Case Review - A 42 year-old female with hematuria
Khoa Vu, MD
History of Present Illness
A 42 year-old woman presented to the emergency room complaining of a 3 week history of blood in her urine. The hematuria started initially with bright red blood, sometimes mixed with clots, and later became intermittent, blood-tinged urine. She denied any pain with urination, abdominal pain, flank pain, or nausea. She also denied any rash, joint pain or swellings, weight loss, hematochezia or melena. She did report recent upper respiratory symptoms, including sore throat, fever, and dry cough, which began about 5 weeks ago and resolved at the time that she noticed the hematuria. She went to see her primary care physician, who then treated her with a 10-day course of cefdinir for a presumed urinary tract infection. However, the hematuria did not resolve. She was then referred to a nephrologist, and was noted to have a creatinine of 4.7mg/dl. She was referred to the emergency department for further evaluation and subsequently admitted to the medicine service for ongoing evaluation.
Past medical history
The patient’s previous medical history is significant for systemic lupus erythematosus (SLE), with her most recent flare 2 months prior to admission. At that time, she was treated with a short steroid taper. As a result of the SLE, she previously developed proliferative glomerulonephritis in 1992. She was treated at that time with pulsed corticosteroids, and her creatinine normalized. She has also had a history of multiple upper respiratory infections, most recently treated with levofloxacin. She also has a history of hypertension, lung abscesses, and rib fractures secondary to osteopenia.
Medications
Amlodipine 5mg daily
Social History
The patient doesn’t smoke or use any recreational drugs. She drinks alcohol occasionally.
Physical examination
On physical exam, the patient was afebrile. Her blood pressure was 125/85 mmHg, her pulse was 80 beats per minute, and her respiratory rate was 16 breaths per minute. She appeared thin for her age. There was no rash on her skin or face. Her lung, heart, and abdominal exams were unremarkable. There was no abdominal or flank tenderness. Palpation of her joints revealed no swelling or tenderness. There was no clubbing or edema in any of her extremities.
Laboratory
The patient was anemic, with a hemoglobin of 9.7gm/dL and a hematocrit of 28.6%. Her creatinine was 4.7mg/dl, while the other electrolytes were within normal limits. Urine analysis demonstrated 3+ protein, 3+ hemoglobin, 50-100 RBCs/hpf, 5-10 WBCs/hpf, trace leukocyte esterase, and 5-10 fine granular casts.
Additional laboratory studies are as follows:
| Pt’s Values | Reference |
|---|---|
| P-ANCA (perinuclear antineutrophilic cytoplasmic antibody): 1:640 | <1:20 |
| C-ANCA (cytoplasmic antineutrophilic cytoplasmic antibody): <1:20 | <1:20 |
| Anti-RNP (ribonucleoprotein) antibody: 16 | <100 |
| Antistreptolysin O titer: 773 | <125 |
| ANA: 640 | <320 |
| Anti-dsDNA Ab: neg | Neg |
| C3: 87 | 70-163 |
| C4: 18 | 12-50 |
Given the patient’s history of lupus nephritis, the presumed diagnosis at this time was rapidly progressive renal failure due to lupus. She was started on pulsed corticosteroids for 3 days. A subsequent kidney biopsy was performed, which showed 5 of 11 glomeruli were crescentic. Electron microscopy, interestingly, showed both characteristics of post-strep glomerulonephritis (1 large subepithelial hump), and of lupus-induced nephritis (mesangial and subendothelial immuno-complex deposits).
The patient was then changed to oral prednisone and started on further immunosuppresive therapy with mycophenolate mofetil (Cellcept). She was subsequently discharged home, and on follow up she continued to do well, with resolving hematuria.
Laboratory studies 10 months later, after the onset of her new symptoms, are as follows:
ASO titer: 160
UA: 2+ protein, 1+ blood, 5 RBC
Cr 1.3
Her medications at the time of discharge were Cellcept 2g daily, Lipitor 40mg daily, Vasotec 40mg daily, Prednisone 5mg qod, Oscal, and Actonel.
DISCUSSION
Lupus nephritis is an autoimmune disease that is caused by the formation of autoantibodies, with subsequent formation of immune complexes (IC) which deposit in the kidney. These antibodies include anti-nuclear antibody (95% sensitive), anti-ds DNA antibody (70% sensitive), anti-LA, and anti-Ro, along with many others less commonly found. Anti-Sm is highly specific for lupus but is only observed in about 30-40% of the patients. Antibodies to SSA and SSB are observed in 15-20% of patients.
The immune complexes are usually formed by cross-reactivity between these autoantibodies and renal antigens. The IC’s are anionic, and therefore cannot get penetrate the anionic barrier of the glomerular capillary wall; hence, they are deposited in the mesangial and the subendothelial space. This location is perivascular, and therefore can lead to activation of the complement system. Thus, this can lead to the formation of chemoattractants C3a/C5a, which thereby activate the inflammatory response. This inflammatory response leads to an influx of neutrophils and mononuclear cells.
Manifestations
Histologically: Mesangial, focal, or diffuse proliferative glomerulonephritis is seenThe urine analysis typically contains red cells, white cells, cellular and granular casts, and proteinuria.
Clinically: There is frequently an acute decline in renal function. Some symptoms associated with nephritis are peripheral edema, secondary to hypertension and hypoalbuminemia, and headache or dizziness. In the most severe of cases, signs and symptoms of cardiac decompensation may be present.
Diagnosis
The evaluation should include a basic metabolic panel, urine analysis, and a 24 hour urinary protein collection. Special tests including ESR, anti-ds DNA antibody, ANA, and complements level (C3 and C4) can be obtained in the right clinical setting. However, the gold standard for diagnosis and classification of lupus nephritis is a renal biopsy.
Classifications
The World Health Organization has divided Lupus Nephritis into 6 classes.
| Class I: Minimal mesangial lupus nephritis | *Light microscopy: normal glomeruli *Immunofluorescence: IC deposits |
| Class II: Mesangial proliferative lupus nephritis | *Light: mesangial hypercellularity or mesangial matrix expansion |
| Class III: Focal lupus nephritis | *Light: <50% of glomeruli are involved with glomerulonephritis and mesangial involvement (crescentic/deposits) |
| Class IV: Diffuse segmental or global lupus nephritis | *Light: >50% glomeruli involved |
| Class V: Membranous lupus nephritis | All of the above plus subepithelial immune deposits |
| Class VI: Advanced sclerosing lupus nephritis | >90% of glomeruli are sclerosed |
The prognosis for lupus nephritis has been improving significantly over the last several decades. In the 1950’s, the 5-year survival rate was 0%. The 10-year survival rate is currently approximately 73%.
Treatment
Class I and II nephritis requires no therapy as the overall prognosis is good. Class III and above requires aggressive steroids and possibly other immunosuppressive therapies. There are a wide variety of immunosuppressive therapies that have produced better control of lupus nephritis. Pulsed steroids and cyclophosphamide (CYC) remain the treatment of choice for lupus-induced glomerulonephritis. However, some studies have shown that there is a fairly large proportion of patients who relapse (44% at 5 years in one study) after an initial response. About 5-15% of patients are refractory to treatment with CYC. Another 30-50% still developed ESRD after 5 years of intravenous CYC. There are also significant and serious side effects associated with CYC, including an increased risk of neoplasia, infections, and gonadal toxicity.
Cellcept (mycophenolate mofetil, MMF) is a relatively new drug that is now being used more often in cases of lupus nephritis. It inhibits autoantibody production, such as the anti-ds DNA antibody. MMF seems to be better tolerated in many patients, especially in those who were refractory to CYC treatment. It has less toxic side effects and is found to be more effective in reducing proteinuria and hematuria. On renal biopsy follow up, patients on MMF have better reduction of glomerular immune deposits, less necrosis, and less crescentic formation as compared to the CYC group.
Dosing
Commonly used dosing for lupus nephritis is prednisone 1mg/kg/day for at least 4 weeks, then tapering to maintenance dosing of 5-10mg/day for 2 years. In more acutely ill patients, high dose pulsed intravenous methylprednisolone for 3 days is used. CCY is given intravenously as a function of body surface area, and commonly used at 500-1000mg/m2 for 6 months, then titrated down to every 2-4 months for between 2-5 years. MMF is started at 500mg orally each day, then increased to 1000mg orally twice daily for between 2-5 years.
Other considerations
Hypertension should be treated aggressively. Angiotensin converting enzyme inhibitors are preferable, unless the patient has significant renal impairment. Hyperlipidemia (secondary to nephrotic syndrome) should also be treated aggressively, with lifestyle modification and drug therapies.
Prognosis
The prognosis of lupus nephritis is a function of the class as noted on renal biopsy. Class I/II have an excellent prognosis, and class III patients do well overall, with only a small number developing progressive renal failure. Class IV/V have a significant number of patients who go on to develop renal failure. Class VI lupus nepritis has a poor prognosis.
REFERENCES
- Kar Neng Lai, Sydney Tang, Chi Chiu Mok. Treatment of lupus nephritis: A revisit. Nephrology 2005; 10: 180-188.
- Sydney Tang, Sing Leung Lui, Kar Neng Lai. Pathogenesis of lupus nephritis: An update. Nephrology 2005; 10: 174-179.
- Gabriella Moroni, Daniela Papaccioli, Giovanni Banfi, Antonio Rarantino and Claudio Ponticelli. Acute post-bacterial glomerulonephritis in renal transplant patients: description of three cases and review of literature. American Journal of Transplantation 2004; 4: 132-136.