Nej m Cpc 1004086

8/12/2019 Nej m Cpc 1004086

1/13

case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 363;5 nejm.org july 29, 2010 463

Founded byRichard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d.,Associate EditorJo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters,Assistant Editor

From the Departments of Medicine (H.B.),HematologyOncology (E.C.A.), Urology(D.M.D.), Radiology (R.N.U.), and Pathol-ogy (R.B.C.), Massachusetts General Hos-pital; and the Departments of Medicine(H.B., E.C.A.), Surgery (D.M.D.), Radiol-ogy (R.N.U.), and Pathology (R.B.C.), Har-vard Medical School both in Boston.

N Engl J Med 2010;363:463-75.

Copyright 2010 Massachusetts Medical Society.

Presentation of Case

Dr. David B. Sykes(HematologyOncology): A 49-year-old man was admitted to thishospital because of erythrocytosis, perinephric collections of f luid, and acute renalfailure.

The patient had been well until 7 years earlier, when routine testing at anotherfacility revealed a hematocrit of 58.1%; the level of erythropoietin was 16.2 mIU permilliliter (reference range, 4.1 to 19.5). Ultrasonography of the abdomen reportedlyrevealed normal-size kidneys, with no hydronephrosis or cysts, and several hepaticlesions (approximately 1 cm in diameter) that were consistent with hemangiomas.A presumptive diagnosis of polycythemia vera was made, and therapeutic phleboto-my was performed every 6 to 8 weeks thereafter. Computed tomography (CT) of theabdomen 8 months later showed no abnormalities. Thirteen months and 16 monthslater, the erythropoietin level was 977 and 1747 mIU per milliliter, respectively.A small IgG kappa paraprotein was detected; testing for urinary Bence Jones pro-tein was negative.

Ten months before admission, shortness of breath and dyspnea on exertion de-veloped. During the next 3 months, the patient was evaluated at another facility.CT of the chest was performed according to a protocol for detection of pulmonaryemboli; the scans showed moderate bilateral pleural effusions, without evidence ofpulmonary embolism. Sampling of the pleural fluid by thoracentesis revealed a tran-

sudative fluid; no organisms were seen on Grams staining, and the culture wassterile. Ultrasonography of the abdomen reportedly revealed multiple new bilateralperinephric cysts and a small amount of ascites. The results of echocardiographywere normal. Levels of albumin, bilirubin, lipase, and amylase and tests of liverfunction were normal; tests for antibodies to double-stranded DNA, viral hepatitis(hepatitis A, B, and C viruses), and human immunodeficiency virus were negative;other results are shown in Table 1. Analysis of a 24-hour urine collection showednormal levels of protein and creatinine clearance.

Six months before admission, pathological examination of a bone marrowbiop-sy specimen showed a mildly hypercellular marrow with trilineage hematopoiesis;

Case 23-2010: A 49-Year-Old Manwith Erythrocytosis, Perinephric Fluid

Collections, and Renal FailureHasan Bazari, M.D., Eyal C. Attar, M.D., Douglas M. Dahl, M.D.,

Raul N. Uppot, M.D., and Robert B. Colvin, M.D.

The New England Journal of Medicine

Downloaded from nejm.org on February 18, 2014. For personal use only. No other uses without permission.

Copyright 2010 Massachusetts Medical Society. All rights reserved.

8/12/2019 Nej m Cpc 1004086

2/13


n engl j med 363;5 nejm.org july 29, 2010464

Table1.

ResultsofLaboratoryTests(Blood,

Fluid,andUrineAnalyses).*

Variable

ReferenceRange,

Adults

1stClinic,

9Mo

before

Admission

1stClinic,

6Mo

before

Admission

2ndClinic,

5Mo

before

Admission

2ndClinic,

4Mo

before

Admission

T

hisHospital,

Ou

tpatientClinic,

6

Daysbefore

Admission

ThisHospital,

OutpatientClinic,

1DaybeforeAdmissio

n

ThisHospital,

3rdand4th

HospitalDays

Blood

Blood

Perinephric

Fluid

U

rine

Blood

Hematocrit(%)

41.053.0

(men)

48.1

44.3

39

41.4

55.0

57.0

55.5

Hemoglobin(g/dl)

13.517.5

(men)

12.2

12.1

10.6

11.0

Platelets(permm

3)

150,0

00350,0

00

193,0

00

609,0

00

339,0

00

506,0

00

378,0

00

427,0

00

288,0

00

Erythropoietin(mIU/ml)

4.016.0

>2000

9648

4515

493

3198

Reticulocytes(%)

0.52.5

2.5

3.4

25-HydroxyvitaminD(ng/ml)

>32

15

13

Sodium(

mmol/liter)

135145

140

141

141

140

137

133

131

90%)but may present asynchronously. Limited descrip-

tions of the findings on pathological examina-tion of the kidneys have been reported in a mi-nority of cases.2,4,5,7,19,35,37One case had dilatedinterstitial spaces with prominent D2-40 stain-ing35; another had dilated lymphatics and glom-eruli in direct contact with dilated interstitialspaces.4

Lymphangiectasis is believed to be a develop-mental abnormality of the lymphatics. A geneticcomponent is suggested by the rare occurrencein siblings4and the occasional association withextrarenal hemangiomas and lymphangiomas.34Acquired injury to the lymphatics due to trauma,scarring, or inflammation is another proposedmechanism.34,38The mechanism that prevents thelymphatics from reconnecting through collater-als, as they do after renal transplantation, is un-known.30,39

Dr. Nancy Lee Harris(Pathology): Dr. Sykes, willyou tell us how the patient is?

Dr. Sykes: The erythropoietin level fell from4500 to 450 mIU per milliliter postoperatively,but within a week, the level rose to more than

4000 mIU per milliliter and has remained at thatlevel. The serum level of VEGF was normal on twooccasions. After discharge, the patient initiallydid well. About 6 months after the initial proce-dure, he noted increasing abdominal protuber-ance, and we suggested that he undergo a repeatCT study. May we review the recent scans?

Dr. Uppot:The immediate postoperative CT scanshows resolution of the left perinephric fluid.

Minimal fluid surrounds the right kidney andappears in the right retroperitoneal space (Fig. 1D).However, a CT scan obtained 7 months latershows a dramatic increase in ascites throughoutthe peritoneum (Fig. 1E).

Dr. Sykes:The fluid (4 liters) was drained at ahospital near the patients home; the composi-tion was identical to that seen in the past. Ap-proximately 12 months after discharge, pain anddiscoloration developed in several of the patientstoes; duplex ultrasonography of the lower limbsdid not reveal venous thrombosis. Test results foranticardiolipin antibodies, lupus anticoagulant,and cryoglobulinemia were negative. Anticoagu-lation was begun, and the discoloration resolvedover a period of 3 to 4 days. The patients treat-

ment was transitioned to warfarin.Approximately 18 months after discharge, thepatient feels well and works full time. He has amoderate amount of free intraperitoneal f luid. Heundergoes therapeutic phlebotomy every 12 weeksto maintain a hematocrit of 45%. His IgG kappamonoclonal gammopathy is stable. Echocardiog-raphy with the injection of agitated saline showeda right-to-left intrapulmonary shunt of 9%; how-

Figure 2 (facing page).Renal-Biopsy Specimens.

Panel A shows a kidney that is normal-appearing aside

from scattered dilated spaces between tubules (arrows).One of the spaces contains material (probably Tamm

Horsfall protein or plasma proteins) that was positive on

periodic acidSchiff staining (arrowhead). Panel Bshows that there are few or no lining cells in the spaces

between the tubules (arrow) that are detectable by anti-bodies to CD34 on immunoperoxidase staining; this an-

tigen is normally expressed on blood and lymphatic en-dothelium. Peritubular capillaries are positive, and a few

are present on the side of the space but do not line thechannel. Tubules are in immediate proximity to the chan-

nels. Panel C shows no immunoperoxidase staining for amarker of lymphatic endothelium D2-40 in the tissue

spaces (arrows). However, small lymphatic vessels areincreased in number in the cortex and extend to a loca-

tion near the glomeruli (arrowhead). An Epon-embedded

section that was 1-m thick (Panel D, toluidine blue)shows no apparent cellular lining in the channel between

the tubules (arrow). Tubules seem to float in the space,and little but the tubular basement membrane separates

the epithelium from the tissue space. Panel E confirmsthe lack of an endothelial lining on electron microscopy

of the spaces (arrow). Panel F shows the presence of di-lated lymphatics along a small artery (arrow) in a sample

obtained during the original needle biopsy, with immu-noperoxidase staining for D2-40.




8/12/2019 Nej m Cpc 1004086

11/13

case records of the massachusetts general hospital


ever, no corresponding abnormality was seen onchest imaging, and his oxygen saturation remainsnormal. Genetic testing for mutations associatedwith HHT was negative.

After consulting with Dr. Noopur Raje of He-matology and Oncology, we recommended thatthe patient begin a course of lenalidomide, withplans to monitor the erythropoietin level, M com-

ponent, and the free fluid in his abdomen. Hehas been reluctant to initiate treatment, since heis feeling well and is concerned about potentialside effects of the medication. The patient and hisdoctors are very interested in any insights fromphysicians who may have seen similar cases orcould provide suggestions for further workup ormanagement of this seemingly unique problem.

A B

DC

FE




8/12/2019 Nej m Cpc 1004086

12/13


n engl j med 363;5 nejm.org july 29, 2010474

Anatomical Diagnoses

Renal lymphangiectasis (hygroma renalis), withdissection of cortical interstitium and capsule byglomerular filtrate or reabsorbed tubular fluid,presumably due to lymphatic obstruction at an un-known site.

Monoclonal gammopathy of undetermined sig-nificance (IgG).

We request that any reader with thoughts about the diagnosis,further evaluation, or treatment contact Dr. David Sykes ([email protected]) or any of the authors.

This case was presented at the Nephrology Grand Rounds,May 5, 2009.

Dr. Attar reports receiving payment for the development ofeducational presentations from Celgene; Dr. Dahl, having anequity interest in Pfizer and Amgen; and Dr. Uppot, receivinggrant funding to Massachusetts General Hospital on his behalffrom SGR Traxtal/Philips.

No other potential conflict of interest relevant to this articlewas reported. Disclosure forms provided by the authors are avail-

able with the full text of this article at NEJM.org.We thank Catherine Stolle, Ph.D., for the sequencing of the

VHL coding region, and David Sykes, M.D., for his assistance in

preparing the case history.

References

Ashraf K, Raza SS, Ashraf O, Memon1.W, Memon A, Zubairi TA. Renal lymph-angiectasia. Br J Radiol 2007;80(954):e117-e118.

Levine E. Renal lymphangiectasia.2.Radiology 1992;182:582. abstract.

Llorente JG, Garcia AD, Sacristan JS,3.

Chicharro GN. Renal lymphangiectasia:radiologic diagnosis and evolution. Ab-dom Imaging 2002;27:637-9.

Meredith WT, Levine E, Ahlstrom4.NG, Grantham JJ. Exacerbation of famil-ial renal lymphangiomatosis during preg-nancy. AJR Am J Roentgenol 1988;151:965-6.

Murray KK, McLellan GL. Renal5.peripelvic lymphangiectasia: appearanceat CT. Radiology 1991;180:455-6.

Upreti L, Dev A, Kumar Puri S. Imag-6.ing in renal lymphangiectasia: report oftwo cases and review of literature. ClinRadiol 2008;63:1057-62.

Younathan CM, Kaude JV. Renal7.peripelvic lymphatic cysts (lymphangi-omas) associated with generalized lymp-hangiomatosis. Urol Radiol 1992;14:161-4.

Tefferi A, Vardiman JW. Classification8.and diagnosis of myeloproliferative neo-plasms: the 2008 World Health Organiza-tion criteria and point-of-care diagnosticalgorithms. Leukemia 2008;22:14-22.

Greer J, ed. Wintrobes clinical hema-9.tology. 11th ed. Philadelphia: LippincottWilliams & Wilkins, 2004.

Ang SO, Chen H, Hirota K, et al. Dis-10.ruption of oxygen homeostasis underliescongenital Chuvash polycythemia. NatGenet 2002;32:614-21.

Swerdlow SH, Campo E, Harris NL, et11.al., eds. WHO classification of tumoursof haematopoietic and lymphoid tissues.4th ed. Geneva: World Health Organiza-tion, 2008.

Krishnan SG, Valderrama E, Wagner12.JD, et al. Monoclonal gammopathy pre-senting as recurrent nephrotic syndrome:

therapeutic implications. Am J Med Sci2007;333:313-6.

Sanders PW. Renal involvement in13.plasma cell dyscrasias. Curr Opin Neph-rol Hypertens 1993;2:246-52.

Gandhi GY, Basu R, Dispenzieri A,14.Basu A, Montori VM, Brennan MD. Endo-

crinopathy in POEMS syndrome: the MayoClinic experience. Mayo Clin Proc 2007;82:836-42.

Lee H, Meier FA, Ma CK, Ormsby AH,15.Lee MW. Eosinophilic globules in 3 casesof glomeruloid hemangioma of the headand neck: a characteristic offering moreevidence for thanatosomes with or with-out POEMS. Am J Dermatopathol 2008;30:539-44.

Caglioti A, Esposito C, Fuiano G, et al.16.Prevalence of symptoms in patients withsimple renal cysts. BMJ 1993;306:430-1.

Bisceglia M, Galliani CA, Senger C,17.Stallone C, Sessa A. Renal cystic diseases:a review. Adv Anat Pathol 2006;13:26-56.

Minor TX, Yeh BM, Horvai AE, Abra-18.hams HM, Meng MV, Stoller ML. Symp-tomatic perirenal serous cysts of mulleri-an origin mimicking renal cysts on CT.AJR Am J Roentgenol 2004;183:1393-6.

Cadnapaphornchai MA, Ford DM, Ty-19.son RW, Lum GM. Cyst ic renal lymphang-iectasia presenting as renal insufficiencyin childhood. Pediatr Nephrol 2000;15:129-31.

Meltzer E, Goshen E, Fridman E, Sidi Y.20.Diffuse lymphangiomatosis a fatal casewith atypical skeletal features. Am J MedSci 2008;336:445-8.

Colucci S, Taraboletti G, Primo L, et21.

al. Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease. J BoneMiner Res 2006;21:207-18.

Sarikaya B, Akturk Y, Bekar U, To-22.paloglu S. Bilateral renal lymphangioma-tosis mimicking hydronephrosis: multi-detector CT urographic findings. AbdomImaging 2006;31:732-4.

Burton IE, Sambrook P, McWilliam LJ.23.Secondary polycythaemia associated withbilateral renal lymphocoeles. PostgradMed J 1994;70:515-7.

Mani NB, Sodhi KS, Singh P, Katariya24.S, Poddar U, Thapa BR. Renal lymphan-giomatosis: a rare cause of bilateral neph-

romegaly. Australas Radiol 2003;47:184-7.Shaheen M, Hilgarth KA, Hawes D,25.

Badve S, Antony AC. A Mexican man withtoo much blood. Lancet 2003;362:806.

Zapzalka DM, Krishnamurti L, Maniv-26.el JC, DiSandro MJ. Lymphangioma of therenal capsule. J Urol 2002;168:220.

Fakhouri F, Grunfeld JP, Hermine O,27.Delarue R. Angiotensin-converting en-zyme inhibitors for secondary erythrocy-tosis. Ann Intern Med 2004;140:492-3.

Eisner BH, Tanrikut C, Dahl DM. Chy-28.luria secondary to lymphorenal fistula.Kidney Int 2009;76:126.

Schacht V, Dadras SS, Johnson LA,29.Jackson DG, Hong YK, Detmar M. Up-regulat ion of the lymphatic marker podo-planin, a mucin-type transmembraneglycoprotein, in human squamous cellcarcinomas and germ cell tumors. Am JPathol 2005;166:913-21.

Colvin RB. Emphatically lymphatic.30.J Am Soc Nephrol 2004;15:827-9.

Ishikawa Y, Akasaka Y, Kiguchi H, et31.al. The human renal lymphatics undernormal and pathological conditions. His-topathology 2006;49:265-73.

Kerjaschki D, Regele HM, Moosberger32.I, et al. Lymphatic neoangiogenesis in hu-man kidney transplants is associated withimmunologically active lymphocytic infil-

trates. J Am Soc Nephrol 2004;15:603-12.Rivalta F. Su due casi di cisti nel tes-33.suto adiposo dellilo del rene. Arch SciMed (Torino) 1889;13:73-85.

Henthorne JC. Peripelvic lymphatic34.cysts of the kidney. A review of the litera-ture on peripelvic cysts. Am J Clin Pathol1938;8:28-38.




8/12/2019 Nej m Cpc 1004086

13/13

case records of the massachusetts general hospital


Ueda S, Yanagida H, Sugimoto K, et35.al. Chronic renal insufficiency in a boywith cyst ic renal lymphangiectasia: mor-phological findings and long-term follow-up. Clin Nephrol 2007;68:416-21.

Wadhwa P, Kumar A, Sharma S, Dogra36.PN, Hemal AK. Renal lymphangiomato-sis: imaging and management of a rare

renal anomaly. Int Urol Nephrol 2007;39:365-8.

Mattoo TK, Giangreco AB, Afzal M,37.Akhtar M. Cystic lymphangiectasia of thekidneys in an infant with nephrotic syn-drome. Pediatr Nephrol 1990;4:228-32.

Sollinger HW, Starling JR, Oberley T,38.Glass NR, Belzer FO. Severe weeping

kidney disease after transplantation: a casereport. Transplant Proc 1983;15:2157-60.

Langer RM, Kahan BD. Incidence,39.therapy, and consequences of lymphoceleafter sirolimus-cyclosporine-prednisoneimmunosuppression in renal transplantrecipients. Transplantation 2002;74:804-8.Copyright 2010 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of theJournalwho uses the Case Records of the Massachusetts General Hospital as a teaching exercise or referencematerial is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of theimages from the CPC, not only those published in theJournal. Radiographic, neurologic, and cardiac studies, gross specimens,and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of theCase Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the currentsubscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].


Documents

Nej m Cpc 1004086