CASE REPORT

Gross Hematuria Rapidly Deteriorated Renal Functionin a Patient with Polycystic Kidney Disease and

Klippel-Trenaunay-Weber SyndromeShogo Kurebayashi*, Kunihiko Hashimoto, Fumie Maki, Youichi Shiotsuka*,

Yukito Kokado* and Masafumi Koga

Abstract

A case of polycystic kidney disease (PKD) associated withKlippel-Trenaunay-Weber syndrome is described. A 58-year-old man with chronic renal failure experienced uri-nary retention following gross hematuria. Intermittentdrainage was necessary for significant urination for fivedays. Thereafter his urinary retention was relieved, butrenal failure progressively developed and hemodialysis wasstarted. Right hydronephrisis and hydroureter disappearedone month later. In spite of relief of obstruction, of whichthe cause was likely blood clots, renal function was not re-stored. Obstructive nephropathy was most likely explicablefor notable deterioration in renal function. Our case mighthave susceptibilities to PKDdevelopment in terms of an-giogenesis.(Internal Medicine 41: 1163-1166, 2002)

Key words: massive hematuria, renal hemorrhage, obstructivenephropathy, hemodialysis, angiogenesis

Introduction

PKDis a renal disease characterized by the growth of nu-merous cysts in the kidneys. Cysts slowly replace much of themass of the kidney, reducing renal function and leading to re-nal failure. PKDis one of the frequent causes of end-stage re-nal disease (ESRD) (1). Indeed, approximately 50% of all PKDpatients result in ESRDand need dialysis or kidney transplan-tation (2). Gross hematuria is highly frequent in PKD. Kaehnyand Gabow (3) and Gabow et al (4) have reported that 37 and42%, respectively, of autosomal dominant PKD(ADPKD) pa-tients experience gross hematuria at some time. Not only isgross hematuria the event which triggers the diagnosis of PKD,

but it also occurs during the course of the disease. Previousstudies showedthat episodes of gross hematuria represent oneof the high risk factors affecting the progression of ESRDinADPKDas well as a gene type ofADPKD1,gender, youngerage at diagnosis and developed hypertension and number ofpregnancies (5, 6). It is suggested that episodes of gross hema-turia have an unfavorable impact on long-term renal function.

Klippel-Trenaunay-Weber syndrome (KTWS), first de-

scribed in 1900 (7), is one of important vascular disorders, butit is quite rare in daily clinical practice. Patients with KTWShave anomalies with the triad of capillary nevus, varicositiesand hemihypertrophy of the extremities. KTWShas been de-scribed by several authors (8-10) as a congenital disorder ofangiogenesis.

Here, we describe a case of renal failure with acute exacer-bation associated with PKDtriggered by the gross hematuria.Gross hematuria in our patient contributed to urinary tract ob-structions, followed by notable deteriorarion on short-stand-ing renal function. To our knowledge, this is the first full casereport of PKDassociated with KTWS.Therefore, we addressetiological discussions on the link between PKDand KTWSin terms of angiogenesis.

Case ReportThe patient was a 58-year-old man with a past medical his-tory of KTWSand an abnormality in urinary analysis. Hismedical history included neither hypertension nor diabetesmellitus. No history of KTWSwas noted in his family. He hadpreviously received several operations of reduction of venousvaricosities and orthopedic procedure for overgrowth of his rightlimb. His attending physician had followed his continuous pro-teinuria and renal insufficiency for these years. He had been instable clinical condition with a serum creatinine level of around4 mg/dl for these years. He suddenly had massive hematuriawith mild flank pain and subsequent urine retention on No-

From the Department of Internal Medicine and *Urology, Kinki Central Hospital, Itami, Hyogo, #Present address: Department of Molecular Medicine, OsakaUniversity Graduate School of Medicine, Suita, Osaka

Received for publication May 20, 2002; Accepted for publication September 7, 2002Reprint requests should be addressed to Dr. Masafumi Koga, the Department of Internal Medicine, Kinki Central Hospital, 3- 1 Kurumazuka, Itami, Hyogo 664-

8533

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Kurebayashi et al

vember 30, 2001. Whena ureter catheter was inserted at theclinic, his urine was drained. Intermittent drainage with a urethercatheter were necessary for urination since the patient com-plained of the inability to urinate for the subsequent five days.On December7, although he was again able to urinate natu-rally, he was referred to our hospital due to an increase in the

Figure 1. A picture of the present patient with Klippel-Trenaunay-Weber syndrome. Multiple hemangiomas andvenous varicosities were shownin the right leg.

serum level of creatinine (7.0 mg/dl); he was admitted to ourhospital on December10, 2001. On admission we observedmultiple simple hemangiomasin the right flank and leg, com-plicated venous varicosities in the right leg (Fig. 1) and an op-eration scar in the femur for osteotomy. His blood pressurewas 140/76 mmHg.He had no complaints of urination. Bio-chemical examination showed that serum creatinine was el-evated to 9.6 mg/dl and blood urea nitrogen, sodium, potasium,chloride, calcium, inorganic phosphate and uric acid were 90mg/dl, 137 mEq/Z, 5.2 mEq/Z, 104 mEq/Z, 8.3 mg/dl, 6.8 mg/dland 9.5 mg/dl, respectively. Arterial blood gas analysis revealedmetabolic acidosis: pH 7.286, PO2 90.7 mmHg, PCO2 29.2mmHg, HCO3" 13.5 mmol//, base excess -13.8 mmol// and sO2

10

8 6-

l2-Gross hematuria

Admission

r~l^Hemodialysis

Urinary retention

2001

Feb. July Nov.Dec. 2002

Jan. Feb.

Figure 2. Clinical course of this patient with deterioration ofrenal function triggered by gross hematuria.

Figure 3. Abdominal CT scan showed hydronephrosis and ureter dilatation (arrow) with complicated cysts. (A) CT obtained onDecember 17, 2001 after admission (left side) and (B) CT on January 25, 2002 (right side).

1164 Internal Medicine Vol. 41, No. 12 (December 2002)

PKDCase Associated with KTWSyndrome

94.2%. These laboratory data indicated rapid exacerbation inrenal failure. Although the volume of urine output returned tothe normal range of more than 1,000 ml a day after his admis-sion, serum creatinine reached a peak of 9.9 mg/dl in the sec-ond day of his admission (Fig. 2). Thus, hemodialysis (HD)was started to improve his uremic state on Day 2 of admission.Maintenance HDhas been performed at a frequency of twiceto three times a week (three times initially and then twice aweek) afterwards.

An ultrasonograph and a computed tomographic (CT) scanof the abdomen revealed enlarged kidneys and multiple cystswith right side predominance. These features were consistentwith the diagnosis of PKD. The CT scan obtained after admis-sion, also showed hydronephrosis in the right kidney and di-lated ureter in the right side (Fig. 3A). These findings werediminished in another CT scan obtained one month after ad-mission (Fig. 3B). These alterations in CT scans indicated theprevious presence of reversible obstructions, which were pre-sumably due to blood coagulations formed from renal bleed-ing. Bladderscopy and cytology study showed sign of neithertumor nor stone.He was discharged on Day 58 following an operation forright inguinal herniation and an examination of brain magneticresonance angiography (MRA). MRAshowed no abnormalfindings in cerebral arteries. Serum creatinine level did not re-turn completely and remained around 6.0 mg/dl on discharge.

Discussion

The previous medical practitioner had noted that the presentpatient continued to have microscopic hematuria and proteinuriaand also had renal insufficiency. This case, however, had neverbeen diagnosed with PKDbefore he was referred to our hospi-tal. Abdominalultrasonograph on admission revealed multiplecysts with complicated cysts in both kidneys. These findingsare compatible with the criteria for PKD(1 1), even there wasno information of PKDinheritance in his family history.It was the first time for the present patient to exhibit mas-sive hematuria 7 days before his admission. No examinationafter admission suggested the presence of tumor or stone. TheCTscan showedhyperdense cysts amongnumerouscysts (datanot shown), which indicated renal hemorrhage. Massive he-maturia in this case must be due to renal hemorrhage. Grosshematuria is one of the potential complications for KTWS.InKTWSpatients, renal hemangioma (12, 13), upper urinary tracthemangioma (14) and bladder hemangioma (15) were identi-fied as the cause of the massive hematuria. No finding of he-mangiomawas detected as far as weexamined. Therefore, wespeculated that the gross hematuria was probably due to PKD.Angiography or MRAcould have supported this speculationcertainly. Bello-Reuss et al observed an extensive capillarynetwork in the cyst wall ofADPKDkidney and vascular mal-formations ( 16). Their protein analysis demonstrated expres-sion of vascular endothelial growth factor (VEGF) in the cyst ,cells and VEGFreceptor in endothelial cells. VEGFis reportedto be one of the growth factors which stimulates angiogenesis

(17). These findings indicate that the process of angiogenesisoccurs in ADPKDand this process may be necessary for cystcells to grow. It is well knownthat several complications areassociated with PKD, such as renal hemorrhage, hypertension,liver cyst, herniation and vascular abnormalities including ce-rebral aneurysm (18). In addition to the growth of cysts, renalbleeding and the formation of aneurysm could result from theangiogenesis process (16).The present case of PKDwas previously diagnosed withKTWSbecause hypertrophy of tissues and bones, hemangio-mas and venous varicosities of the affected right lower limbwere present. Thesemanifestations are comparableto those ofthe first case reported by Klippel and Trenaunay (7). It is gen-erally thought to occur sporadically, although a few studies( 1 9-2 1) have reported familial occurrence in extensive evalua-tions of relatives of KTWSpatients. In most cases of KTWS,somatic findings of the triad are distributed, suggesting somaticmutation of an as-yet-unknowngene. Onecandidate site ofgene localization could be on chromosomearm 5q or lip.Whelan et al (22) demonstrated a case of KTWsyndrome as-sociated with reciprocal translocation t(5; 1 1)(ql3.3;pl5. 1). Twostudies have showna clue to elucidate a part of the etiology ofKTWS.Klessinger and Christ (23) demonstrated that the no-tochord acts as a barrier to keep endothelial cells from cross-ing the midline of the embryo. Their results could be of sig-nificance to explain the patterning of vascular anomalies, whichgenerally appear in one-half side of the body of KTWS.Thepresent case showed the KTWStriad in the right side. It isnoteworthy that enlargement and cysts of the kidney were domi-nant in the right side. These findings may possibly support theassociation with PKDin the present case of KTWS.Moreover,Sumoyet al (24) demonstrated that blood vessel formation haddefects in zebrafish mutant for notochord formation. These tworeports suggest that the genetic alteration responsible for KTWSmay be located in endothelial cells altered in the process ofvessel formation. Thus, KTWSis described as "a congenitaldisorder of angiogenesis and vasculogenesis" (8-10), also called"asymmetric vascular syndrome" (25). As described above,angiogenesis is also fundamental to the pathological processin ADPKD(16). Therefore, we suppose that a factor critical toangiogenesis and vasculogenesis in KTWSmight contributeto PKDdevelopment including the growth of renal cysts andthe renal bleeding in the present case.Disappearance of hydronephrosis and the dilated ureter in-dicated that the obstruction in the right ureter wasreversiblyrelieved. Wefound no evidence of stone or tumor. The cause ofurinary obstruction must be blood coagulation in the right up-per urinary tract. It is possible that abnormal coagulopathymight be in part involved in the formation of blood clots in theurinary tract. In fact, cases with KTWSwere reported to com-plicate coagulopathy sequential to hemorrhageafter routinegynecologic procedure (9) and after cesarean delivery (26).Obstructive nephropathy is a term commonlyused to describeobstruction of the urinary tract and its consequences (27). Sev-eral derangements occur in long-term obstructive nephropa-thy, including decreased renal blood flow, abnormalities in tu-

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Kurebayashi et al

bular function and renal increased fibrosis (27, 28). It was re-ported that an array of growth factors, vasoactive peptides andcytokines are involved in obstructive nephropathy (29). Anobstruction persisting longer than two weeks could mainly ex-plain the progressive deterioration of renal failure. The renalinsufficiency in the present case prior to incident of massivehematuria is suspected to be susceptible to the notable deterio-ration of renal function due to obstructive nephropathy.In summary, we presented a case with PKDand KTWS,inwhich gross hematuria had discernable impact on the rapidprogression of renal failure. Wespeculate that blood clots con-sequent to gross hematuria resulted in obstructive nephropa-thy. It is important to pay close attention to an insidious ob-struction of the urine tract in cases of progressive renal dys-function after gross hematuria even if urine output is not de-creased.

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