Rebin Titus

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Clinical Case Conference

• Rebin Titus

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Presenting history

• 71-year-old Caucasian female with past medical
  history notable for hypertension and arthritis,
  transferred from Roswell secondary to acute renal
  failure
• She was of her usual state of health up until 4
  months ago, when she developed swelling of her
  hands and feet.
• She reports that she was gardening one day 4
  months ago and the next day she woke up with
  joint pain, swelling of the bilateral upper and
  lower extremities especially the hands, wrist and
  ankles.

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Presenting history

• Since then, she has been admitted to the hospital
  numerous times for the same complaints
• Patient still complains of pain and swelling in
  multiple joints on day of presentation and states
  that her swelling waxes and wanes
• Since April, she has had an extensive workup, and
  was being followed by an internist, nephrologist
  and rheumatologist.
• She also reports some difficulty breathing, along
  with difficulty swallowing.

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Past Medical History

• Hypertension.
• Polyarthritis.
• Diverticulosis with history of diverticulitis
• Over past 4 months
• Acute renal failure.
• Anemia of unknown etiology.
• Dysphagia.
• Dyspnea
• Worsening hypertension.

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Past Surgical History

• Bilateral knee replacements.
• Right shoulder surgery.
• Colon resection.

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History (contd.)

• Social History Patient smoked ½ pack per day for
  20 years, quit 4 years ago, has not started
  back. Patient is a social drinker, states she
  drinks 3-4 alcoholic beverages a week. No use of
  illicit drugs. Lives in Roswell
• Family History Positive for lymphoma in father.
  

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Medications

• Alendronate
• Amlodipine
• Epoetin
• Metoprolol
• Morphine
• Omeprazole
• Zofran
• Prednisone 15 mg
• Ambien.

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PE

• Vitals Temp 95.6 BP 162/90 HR 83, RR 16 O2
  sat 93 on room air.
• Gen appearance Comfortable, in no distress
• HEENT PERRLA, normal conjunctivae, moist MM,
  eyes
• Neck Supple, no lymphadenopathy
• Lungs CTAB
• CVS S1, S2, RRR, no M/R/G
• Abd Soft, BS , NT/ND
• Ext No C/C trace edema around ankles
• Mildly edematous joints of both hands with ulnar
  deviation, slighlty tender with taut skin

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PE (contd.
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Labs (8/2)

• CBC WBC 12.5 , H/H 10.3 and 30.8, platelets
  126K.
• BMP Sodium 136, potassium 4.3, chloride 104, C02
  21, glucose 95, BUN 79, creatinine 4.3, calcium
  8.3.
• LFT ALT 28, AST 31. Total bilirubin 0.9.
• Iron studies Iron level 53. TIBC 233.
  Transferrin 23. Ferritin level 1,727.
• TSH 2.87. Free T4 1.29.
• Spot Urine with protein 123, creat 47. UA
  positive for moderate blood, sp gravity 1.009

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Other labs from Roswell

• ASO negative. RF negative.
• ANA negative. Ds-DNA pending.
• RNP pending. Scleroderma antibody negative along
  with reports from the nephrologist of p-ANCA and
  c-ANCA negative.
• Creatinine on 6-15-09 at 0.8 with subsequent rise
  approximately 2.5 to 3.0 without return to
  baseline.

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Admission day 2,3,4

• Doing well, good urine output, no complaints
• Continued on home meds
• Creatinine continuing to trend upwards 4.5, 4.6,
  4.9, BUN in the 70-80s
• BP also trending up

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Admission day 5

• Continues to do well
• Producing good urine output
• BP uncontrolled, systolics in the 180-200s
• Creatinine now up to 5.5, BUN 95, GFR 10
• Biopsy scheduled

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Admission day 6, 7

• Biopsy results suspicious for thrombotic
  microangiopathy, suspicion for scleroderma
• Started on low dose captopril
• Low dose steroids stopped
• Creatinine continues to rise, rapidly
  progressing, now up to 6.7, BUN 116, GFR 8
• BP continues to be uncontrolled
• Pt now is tired and fatigued, urine output
  decreased

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Biopsy

• Thrombotic microangiopathy
• The histologic appearance is consistent either
  with malignant hypertension, scleroderma renal
  crisis, hemolytic uremic syndrome or cancer
  chemotherapy
• Moderate increase of mesangial matrix. The
  interlobular arteries show moderate narrowing.
  Minimal lymphocytic infiltration is seen in the
  interstitial tissue. Less than 10 of renal
  parenchyma is lost by tubular loss and atrophy
  and interstitial fibrosis.
• IgA, IgG, IgM, C1q, C3, C4 and albumin are
  negative. No immunoglobulins, complements,
  albumin or fibrinogen seen along the tubular
  basement membrane or blood vessel wall.

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Marked thickening of vessel wall with narrowed
lumen
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Thrombi in capillary loops and arteriole
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Thrombi in capillary loops and arteriole
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Loss of parenchyma by interstitial fibrosis and
tubular atrophy
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Admission day 7,8

• Increasing doses of captopril, upto 50 mg tid
• BP some better 150-190s systolics
• Now being treated as a scleroderma renal crisis
• Creatinine continues to rise 7.4, 8.2 BUN 115,
  117,

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Admission day 9,10

• Creatinine 9, BUN 117, K 5.4, with some altered
  mentation, also some nausea, low appetite
• Decision made to dialyze secondary to uremic
  symptoms
• Tunnel catheter placed
• BP now under good ctrl

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Admission day 11,12

• Patient tolerated dialysis well, improved
• Creatinine down to 5.9, BUN 60, other lytes
  normal
• BP well controlled on captopril
• Induction for dialysis

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Admission day 13, 14, 15

• Continues hemodialysis daily
• Creatinine down to 5.1, 5.5
• Tunnel catheter placed
• Set up for routine hemodialysis in Roswell
• Discharged home

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Scleroderma renal crisis

• Abrupt onset of moderate to severe hypertension
• Urine sediment that is normal or reveals only
  mild proteinuria with few cells or casts
• Progressive renal failure
• Severe and life-threatening

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Scleroderma renal crisis

• Can develop in approximately 10 to 20 percent of
  patients with the diffuse cutaneous form of
  systemic sclerosis and much less frequently in
  limited cutaneous systemic sclerosis.
• Despite the widespread use of ACE inhibitors for
  the treatment of scleroderma renal crisis,
  morbidity and mortality remain high.

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Prevalence

• Approximately one-half of scleroderma patients
  show some evidence of renal involvement, such as
  proteinuria, a mild elevation in the creatinine
  concentration, and/or hypertension
• Scleroderma renal crisis (SRC) develops in up to
  20 percent of patients with diffuse cutaneous
  systemic sclerosis, although its incidence
  appears to be declining

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Risk factors

• Diffuse skin involvement
• Glucocorticoid use
• Presence of certain autoantibodies like anti-RNA
  polymerase antibodies .

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Clinical Features

• Occurs within the first five years of the onset
  of the disease. In one series, renal crisis
  occurred at a median duration of 7.5 months from
  the onset of the disease. In some cases, SRC is
  the initial manifestation of systemic sclerosis.

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Clinical features

• Acute renal failure, usually in the absence of
  previous kidney disease.
• Abrupt onset of moderate to marked hypertension,
  often accompanied by manifestations of malignant
  hypertension, such as hypertensive retinopathy
  and hypertensive encephalopathy.
• In approximately 10 percent of patients, SRC
  occurs in the presence of normal blood pressure.
  However, some of these patients have blood
  pressures that are still higher than the
  patient's baseline. These patients tend to have a
  worse renal outcome and higher mortality than
  patients with SRC who are hypertensive.
• The urine sediment is usually normal or reveals
  only mild proteinuria with few cells or casts.
  Nephrotic range proteinuria is uncommon.

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Pathology

• Pathological hallmarks of scleroderma or systemic
  sclerosis
• Uncontrolled accumulation of collagen
• Widespread vascular lesions characterized by
  thickening of the vascular wall and narrowing of
  the vascular lumen.

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Pathology

• The primary histopathologic changes in the kidney
  are localized in the small arcuate and
  interlobular arteries and the glomeruli. The
  characteristic finding is intimal proliferation
  and thickening that leads to narrowing and
  obliteration of the vascular lumen, with
  concentric "onion-skin" hypertrophy.
• SRC is a thrombotic microangiopathy similar to
  malignant nephrosclerosis, TTP/HUS, radiation
  nephritis, chronic transplantation rejection, and
  the antiphospholipid antibody syndrome.
• Because of the similar renal histologic findings,
  renal biopsy does NOT definitively establish the
  diagnosis of SRC.

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Histology
Light micrograph showing fibrinoid necrosis in
the preglomerular afferent arteriole (arrow) in
scleroderma renal crisis. The normal muscle layer
of the media has been replaced by the fibrinoid
material
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Other features of SRC to make diagnosis

• Digital tip pitting and scarring, and nailfold
  microvascular changes with capillary dilatation
• Evidence of gastrointestinal involvement (such as
  esophageal or small bowel dysmotility)
• interstitial lung disease or pulmonary
  hypertension
• The presence of serum autoantibodies against RNA
  polymerase. By contrast, the presence of
  anti-centromere antibodies appears to be
  protective against the development of SRC.

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Prevention

• No prospective studies that demonstrate that the
  avoidance and/or administration of any agent
  lowers the incidence or severity of SRC have been
  performed.
• ACE Inhibitors There is no clear evidence of a
  preventive effect of ACE inhibitors among
  patients with systemic sclerosis
• Retrospective and case-control studies have
  largely found neither benefit nor harm with ACE
  inhibitors related to the development of SRC
• A multicenter randomized, double-blind,
  placebo-controlled study of 210 patients
  evaluated the efficacy of daily quinapril(80
  mg/day or the maximum tolerated dosage) for the
  prevention of vascular damage in systemic
  sclerosis. At two to three years, quinapril did
  not affect the occurrence of vascular
  complications, such as Raynaud phenomenon or
  ischemic digital ulcers, and had no effect on
  renal function.
• Avoidance of glucocorticoids 

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Treatment

• The mainstay of therapy is effective and prompt
  blood pressure control, which improves or
  stabilizes renal function in up to 70 percent of
  cases and improves patient survival (survival at
  one year of 80 percent). The success with
  antihypertensive therapy is dependent upon its
  initiation before irreversible renal damage has
  occurred.
• The optimal class of antihypertensive agents is
  ACE inhibitors. Compared to other
  antihypertensive agents, a number of
  nonrandomized, uncontrolled retrospective and
  prospective studies have shown that the ACE
  inhibitors are associated with greater
  antihypertensive efficacy, better preservation of
  renal function, and improved survival in patients
  with scleroderma renal crisis

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Initial goals of therapy

• Captopril has the advantages of rapid onset (peak
  effect at 60 to 90 minutes) and short duration of
  action, which permit rapid dose titration.
  Intravenous enalaprilat is not routinely used.
• The principal goal of initial captopirl therapy
  is to return the patient to his or her previous
  baseline blood pressure within 72 hours
• If evidence of central nervous system involvement
  like encephalopathy or papilledema, may add
  intravenous nitroprusside

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Outcomes

• Despite treatment with ACE inhibitors,
  approximately 20 to 50 percent of patients with
  SRC progress to end-stage renal disease.
• However, among patients with SRC who require
  dialysis during the acute episode, an appreciable
  proportion recover sufficient renal function to
  discontinue dialysis

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ACE Inhibitor studies

• A prospective observational cohort study study
  from Georgetown University reported patient
  outcomes in 145 patients with SRC who were
  continuously treated with ACE inhibitors
• 28 patients (19 ) died at a mean of three
  months, 18 of whom required dialysis.
• 55 patients (38 ) did not require dialysis.
  These patients had a mean peak serum creatinine
  concentration of 3.8 mg/dL that fell to 1.8 at
  7.1 years. Only two had slow deterioration of
  renal function, requiring dialysis at four and
  six years.
•  28 patients (19 ) required permanent dialysis.
• 34 patients (23 overall, 43 of all patients
  requiring early dialysis, and 55 of patients
  requiring early dialysis who did not die) were
  able to discontinue dialysis after 2 to 18 months
  (mean eight months). The mean serum creatinine
  was 2.7 mg/dL when dialysis was discontinued that
  fell to 2.2 mg/dL at 6.1 years.
• In an earlier report from the same group cited
  above, there was no recovery of renal function in
  patients not treated with ACE inhibitors

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ACE Inhibitor studies

• In a retrospective single center study from
  London in 2007, of 110 patients with SRC (mean
  blood pressure of 193/114 mmHg), 108 were treated
  with ACE inhibitors. ACE inhibitor therapy was
  titrated to reduce the systolic blood pressure by
  20 mmHg per day. Dialysis was required in 72
  patients (64 ), 24 of whom (33 ) recovered
  sufficient renal function to discontinue
  dialysis. At three years, renal function improved
  (mean 23 mL/min) among non-dialysis-dependent
  patients. Approximately 40 percent of patients
  required permanent dialysis. Overall patient
  survival at one and five years was 82 and 59
  percent, respectively, with the poorest survival
  seen in those requiring dialysis.

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Other therapies (not proven)

• Angiotensin II receptor blockers might be
  expected to be effective, but the efficacy of
  these drugs has not yet been established.
• Intravenous prostacyclin, which is believed to
  help the microvascular lesion, has been
  administered at the onset of hypertensive renal
  crisis based upon anecdotal observations of
  benefit.
• Fish oil is sometimes prescribed in view of its
  theoretically beneficial hemodynamic and
  antiplatelet properties.

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Mortality

• SRC is a potentially life-threatening
  complication. Prior to the widespread use of ACE
  inhibitors, almost all patients with significant
  renal involvement died within one year (compared
  to a 35 percent cumulative seven-year survival in
  all patients).
• Survival of patients with SRC treated with ACE
  inhibitors is significantly better
• In a review of 110 patients with SRC, one-year
  patient survival was 76 percent in patients
  treated with ACE inhibitors compared to 15
  percent in patients treated with other drugs.

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Summary

• As many as 50 percent of scleroderma patients
  have clinical evidence of renal involvement, such
  as mild proteinuria, elevated serum creatinine
  concentration, or hypertension
• SRC develops in up to 10 to 20 percent of
  patients with diffuse cutaneous systemic
  sclerosis. It is characterized by acute renal
  failure, abrupt onset of moderate to marked
  hypertension, a normal urinalysis or a urine
  sediment with only mild proteinuria and/or signs
  of microangiopathic hemolytic anemia.
• The characteristic histologic finding in the
  kidney in SRC is intimal proliferation and
  thickening that leads to narrowing and
  obliteration of the vascular lumen, with
  concentric "onion-skin" hypertrophy

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Summary

• The diagnosis of SRC is based upon characteristic
  findings which include new onset of blood
  pressure gt150/85 mmHg and progressive decline in
  renal function, although a few patients are
  normotensive. Additional findings may include
  microangiopathic hemolytic anemia and
  thrombocytopenia, features of malignant
  hypertension, new onset proteinuria or hematuria
  (excluding other causes)
• SRC must be distinguished from other forms of
  thrombotic microangiopathy, particularly TTP/HUS
• The principal goal of initial ACE Inhibitor
  (captopril) therapy is to return the patient to
  his or her previous baseline blood pressure
  within 72 hours

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Thank you for your attention