< Presentation of Case >
A 58-year-old woman presented to the emergency room (ER) with lower leg edema and decreased urine output for two weeks. This woman had received a diagnosis of diabetes mellitus for 5 year, for which she was currently receiving metformin and glipizide. Her fasting blood glucose level and HbA1C were around 110 mg/dl and 6.5 %, respectively. Her baseline blood urea nitrogen (BUN) and serum creatinine (Cr) 6 months earlier was 20 and 1.5 mg/dl, respectively. Two weeks earlier prior to this evaluation, pitting edema gradually developed at both lower legs with decreased urine amount. She also reported non-specific myalgias and bone pain for a month. She denied taking alcohol or Chinese herbs recently. There was no family history of kidney disease or other systemic diseases.
At ER, the physical examination revealed a well-developed woman with ill-looking. The body height was 156 cm and weight was 60 kg. The heart rate was 90 bpm, the temperature 37.0 ℃, and the blood pressure 162/88 mmHg. There was mild pale conjunctiva but no icteric sclera. The heart beat was regular without murmurs. Auscultation of the lung fields showed bilateral basal crackles. There was no remarkable finding on examination of the abdomen. Moderate pitting edema of the lower legs was noted. The estimated daily urine output was around 400 ml. She was admitted for assessment of her renal impairment.
< Laboratory and Image Study >
1. CBC and differential count
| Date |
WBC
K/μL |
Hgb
g/dL |
MCV
fL |
Hct
% |
Plt
K/μL |
Band
% |
Neu
% |
Lym
% |
Eos
% |
Baso
% |
Mono
% |
ER |
17.42 |
9.5 |
86.4 |
26.6 |
112 |
20 |
45 |
30 |
1 |
1 |
3 |
Admission |
17.40 |
10.02 |
87.2 |
29.8 |
112 |
20 |
44 |
31 |
1 |
1 |
3 |
2. Biochemistry
| Date |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
Cl
mmol/l |
Ca
mg/dl |
AST/ALT
U/L |
LDH
U/L |
Albumin/globulin
g/dl |
ER |
96 |
9.1 |
125 |
5.8 |
98 |
10.9 |
20/38 |
538 |
2.4/3.4 |
Admission-1 |
97 |
9.2 |
126 |
5.6 |
97 |
10.8 |
N/A |
N/A |
N/A |
Admission-2 |
57 |
6.5 |
130 |
4.9 |
N/A |
10.6 |
N/A |
450 |
3.0/3.5 |
Admission-3 |
43 |
5.3 |
137 |
4.7 |
N/A |
10.1 |
N/A |
N/A |
N/A |
3. Urinalysis
Date |
Appearance |
Specific
gravity |
pH |
Protein
mg/dl |
Glucose |
Ketone |
Occult
blood |
ER |
yellow, clear |
1.010 |
6.1 |
100 |
-- |
-- |
+ |
Admission-1 |
yellow, clear |
1.008 |
6.5 |
100 |
-- |
-- |
+ |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Bacteria |
ER |
0.1 |
-- |
10-20 |
5-10 |
-- |
-- |
-- |
Admission-1 |
0.1 |
-- |
10-20 |
5-10 |
-- |
waxy |
-- |
24 hours urine protein: 2.9 g
4. Urine and plasma electropheresis: Monoclonal gamma-globulin spike is present
5. Serology study: ANA, anti-HCV, cryoglobulin: negative; C3 and C4: within normal limits
6. Renal sonography: Bilateral kidneys are of normal size. No cystic lesion, mass, or hydronephrosis is identified. It is compatible with parenchymal renal disease.
7. Bone marrow biopsy: A bone marrow biopsy showed more than 80% of myeloma cells with immature and clustered plasma cells.
8. Renal biopsy: Large amount of homogenous eosinophilic material deposition in the glomeruli, intravascular, intratubular and interstitial space. Mixed acute and chronic tubular injury including inflammatory cell infiltration (mainly lymphocyte and plasma cells), tubular atrophy and fibrosis were seen. No evidence of vasculitis. Immunoflurorescent study and immunostains for immunoglobulins were positive for lambda light chain.
< Course and Treatment >
At ER, treatment was initiated for acute renal failure with hyperkalemia and fluid overload. However, the urine output was not responsive to the diuretics; thus, she was placed on hemodialysis the day after hospitalization. Because of her non-specific bone pain, reverse albumin/globulin ratio, presence of proteinuria and monoclonal gamma-globulin spike in protein electrophoresis, bone marrow and kidney biopsy were performed to reveal multiple myeloma and light chain-related kidney disease, the cast nephropathy, respectively. After her general condition and renal function were stable, she was transferred to hematology ward for further treatment.
< Analysis >
Cast nephropathy是一種腎臟的inflammatory tubulointerstitial疾病。其病理特徵主要是在multiple myeloma的病患，其腎元(nephron)的遠端，如distal tubules及collecting ducts，可見到proteinaceous cast，但若cast量夠多時，在proximal tubule及glomeruli也都可見到。這些cast主要特色為是由均質、嗜酸性且不含細胞的蛋白質所形成，這些蛋白質主要是light chain及Tamm-Horsfall glycoprotein所構成，即所謂的Bence Jones protein。有報告指出在腎功能異常的myeloma病患中，約63-87%是因cast nephropathy所引起。導致cast nephropathy的可能原因包括如 (1) Bence Jones proteins對tubular cells的直接毒性 (2) protein complex在腎元的遠端的蓄積 (3) tubular fluid的pH (4) renal plasma flow及GFR的下降 (5)全身性的電解質及水分異常 (如hypercalcemia及dehydration)。由於這些蛋白質的蓄積，就會進而引起後續的tubule受損及萎縮，而這也是一般所說的myeloma kidney的特徵。雖然有超過50%的multiple myeloma病患是死於腎衰竭，但是myeloma造成腎衰竭的原因很多，myeloma kidney一般是特指因proteinaceous cast蓄積導致的腎衰竭。不過要強調的是，雖然在部分cast nephropathy病例中可見到glomeruli內也存在cast，但就glomeruli本身而言，其結構是正常。腎臟切片除了可幫助確定診斷為cast nephropathy外，還可排除其他可能的病因。
在併發cast nephropathy的myeloma病患，其腎臟功能的惡化在myeloma的任何時期都可發生，有55%的病患是在診斷出有myeloma前即以腎衰竭表現。初期表現可能只有腎功能惡化或非特異性蛋白尿。如本例。雖然病患有糖尿病，但要小心不要將所有糖尿病患的腎功能惡化都歸因於糖尿病的自然病程。另外在本病例中，並未發現明顯惡化腎功能的危險因子，但在半年內從穩定的腎功能惡化至接受透析治療，這在穩定的糖尿病患中並不常見，因此臨床醫師必須要小心隱藏的其他病因，如本例的myeloma。當一位大於40歲的病患以蛋白尿(通常接近3 g/day)、腎功能惡化的程度可輕可重、腎臟大小正常或偏大、hypoalbuminemia及albumin/globulin 比例異常求診時，必須要考慮到cast nephropathy的可能性。高血壓並不是cast nephropathy的常見併發症，但若腎功能已相當差或已瀕臨接近須接受透析程度(如本例)，則就可能高血壓。雖然腎臟切片所見到的intraluminal cast即可診斷cast nephropathy，但重要的是診斷出其根本病因為myeloma，而此時病患如血、尿及bone marrow中的monoclonal immunoglobulin或light chain的檢驗幾乎都是陽性的。
在治療方面，基本上分為針對腎臟功能的非特異性治療及針對myeloma的特異性治療。當病患已出現腎功能惡化時，治療考量與治療一般腎衰竭並無太大差異，以穩定生命徵象、維持電解質平衡及保持適當尿量為主，若有需要就接受血液透析，但須注意可能伴隨的貧血，血小板低下或因腎功能惡化導致的凝血功能異常。另外在某些病患，還要考慮可能伴隨的hyperviscosity syndome而給予適當的治療。當然因myeloma造成的cast nephropathy，最特異性的治療就是給予針對myeloma的化學治療來降低過多的immunoglobulin，當然在此類腎功能已不佳的病患，之後化學治療藥物可能造成的傷害也必須注意。
< References >
- Primer on Kidney Diseases. 4th ed
- Nephrology 2005;10, 594–596
- Medscape: Light Chain-Associated Renal Disorders
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Case Discussion
繼續教育考題