Renal Function: MRI's, eGFR, and other 'New' News

Renal Function: MRI's, eGFR, and other 'New' News

Keelyn Ericson, MDApril 24th, 2008

OverviewMRI Contrast Agents : Nephrogenic Systemic Fibrosis.

Hypertension : New treatment options.

Sodium Bicarbonate : Radiocontrast nephropathy made worse?

eGFR : When and how to use it.

Warning

MRI Contrast Agents:Nephrogenic Systemic Fibrosis.

Nephrogenic fibrosing dermopathy Probably more properly referred to as Nephrogenic Systemic Fibrosis:

From Galan, Cowper, et.al.Nephrogenic systemic fibrosis (NSF) is a recently identified fibrosing disorder seen only in patients with kidney failure. It is characterized by two primary features:

Thickening and hardening of the skin overlying the extremities and trunkMarked expansion and fibrosis of the dermis in association with CD34-positive fibrocytes.

Nephrogenic fibrosing dermopathy What the heck is this?Who is at risk?Who needs to know about it?How does it occur?What are the options?Is there a treatment for it?Is it serious?ReviewHuh?

Nephrogenic fibrosing dermopathyHuh?Nephro- : Greek (nephros) - kidney-genic : Greek (gens) bornFibrosing : Latin fibrae (fiber) fiber[forming]Dermo- : Greek (derma) skin, hide-pathy : Greek (pathos) passion, suffering, or (more commonly) disease

Nephrogenic fibrosing dermopathyHuh?Nephro- : Greek (nephros) - kidney-genic : Greek (gens) bornFibrosing : Latin fibrae (fiber) fiber[forming]Dermo- : Greek (derma) - "skin, hide-pathy : Greek (pathos) passion, suffering, or (more commonly) disease

[Kidney-born Fiber-forming Skin-disease]

AKA : Nephrogenic Systemic Fibrosis [Kidney-born Systemic Fiber-forming-state]

What the heck is this?It can make you look like this!

What the heck is this?SeriouslyThe typical course begins with subacute swelling of distal parts of the extremities and is followed in subsequent weeks by severe skin induration and sometimes anatomic extension to involve thighs, antebrachium, and lower abdomen. The skin induration may be aggressive and associated with constant pain, muscle restlessness,and loss of skin flexibility. 6

(All photos: 10)

What the heck is this?In some cases, NSF leads to serious physical disability, including wheelchair requirement. NSF initially was observed in and thought to affect solely the skin (thus the initial term nephrogenic fibrosing dermopathy), but morerecent patient reports have demonstrated that several organsmay be involved. 6

What the heck is this?Yellow asymptomatic scleral plaques are common. (They dont affect vision.)

What the heck is this?Fibrotic forearm skin.

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997How do we know?

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997How do we know?Prior tissue samples (skin biopsies) have been reviewed; no cases were found similar to samples identified for NSF since 1997.

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997The disease has only been found in patients with renal diseaseHow do we know?

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997The disease has only been found in patients with renal diseaseHow do we know?Of approximately 300+ cases identified through 2008, none have come from patients with normal renal function

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997The disease has only been found in patients with renal diseaseMultiple associations have been identified; the most common, by far, has been with the administration of Gadolinium contrast agentsBut does that mean anything?

How does it occur?Etiology and PathogenesisThe disease did not exist prior to 1997The disease has only been found in patients with renal diseaseMultiple associations have been identified; the most common, by far, has been with the administration of Gadolinium contrast agentsBut does that mean anything?We think so

How does it occur?Gd deposited in vessel walls of the skin

How does it occur?Sodium, Phosphate, and Calcium are found in vessel walls along with Gd many ESRD (dialysis) patients and Chronic Kidney Disease patients already have Ca/Phos metabolism disease (known commonly as secondary hyperparathyroid disease).

How does it occur?This is thought to lead to activation of some kind of fibrotic or scarring factor.Abnormal activation of fibrocytes is consistent with one theory of the pathogenesis of NSF.

How does it occur?I thought Gadolinium was fairly safe.

How does it occur?I thought Gadolinium was fairly safe.Gd-DTPA (Gd-Diethylene triamine pentaacetic acid or gadodiamide) was introduced in 1988 as a paramagnetic contrast agent for use in MRI scans and was believed to be safe for patients with impaired renal function. Free Gd ions can form precipitates with anions, such as phosphate, because of its poor solubility, and it is considered highly toxic in its ionic form. Marckmann et al have posited that NFD may result from liberated Gd ions deposited in the tissues. These molecules are known to be extremely toxic and to produce deposits of Gd with calcium phosphates in the tissues of rodents.

How does it occur?English please

How does it occur?English please

Renal failure + Gadolinium += NSF(High risk)

Renal failure + + Other stuff = NSF(Perhaps)

+ Gadolinium + Other stuff = NSF(Never)

Renal failure + Gadolinium + Other stuff = NSF(High risk)

(Other Stuff)

Vascular manipulation

High dose Epo/Aranesp

Clotting events

Underlying clotting abnormalities (hypercoagulable states)

Who is at risk?Renal Failure patients

All cases so far are associated with subjects who have renal failure.

Not all subjects with Chronic Kidney Disease (CKD) are at risk. Those with lower kidney function (esp. those on dialysis) are at higher risk, it seems.

A cutoff of GFR 1.5)

ANY case of acute renal failure is a contraindication for use of Gd contrast agents (a transiently low or quickly worsening renal function, that is).

Who is at risk?Additional Factors

Renal patients [read CKD] who have recently had a vascular manipulation (fistula placement for example)

Renal patients who have recently had a DVT, PE, thrombosis, or who are hypercoagulable (Factor V Leiden deficiency, etc.)

Renal patients who are on very high doses of Aranesp/Epo

Is it serious?In some cases, NSF leads to serious physical disability including wheelchair requirement.

it is now known that several organs suchas liver, lungs, muscles and heart may be involved. Organ involvement may explain the suspected increased mortality of patients with NSF.

There is no established treatment for NSF,

Severely affected patients may be unable to walk, or fully extend the joints of their arms, hands, legs, and feet. Complaints of muscle weakness are common. Approximately 5% of patients have a rapidly progressive (fulminant) course.

Who needs to know about it?Radiologists *

Nephrologists *

Who needs to know about it?Radiologists *

Nephrologists *Nephrology staff members **

Primary Care providers **Primary Care staff members **

Who needs to know about it?Radiologists *Radiology Technicians and staff

Nephrologists *Nephrology staff members **Dialysis nursing staff

Primary Care providers **Primary Care staff members **

Is there a treatment for it?

Is there a treatment for it?Immune globulin (IgG)

Is there a treatment for it?Immune globulin (IgG)Unproven case series small

Is there a treatment for it?Immune globulin (IgG)Plasmapheresis

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisUnproven likely no help

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)Failure

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)Ultraviolet (UVA) therapy

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)Ultraviolet (UVA) therapyUnproven no profound benefit so far

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)Ultraviolet (UVA) therapyExtracorporeal Photopheresis (huh?)

Is there a treatment for it?Immune globulin (IgG)PlasmapheresisSteroids with chemo (cytoxan, et al)Ultraviolet (UVA) therapyExtracorporeal Photopheresis (huh?)Removal of blood and exposing it to photoactivated chemotherapy then reinfusing the bloodUnproven - possible benefit


Renal Transplantation


Renal TransplantationUnproven probable benefit


Renal TransplantationResumption of normal renal functionSuccessful obviously rare in all but acute failure cases


Renal TransplantationResumption of normal renal function

In summary no proven treatment exists except for the resumption of normal renal function which in chronic renal failure patients is only available by way of transplantation.

What are the options?Acute Renal Failure

GFR >60mL/min CKD Stage 2 or 1

GFR >30mL/min 15mL/min

Review

Nephrogenic Systemic FibrosisISonly found in patients with moderate to severe renal impairment

IS NOTFound in patients without renal failureThere are no reports of NSF in patients with normal kidneyfunction. Around 200 million patients have had injections of agadolinium-based contrast agent since the early 1980s. A population of more than 30 million patients has received gadodiamide. So, in patients without ESRD, all gadolinium-based contrast agents seem to be safe. 5

Most cases reported involve patients with a GFR of

Nephrogenic Systemic FibrosisISFound in patients who have NOT received Gd contrast agentsIS NOTUsually seen outside of cases related to Gadolinium (Gd) contrast agentsSeveral NSF cases reported by Marckmann were exposed to gadodiamide earlier without developing signs of NSF. This observation suggests that gadodiamide was a necessary, but not a sufficient cause of NSF. Certain other factors must have played a role, but they were not able to identify any such cofactor. Also, the fact that NSF can develop in patients in whom it cannot be documented that they have had a gadolinium-based agent speaks in [favor] of a cofactor. 5

Nephrogenic Systemic FibrosisISProven to affect the skin, vasculature, and internal organs

Found to occur between 2 days and 18 months after Gd exposureIS NOTLimited to skin involvement

Only acute in nature though most cases occur within one month of contrast load

Nephrogenic Systemic FibrosisISSeen in patients already on dialysis

Almost exclusively seen in patients exposed to Gadodiamide (Omniscan)

IS NOTDirectly caused by dialysisOnly found in patients on dialysis- Thought to be seen in patients receiving other types of Gd contrast, but the FDA has ruled other agents as high risk as well

Nephrogenic Systemic FibrosisISA new disease

Debilitating and deadly

Avoidable

IS NOTCurable

Curable

Curable

HypertensionNew Treatment Options.

Hypertension : New treatment options 18Defining hypertension

Hypertension : New treatment optionsDefining hypertensionPressures >140/90? (Screening)

Hypertension : New treatment optionsDefining hypertensionPressures >140/90?Pressures >130/80? (Diabetics, CKD)

Hypertension : New treatment optionsDefining hypertensionPressures >140/90?Pressures >130/80? (Diabetics, CKD)Pressures >120/80? (Optimal/Normal)

Hypertension : New treatment optionsDefining hypertensionPressures >140/90?Pressures >130/80? (Diabetics, CKD)Pressures >120/80? (Optimal/Normal)Pressures >115 systolic? (statistical increase in cardiac risk)

Hypertension : New treatment optionsDefining hypertensionPressures >140/90?Pressures >130/80? (Diabetics, CKD, and CAD)Pressures >120/80? (Optimal)Pressures >115 systolic? (statistical increase in cardiac risk)

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertension

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionOffice measurements vs.. home measurements 19

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionOffice measurements vs. home measurements 19Ambulatory measurements when? 20

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionOffice measurements vs. home measurements 19Ambulatory measurements when? 20Pulse wave velocity measurement 21

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionHypertension and the Kidney

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionHypertension and the KidneyAldosteroneReninUric AcidVitamin DRenal Artery Stenosis (Renovascular hypertension)

Hypertension : New treatment optionsDefining hypertensionMeasuring hypertensionHypertension and the Kidney

Treatment of hypertension

Hypertension : New treatment optionsSomething old

Something new

Something used

Something blue

Hypertension : New treatment optionsSomething oldB-blockersChlorthalidone

Something newAliskiren (Tekturna)

Something borrowedACEIs and ARBs

Something blueNebivolol (Bystolic)

B-BlockersASCOT (Anglo-Scandinavian Cardiac Outcome Trial)LIFE (Losartan Intervention for Endpoints)

These trials show poorer outcomes in endpoints for B-blockers versus all other agents when used as first line agents for blood pressure control (CV mortality, all-cause mortality, Stroke, new dx of diabetes) cardioprotective effects are still significant, though.

B-BlockersASCOT (Anglo-Scandinavian Cardiac Outcome Trial)LIFE (Losartan Intervention for Endpoints)

the British Hypertension Society has removed B-blockers from its treatment algorithm for primary uncomplicated hypertension. 18

ChlorthalidoneHygroton (Chlorthalidone) is a thiazide diuretic similar to HCTZ recently used in the Systolic Hypertension in the Elderly Program (SHEP) as well as other trials.

ChlorthalidoneHygroton (Chlorthalidone) is a thiazide diuretic similar to HCTZ recently used in the Systolic Hypertension in the Elderly Program (SHEP) as well as other trials.Compared to HCTZ its BP lowering effect is similarly efficacious

ChlorthalidoneHygroton (Chlorthalidone) is a thiazide diuretic similar to HCTZ recently used in the Systolic Hypertension in the Elderly Program (SHEP) as well as other trials.Compared to HCTZ its BP lowering effect is similarly efficaciousNocturnal BP control was significantly improved from HCTZ (n=30). 26

AliskirenTekturna from Novartis

AliskirenTekturna from NovartisWhy not sooner?

AliskirenTekturna from NovartisWhy not sooner? Bioavailability (2.5%)

AliskirenTekturna from NovartisWhy not sooner?What is it?

Aliskirenis an orally active, nonpeptide, potent renin inhibitor. per the FDA prescribing information insert

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?

Aliskiren 20

Aliskiren 14

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?How WELL does it work? 21,22Systolic BP drops 10-20 mmHg Diastolic BP drops 5-20 mmHg

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?How WELL does it work?Systolic BP drops 15-20 mmHgDiastolic BP drops 5-20 mmHgIn combination with other antihypertensives, an additional 5-10 mmHg drop can be expected in many cases

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?How WELL does it work?Side effects?

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?How WELL does it work?Side effects?Similar to other RAAS blockade agents

Hyperkalemia, Hypotension, Angioedema, Cough (50% of the incidence of ACE-inhibitors), Hyperuricemia, Teratogenic effects

AliskirenTekturna from NovartisWhy not sooner?What is it?How does it work?How WELL does it work?Side effects?

So is it worth using?

ACEi and ARBDistinctions between ACEi and ARB therapy are becoming smaller and smaller

ACEi and ARBDistinctions between ACEi and ARB therapy are becoming smaller and smallerACEi and ARB therapy were not significantly different in their effect on death, cardiovascular events, lipid levels, progression to diabetes (i.e. metabolic effect), LV mass, or renal disease. 27

ACEi and ARBDistinctions between ACEi and ARB therapy are becoming smaller and smallerACEi and ARB therapy were not significantly different in their effect on death, cardiovascular events, lipid levels, progression to diabetes (i.e. metabolic effect), LV mass, or renal disease. 27ACEi and ARB therapy is equal when compared for proteinuria control; together they are even betterOf note here no trials for adverse effect increases have been made to date; all trials have been fairly short 28

NebivololBystolic from Mylan Laboratories and Forest LaboratoriesB1-selective antagonist (with B2 activity in high doses)

Nebivolol15Bystolic from Mylan Laboratories and Forest LaboratoriesB1-selective antagonist (with B2 activity in high doses)Reportedly: less Erectile Dysfunction, less problematic airway symptoms (e.g., asthma exacerbations : B2 effects), less fatigue, less alteration of insulin, glucose, and lipid levelsNitric Oxide production (B3 stimulation?) which leads to further vasodilatation L-arginine/nitric oxide pathway

Nebivolol15Bystolic from Mylan Laboratories and Forest LaboratoriesB1-selective antagonist (with B2 activity in high doses)Reportedly: less Erectile Dysfunction, less problematic airway symptoms (e.g., asthma exacerbations : B2 effects), less fatigue, less alteration of insulin, glucose, and lipid levelsNitric Oxide production (B3 stimulation?) which leads to further vasodilatation L-arginine/nitric oxide pathwayThe new Viagra ?

Nebivolol15Bystolic from Mylan Laboratories and Forest LaboratoriesB1-selective antagonist (with B2 activity in high doses)

Is it worth using?

Nebivolol15Bystolic from Mylan Laboratories and Forest LaboratoriesB1-selective antagonist (with B2 activity in high doses)

Is it worth using?As effective at BP control 23Improved coronary flow vs.. atenolol in one study 24Possible improved overall efficacy in patients with decreased vascular compliance (NO-pathway vasodilatory effects) 25

BICARB

Sodium Bicarbonate :Radiocontrast Nephropathy Made Worse?

Sodium Bicarb and ConNephOld wisdom and new studies have shown some preference for hydration and, in some cases hydration with alkali to prevent contrast nephropathy.

Sodium Bicarb and ConNephOld wisdom and new studies have shown some preference for hydration and, in some cases hydration with alkali to prevent contrast nephropathy. (Below is Merten, et al)The primary end point of contrast-induced nephropathy occurred in 8 patients (13.6%) infused with sodium chloride but in only 1 (1.7%) of those receiving sodium bicarbonate (mean difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; P =.02) [n=119]. 29

Sodium Bicarb and ConNephNew evidence? (From et al, below)After adjustment for total volume of hydration, medications, age, gender, prior creatinine, contrast iodine load, prior exposure to contrast material, type of imaging study, heart failure, hypertension, renal failure, multiple myeloma, and diabetes mellitus, use of sodium bicarbonate alone was associated with an increased risk of contrast nephropathy compared with no treatment (odds ratio 3.10, 95% confidence interval 2.28 to 4.18; P < 0.001) [n=11,516]. 30

Sodium Bicarb and ConNephNew evidence? (From et al, below)N-AC with or without NaHCO3 did not change outcomes

Sodium Bicarb and ConNephNew evidence? (From et al, below)Difference ?Merten, et al A prospective, single-center, randomized trial

From, et al retrospective, single-center analysis

Sodium Bicarb and ConNephNew evidence? (From et al, below)Difference ?Multiple trials including bicarbonate have been performed, many showing some benefit with the alkalimore studies will need to be done

eGFRWhen and How to Use It.

eGFRestimated Glomerular Filtration RateGFR = [Substance x]u x Urinary Flow Rate[Substance x]p


eCrCl = (140-Age) x Mass(kg) x 0.85 (if female)72 x Serum Creatinine (mg/dL)


eCrCl = (140-Age) x Mass(kg) x 0.85 (if female)72 x Serum Creatinine (mg/dL)

eGFR = 170 x sCr-0.999 x age-0.176 x BUN-.170 x Albumin0.318(x 0.762 if female) (x 1.180 if black)

eGFRestimated Glomerular Filtration Rate

eGFR = 170 x sCr-0.999 x age-0.176 x BUN-.170 x Albumin0.318(x 0.762 if female) (x 1.180 if black)

eGFRValues are not normalized for BSA.Values are usually listed separately for African Americans and non-African Americans.Values are more inaccurate for eGFRs that approach normal levels.Values consistently overestimate true GFRs for patients that have severely decreased GFRs.

eGFRWhen:the pt is at his/her assumed baseline renal function.the patient is aged (>60 yo).the patient has known advanced CKD.

eGFRWhen:the pt is at his/her assumed baseline renal function.the patient is aged (>60 yo).the patient has known advanced CKD.How:as a backup estimate to your own. to estimate TtD (time to dialysis).to help determine the time for consultation.

eGFROk, I dont have an eGFR available to me.

eGFROk, I dont have an eGFR available to me.When 1 is not 1

eGFROk, I dont have an eGFR available to me.When 1 is not 1Baseline 1.0

eGFROk, I dont have an eGFR available to me.When 1 is not 1Baseline 1.0Subtract 0.1 if female, >65 yo, small-framedSubtract 0.3 if physically debilitated or cachecticAdd 0.1 if muscular or if fit and >200 lbs.Add 0.2 if plays professional football

eGFROk, I dont have an eGFR available to me.When 1 is not 1Baseline 1.0Subtract 0.1 if female, >65 yo, small-framedSubtract 0.2 if physically debilitated or cachecticAdd 0.1 if muscular or if fit and >200 lbs.Add 0.2 if plays professional footballMy pt. is a 72 yo white female who is 50; her Cr is 1.4 mg/dL today.

eGFROk, I dont have an eGFR available to me.When 1 is not 1Baseline 1.0Subtract 0.1 if female, >65 yo, small-framedSubtract 0.2 if physically debilitated or cachecticAdd 0.1 if muscular or if fit and >200 lbs.Add 0.2 if plays professional football1.0 0.1(female) -0.1(>65yo) -0.1(small) = 0.7Divide the result by the current Cr (0.7 / 1.4 = 0.5)In this case the eGFR is 50% normal and CrCl is ~35-45 mL/min.

eGFRCKD StagingStage 1 : GFR >= 90mL/minStage 2 : GFR >=60 and =30 and 15 and

Refreshment time

BibliographyNephrol Dial Transplant. 2006 Mar;21(3):697-700. Epub 2005 Dec 2.Kuo, PH, Kanal, E, Abu-Alfa, AK, Cowper, SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007; 242:647.LeBoit, PE. What nephrogenic fibrosing dermopathy might be. Arch Dermatol 2003; 139:928.Proc (Bayl Univ Med Cent). 2007 Oct;20(4):408-17. Eur Radiol. 2006 Dec;16(12):2619-21. Epub 2006 Oct 24. J Am Soc Nephrol. 2006 Sep;17(9):2359-62. Epub 2006 Aug 2. Acta Radiol. 2001 May;42(3):339-41. Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Accessed 12/31/2007.Diagn Interv Radiol 2006; 12:161-162.Shawn E Cowper, MD. Via UpToDatehttp://www.rxlist.com/cgi/generic/omniscan_wcp.htmhttp://samugliestdog.com/Dominik N. Mller, and Friedrich C. Luft, Direct Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage, Clin J Am Soc Nephrol 1: 221-228, 2006.

BibliographyMancia G, Backer G, et al., Task Force for the Management of Arterial Hypertension of the ESH and of the ESC, J Hypertension 25:1105-1187, 2007.Gosgnach W, Boixel C, Nevo N, et. al., J Cardiovascular Pharm. 38:191-199, 2001.Agabiti RE, et al., Drugs 67:1097-1107, 2007.Celik T, J Hypertension 24:591-596, 2006.Textor S, Townsend R, NephSAP, 7:2 68-108.Ohkubo T, Kikuya M, et.al., J Am Coll Cardiology, 46:508-515, 2005.Image:Renin-angiotensin-aldosterone system.pngStrasser RH, et.al., J Hum Hypertension, 49:1047-1055, 2007.Pool JL, etal, Am J Hypertension, 20:11-20, 2007.Veverka A, et.al., Ann Pharmacotherapy, 40:1353-1360, 2006.Gullu H, Erdogan D, et.al., Heart, 92:1690-1691, 2006.Agabiti RE, et.al., Drugs, 67:1097-1107, 2007.Sica DA, Hypertension 47:352-358, 2006.

BibliographyAnnals of Internal Med, 148:16-29, 30-48, 2008.MacKinnon M, Shurraw S, et.al., Am J Kidney Dis, 48:8-20, 2006.JAMA, 2004 May 19;291(19):2328-34. Clin J Am Soc Nephrol. 2008 Jan;3(1):10-8. Epub 2007 Dec 5.

Renal Function: MRI's, eGFR, and other 'New' News

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