Adult Medical Issues in Cystinosis--William Gahl, M.D.

Section on Human Biochemical GeneticsMGB, NHGRI, NIH

Adult Medical Issues in CystinosisCRN ConferenceSan Antonio, TXJuly 19-21, 2007William A. Gahl, MD, PhDDHHS, NIH, NHGRI301-402-2739bgahl@helix.nih.gov

CYSTINOSIS NATURAL HISTORYAgeBirthInfancyAge 10Clinical ManifestationNoneRenal tubular FanconisyndromeGrowth retardationRenal failurePhotophobiaHypothyroidism

Renal Allografts in Cystinosis- Patients do well.- Disease does not recur in graft.- Cystine accumulation continues inother organs, causing posttransplantcomplications.

CYSTINOSIS NATURAL HISTORYPost-Transplant ComplicationsDiabetes mellitusCorneal and retinal damageMyopathySwallowing difficultyVascular and cerebral calcificationLiver damagePseudotumor cerebriMale hypogonadismDecreased lung functionDeath

Band keratopathy ina 14-year old girl

22-year old withcystinosis,myopathy, andswallowingdifficulty. Died ofaspiration.Cystinosis patientwith atrophy oftongue muscles.

Vacuolar Myopathy of CystinosisVariation in fibersize, type I fiberatrophy, ringfibersIntracellularVacuoles

Cystine crystalsin muscleCystine crystalsin hand muscle

Transmission EM ofcystine crystalswithin lysosomes ofperimesial cellScanning EM of cystinecrystals within cellularlysosomes of muscle

Swallowing DifficultyPooling invalleculae andpyriform sinusesRare doublebolus

4.54(5)3.5(4)(4)3(4)(3)(4) (3)2.5(6)(4)2(23)(8)1.5(3)1(18)(5)0.500 0.5 1 1.5 2 2.5 3 3.5 4 4.5General Muscle Score

Coronary Artery CalcificationCoronaryangiogramof 25-yearold man

LADRCACircumflexChest CT of 25-year old man withcystinosis

Cerebral atrophyin a 24-year oldmanCerebralcalcifications in anadult withcystinosisPseudotumor cerebri;increased intracranialpressure

Liver Disease17 mo: Diagnosis; no cysteamine9 y: Renal failure9-16 y: Peritoneal dialysis, peritonitis17 y: Cadaveric renal allograft17-19 y: Liver disease– Hematemesis; hepatosplenomegaly,ascites, gastroesophageal varices– Portal hypertension; sclerotherapy,banding–Anemia, hyperammonemia, 100 u of blood19 y: Died of bacterial peritonitis

Gastric varixDuodenal varix

Mild portalfibrosisIncreased reticulinstaining with nodularity;Nodular RegenerativeHyperplasia

100 Nephropathic CystinosisAdults (NIH, 1986-2006)Age (y) 26.2 + 0.6 (18-45)Transplanted 92/100 92%(Mean age 12.3 + 0.4 y)Hypothyroid 75/100 75%Male hypogonadism 39/53 74%Poor lung function 53/77 69%Impaired swallowing 58/97 60%

100 Nephropathic CystinosisAdults (NIH, 1986-2006)Myopathy 50/100 50%Cholesterol 31/94 33%>200 mg/dLRetinopathy 32/100 32%Calcified coronaries 16/52 31%Diabetes mellitus 24/100 24%Calcified basal ganglia 21/95 22%DEATH 33/100 33%(Mean age 28.5 + 1.1 y)

Adult Cystinosis Patients(NIH, 1986-2006)Causes of Death (N=33)Sepsis [bowel perf. (3); peritonitis] 9Unknown; sudden death 8Uremia [refused dialysis (3)] 5Pneumonia/Aspiration 5Liver disease 3CNS deterioration 2Lymphoma 1

HS-CH 2 -CH 2 -NH 2CYSTEAMINE

NIH Intent-to-treat Analysis forOral Cysteamine (1960-1992)TreatmentPredicted age atwhich creatclearanceis zero (years)No cysteamine 9.5Partial cysteamine 20.0Excellent cysteamine 74.3

Renal Failure in Cystinosis100% not inrenalfailureCysteamine50Control159 1317Age -years

4Muscle Cystine321No Cysteamine010 2030Age (years)Cysteamine

Cysteamine Effect: Cystinosis LiverUntreated 10 year oldCysteamine-treated 9 year old

CYSTEAMINE EYEDROPSUntreated Treated3-year old20-year old

- Approved August 15, 1994- Approved for pre-transplantpatients only- Cost remains reasonable: ~$3000-$5000/year in U.S.

Pre-transplant, oral cysteaminetherapy:- Preserves renal function- Allows for a normal growth rate- Preserves thyroid function- Depletes muscle & liver of cystine

Nephropathic Cystinosis: OralCysteamine TherapyMost cystinosis patients begun oncysteamine therapy early (1-2years of age) still require a renaltransplant in their late teens orearly twenties.

Post-Transplant CystinosisComplicationCysteamine helps?Swallowing difficultyYesVascular calcificationsYesRetinopathyYesDiabetes mellitusYesMyopathyYesPulmonary dysfunction YesDeathYesHypercholesterolemiaYesLiver damage ?Pseudotumor cerebri ?Male hypogonadism ?

101 Cystinosis Patients4.54Swallowing Severity Score3.532.521.510.500 5 10 15 20 25 30 35 40 45Years Years Without Cysteamine

101 Cystinosis Patients4.54Swallowing Severity Score3.532.521.510.500 5 10 15 20 25Years Years With Cysteamine

41 Post-Transplant Cystinosis Patients hadChest CT Scans:28 Normal (mean age 22 y)13 Coronary Artery Calcification (mean age 36 y)10080604020Years OffCysteamineYears OnC t i00-10 11-20 21-30 31-40Years On or Off Cysteamine

60%50%n=1040%n=3830%% OF PATIENTS WITH DIABETES20%10%0%60%50%40%30%n=28n=240-10 11-20 21-30 31-40Years OFF Cysteaminen=7320%n=2210%0%n=5 n=00-10 11-20 21-30 31-40Years ON Cysteamine

90%80%n=1070%n=3860%% OF PATIENTS WITH MYOPATHY50%40%30%20%10%0%90%80%70%60%50%40%30%n=28n=240-10 11-20 21-30 31-40Years OFF Cysteaminen=73n=2220%10%0%n=5n=00-10 11-20 21-30 31-40Years ON Cysteamine

100%90%n=28n=10% OF PATIENTS WITH PULMONARY DYSFUNCTION80%70%60%50%40%30%20%10%0%100%90%80%70%60%50%40%30%20%10%0%n=18n=210-10 11-20 21-30 31-40Years OFF Cysteaminen=53n=20n=4n=00-10 11-20 21-30 31-40Years ON Cysteamine

60%n=3850%40%30%n=28n=1020%% OF PATIENTS WITH DEATH10%0%60%50%40%30%n=240-10 11-20 21-30 31-40Years OFF Cysteaminen=7320%10%n=220%n=5n=00-10 11-20 21-30 31-40Years ON Cysteamine

100 Adult Cystinosis PatientsCysteamine N Age (y) On (y) Off (y)< 8 y 61 27.0 2.0 25.0(+0.3) (+0.8)> 8 y 39 25.8 15.1 10.7(+0.9) (+1.6)

100 Adult Cystinosis PatientsTransplantedCysteamine N % Age (y) Deceased< 8 y 61 100 11.0 30 (49%)(+0.4)> 8 y 39 79 14.8 3 (8%)(+0.8)p

100 Adult Cystinosis PatientsCholesterol Height WeightCysteamine N (mg/dL) (cm) (kg)< 8 y 61 195 143.6 45.3(+8) (+1.4) (+1.4)> 8 y 39 170 154.7 53.2(+7) (+1.7) (+1.7)p < 0.02

100 Adult Cystinosis PatientsCysteamine N # Complications*/Patient< 8 y 61 4.0 + 0.3> 8 y 39 2.2 + 0.3p

Effect of Oral Cysteamine onthe Late Complications ofNephropathic Cystinosis:IT HELPS!

Cystinosis - OutcomesBorn in:• 1955 - Death in infancy/childhood• 1965 - Death or transplant,complications• 1975 - Death or transplant,complications• 1985 - Delay until age 15-25 intransplant– Expect no late complicationsEarly diagnosis is critical!

Nephrogenic FibrosingDermopathy

Nephrogenic FibrosingDermopathy• Entity first reported in 1997• 15 patients on chronic dialysis developed scleroderma-like disease• Most rapidly progressive and debilitating -- no apparentbenefit to range of anti-inflammatory and immunosuppressive drugs• Cause unknown:? Dialysate or dialyzer toxin? Erythropoietin? Occult infection? Autoimmunity

NFD: More than skin deep• Pathology findings indicated that it is asystemic fibrosing disorder – renamed:“nephrogenic systemic fibrosis”• Fibrosis• Skeletal muscle• Myocardium• Lung and pulmonary vasculature• Diaphragm

Nephrogenic SystemicFibrosis• Registry established at Yale• 215 definitive cases (spectrum ofdisease?)• Not all cases on dialysis but all had renalinsufficiency• Eureka moment!! Spring 2006, Austrian andDanish clinicians noted most cases had MRIprocedures within previous month –Gadolinium proposed as likelyculprit

June 2006 (25 cases); updated December 2006• FDA has received reports of 90 patients withmoderate to end-stage kidney disease whodeveloped NSF/NFD after they had an MRI orMRA with a gadolinium-based contrast agent.• Patients with moderate to end-stage kidneydisease who receive an MRI or MRA with a•gadolinium-based contrast agent may getNSF/NFD which is debilitating and may causedeath.

FOR IMMEDIATE RELEASEMay 23, 2007FDA Requests Boxed Warning for Contrast Agents Used to ImproveMRI Images

Risk Mitigation Strategy• Eliminate higher-risk Gadolinium cmpds:those with low-affinity of Gad for chelate• Consider alternative imaging techniquesin patients with eGFR

Cystinosis Past: TheNatural HistoryAR; 1 in 200,000 birthsLysosomal storage diseasedue to impaired transport ofcystine out of lysosomes(Crystals in many tissues)Damage to many organs(Especially kidney)

Transmission EMof conjunctival cell(Dr. T. Kuwabara)Scanning EM ofliver Kupfer cell(Dr. Kamal Ishak)

Cystinosis: Future- New cystine-depleting agents, studiedin mouse models- Better delivery to the GI tract- Better transplant methods & meds- Approval of Cystagon for posttransplantpatients- Approval of cysteamine eyedrops- Newborn screening!

N=89 N=32 N=24 N=9100%90%80%70%60%50%40%No retinopathyRetinopathy30%20%10%0%0-10 years 11-20 years 21-30 years 31-40 yearsFrequency of retinopathy increases with time OFF cysteamine treatment.

N=108 N=38 N=9100%90%80%70%60%50%40%No retinopathyRetinopathy30%20%10%0%0-10 years 11-20 years 21-30 yearsFrequency of retinopathy decreases with time ON cysteamine treatment.