic urine which promoted UA crystal formation within renal tubules and in epithelial cells which then caused cellular injury and the release of cytokines, leading to an altered regulation of the renal blood flow. The importance of microscopic techniques in the diagnosis is stressed along with the significance for managing both acute and chronic renal failure.

Published by S. Karger AG, Basel | DOI: 10.1093/ndt/gft378


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Rheuma - Inwieweit ist eine Azidose beteiligt?

Rheuma Bei der Entstehung und dem Unterhalt von entzündlichen Vorgängen, wie bei rheumatischen Erkrankungen, spielen die in Weichteilen, im Bindegewebe, an den Sehnen und in den Gelenken abgelagerten sauren Stoffwechselendprodukte neben anderen Faktoren eine mit auslösende beziehungsweise eine verschlimmernde Rolle.

weiter  

Osteoporose durch chronische Azidose

Gicht im Zeh

Gerade bei älteren Patienten trägt eine Übersäuerung möglicherweise erheblich zur Entstehung einer Osteoporose bei. Untersuchungen zeigten, dass besonders bei Frauen nach den Wechseljahren die Übersäuerung zu einer bedeutsamen Zunahme des Knochenabbaus führt.

 

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