REBIN TITUS

Clinical Case Conference

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.

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.

Past Medical History

Hypertension. Polyarthritis. Diverticulosis with history of diverticulitisOver past 4 months:Acute renal failure.Anemia of unknown etiology.Dysphagia. DyspneaWorsening hypertension.

Past Surgical History

Bilateral knee replacements. Right shoulder surgery.Colon resection.

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.

Medications

AlendronateAmlodipineEpoetinMetoprololMorphineOmeprazoleZofranPrednisone 15 mgAmbien.

PE

Vitals: Temp: 95.6; BP 162/90; HR 83, RR 16; O2 sat 93% on room air.

Gen appearance: Comfortable, in no distressHEENT: PERRLA, normal conjunctivae,

moist MM, eyesNeck: Supple, no lymphadenopathyLungs: CTABCVS: S1, S2, RRR, no M/R/GAbd: Soft, BS +, NT/NDExt: No C/C trace edema around anklesMildly edematous joints of both hands with

ulnar deviation, slighlty tender with taut skin

PE (contd.

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

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.

Admission day # 2,3,4

Doing well, good urine output, no complaints

Continued on home medsCreatinine continuing to trend upwards:

4.5, 4.6, 4.9, BUN in the 70-80’sBP also trending up

Admission day # 5

Continues to do wellProducing good urine outputBP uncontrolled, systolics in the 180-200’sCreatinine now up to 5.5, BUN 95, GFR 10Biopsy scheduled

Admission day # 6, 7

Biopsy results suspicious for thrombotic microangiopathy, suspicion for scleroderma

Started on low dose captoprilLow dose steroids stoppedCreatinine continues to rise, rapidly

progressing, now up to 6.7, BUN 116, GFR 8BP continues to be uncontrolledPt now is tired and fatigued, urine output

decreased

Biopsy

Thrombotic microangiopathyThe 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.

Marked thickening of vessel wall with narrowed lumen

Thrombi in capillary loops and arteriole

Thrombi in capillary loops and arteriole

Loss of parenchyma by interstitial fibrosis and tubular atrophy

Admission day # 7,8

Increasing doses of captopril, upto 50 mg tidBP some better 150-190’s systolicsNow being treated as a scleroderma renal

crisisCreatinine continues to rise 7.4, 8.2; BUN

115, 117,

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 placedBP now under good ctrl

Admission day # 11,12

Patient tolerated dialysis well, improvedCreatinine down to 5.9, BUN 60, other lytes

normalBP well controlled on captoprilInduction for dialysis

Admission day #13, 14, 15

Continues hemodialysis dailyCreatinine down to 5.1, 5.5Tunnel catheter placedSet up for routine hemodialysis in RoswellDischarged home

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

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.

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

Risk factors

Diffuse skin involvementGlucocorticoid usePresence of certain autoantibodies like anti-

RNA polymerase antibodies .

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.

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.

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.

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.

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

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.

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 

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

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

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

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

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.

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.

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.

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

Summary

The diagnosis of SRC is based upon characteristic findings which include new onset of blood pressure >150/85 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

Thank you for your attention