nefro abstracts

8/10/2019 Nefro Abstracts

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When Blockade of the Renin-Angiotensin System Becomes a Two-EdgedSword

Am J Hypertens(2013)26 (6):721-722first published online April 7, 2013

See the Original Article on page 727.

Why do some drugs that inhibit the renin-angiotensin system (RAS) fail toprovide cardiovascular protection or possibly even cause harm when addedto standard therapies in high-risk patients?1,2Why, in comparison with a

single drug that inhibits the RAS, is the combination of 2 RAS inhibitors nomore effective or even possibly harmful? 35The reasoned analysis by

Sealey et al.6in this issue of the Journal suggests that excessive sodium-

volume depletion caused by overzealous use of diuretics and salt restriction

in subsets of patients might help explain why, in some clinical trials,additional treatment with either 1 or 2 RAS inhibitors has failed to improve

cardiovascular outcomes or even appeared to be harmful.Excessive sodium-volume depletion and cardiovascular risk

Sealey et al.6 observed that, compared with patients with relatively low or normal plasma reninactivity (PRA) levels, patients with high PRA levels in various clinical trials tended to have

greater cardiovascular mortality rates and evidence of greater sodium-volume depletion: lower

blood pressures (BPs), lower brain natriuretic peptide levels, and higher blood urea nitrogen anduric acid levels. Use of diuretics was also greater in subjects with high PRA than in those with

lower PRA. Although RAS-blocking drugs can cause reactive rises in PRA, the use of RAS-

blocking drugs was not greater in the subjects with high PRA. Sealey et al.6 surmise that, in

subsets of patients, excessive diuretic use and/or dietary salt restriction induced high PRA levelsand contributed to the greater sodium-volume depletion and greater cardiovascular risk.

Plasma Renin Activity (PRA) Levels and Antihypertensive Drug Use in a Large

Healthcare SystemAm J Hypertens (2012) 25 (3): 379-388

Abstract

Background:Although hypertension guidelines have utility in treating uncomplicated hypertension, they

often overlook the pathophysiologic basis and heterogeneity of hypertension. This may explain the relatively

poor hypertension control rates. A proposed approach is to guide addition and subtraction of medications using

ambulatory plasma renin activity (PRA) values. To evaluate the heterogeneity of hypertension and the

medication burden associated with it, we investigated medication usage in relation to PRA among hypertensive

patients within a large ethnically diverse organization.

Methods:A cross sectional data analysis was performed of hypertensive subjects with PRA measurements in

the Kaiser Permanente Southern California database between 1 January 1998 and 31 October 2009.

Results:Among 7,887 such patients 0, 1, 2, 3 medication usage was 16%, 20%, 24%, 40% respectively. PRA

levels ranged 1000-fold. Across PRA quartiles (Q1 to Q4) 3 meds were prescribed to 50%, 40%, 34%, 37%.

From low to high PRA quartiles there was no usage trend for angiotensin converting enzyme inhibitors

(ACEIs)/ angiotensin receptor blockers (ARBs) (71%), but diuretics increased (52%, 53%, 57%, 68%),

calcium channel blocker's (CCB) fell (56%, 53%, 51%, 42%), and -blockers fell (77%, 61%, 49%, 41%).

Moreover, systolic BP fell (146, 142, 140, 135 mm Hg), blood urea nitrogen (BUN) rose (16, 17, 18, 20mg/dl), serum uric acid rose (6.1, 6.3, 6.5, 6.9 mg/dl), and chronic kidney disease rose (22%, 22%, 23%, 27%).


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Conclusions:Polytherapy was the norm for treating hypertension. Lower PRAs were associated with higher

blood pressures and more medications. Higher PRAs were associated with lower pressures and fewer

medications. The results indicate that opportunities exist to simplify antihypertensive therapy by using current

ambulatory PRA levels to guide drug selections and subtractions.

Urinary Angiotensin-Converting Enzyme2 in Hypertensive Patients May BeIncreased by Olmesartan, an AngiotensinII Receptor Blocker

1. Am J Hypertens (2015) 28 (1): 15-21.doi: 10.1093/ajh/hpu086First published online: May 18, 2014

Abstract

BACKGROUNDAngiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and convertsangiotensin (Ang) II to Ang-(17), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in

patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remainunclear.

METHODSOf participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication

(n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channelblockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers

losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, andurinary ACE2 level was measured.

RESULTSGlucose and hemoglobin A1c were significantly higher in patients treated with enalapril,

telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) wassignificantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was

higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary

ACE2 level was positively correlated with systolic blood pressure (r= 0.211;P= 0.003), UACR (r=0.367;P< 0.001), and estimated salt intake (r= 0.260;P< 0.001). Multivariable regression analysis after

adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independentpredictor of urinary ACE2 level.

CONCLUSIONSIn contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary

ACE2 level, which could potentially offer additional renoprotective effects.

Efficacy and Safety of Angiotensin Receptor Blockers in Older Patients: A Meta-

Analysis of Randomized TrialsAm J Hypertens first published online November 11, 2014

Abstract

BACKGROUNDThe efficacy and safety of angiotensin receptor blockers (ARBs) in the older population is

unclear.

OBJECTIVESTo determine the efficacy and safety of ARBs in older patients.

METHODSRandomized trials that compared ARBs to control and reported clinical outcomes in patients with

a mean age of 65 years or older were included. Random-effects summary risk ratios (RRs) were constructed.

RESULTSA total of 16 trials met our selection criteria, which yielded 113,386 patients. ARBs wereassociated with a marginal increased risk of all-cause mortality (RR: 1.03, 95% confidence interval (CI): 1.00

1.06,P= 0.05), a nonsignificant increased risk of myocardial infarction (RR: 1.04, 95% CI: 0.961.12,P=


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0.36), a marginal reduction in heart failure hospitalization (RR: 0.86, 95% CI: 0.741.00,P= 0.06), and a

significant reduction in the risk of stroke (RR: 0.93, 95% CI: 0.870.99,P= 0.03). ARBs were associated with

an increased risk of acute kidney injury (RR: 1.48, 95% CI: 1.241.77,P< 0.001), hypotension (RR: 1.56,

95% CI: 1.241.97,P< 0.001), and hyperkalemia (RR: 1.57, 95% CI: 1.132.19,P= 0.008). On the

sensitivity analysis including placebo-controlled trials, the risk of all-cause mortality was no longer significant

(P= 0.2), while the remainder of the outcomes did not change.

CONCLUSIONIn older patients, the benefit of ARBs compared with control was strongest for strokereduction, with no (or weak) associations for all-cause mortality, myocardial infarction, and heart failure

hospitalization. Benefit was offset by an increased risk of acute kidney injury, hypotension, and hyperkalemia.

Thus, ARBs should be used with caution in older patients when clinically indicated.

Systolic Blood Pressure and Outcomes in Stage 34 Chronic Kidney DiseasePatients: Evidence from a Taiwanese CohortAm J Hypertens (2014) 27 (11): 1396-1407 first

published online April 11, 2014

Abstract

BACKGROUNDSystolic blood pressure (SBP) goal for chronic kidney disease (CKD) patients is 140mm

Hg. However, the SBP target provides no suggested lower limit, and some studies indicate that a lower SBPtarget may be harmful. We aimed to investigate the J-shaped relationship between SBP and clinical outcomes

in CKD patients and the factors that modify this relationship.

METHODSThis prospective observational study enrolled 2,144 CKD stage 34 patients between November

2002 and May 2009 and followed them until July 2010 or death. Patients included were also enrolled within

the Integrated CKD Care Program for Delaying Dialysis in a medical center and its branch hospital.

Demographic, clinical, laboratory, and disease variables at baseline and end of observation were measured.

RESULTSIn diabetic CKD patients, the hazard ratio (HR) at SBP 96110mm Hg vs. 111120mm Hg was

2.52 (95% confidence interval (CI) = 1.135.58) for cardiovascular outcomes and was 3.14 (95% CI = 1.16

8.49) for renal outcomes. In nondiabetic CKD patients, this J-shaped relationship was not seen. Heavy

proteinuria was further found to modify the J-shaped relationship in diabetic CKD patients. The HR for renal

outcomes at SBP 96110mm Hg vs. 111120mm Hg was 4.07 (95% CI = 1.1813.99) in diabetic CKD

patients with heavy proteinuria vs. 1.72 (95% CI = 0.1322.5) in those without heavy proteinuria.

CONCLUSIONSDiabetic CKD patients have a J-shaped relationship between SBP and cardiovascular or

renal outcomes, but nondiabetic CKD patients do not. The optimal SBP range might be narrower in the

diabetic CKD patients.

Sodium Intake and Renal Outcomes: A Systematic ReviewAm JHypertens (2014) 27 (10): 1277-1284 first published online February 7, 2014

Abstract

BACKGROUNDSodium intake is an important determinant of blood pressure; therefore, reduction of intake

may be an attractive population-based target for chronic kidney disease (CKD) prevention. Most guidelines

recommend sodium intake of 4.6g/day) was associated with adverse outcomes (vs. moderate/low), while

none reported an increased risk with moderate intake (vs. low). Three studies (n = 6,342) included patients


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without CKD. Two cohort studies (n = 6,155) reported opposing directions of association between low (vs.

moderate) sodium intake and renal outcomes, and one clinical trial (n = 187) reported a benefit from low

intake (vs. moderate) on proteinuria but an adverse effect on serum creatinine.

CONCLUSIONSAvailable, but limited, evidence supports an association between high sodium intake

(>4.6g/day) and adverse outcomes. However, the association with low intake (vs. moderate) is uncertain, with

inconsistent findings from cohort studies. There is urgent need to clarify the long-term efficacy and safety of

currently recommended low sodium intake in patients with CKD.

What Level of Sodium Intake Worsens Renal Outcomes?Am JHypertens (2014) 27 (10): 1243-1244 first published online May 10, 2014

Sodium consumption in the United States is approximately 3,500mg/day as estimated from

urinary sodium collections.1Although there is consensus that this is too much sodium,

there remains lively debate as to what reduction in sodium is beneficial and safe. This is

reflected in differences of opinion of knowledgeable consensus panels, such as those from

the American Heart Association, which recommends restricting sodium to


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CONCLUSIONSThese results raise the hypothesis that relative aldosterone excess may have a deleterious

effect on the development of hypertension by contributing to salt/volume-related hypertension.

Combination Therapy of Amlodipine and Atorvastatin Has More BeneficialVascular Effects Than Monotherapy in Salt-Sensitive HypertensionAm J

Hypertens (2014) 27 (6): 873-880 first published online January 11, 2014

Abstract

BACKGROUNDCurrent treatment for the secondary prevention of cardiovascular diseases frequently

involves the prescription of several combination therapies, particularly antihypertensive medications and

HMG-CoA reductase inhibitor. We have previously shown that in salt-sensitive hypertension either a statin or

the calcium channel blocker amlodipine (Aml) have vasoprotective effects. Here, we investigated in aortas

from Dahl salt-sensitive (DS) rats the effects of Aml, the statin atorvastatin (AT), and their combination on

endothelial function, superoxide (O2) production, and the expression of endothelial nitric oxide synthase

(eNOS), chemokine monocyte chemoattractant protein-1 (MCP-1), and lectin-like oxidized LDL receptor-1

(LOX-1).

METHODSGroups of DS rats were fed either normal-salt (NS, 0.5% NaCl) or high-salt (HS, 4% NaCl) diet

or a HS diet with AT (15mg/kg/day), Aml (5mg/kg/day) or combination of AT/Aml for 6 weeks.RESULTSRats on the HS diet developed hypertension, aortic hypertrophy, accompanied by increased plasma

C-reactive protein (CRP), aortic O2, MCP-1 (80%), and LOX-1 (55%) expression and reduced eNOS and

endothelial-dependent relaxation to acetylcholine (EDR). Aml reduced systolic blood pressure (SBP), aortic

hypertrophy, plasma CRP, vascular O2, and MCP-1 expression and improved eNOS and EDR. AT reduced

aortic hypertrophy and plasma CRP, improved EDR, and normalized vascular O2, eNOS, and

proinflammatory gene expression with mild reduction in SBP. Combination therapy further reduced the SBP

and normalized aortic hypertrophy, EDR, and plasma CRP.

CONCLUSIONSThe combination therapy of Aml/AT has an additive beneficial effect on the vasculature.

These novel findings may provide scientific basis for the combination therapy of statins with antihypertensive

agents to reduce and prevent cardiovascular diseases.

An Observational Cohort Study of the Effect of Hypertension on the Loss ofRenal Function in Pediatric Kidney RecipientsAm J Hypertens (2014) 27 (4): 579-585 first publishedonline August 16, 2013

Abstract

BACKGROUNDPost-transplant hypertension impacts negatively on renal graft survival. Our primary

objective was to analyze the effect of hypertension on the glomerular filtration rate (GFR) slope.

METHODSAll clinical charts of children who underwent renal transplantation since the introduction of theroutine use of ambulatory blood pressure monitoring (ABPM) were reviewed. Eligibility criteria for inclusion

were measurement of GFR at 3 months, at 1 year post-transplant, and thereafter at yearly intervals; ABPMperformed annually after transplantation; and functioning graft for a minimum of 2 years.

RESULTSSixty-eight (39 males) of 79 patients, aged 9.15.3 years, met the inclusion criteria. The meanfollow-up was 6.22.8 years. Twenty-four patients had normotension or controlled hypertension throughouttheir follow-up (normotensive group). Forty-four patients had hypertension or noncontrolled hypertension at

some point(s) during the follow-up period (hypertensive group). GFR slope was 1.6ml/min/1.73 m2per year

(95% confidence interval (CI = 3.7 to 0.4) in the normotensive group and 2ml/min/1.73 m2per year (95%

CI = 3 to 1.1) in the hypertensive group (P= 0.42). There was no difference between groups with regard to

the change in GFR values from 3 months to 1 year and to last control (P= 0.87). At most recent control, the

overall prevalence of controlled hypertension was 78.2% (95% CI = 63.689.1).


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WKD has become the most successful effort to raise awareness

among policymakers and the general public about the

importance of kidney disease. The topic for WKD 2014 is CKD

in older people. This article reviews the key links between

kidney function, age, health and illness and discusses the

implications of the aging population for the care of people with

CKD.

Beyond blood pressure: evidence for cardiovascular, cerebrovascular, and renalprotective effects of reninangiotensin system blockersTher Adv Cardiovasc Dis April

2012 6: 81-91, first published on April 23, 2012

Abstract

For patients with hypertension, effective control of blood pressure (BP) reduces cardiovascular (CV), andrenal risk. Antihypertensive agents that offer benefits that extend beyond those associated with BPreduction alone, to include tissue protective effects and effects on the vasculature, may be of benefit formany patients with increased CV risk due to comorbidities or prior history of CV events. Reninangiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin IIreceptor blockers (ARBs)] are guideline-recognized, highly effective antihypertensive agents that exerttheir BP-lowering action through different mechanisms at different levels of the RAS. Large-scale clinicalstudies suggest that small, between-treatment differences in BP lowering do not account for observedoutcome differences between RAS blockers and other antihypertensive agents. Analysis of data from

seminal clinical studies and meta-analyses identify that, controlling for effects on BP control, RASblockers may be more effective than calcium channel blockers (CCBs) in reducing risk of myocardialinfarction and congestive heart failure; ARBs may be more effective than either ACEIs or blockers instroke prevention; CCBs may be more effective than RAS blockers in stroke prevention; and ARBs maybe more effective than blockers in reducing left ventricular hypertrophy. This review considers therationale and evidence for benefits of RAS blockade beyond BP lowering, and highlights the differencesbetween ARBs and ACEIs, and between agents within these drug classes.

Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers onAll-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients WithDiabetes Mellitus: A Meta-analysis

Cheng J, Zhang W, Zhang X et al.JAMA Intern Med. 2014 Mar 31

BackgroundDiabetes mellitus (DM) is a strong independent risk factor for cardiovascular disease (CVD), and associated withmacrovascular complications. The renin-angiotensin-aldosterone system (RAAS) is an important regulator of CV andrenal function [1,2]. Suppression of RAAS activity has been found to reduce CV mortality and all-cause mortality [3-6].The cardioprotective effects of RAAS-blockade have, however, recently been questioned. The NonInsulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril


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(DIABHYCAR) study [7] found that angiotensin-converting enzyme inhibitors (ACEI) had no effects on CV events inpatients with type 2 DM (T2DM) and albuminuria, and in another study a higher rate of fatal CV events was observedwith olmesartan in T2DM patients (ROADMAP study [8]).The American Diabetes Association recommends that patients with DM and hypertension be treated with atherapeutic regimen that should include an ACEI or an angiotensin II receptor blocker (ARB) [9]. Both types of drugsinhibit angiotensin II, but via a different mechanism of action.

A recent meta-analysis demonstrated that ACEIs and ARBs differently affected all-cause mortality in patients with

hypertension. This difference may also be relevant in the treatment of DM. This meta-analysis evaluated the effect ofACEIs and ARBs separately vs. placebo or other medications, on all-cause mortality, CV death, and CV events inpatients with DM.35 trials, enrolling 56444 patients, were included in this analysis, 23 of which evaluated ACEIs and 13 compared

ARBs with control therapy.

Main results

In 20 prospective trials, ACEIs were associated with a statistically significant 13% reduction in all-cause mortalityas compared with control therapy (RR: 0.87, 95%CI: 0.78-0.98, P=0.02). There was no difference betweencomparisons with placebo or active treatment.

Based on 13 studies of 23 RCTs, a significant 17% reduction of CV deaths was seen with ACEIs as compared withcontrol therapy (RR: 0.83, 95%CI: 0.70-0.99, P=0.04). There was no interaction with comparison with placebo oractive treatment.

No significant decrease in all-cause mortality was seen with ARBs as compared with control therapy, based on 11studies (RR: 0.94, 95%CI: 0.82-1.08, P=0.39). No difference was seen with respect to type of control treatment.

With respect to CV mortality, no difference was seen between ARB treatment and control therapy (RR: 1.21,95CI:081-1.80, P=0.35), without an interaction for type of control treatment. Heterogeneity across trials was significant,which disappeared when 2 trials involving olmesartan were excluded. When comparing only olmesartan withcontrol therapy, a significant increase in the risk of CV death was seen (2 trials, 5024 patients, RR: 4.10, 95%CI:1.68-9.98, P=0.002).

Major CV events were significantly reduced with ACEI (RR: 0.86, 95%CI: 0.77-0.95). ACEI therapy also reducedthe risk of myocardial infarction (RR: 0.79, 95%CI: 0.65-0.95, P=0.01) and heart failure (RR: 0.81, 95%CI: 0.71-0.93, P=0.002), but not stroke (RR: 0.95, 95%CI: 0.86-1.04, P=0.28).

ARBs did not give a significant decrease in the risk of major CV events (RR: 0.94, 95%CI: 0.85-1.01, P=0.07).There were no significant effects of ARBs on myocardial infarction (RR: 0.89, 95%CI: 0.74-1.07, P=0.22) or stroke(RR: 1.00, 95%CI: 0.89-1.12, P=0.94). Risk of heart failure was reduced with ARBs (RR: 0.70, 95%CI: 0.59-0.82,P


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METHODS:

We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between

January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration

rate (eGFR) < or = 50 ml per minute per 1.73 m2, were identified. In-patient prescriptions were captured if

they were written after clinical notes indicated impaired renal function, or > or = 1 day after renal function

tests were performed. We determined what proportion of these prescriptions required dose adjustmentand whether drug doses were appropriately adjusted.

RESULTS:

We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries

for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription

entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients,

69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses

were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no

doses had been correctly adjusted.

CONCLUSION:

Consistent with international studies, drug dose adjustment in patients with renal impairment in a South

African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in

renal impairment should be considered, including automated eGFR reporting and computerised aids to

guide drug dosing, that account for renal impairment.

J Nephrol.2009 Jul-Aug;22(4):497-501.

Inappropriate drug dosage adjustments in patients with renalimpairment.

Markota NP1,Markota I,Tomic M,Zelenika A.

Author informationAbstract

BACKGROUND:

The aim of this study was to determine whether appropriate dosage adjustments were made in patients

with renal impairment discharged from the Department of Internal Medicine and to evaluate a possible

role for family medicine physicians in reducing the number of inadequate drug dosages.

METHODS:

The study included all patients discharged from the Department of Internal Medicine. Data regarding

serum creatinine levels, age, sex and prescribed drugs and their dosage were collected from the patients'

medical records and discharge letters after discharge from hospital. We calculated the estimated

glomerular filtration rate (GFR) using the abbreviated MDRD equation. Drug dosage adequacy wascontrolled in the patients with GFR less than 60 ml/min per 1.73 m2.

RESULTS:

At the time of discharge from the hospital, 161 of 712 patients (22.6%) had estimated GFR


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the combination of ACE inhibitors and spironolactone amounted to 65.6% of the inadequate prescriptions.

There were significantly more incorrect drug dosages in women.

CONCLUSION:

Drug dosage in patients with renal impairment can be improved. Since a computerized dynamic alert

system is not available in our hospital the role of family medicine physicians is significant in reducing the

number of inadequate drug dosages at hospital discharge.

Ann Pharmacother.2009 Jun;43(6):1064-83. doi: 10.1345/aph.1L194. Epub 2009 May 19.

Low-molecular-weight heparins in renal impairment and obesity:available evidence and clinical practice recommendations acrossmedical and surgical settings.

Nutescu EA1,Spinler SA,Wittkowsky A,Dager WE.


OBJECTIVE:

To develop practical recommendations for the use of low-molecular-weight heparins (LMWHs) as

prophylaxis and treatment of venous thromboembolism and acute coronary syndromes in patients with

impaired renal function or obesity.

DATA SOURCES:

Multiple MEDLINE searches were performed (November 2008) to identify studies for inclusion, using a

comprehensive list of search terms including, but not limited to, LMWH, enoxaparin, dalteparin,

tinzaparin, obesity, weight, renal, kidney, elderly, monitoring, and anti-Xa.

STUDY SELECTION AND DATA EXTRACTION:

Only articles published in English that were relevant for this review were included.

DATA SYNTHESIS:

In the majority of patients, standardized prophylaxis or treatment doses of LMWHs can be used without

the need for monitoring and adjusting regimens. For patients with severe renal impairment (estimated

creatinine clearance [CrCl] or =

40 kg/m(2)). The use of total body weight is appropriate for therapeutic doses of LMWH in obese patients.

Laboratory monitoring of the anticoagulation effect of LMWHs is generally not necessary, but should beconsidered in patients with morbid obesity (weight >190 kg), those with severe renal impairment, and

those with moderate renal impairment with prolonged (>10 days) LMWH use. When anti-Xa activity is

monitored, it should be determined using a chromogenic method and a calibration curve based on the

LMWH used.
http://www.ncbi.nlm.nih.gov/pubmed/19458109http://www.ncbi.nlm.nih.gov/pubmed/19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Nutescu%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Nutescu%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Spinler%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Spinler%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Spinler%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Wittkowsky%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Wittkowsky%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Wittkowsky%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Dager%20WE%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Dager%20WE%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Dager%20WE%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/19458109http://www.ncbi.nlm.nih.gov/pubmed/19458109http://www.ncbi.nlm.nih.gov/pubmed/19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Dager%20WE%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Wittkowsky%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Spinler%20SA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/?term=Nutescu%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=19458109http://www.ncbi.nlm.nih.gov/pubmed/19458109


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CONCLUSIONS:

Additional data are needed for specific dose guiding in obese and renally impaired patients, who are often

excluded from larger clinical trials. Practice recommendations are made based on available evidence and

authors' clinical opinions.

G Ital Nefrol.2010 Nov-Dec;27(6):649-54.

[The risk of bleeding associated with low molecular weightheparin in patients with renal failure].

[Article in Italian]

Lai S1,Barbano B,Cianci R,Gigante A,Di Donato D,Asllanaj B,Dimko M,Mariotti A,MorabitoS,Pugliese F.Author informationAbstract

Cardiovascular mortality and morbidity are higher in patients with chronic renal disease than in the

general population. Patients with chronic renal disease are in the highest risk group for thromboembolicdisease and many clinical trials have demonstrated the greater safety and efficacy of low-molecular-

weight heparin (LMWH) versus unfractionated heparin (UFH). LMWH is cleared only by the kidneys while

UFH is cleared by the renal and hepatic routes. Furthermore, LMWH has a significant accumulative effect

in patients with impaired renal function (creatinine clearance


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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Meta-analysis: low-molecular-weight heparin and bleeding in patientswith severe renal insufficiency

Review published: 2006.

Bibliographic details: Lim W, Dentali F, Eikelboom J W, Crowther M A. Meta-analysis: low-molecular-

weight heparin and bleeding in patients with severe renal insufficiency. Annals of Internal

Medicine 2006; 144(9): 673-684. [PubMed]

Quality assessment

This well-conducted review assessed anti-Xaheparinlevels andbleedingevents in patients with severe

renal insufficiency who were receiving low molecular weight heparin. It concluded that

standardtherapeuticdoses ofenoxaparinled to higher anti-Xa heparin levels and increased the risk ofmajor bleeding. These conclusions are limited by the observational nature of the included studies. Full

critical summary

Abstract

BACKGROUND:Dose adjustment or laboratory monitoring of low-molecular-weightheparin(LMWH) is

commonly recommended for patients with severe renal insufficiency (creatinine clearance < or =30

mL/min), but the basis for this recommendation is unclear.

PURPOSE:To compare levels of anti-Xaheparinand risk for majorbleedingin LMWH-treated patients

with a creatinine clearance of 30 mL/min or less versus those with a creatinine clearance greater than 30

mL/min by using standard weight-adjustedtherapeuticdoses, empirically adjusted doses, or prophylacticdoses of LMWH.

DATA SOURCES:Electronic databases (MEDLINE, EMBASE, and the Cochrane Library) searched to

December 2005 with no language restrictions. The authors also searched reference lists and contacted

experts.

STUDY SELECTION:Observational or subgroups of randomized studies that included non -dialysis-

dependent patients with varying degrees of renal function who were treated with LMWH and reported

creatinine clearance and anti-Xa levels or majorbleeding.

DATA EXTRACTION:Two reviewers independently selected studies and extracted data on patient

characteristics, renal function, LMWH treatment, anti-Xa levels, and majorbleeding.The pooled odds

ratio of major bleeding in patients with a creatinine clearance of 30 mL/min or less was calculated by

using the Peto method.

DATA SYNTHESIS:Eighteen studies using 3 preparations of LMWH (15 studies using enoxaparin,2

usingtinzaparin,and 1 usingdalteparin)were included. Peak anti-Xa levels measured 4 hours after

asubcutaneous injectionwere statistically significantly higher in patients with a creatinine clearance of 30

mL/min or less compared with those with a creatinine clearance greater than 30 mL/min in studies that

used a standardtherapeuticdose of enoxaparin (4 studies) but not in studies of empirically dose-adjusted
http://www.ncbi.nlm.nih.gov/pubmed/16670137http://www.ncbi.nlm.nih.gov/pubmed/16670137http://www.ncbi.nlm.nih.gov/pubmed/16670137http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022165http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022165http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022165http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012432http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012432http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012432http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009801http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009801http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022224http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022224http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022224http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022224http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009801http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012432http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022165http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?LinkFrom=OAI&ID=12006008200http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010108http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022343http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023358http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010545http://www.ncbi.nlm.nih.gov/pubmed/16670137


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enoxaparin (3 studies). Data were insufficient to assess the relationship between anti-Xa and renal

function for prophylactic doses of enoxaparin and therapeutic doses of tinzaparin or dalteparin. In 12

studies involving 4971 patients, LMWH was associated with a statistically significant increase in the risk

for majorbleedingin patients with a creatinine clearance of 30 mL/min or less compared with those with a

creatinine clearance greater than 30 mL/min (5.0% vs. 2.4%; odds ratio, 2.25 [95% CI, 1.19 to 4.27]; P =

0.013). When analyzed according to LMWH preparation, major bleeding was increased when a standardtherapeutic dose of enoxaparin was used (8.3% vs. 2.4%; odds ratio, 3.88 [CI, 1.78 to 8.45]) but may not

be increased when an empirically adjusted dose of enoxaparin is used (0.9% vs. 1.9%; odds ratio, 0.58

[CI, 0.09 to 3.78]; P = 0.23 for heterogeneity). There were insufficient studies to assess the risk for major

bleeding with tinzaparin, dalteparin, and prophylactic doses of enoxaparin.

LIMITATIONS:The data fortinzaparinanddalteparinwere limited. Data are observational, and the

potential for confounding cannot be excluded.

CONCLUSIONS:Non-dialysis-dependent patients with a creatinine clearance of 30 mL/min or less who

are treated with standardtherapeuticdoses ofenoxaparinhave elevated levels of anti-Xa and an

increased risk for majorbleeding.Empirical dose adjustment of enoxaparin may reduce the risk for

bleeding and merits additional evaluation. No conclusions can be made regarding other LMWHs.

Intern Med J.2014 Jan;44(1):77-85. doi: 10.1111/imj.12291.

Dose adjustment guidelines for medications in patients withrenal impairment: how consistent are drug information sources?

Khanal A1,Castelino RL,Peterson GM,Jose MD.


BACKGROUND:

It is known that patients with renal disease are often administered inappropriate dosages of drugs. A lack

of quantitative data in the available drug information sources and inconsistency in dosing information may

augment the problem of dosing error.

AIMS:

To determine the concordance among five drug information sources regarding the dosing

recommendations provided for drugs considered problematic in patients with renal impairment and to

determine the consistency among the sources regarding the definition of renal impairment and

categorisation of chronic kidney disease.

METHODS:

Five standard drug information sources were reviewed for 61 drugs recommended to be used withcaution in renal impairment. Information on recommendations for dosage adjustment in renal impairment

was extracted and analysed. Further, the definition and classification of renal impairment were recorded.

The recommendation for each drug was coded into six different categories and the intersource reliability

was calculated.

RESULTS:

Only slight agreement was observed among the sources (Fleiss Kappa: 0.3). Qualitative data were not

well defined, and there was a lack of consistency in quantitative values. Some drugs marked as
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contraindicated in one source were not mentioned as such in others. Also, drugs considered as not

requiring dosage adjustment in one source had explicit recommendations in other sources. The definition

and classification of renal impairment differed among the five information sources.

CONCLUSIONS:

There should be an evidence-based approach to drug dosage adjustment in order to bring uniformity to

the recommendations. Regular updating of the content of the drug information sources is also important.

Drug Saf.2001 Jan;24(1):19-38.

Anticancer drug-induced kidney disorders.

Kintzel PE1.Author informationAbstract

Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be

categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying

pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage

results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular

precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease,

renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a

consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods

used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction

generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and

prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to

disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and

management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to

administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is

commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of

streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renaltubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related

renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities,

such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin

has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes

to cisplatin-induced nephrotoxicity include amifostine, sodium thiosulfate and diethyldithiocarbamate.

Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal

wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have

occurred with ifosfamide treatment. High dose azacitidine causes renal dysfunction manifested by tubular

acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids. Haemolytic

uraemia is a rare adverse effect of gemcitabine. Methotrexate can cause increased serum creatinine

levels, uraemia and haematuria. Acute renal failure is reported following administration of high dose

methotrexate. Urinary alkalisation and hydration confer protection against methotrexate-induced renal

dysfunction. Dose-related nephrotoxicity, including acute renal failure, are reported subsequent to

treatment with pentostatin and diaziquone. Acute renal failure is a rare adverse effect of treatment with

interferon-alpha. Haemolytic uraemic syndrome occurs with mitomycin administration. A mortality rate of

50 to 100% is reported in patients developing mitomycin-induced haemolytic uraemic syndrome. Capillary

leak syndrome occurring with aldesleukin therapy can cause renal dysfunction. Infusion-related

hypotension during infusion of high dose carmustine can precipitate renal dysfunction
http://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/?term=Kintzel%20PE%5BAuthor%5D&cauthor=true&cauthor_uid=11219485http://www.ncbi.nlm.nih.gov/pubmed/?term=Kintzel%20PE%5BAuthor%5D&cauthor=true&cauthor_uid=11219485http://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/?term=Kintzel%20PE%5BAuthor%5D&cauthor=true&cauthor_uid=11219485http://www.ncbi.nlm.nih.gov/pubmed/11219485?dopt=Abstract

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