< Presentation of Case >
A 25-year-old woman who had been otherwise well was transferred from a local health care clinic for further investigation of her abnormal renal function. This single young lady works as an accountant and stated having regular life style. She could not recall any remarkable symptom in recent six months except mild exercise intolerance. She denied any systemic disease, taking medications, or a history of exposure to heavy metals, toxic chemical substances or Chinese herbal remedies. She drank only on social occasions but denied smoking. There was no renal disease in the family history. Both her parents have been diagnosed with hypertension that was well-controlled with anti-hypertensive medications. A month ago, she underwent her first annual health exam at a local health care clinic where abnormal renal function, normocystic normochromic anemia, and hyperuricemia were noted (See laboratory test results).
At the outpatient clinic, the physical examination revealed a well-developed young woman without ill-looking but she appeared pale. The heart rate was 82 beats per minute, temperature 36.8 ℃, and blood pressure 110/68 mmHg. There was pale conjunctiva but no icteric sclera. The heart beat was regular without murmurs. Auscultation of the lung fields was normal. Abdomen examination was normal. No lower leg edema was noted.
< Laboratory and Image Study >
1. CBC and differential count
| Day after admission |
WBC
K/μL |
Hgb
g/dL |
MCV
fL |
MCHC
% |
Hct
% |
Plt
K/μL |
Band
% |
Seg
% |
Lym
% |
Health Clinic |
6.58 |
9.3 |
92 |
32 |
28.4 |
415 |
0 |
62 |
2.0 |
OPD-1 |
6.62 |
9.5 |
90 |
32 |
28.6 |
420 |
0 |
68 |
2.2 |
OPD-2 |
6.68 |
9.7 |
92 |
33 |
28.8 |
425 |
N/A |
N/A |
N/A |
OPD-3 |
6.84 |
10.6 |
94 |
35 |
30.8 |
430 |
N/A |
N/A |
N/A |
N/A: not applicable
2. Biochemistry
Day after
admission |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
Ca
mg/dl |
P
mg/dl |
GOT
U/l |
GPT
U/l |
Uric acid
mg/dl |
Albumin
g/dl |
Health Clinic |
25 |
2.3 |
138 |
4.0 |
10.0 |
3.8 |
26 |
24 |
9.5 |
4.2 |
OPD-1 |
26 |
2.2 |
137 |
4.2 |
10.3 |
3.8 |
24 |
24 |
9.4 |
N/A |
OPD-2 |
26 |
2.4 |
137 |
4.1 |
10.1 |
3.9 |
N/A |
N/A |
9.0 |
4.2 |
OPD-3 |
28 |
2.6 |
139 |
4.0 |
10.2 |
3.8 |
N/A |
N/A |
8.4 |
N/A |
3. Urinalysis
Date |
Appearance |
Specific gravity |
pH |
Protein |
Glucose |
Ketone |
Occult
blood |
Health Clinic |
yellow, clear |
1.004 |
6.5 |
-- |
-- |
-- |
-- |
OPD-1 |
yellow, clear |
1.002 |
6.7 |
-- |
-- |
-- |
-- |
OPD-2 (first morning voiding) |
yellow, clear |
1.003 |
6.6 |
-- |
-- |
-- |
-- |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial
cells |
Cast |
Bacteria |
Health Clinic |
0.1 |
-- |
-- |
<5 |
-- |
waxy |
-- |
OPD-1 |
0.1 |
-- |
-- |
<5 |
-- |
waxy |
-- |
OPD-2 (first morning voiding) |
0.1 |
-- |
-- |
-- |
1-3 |
waxy |
-- |
4. Blood iron profile (done at OPD-1): total serum iron, 144 μg/dL (reference, 60-160); ferritin,: 126 ng/mL (12-160); total iron-binding capacity, 400 μg/dL (250-460)
5. Renal sonography: Bilateral kidneys are of normal size. Loss of corticomedullary differentiation was noted. No obvious cystic lesion was identified. The findings were consistent with parenchymal renal disease.
6. Computed tomography (CT) of the abdomen with administration of contrast medium: Bilateral normal-sized kidneys. No space-occupying lesion or obstruction was seen along the urinary tract. Multiple cysts sized 0.5 to 2 mm are seen in the medullar and around corticomedullary region. No other remarkable finding was seen.
< Course and Treatment >
This young woman presented with normocytic normochromic anemia, hyperuricemia, low specific urine gravity of the first voiding specimen in the morning and impaired renal function. In addition, the abdomen CT identified multiple tiny cysts located around the corticomedullary region. Based on the laboratory and imaging studies, this young woman was tentatively diagnosed as medullary cystic kidney disease (MCKD). However, MCKD is a genetic disease inherited in an autosomal dominant pattern which is not compatible with her family history. We hypothesized there might be a de novo mutation of the MCKD causal gene in this patient. This may explain that she is the only one that is affected in her family. The further confirmative diagnosis will be done using molecular genetic analysis to identify the causal gene, either MCKD1 or MCKD2. We have sent the blood sample to a genetic laboratory for identification of mutation. Renal biopsy was not considered since it may not provide extra information regarding treatment or future prognosis. Since MCKD has two clinical variants, MCKD type 1 and type 2 depends on the age of ESRD onset, it was too early to define which type this patient might have without long-term follow up. However, all MCKD patients will inevitably progress to end-stage renal disease in their later life. There is no definite or useful treatment for MCKD and our treatment plan was basically adopted from the treatment that is used for patients with chronic kidney disease, such as diet modification, and blood pressure and proteinuria monitoring. Her hyperuricemia was treated with diet modification and allopurinol. The normocytic normochromic anemia was considered to be associated with inadequate erythropoietin (EPO) production in MCKD, and therefore, EPO was prescribed to correct her anemia. This patient was then regularly followed up at the outpatient clinic. We will start to treat patient with ACEI or ARB when any proteinuria and elevated blood pressure was noted.
< Analysis >
Medullary cystic kidney disease (MCKD) 和nephronophthisis (NPH) 是型態上類似的遺傳疾病。兩者的相似處包括，都屬於遺傳性的ciliopathy、腎臟大小正常或稍小、都具有兩側corticomedullary cysts及tubulointerstitial sclerosis，並且最後都會造成末期腎病變 (end-stage renal disease, ESRD)，因此許多文獻或教科書都將兩者一起討論，或統稱為nephronophthisis-medullary cystic kidney disease complex，但隨著分子遺傳學的進步，又有逐漸將兩者區分的趨勢。兩者在型態上相當的接近，臨床上在早期也都沒有太明顯的症狀，頂多有多尿的現象，至於晚期兩者的症狀則都是以末期腎病變的症狀為主。儘管如此，medullary cystic kidney disease 和 nephronophthisis 之間還是有所差異。Nephronophthisis是屬於隱性遺傳 (autosomal recessive, AR)，而MCKD則為顯性遺傳(autosomal dominant, AD)。基本上，nephronophthisis發病較早，從嬰幼兒到青少年都有，因此nephronophthisis又可依據發病年紀分為三型: infantile型、juvenile型及adolescent型，其中最常見的為juvenile型。Infantile型的主要特色為在兩歲前逐漸進展到末期腎病變，是由於NPHP2基因的突變所導致。組織學上可見collecting duct的cystic dilatation，但通常無tubular basement membrane的變化，臨床上則會有嚴重高血壓及稍大的腎臟。Juvenile型的特色為在十幾歲左右會進展到末期腎病變 (平均13歲)，總共與7個基因的突變有關 (NPHP1、NPHP4、NPHP5、NPHP6、NPHP7、NPHP8及NPHP9)。組織學上可見到small medullary cysts、extensive及advanced tubular atrophy、增厚的tubular basement membrane及明顯的interstitial fibrosis。而adolescent型則是在20歲左右進展到末期腎病變，並與NPHP3基因突變有關，組織學變化則類似juvenile型。
MCKD則以成年期發生的末期腎病變為主要特徵，除了hyperuricemia及gout以外，少腎外器官的侵犯。MCKD第一型的病患多在62歲左右發生末期腎病變，是因為MCKD1基因突變所導致。而MCKD第二型的病患則較早發生末期腎病變，平均約在32歲，是由於MCKD2基因突變導致。Nephronophthisis-medullary cystic kidney disease發生的機率相當低，年發生率約0.05%。男女之間發生率並無差別，但nephronophthisis是在20歲前發生末期腎病變的最主要遺傳性腎病變。Nephronophthisis-medullary cystic kidney disease complex 以歐美報告居多，但是台灣也曾報告過一些病例。
在診斷方面，病史、實驗診斷及影像學檢查都很重要。由於NPH及MCKD都是以tubular injury為主，因此兩者的臨床表現及症狀也類似，早期以尿液濃縮能力下降為主、伴有尿鈉流失及最後不可逆的進展到末期腎病變。尿液濃縮能力下降可以在腎功能惡化前就出現。因為尿液濃縮能力下降，所以會出現多尿、尿床或夜晚需要頻繁喝水。另外，若睡眠時沒有進食水分，早上解的第一次尿應是最濃縮的，但在NPH及MCKD的病患，如本病例，即使一夜未飲用任何液體，但可注意到尿液的specific gravity仍偏低(OPD-2)，這也代表了尿液濃縮能力的下降。此外尿液檢查少見蛋白尿及血尿。一般當病患發病時，都可見到貧血，由於erythropoietin (EPO)是由peritubular capillary的內皮細胞製造，在nephronophthisis-medullary cystic kidney disease complex間接受到影響，導致EPO的合成減少，進而引起貧血，但是MCKD及NPH的貧血嚴重程度與腎功能惡化的程度並不成比例，即使腎功能並未太差，貧血卻是相對較嚴重。影像學檢查方面，腎臟超音波的檢查並不具特異性，腎臟的大小並不會有太大變化，但可見到cortex與medulla之間的界限 (corticomedullar differentiation) 消失，由於cyst相當小，所以腎臟超音波不一定能發現cortex與medulla之間的cyst。因此即使腎臟超音波沒有發現cyst，也不能據此排除nephronophthisis-medullary cystic kidney disease complex的可能。最具特異性的影像學檢查為contrast-enhanced thin-section CT。在1至2 mm厚度的橫切面下，可以在medulla及corticomedullary junction發現許多約0.5至2mm的cysts。根據以上表現，若單獨根據症狀、實驗診斷及影像學檢查，兩者相當類似，有時不易區分，不過兩者之間仍可依發生腎病變的年紀及遺傳模式來區分，這說明了病史在診斷NPH及MCKD上的重要。一般來說，nephronophthisis發生末期腎病變的年紀約在25歲或之前，若在25歲之後，則要考慮medullary cystic kidney disease。另外，nephronophthisis會有較多的腎外併發症，如oculomotor apraxia,、retinitis pigmentosa及liver fibrosis等，而MCKD的腎外併發症則局限在hyperuricemia 及 gout。此外，nephronophthisis-medullary cystic kidney disease complex在組織學上也有一些特殊變化，然而由於腎臟切片對病患的預後並無影響，所以如果根據病史及非侵入性檢查已可確定診斷時，並無必要進一步做腎臟切片。再加上近來許多醫院開始提供分子遺傳的診斷，若根據臨床表現及分子遺傳的輔助診斷，要確定病患的診斷幾乎沒有問題，也更沒有做腎臟切片的必要。不過若做了腎臟切片，在組織學上可見到nephronophthisis與medullary cystic kidney disease之間並無不同，基本上歸納起來就是以tubule、間質的變化及cyst的形成為主。早期可見到不完整的tubular basement membrane及不規則的增厚，晚期則會見到tubular atrophy、corticomedullar junction區域有cyst的形成及interstitial fibrosis，而cyst主要是由distal convoluted tubule 及 medullary collecting duct處形成。
在治療方面，目前並無特定治療方法，所以是以症狀治療為主。如貧血就以EPO治療、有腎衰竭的症狀也依一般慢性腎病原則處理，其他並無差別。由於病患最終都一定會進展到末期腎病變，因此病患的心理建設、慢性腎病教育及定期追蹤都是相當重要的。進展到末期腎病變後，可以接受透析治療或腎臟移植，目前並無移植後復發報告。
< References >
- Primer on Kidney Diseases. 4th edition.
- eMedicine: Medullary cystic disease
|
Case Discussion
繼續教育考題