Chronic kidney disease: Difference between revisions

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'''Chronic kidney disease''' is defined as "kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for 3 months or more, irrespective of cause. Kidney damage in many kidney diseases can be ascertained by the presence of albuminuria, defined as albumin-to-creatinine ratio >30 mg/g in two of three spot urine specimens."<ref name="pmid15882252">{{cite journal |author=Levey AS, Eckardt KU, Tsukamoto Y, ''et al'' |title=Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO) |journal=Kidney Int. |volume=67 |issue=6 |pages=2089–100 |year=2005 |pmid=15882252 |doi=10.1111/j.1523-1755.2005.00365.x}}</ref>
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In medicine, '''chronic kidney disease (CKD)''' is defined as "[[kidney]] damage or [[glomerular filtration rate]] (GFR) <60 mL/min/1.73 m(2) for 3 months or more, irrespective of cause. Kidney damage in many kidney diseases can be ascertained by the presence of albuminuria, defined as albumin-to-creatinine ratio >30 mg/g in two of three spot urine specimens."<ref name="pmid15882252">{{cite journal |author=Levey AS, Eckardt KU, Tsukamoto Y, ''et al'' |title=Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO) |journal=Kidney Int. |volume=67 |issue=6 |pages=2089–100 |year=2005 |pmid=15882252 |doi=10.1111/j.1523-1755.2005.00365.x}}</ref>
 
These definitions are generally applicable in [[veterinary medicine]]. CKR is common among geriatric cats and dogs.


==Classification==
==Classification==
Line 8: Line 11:
*Stage 3 - [[glomerular filtration rate]] is 30-59 ml/min/1.73 m<sup>2</sup>
*Stage 3 - [[glomerular filtration rate]] is 30-59 ml/min/1.73 m<sup>2</sup>
*Stage 4 - [[glomerular filtration rate]] is 15-29 ml/min/1.73 m<sup>2</sup>
*Stage 4 - [[glomerular filtration rate]] is 15-29 ml/min/1.73 m<sup>2</sup>
*Stage 5 - [[glomerular filtration rate]] is less than 15 ml/min/1.73 m<sup>2</sup> or on [[dialysis]]
*Stage 5 - [[glomerular filtration rate]] is less than 15 ml/min/1.73 m<sup>2</sup> or on [[renal dialysis]]; also callled '''end-stage renal disease (ESRD)'''
 
Classification may be improved by considering [[proteinuria]].<ref name="pmid21200034">{{Cite journal
| doi = 10.1059/0003-4819-154-1-201101040-00003
| volume = 154
| issue = 1
| pages = 12 -21
| last = Tonelli
| first = Marcello
| coauthors = Paul Muntner, Anita Lloyd, Braden J. Manns, Matthew T. James, Scott Klarenbach, Robert R. Quinn, Natasha Wiebe, Brenda R. Hemmelgarn
| title = Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease
| journal = Annals of Internal Medicine
| accessdate = 2011-01-04
| date = 2011-01-04
|pmid=21200034
| url = http://www.annals.org/content/154/1/12.abstract
}}</ref>
 
==Etiology/cause==
Bilateral [[renal artery stenosis]] (RAS) may cause 5% to 15% of cases of chronic kidney disease.<ref name="pmid8460859">{{cite journal |author=Rimmer JM, Gennari FJ |title=Atherosclerotic renovascular disease and progressive renal failure |journal=Ann. Intern. Med. |volume=118 |issue=9 |pages=712–9 |year=1993 |month=May |pmid=8460859 |doi= |url=http://www.annals.org/cgi/pmidlookup?view=long&pmid=8460859 |issn=}}</ref>
 
==Prevalence==
Thirteen percent of adults in the [[United States of America]] have chronic kidney disease as defined by the [http://www.kidney.org/professionals/kdoqi/ Kidney Disease Outcomes Quality Initiative] (KDOQI).<ref name="pmid17986697">{{cite journal| author=Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P et al.| title=Prevalence of chronic kidney disease in the United States. | journal=JAMA | year= 2007 | volume= 298 | issue= 17 | pages= 2038-47 | pmid=17986697
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=17986697 | doi=10.1001/jama.298.17.2038 }} </ref> The prevalence is reduced to 11% if isolated [[microalbuminuria]] (CKD-1) is not included.<ref  name="pmid17986697"/> However, using otehr criteria, the prevalence is 2.9%.<ref name="pmid19231766">{{cite journal| author=Rutkowski M, Mann W, Derose S, Selevan D, Pascual N, Diesto J et al.| title=Implementing KDOQI CKD definition and staging guidelines in Southern California Kaiser Permanente. | journal=Am J Kidney Dis | year= 2009 | volume= 53 | issue= 3 Suppl 3 | pages= S86-99 | pmid=19231766
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=19231766 | doi=10.1053/j.ajkd.2008.07.052 }} </ref>
 
Routine reporting of the estimated [[glomerular filtration rate]] has increased the number of referrals to [[nephrology|nephrologist]]s<ref name="pmid20332400">{{cite journal| author=Hemmelgarn BR, Zhang J, Manns BJ, James MT, Quinn RR, Ravani P et al.| title=Nephrology visits and health care resource use before and after reporting estimated glomerular filtration rate. | journal=JAMA | year= 2010 | volume= 303 | issue= 12 | pages= 1151-8 | pmid=20332400 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20332400 | doi=10.1001/jama.2010.303 }} </ref>; however, the benefit is uncertain<ref name="pmid19176794">{{cite journal| author=den Hartog JR, Reese PP, Cizman B, Feldman HI| title=The costs and benefits of automatic estimated glomerular filtration rate reporting. | journal=Clin J Am Soc Nephrol | year= 2009 | volume= 4 | issue= 2 | pages= 419-27 | pmid=19176794
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=19176794 | doi=10.2215/CJN.04080808 | pmc=PMC2637597 }} </ref>.


==Signs and symptoms==
==Signs and symptoms==
[[Uremia]], "the illness accompanying kidney failure", may have subtle manifestations when the [[glomerular filtration rate]] falls below 60 ml/min/1.73 m<sup>2</sup> <ref name="pmid17898101">{{cite journal |author=Meyer TW, Hostetter TH |title=Uremia |journal=N. Engl. J. Med. |volume=357 |issue=13 |pages=1316–25 |year=2007 |pmid=17898101 |doi=10.1056/NEJMra071313}}</ref>
[[Uremia]], "the illness accompanying kidney failure", may have subtle manifestations when the [[glomerular filtration rate]] falls below 60 ml/min/1.73 m<sup>2</sup>.<ref name="pmid17898101">{{cite journal| author=Meyer TW, Hostetter TH| title=Uremia. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 13 | pages= 1316-25 | pmid=17898101
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17898101 | doi=10.1056/NEJMra071313 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>
 
[[Anemia of chronic disease]] commonly coexists with CKD.
 
==Medical treatment==
The [http://www.nkdep.nih.gov/ National Kidney Disease Education Program] provides guidance on dosing drugs in patients with reduced [[glomerular filtration rate]].<ref>The National Kidney Disease Education Program. (2009) [http://www.nkdep.nih.gov/professionals/ Chronic Kidney Disease and Drug Dosing: Information for Providers] National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),  National Institutes of Health (NIH), U.S. Department of Health & Human Services (DHHS).</ref>
 
===Referral to a nephrologist===
[[Clinical practice guideline]]s by the National Kidney Foundation recommend referral to a nephrologist when there is diagnostic uncertainty or the [[glomerular filtration rate]] is less than 30 30 mL/min/1.73 m<sup>2</sup>.<ref name="pmid12859163">{{cite journal| author=Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al.| title=National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. | journal=Ann Intern Med | year= 2003 | volume= 139 | issue= 2 | pages= 137-47 | pmid=12859163 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12859163 }} (also online at the [http://www.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm National Kidney Foundation]</ref>


==Treatment==
===Medications===
===Medications===
Various drugs have been studied for slowing the progression of chronic kidney disease.<ref name="pmid17943769">{{cite journal |author=Robertson L, Waugh N, Robertson A |title=Protein restriction for diabetic renal disease |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD002181 |year=2007 |pmid=17943769 |doi=10.1002/14651858.CD002181.pub2 |url=http://dx.doi.org/10.1002/14651858.CD002181.pub2 |issn=}}</ref><ref name="pmid16625550">{{cite journal |author=Fouque D, Laville M, Boissel JP |title=Low protein diets for chronic kidney disease in non diabetic adults |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD001892 |year=2006 |pmid=16625550 |doi=10.1002/14651858.CD001892.pub2 |url=http://dx.doi.org/10.1002/14651858.CD001892.pub2 |issn=}}</ref><ref name="pmid17054288">{{cite journal |author=Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC |title=Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD006257 |year=2006 |pmid=17054288 |doi=10.1002/14651858.CD006257 |url=http://dx.doi.org/10.1002/14651858.CD006257 |issn=}}</ref>
{| class="wikitable"
|+ Systematic reviews by the Cochrane Collaboration on treatments for chronic kidney disease
! Treatment !! Setting !!  Results
|-
| Protein restriction<ref name="pmid17943769"/> || Diabetic renal disease || [[relative risk ratio|relative risk]] of end stage renal disease or death:<br/><center>0.23</center>
|-
| Protein restriction<ref name="pmid16625550"/> || Non-diabetic renal disease || [[relative risk ratio|relative risk]] of renal death:<br/><center>0.69</center>
|-
| Angiotensin converting enzyme inhibitors<ref name="pmid17054288"/> || Diabetic renal disease ||&nbsp;
|}
====Aldosterone antagonists====
[[Aldosterone antagonist]]s may reduce [[proteinuria]] according to a [[systematic review]] by the [[Cochrane Collaboration]].<ref name="pmid19588415">{{cite journal| author=Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF| title=Aldosterone antagonists for preventing the progression of chronic kidney disease. | journal=Cochrane Database Syst Rev | year= 2009 | volume=  | issue= 3 | pages= CD007004 | pmid=19588415
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19588415 | doi=10.1002/14651858.CD007004.pub2 }}</ref>
====Angiotensin inhibition====
====Angiotensin inhibition====
Angiotensin can be inhibited with either [[angiotensin converting enzyme inhibitor]]s  or [[angiotensin II receptor antagonist]]s.
[[Angiotensin]] can be inhibited with either [[angiotensin-converting enzyme inhibitor]]s<ref name="pmid12965979">{{cite journal |author=Jafar TH, Stark PC, Schmid CH, ''et al'' |title=Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis |journal=Ann. Intern. Med. |volume=139 |issue=4 |pages=244–52 |year=2003 |pmid=12965979 |doi=}}</ref> or [[angiotensin II receptor antagonist]]s. These medications can help patients with an elevated creatinine,<ref name="pmid11729254">{{cite journal |author=Ruggenenti P, Perna A, Remuzzi G |title=ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy |journal=J. Am. Soc. Nephrol. |volume=12 |issue=12 |pages=2832–7 |year=2001 |pmid=11729254 |doi=}}</ref> including those with a creatinine of 1.5 to 5.0 mg per deciliter.<ref name="pmid16407508">{{cite journal |author=Hou FF, Zhang X, Zhang GH, ''et al'' |title=Efficacy and safety of benazepril for advanced chronic renal insufficiency |journal=N. Engl. J. Med. |volume=354 |issue=2 |pages=131–40 |year=2006 |pmid=16407508 |doi=10.1056/NEJMoa053107}}</ref>
 
Combining [[angiotensin-converting enzyme inhibitor]]s and [[angiotensin II receptor antagonist]]s increases effect, but at uncertain increase in [[drug toxicity]] such as [[hyperkalemia]] according to a [[meta-analysis]].<ref name="pmid17984482">{{cite journal |author=Kunz R, Friedrich C, Wolbers M, Mann JF |title=Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease |journal=Ann. Intern. Med. |volume=148 |issue=1 |pages=30–48 |year=2008 |month=January |pmid=17984482 |doi= |url=http://www.annals.org/cgi/content/full/148/1/30 |issn=}}</ref> Adding an aldosterone receptor antagonist such as [[spironolactone]] may add further benefit, but presumably more [[hyperkalemia]].<ref name="pmid18423812">{{cite journal |author=Tylicki L, Rutkowski P, Renke M, ''et al'' |title=Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial |journal=Am. J. Kidney Dis. |volume=52 |issue=3 |pages=486–93 |year=2008 |month=September |pmid=18423812 |doi=10.1053/j.ajkd.2008.02.297 |url=http://linkinghub.elsevier.com/retrieve/pii/S0272-6386(08)00467-8 |issn=}}</ref>
 
====Erythropoeitin====
{{main|Erythropoeitin}}
 
====Secondary hyperparathyroidism====
[[Clinical practice guideline]]s from the "[http://www.kdigo.org/ Kidney Disease: Improving Global Outcomes (KDIGO)]" address management of [[renal osteodystrophy]].<ref name="pmid16641930">{{cite journal| author=Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K et al.| title=Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). | journal=Kidney Int | year= 2006 | volume= 69 | issue= 11 | pages= 1945-53 | pmid=16641930
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16641930 | doi=10.1038/sj.ki.5000414 }} [http://www.kdigo.org/clinical_practice_guidelines/kdigo_guideline_for_ckd-mbd.php Free full text]</ref><ref name="pmid14520607">{{cite journal| author=National Kidney Foundation| title=K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. | journal=Am J Kidney Dis | year= 2003 | volume= 42 | issue= 4 Suppl 3 | pages= S1-201 | pmid=14520607 | url=http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm }} </ref>
* Phosphate binders (calcium carbonate 650 mg tabs three times - Calcichew<sup>™</sup>, Titrala<sup>™</sup>) or calcium acetate (Phosex<sup>™</sup>, PhosLo<sup>™</sup>) per day by mouth.
* Vitamin D preparations such as [[calcitriol]] (0.25-0.5 µg orally once per day) or intravenous paricalcitol (Zemplar<sup>™</sup>)are given once a patient has Stage 3 disease in order to prevent secondary [[hyperparathyroidism]].
* Calcimimetic such as [[cinacalcet]] (Sensipar<sup>™</sup>) may help.
 
If hypercalcemia develops, guidelines are available for management.<ref name="pmid14520607b">{{cite journal| author=National Kidney Foundation| title=K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. | journal=Am J Kidney Dis | year= 2003 | volume= 42 | issue= 4 Suppl 3 | pages= S1-201 | pmid=14520607 | url=http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm }} (see [http://www.kidney.org/professionals/KDOQI/guidelines_bone/guidestate.htm recommendations])</ref>
 
====Allopurinol====
A single randomized controlled trial found that giving allopurinol to hyperuricemic patients with chronic kidney disease had a [[relative risk ratio]] of 0.35 in the prevention of "significant deterioration in renal function and dialysis dependence."<ref name="pmid16377385">{{cite journal |author=Siu YP, Leung KT, Tong MK, Kwan TH |title=Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level |journal=Am. J. Kidney Dis. |volume=47 |issue=1 |pages=51–9 |year=2006 |month=January |pmid=16377385 |doi=10.1053/j.ajkd.2005.10.006 |url=http://linkinghub.elsevier.com/retrieve/pii/S0272-6386(05)01518-0 |issn=}}</ref>
 
===Treatment of associated diseases===
====Anemia====
[[Clinical practice guideline]]s guide management for both adults<ref name="pmid16678661">{{cite journal| author=KDOQI. National Kidney Foudnation| title=II. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. | journal=Am J Kidney Dis | year= 2006 | volume= 47 | issue= 5 Suppl 3 | pages= S16-85 | pmid=16678661 | doi=10.1053/j.ajkd.2006.03.012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16678661  }} [http://www.kidney.org/professionals/kdoqi/guidelines_anemia/ Full text]</ref> and children<ref name="pmid16678669">{{cite journal| author=KDOQI. National Kidney Foundation| title=III. Clinical practice recommendations for anemia in chronic kidney disease in children. | journal=Am J Kidney Dis | year= 2006 | volume= 47 | issue= 5 Suppl 3 | pages= S86-108 | pmid=16678669 | doi=10.1053/j.ajkd.2006.03.020 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16678669  }} [http://www.kidney.org/professionals/kdoqi/guidelines_anemia/ Full text]</ref>.
 
[[Anemia of chronic disease]] is associated with CKD, and may be directly regulated by [[hepcidin]] in [[human iron metabolism]].
In patients with chronic kidney disease, the goal [[hemoglobin]] should be 11.3 g per deciliter according to a [[randomized controlled trial]] of [[erythropoetin]] that found targeting a hemoglobin level of 13.5 g per deciliter increased adverse events.<ref name="pmid17108343">{{cite journal |author=Singh AK, Szczech L, Tang KL, ''et al'' |title=Correction of anemia with epoetin alfa in chronic kidney disease |journal=N. Engl. J. Med. |volume=355 |issue=20 |pages=2085–98 |year=2006 |pmid=17108343 |doi=10.1056/NEJMoa065485}}</ref> However, the setting or target hemoglobin levels may increase adverse effects.<ref name="pmid20843249">{{cite journal| author=Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA et al.| title=Erythropoietic response and outcomes in kidney disease and type 2 diabetes. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 12 | pages= 1146-55 | pmid=20843249 | doi=10.1056/NEJMoa1005109 }} </ref>
 
Erythropoietin may increase hypertension patients with chronic kidney disease.<ref name="pmid2747747">{{cite journal |author=Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW |title=Treatment of the anemia of progressive renal failure with recombinant human erythropoietin |journal=N. Engl. J. Med. |volume=321 |issue=3 |pages=158–63 |year=1989 |pmid=2747747 |doi=}}</ref>  The use of when the hemoglobin is less than 9 g per deciliter may increase the risk of [[stroke]] according to a [[randomized controlled trial]].<ref name="pmid19880844">{{cite journal| author=Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU et al.| title=A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 21 | pages= 2019-32 | pmid=19880844 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19880844 | doi=10.1056/NEJMoa0907845 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20231563 Review in: Ann Intern Med. 2010 Mar 16;152(6):JC3-9] </ref>
 
In patients who require [[renal dialysis]], iron should be given with erythropoietin.<ref name="pmid8914038">{{cite journal |author=Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE |title=A randomized controlled study of iron supplementation in patients treated with erythropoietin |journal=Kidney Int. |volume=50 |issue=5 |pages=1694-9 |year=1996 |pmid=8914038 |doi=}}</ref>
 
====Coronary heart disease====
[[Coronary heart disease]] is common among patients with chronic kidney disease.
 
====Hypertension====
{| class="wikitable" align="right"
|+ AASK  trial<ref  name="pmid20818902">{{cite journal| author=Appel LJ,  Wright JT,  Greene T, Agodoa LY, Astor BC, Bakris GL et al.|  title=Intensive  blood-pressure control in hypertensive chronic kidney  disease. |  journal=N Engl J Med | year= 2010 | volume= 363 | issue= 10 |  pages=  918-29 | pmid=20818902 | doi=10.1056/NEJMoa0910975 }}  </ref>
! rowspan="2"| Patients!!colspan="3"|Results at 3-6.4 yr
|-
! Intervention!!Control!!Hazard ratio
|-
| All patients||align="center"|44%||align="center"|46%|| 0.9 (0.8 - 1.1)
|-
|  protein-to-creatinine ratio <  0.22||align="center"|41%||align="center"| 36%|| 1.2 (0.9 - 1.5)
|-
|  protein-to-creatinine ratio > 0.22||align="center"| 75%||align="center"| 85%|| 0.7 (0.6 - 0.9)
|}
 
* Intensive blood-pressure control had no effect on progression of kidney disease according to the AASK [[randomized controlled trial]].<ref name="pmid12435255">{{cite journal| author=Wright JT, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J et al.| title=Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. | journal=JAMA | year= 2002 | volume= 288 | issue= 19 | pages= 2421-31 | pmid=12435255 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12435255  }} </ref><ref  name="pmid20818902"/>
* [[Angiotensin-converting enzyme inhibitor]]s may help according to the REIN trial.<ref name="pmid9217756">{{cite journal| author=| title=Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) | journal=Lancet | year= 1997 | volume= 349 | issue= 9069 | pages= 1857-63 | pmid=9217756 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9217756  }} </ref>
* Thiazide may be as beneficial as [[angiotensin-converting enzyme inhibitor]]s  according to the ALLHAT trial.<ref name="pmid15851647">{{cite  journal| author=Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT,  Whelton PK et al.| title=Renal outcomes in high-risk hypertensive  patients treated with an angiotensin-converting enzyme inhibitor or a  calcium channel blocker vs a diuretic: a report from the  Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack  Trial (ALLHAT). | journal=Arch Intern Med | year= 2005 | volume= 165 |  issue= 8 | pages= 936-46 | pmid=15851647 |  doi=10.1001/archinte.165.8.936 | pmc= |  url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15851647  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16134919  Review in: ACP J Club. 2005 Sep-Oct;143(2):45] </ref> This trial excluded patients with a serum creatinine over 2.
 
Regarding which medication to add to add is [[angiotensin-converting enzyme inhibitor]]s are not adequate:
* Aliskiren is an oral direct renin inhibitor that, according to a [[randomized controlled trial]] which added aliskiren  to losartain, may have "renoprotective effects that are independent of its blood-pressure-lowering effect in patients with [[hypertension]], [[diabetes mellitus type 2|type 2 diabetes]], and nephropathy."<ref name="pmid18525041">{{cite journal |author=Parving  HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK |title=Aliskiren  combined with losartan in type 2 diabetes and nephropathy |journal=N.  Engl. J. Med. |volume=358 |issue=23 |pages=2433–46 |year=2008  |month=June |pmid=18525041 |doi=10.1056/NEJMoa0708379 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18525041&promo=ONFLNS19 |issn=}}</ref>
* Among patients already taking benazepril, amlodipine may be more effective than hydrochlorothiazide at preventing progression of renal disease.<ref name="pmid20170948">{{cite journal| author=Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K et al.| title=Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. | journal=Lancet | year= 2010 | volume= 375 | issue= 9721 | pages= 1173-81 | pmid=20170948 | doi=10.1016/S0140-6736(09)62100-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20170948  }} </ref>
* [[Angiotensin II receptor antagonist]]s can be added to [[angiotensin-converting enzyme inhibitor]]s to increase effect, but at uncertain increase in [[drug toxicity]] such as [[hyperkalemia]], according to a [[meta-analysis]].<ref name="pmid17984482"/>
* [[Aldosterone]] blocking agents may help as a second<ref name="pmid18215698">{{cite journal| author=Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ| title=Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. | journal=Am J Kidney Dis | year= 2008 | volume= 51 | issue= 2 | pages= 199-211 | pmid=18215698 | doi=10.1053/j.ajkd.2007.10.040 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18215698  }} </ref> or even third<ref name="pmid19588415"/> medication.
 
===Renal replacement therapy===
{{main|Renal replacement therapy}}
==Veterinary treatment==
One of the cornerstones of veterinary management of CKD is daily, or more frequent, administration of subcutaneous fluids. With proper technique, the  loose skin of dogs and cats makes such administration quite comfortable; many owners combine it with grooming or stroking. Supplementary medications are less commonly used, possibly due to the difficulty of administration, but there is increasing use of bolus administration through the subcutaneous line, not even noticed by the patient.
 
Prepared low-protein foods are available by veterinary prescription, but protein restriction is more difficult in carnivores, especially obligate carnivores such as cats.
 
==Prognosis==
The estimated [[glomerular filtration rate]] and the urinary albumin/creatinine ratio can help predict who will progress to CKD5.<ref name="pmid19357254">{{cite journal |author=Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR |title=Combining GFR and Albuminuria to Classify CKD Improves Prediction of ESRD |journal=J. Am. Soc. Nephrol. |volume= |issue= |pages= |year=2009 |month=April |pmid=19357254 |doi=10.1681/ASN.2008070730 |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=19357254 |issn=}}</ref>


==References==
==References==
<references/>
<small>
<references>
 
</references>
</small>


==External links==
==External links==
* [[http://www.nkdep.nih.gov/professionals/gfr_calculators/ National Kidney Disease Education Program - GFR Calculators]]
* [http://www.nkdep.nih.gov/professionals/gfr_calculators/ National Kidney Disease Education Program - GFR Calculators][[Category:Suggestion Bot Tag]]

Latest revision as of 09:31, 18 September 2024

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In medicine, chronic kidney disease (CKD) is defined as "kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for 3 months or more, irrespective of cause. Kidney damage in many kidney diseases can be ascertained by the presence of albuminuria, defined as albumin-to-creatinine ratio >30 mg/g in two of three spot urine specimens."[1]

These definitions are generally applicable in veterinary medicine. CKR is common among geriatric cats and dogs.

Classification

There are five stages:[1]

Classification may be improved by considering proteinuria.[2]

Etiology/cause

Bilateral renal artery stenosis (RAS) may cause 5% to 15% of cases of chronic kidney disease.[3]

Prevalence

Thirteen percent of adults in the United States of America have chronic kidney disease as defined by the Kidney Disease Outcomes Quality Initiative (KDOQI).[4] The prevalence is reduced to 11% if isolated microalbuminuria (CKD-1) is not included.[4] However, using otehr criteria, the prevalence is 2.9%.[5]

Routine reporting of the estimated glomerular filtration rate has increased the number of referrals to nephrologists[6]; however, the benefit is uncertain[7].

Signs and symptoms

Uremia, "the illness accompanying kidney failure", may have subtle manifestations when the glomerular filtration rate falls below 60 ml/min/1.73 m2.[8]

Anemia of chronic disease commonly coexists with CKD.

Medical treatment

The National Kidney Disease Education Program provides guidance on dosing drugs in patients with reduced glomerular filtration rate.[9]

Referral to a nephrologist

Clinical practice guidelines by the National Kidney Foundation recommend referral to a nephrologist when there is diagnostic uncertainty or the glomerular filtration rate is less than 30 30 mL/min/1.73 m2.[10]

Medications

Various drugs have been studied for slowing the progression of chronic kidney disease.[11][12][13]

Systematic reviews by the Cochrane Collaboration on treatments for chronic kidney disease
Treatment Setting Results
Protein restriction[11] Diabetic renal disease relative risk of end stage renal disease or death:
0.23
Protein restriction[12] Non-diabetic renal disease relative risk of renal death:
0.69
Angiotensin converting enzyme inhibitors[13] Diabetic renal disease  

Aldosterone antagonists

Aldosterone antagonists may reduce proteinuria according to a systematic review by the Cochrane Collaboration.[14]

Angiotensin inhibition

Angiotensin can be inhibited with either angiotensin-converting enzyme inhibitors[15] or angiotensin II receptor antagonists. These medications can help patients with an elevated creatinine,[16] including those with a creatinine of 1.5 to 5.0 mg per deciliter.[17]

Combining angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists increases effect, but at uncertain increase in drug toxicity such as hyperkalemia according to a meta-analysis.[18] Adding an aldosterone receptor antagonist such as spironolactone may add further benefit, but presumably more hyperkalemia.[19]

Erythropoeitin

For more information, see: Erythropoeitin.


Secondary hyperparathyroidism

Clinical practice guidelines from the "Kidney Disease: Improving Global Outcomes (KDIGO)" address management of renal osteodystrophy.[20][21]

  • Phosphate binders (calcium carbonate 650 mg tabs three times - Calcichew™, Titrala™) or calcium acetate (Phosex™, PhosLo™) per day by mouth.
  • Vitamin D preparations such as calcitriol (0.25-0.5 µg orally once per day) or intravenous paricalcitol (Zemplar™)are given once a patient has Stage 3 disease in order to prevent secondary hyperparathyroidism.
  • Calcimimetic such as cinacalcet (Sensipar™) may help.

If hypercalcemia develops, guidelines are available for management.[22]

Allopurinol

A single randomized controlled trial found that giving allopurinol to hyperuricemic patients with chronic kidney disease had a relative risk ratio of 0.35 in the prevention of "significant deterioration in renal function and dialysis dependence."[23]

Treatment of associated diseases

Anemia

Clinical practice guidelines guide management for both adults[24] and children[25].

Anemia of chronic disease is associated with CKD, and may be directly regulated by hepcidin in human iron metabolism. In patients with chronic kidney disease, the goal hemoglobin should be 11.3 g per deciliter according to a randomized controlled trial of erythropoetin that found targeting a hemoglobin level of 13.5 g per deciliter increased adverse events.[26] However, the setting or target hemoglobin levels may increase adverse effects.[27]

Erythropoietin may increase hypertension patients with chronic kidney disease.[28] The use of when the hemoglobin is less than 9 g per deciliter may increase the risk of stroke according to a randomized controlled trial.[29]

In patients who require renal dialysis, iron should be given with erythropoietin.[30]

Coronary heart disease

Coronary heart disease is common among patients with chronic kidney disease.

Hypertension

AASK trial[31]
Patients Results at 3-6.4 yr
Intervention Control Hazard ratio
All patients 44% 46% 0.9 (0.8 - 1.1)
protein-to-creatinine ratio < 0.22 41% 36% 1.2 (0.9 - 1.5)
protein-to-creatinine ratio > 0.22 75% 85% 0.7 (0.6 - 0.9)

Regarding which medication to add to add is angiotensin-converting enzyme inhibitors are not adequate:

Renal replacement therapy

For more information, see: Renal replacement therapy.

Veterinary treatment

One of the cornerstones of veterinary management of CKD is daily, or more frequent, administration of subcutaneous fluids. With proper technique, the loose skin of dogs and cats makes such administration quite comfortable; many owners combine it with grooming or stroking. Supplementary medications are less commonly used, possibly due to the difficulty of administration, but there is increasing use of bolus administration through the subcutaneous line, not even noticed by the patient.

Prepared low-protein foods are available by veterinary prescription, but protein restriction is more difficult in carnivores, especially obligate carnivores such as cats.

Prognosis

The estimated glomerular filtration rate and the urinary albumin/creatinine ratio can help predict who will progress to CKD5.[38]

References

  1. ↑ 1.0 1.1 Levey AS, Eckardt KU, Tsukamoto Y, et al (2005). "Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney Int. 67 (6): 2089–100. DOI:10.1111/j.1523-1755.2005.00365.x. PMID 15882252. Research Blogging.
  2. ↑ Tonelli, Marcello; Paul Muntner, Anita Lloyd, Braden J. Manns, Matthew T. James, Scott Klarenbach, Robert R. Quinn, Natasha Wiebe, Brenda R. Hemmelgarn (2011-01-04). "Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease". Annals of Internal Medicine 154 (1): 12 -21. DOI:10.1059/0003-4819-154-1-201101040-00003. PMID 21200034. Retrieved on 2011-01-04. Research Blogging.
  3. ↑ Rimmer JM, Gennari FJ (May 1993). "Atherosclerotic renovascular disease and progressive renal failure". Ann. Intern. Med. 118 (9): 712–9. PMID 8460859. [e]
  4. ↑ 4.0 4.1 Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P et al. (2007). "Prevalence of chronic kidney disease in the United States.". JAMA 298 (17): 2038-47. DOI:10.1001/jama.298.17.2038. PMID 17986697. Research Blogging.
  5. ↑ Rutkowski M, Mann W, Derose S, Selevan D, Pascual N, Diesto J et al. (2009). "Implementing KDOQI CKD definition and staging guidelines in Southern California Kaiser Permanente.". Am J Kidney Dis 53 (3 Suppl 3): S86-99. DOI:10.1053/j.ajkd.2008.07.052. PMID 19231766. Research Blogging.
  6. ↑ Hemmelgarn BR, Zhang J, Manns BJ, James MT, Quinn RR, Ravani P et al. (2010). "Nephrology visits and health care resource use before and after reporting estimated glomerular filtration rate.". JAMA 303 (12): 1151-8. DOI:10.1001/jama.2010.303. PMID 20332400. Research Blogging.
  7. ↑ den Hartog JR, Reese PP, Cizman B, Feldman HI (2009). "The costs and benefits of automatic estimated glomerular filtration rate reporting.". Clin J Am Soc Nephrol 4 (2): 419-27. DOI:10.2215/CJN.04080808. PMID 19176794. PMC PMC2637597. Research Blogging.
  8. ↑ Meyer TW, Hostetter TH (2007). "Uremia.". N Engl J Med 357 (13): 1316-25. DOI:10.1056/NEJMra071313. PMID 17898101. Research Blogging.
  9. ↑ The National Kidney Disease Education Program. (2009) Chronic Kidney Disease and Drug Dosing: Information for Providers National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), U.S. Department of Health & Human Services (DHHS).
  10. ↑ Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al. (2003). "National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.". Ann Intern Med 139 (2): 137-47. PMID 12859163. (also online at the National Kidney Foundation
  11. ↑ 11.0 11.1 Robertson L, Waugh N, Robertson A (2007). "Protein restriction for diabetic renal disease". Cochrane Database Syst Rev (4): CD002181. DOI:10.1002/14651858.CD002181.pub2. PMID 17943769. Research Blogging.
  12. ↑ 12.0 12.1 Fouque D, Laville M, Boissel JP (2006). "Low protein diets for chronic kidney disease in non diabetic adults". Cochrane Database Syst Rev (2): CD001892. DOI:10.1002/14651858.CD001892.pub2. PMID 16625550. Research Blogging.
  13. ↑ 13.0 13.1 Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC (2006). "Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease". Cochrane Database Syst Rev (4): CD006257. DOI:10.1002/14651858.CD006257. PMID 17054288. Research Blogging.
  14. ↑ 14.0 14.1 Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF (2009). "Aldosterone antagonists for preventing the progression of chronic kidney disease.". Cochrane Database Syst Rev (3): CD007004. DOI:10.1002/14651858.CD007004.pub2. PMID 19588415. Research Blogging.
  15. ↑ Jafar TH, Stark PC, Schmid CH, et al (2003). "Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis". Ann. Intern. Med. 139 (4): 244–52. PMID 12965979. [e]
  16. ↑ Ruggenenti P, Perna A, Remuzzi G (2001). "ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy". J. Am. Soc. Nephrol. 12 (12): 2832–7. PMID 11729254. [e]
  17. ↑ Hou FF, Zhang X, Zhang GH, et al (2006). "Efficacy and safety of benazepril for advanced chronic renal insufficiency". N. Engl. J. Med. 354 (2): 131–40. DOI:10.1056/NEJMoa053107. PMID 16407508. Research Blogging.
  18. ↑ 18.0 18.1 Kunz R, Friedrich C, Wolbers M, Mann JF (January 2008). "Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease". Ann. Intern. Med. 148 (1): 30–48. PMID 17984482. [e]
  19. ↑ Tylicki L, Rutkowski P, Renke M, et al (September 2008). "Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial". Am. J. Kidney Dis. 52 (3): 486–93. DOI:10.1053/j.ajkd.2008.02.297. PMID 18423812. Research Blogging.
  20. ↑ Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K et al. (2006). "Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).". Kidney Int 69 (11): 1945-53. DOI:10.1038/sj.ki.5000414. PMID 16641930. Research Blogging. Free full text
  21. ↑ National Kidney Foundation (2003). "K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.". Am J Kidney Dis 42 (4 Suppl 3): S1-201. PMID 14520607.
  22. ↑ National Kidney Foundation (2003). "K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.". Am J Kidney Dis 42 (4 Suppl 3): S1-201. PMID 14520607. (see recommendations)
  23. ↑ Siu YP, Leung KT, Tong MK, Kwan TH (January 2006). "Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level". Am. J. Kidney Dis. 47 (1): 51–9. DOI:10.1053/j.ajkd.2005.10.006. PMID 16377385. Research Blogging.
  24. ↑ KDOQI. National Kidney Foudnation (2006). "II. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults.". Am J Kidney Dis 47 (5 Suppl 3): S16-85. DOI:10.1053/j.ajkd.2006.03.012. PMID 16678661. Research Blogging. Full text
  25. ↑ KDOQI. National Kidney Foundation (2006). "III. Clinical practice recommendations for anemia in chronic kidney disease in children.". Am J Kidney Dis 47 (5 Suppl 3): S86-108. DOI:10.1053/j.ajkd.2006.03.020. PMID 16678669. Research Blogging. Full text
  26. ↑ Singh AK, Szczech L, Tang KL, et al (2006). "Correction of anemia with epoetin alfa in chronic kidney disease". N. Engl. J. Med. 355 (20): 2085–98. DOI:10.1056/NEJMoa065485. PMID 17108343. Research Blogging.
  27. ↑ Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA et al. (2010). "Erythropoietic response and outcomes in kidney disease and type 2 diabetes.". N Engl J Med 363 (12): 1146-55. DOI:10.1056/NEJMoa1005109. PMID 20843249. Research Blogging.
  28. ↑ Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW (1989). "Treatment of the anemia of progressive renal failure with recombinant human erythropoietin". N. Engl. J. Med. 321 (3): 158–63. PMID 2747747. [e]
  29. ↑ Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU et al. (2009). "A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.". N Engl J Med 361 (21): 2019-32. DOI:10.1056/NEJMoa0907845. PMID 19880844. Research Blogging. Review in: Ann Intern Med. 2010 Mar 16;152(6):JC3-9
  30. ↑ Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (1996). "A randomized controlled study of iron supplementation in patients treated with erythropoietin". Kidney Int. 50 (5): 1694-9. PMID 8914038. [e]
  31. ↑ 31.0 31.1 Appel LJ, Wright JT, Greene T, Agodoa LY, Astor BC, Bakris GL et al. (2010). "Intensive blood-pressure control in hypertensive chronic kidney disease.". N Engl J Med 363 (10): 918-29. DOI:10.1056/NEJMoa0910975. PMID 20818902. Research Blogging.
  32. ↑ Wright JT, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J et al. (2002). "Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.". JAMA 288 (19): 2421-31. PMID 12435255. [e]
  33. ↑ (1997) "Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)". Lancet 349 (9069): 1857-63. PMID 9217756. [e]
  34. ↑ Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Whelton PK et al. (2005). "Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).". Arch Intern Med 165 (8): 936-46. DOI:10.1001/archinte.165.8.936. PMID 15851647. Research Blogging. Review in: ACP J Club. 2005 Sep-Oct;143(2):45
  35. ↑ Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK (June 2008). "Aliskiren combined with losartan in type 2 diabetes and nephropathy". N. Engl. J. Med. 358 (23): 2433–46. DOI:10.1056/NEJMoa0708379. PMID 18525041. Research Blogging.
  36. ↑ Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K et al. (2010). "Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.". Lancet 375 (9721): 1173-81. DOI:10.1016/S0140-6736(09)62100-0. PMID 20170948. Research Blogging.
  37. ↑ Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ (2008). "Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review.". Am J Kidney Dis 51 (2): 199-211. DOI:10.1053/j.ajkd.2007.10.040. PMID 18215698. Research Blogging.
  38. ↑ Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR (April 2009). "Combining GFR and Albuminuria to Classify CKD Improves Prediction of ESRD". J. Am. Soc. Nephrol.. DOI:10.1681/ASN.2008070730. PMID 19357254. Research Blogging.

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