Hydronephrosis and polycythemia

HYDRONEPHROSIS

IR\‘IN ELLIOT

HIRSCH, LEITER,

AND POLYCYTHEMIA

AI. II.

31. D.

From the Department 1ledical Center, New

of Urology Beth York, New York

Israel

ABSTRACT--Polyu4themia is consistently produced in animals undergoing expcrimcntal hl4tlrorlrJIJlro.~i.V. This hematologic rcj.sponsc is thought to he mediated by a lnicro~ir~lllator!4 i~1st~ltal;d a mow accelerated elaboration of erythropoietin by the hydronephrotic kidney, While an associatiol1 lwttcrcrl hydroncphrosis and polyc!4themia has beer1 reported iu humans. it is a rclatiuely rare cwwt. Further .vtudies are necessary to cxplaiu why this should he so. as tie11 a.Eto c’ollfirm that the 1’ol!4c,yrhc~nlia in humans is .secondar!4 to an increased prod~~ction of crytlzropoictilr.

Hemntologic changes in response to renal aberrations run the gamut of anemia to erythrocytosis. Chronic renal failure is invariably associated with anemia hased on erythropoietic failure, whereas certain renal lesions such as hypernephroma, Wilms tumor, renal adenoma, and cystic disease ma\’ he accompanied l,,r polycythemia that resol\.es with nephrectonr\.. Central to these obser\-ations is the notion of hemopoibtinc and the humoral stimulus for hematopoiesis first described b!, Cal-not and Deflandre in 1906.’ Data accum1xlated over the past two decades support a renal role in eq-thropoiesis2 4 and localization of er\-thropoietill production to, among other sites, the juxtaglomerular cells.>.” When elaborated, this mucoprotein effects differentiation of bone marrow. stem cells into erythrocyte precursors. Less generall), appreciated, and certainly less well docr~mented, is unilateral hydronephrosis as another example of’renal disease with associated polycythemia. Elevated serum er!pthropoietin le\,els, howe\rer, have been reported in patients with unilateral h>.dronephrosis a11c1 have normalized following nephrectomy.;.’ In an attempt to document this association and establish criteria fi)r diagliosis, this report siiinmarizes 11 case reports of‘ associated polyc!Themia with unilateral h!~droi~cll’lii-osis, adds an additional case. and reviews the eqthropoictic response to experiniental h~.dl.ot~C~l~hrosis in animals.

Case

Report

A sixty-nine-year-old man was admitted for surgical treatment of left obstructed megaureter known to have existed for twel\re l-ears, and accompanied by refractory reciment urinary tract infection. Ten )‘ears previously a rorbtine blood count re\~ealed erythroqrtosis (hemoglobin 21 Gm/lOO ml! which had since lxen treated tq periodic vencsection. He had a seven-year histoq of hypertension, well controlled l,,r medication. Physical examination was unrelnarkable. Urinalysis showed 10 to 20 white bloodcells with Hemoglobin was 19.6 occasional clumps. Gm /lOO ml and hematocrit ,57.7%. Red blood cell count was 6,14O,OOO/cu nlm; white blood cell count was 7,8OO/cu nlm. Serum yr!.thropoietin \vas 75 mIV/rnl (normal:15-59 mIlJ/ml). Intra\~enous p!.elogram (IVP) showed distal grade 2 ureterectasis and h>dronephrosis and narrowing of the left ureterovesical junction (Fig. 1). A stone was present in the left lower cal~~x. After serial \,enesections preoperative hemoglobin was 17.1 Gn1/IOO ml and hematocrit 49.3%. ‘Phc patient 11nder\vent distal Ieft 11reteral tapering and ur~teroneoc!.stostom~. Six months later an I\‘P showt~d left h-dronephrosis unchanged from the prcq~erati\~e stud!.. Hemog:lol)in was 15.2 Gn1/100 ml, hcmatocrit 43. lc/c, and sc’riim c,r!,tlliropoietin Ic\zel reniainc4 elevated.

and then correlating these ropoietic response, with the parenchymal thickness of the nephrectomized kidney, the!, determined that the pressure generated kvithin the renal pelvis is the critical factor in the de\~elopnient of er>?hrocytosis. While these investigators did not measure serum erythropoietin levels, the!. noted that the er!.thropoietic response (as measured in terms of and red hlootl cell hemoglobin, hematocrit, count) can be classified according to the degree and pattern of pelvic pressure produced.

Experimental

Hydronephrosis

The erythropoietic response to experimentall!, induced hydronephrosis has been studied b? ureteral ligation and determination of various resultant erythropoietic parameters. Comparing unilaterally ligated rabbit ureters with controls, Volzhskaya!’ observed: (1) the mean erythropoietic activity is highest in the acute phase and continues as long as three months after ligation; (2) serum erythropoietin levels are nearly double those of controls; (3) there is elevation in hemoglobin, hematocrit, and red blood cell count in the experimental group; and (4) loose ligation and partial ureteral obstruction yielded the most impressi\,e elevations of these erythropoietic parameters. This final observation was further elucidated b, Toyama and Mitus”’ who quantitated the degree ofhydronephrotic pressure in the renal pelvis and the ensuing levels of erythrocytosis. Studying manometrically controlled renal pelvic pressures after ureteral ligation and the resulting eryth-

They observed erythrocytosis in 60 per cent of laborator\. animals, the onset ofwhich was as earl! as t\vo to’three Lveeks: it eventually subsided. In rabbits with low-pressure hydronephrosis (intrapel\ic pressures ranging from 23 to 33 cm water) erythrocytosis developed, whereas in those with high-pressure hyclronephrosis (greater than 37 cm H,O) erythrocytosis did not de\,elop. Those with intermittent hydronephrosis produced b!r periodic removal of urine from the obstructed renal pelvis demonstrated the highest incidence of erythrocytosis, the most prolonged response, and the best preserlred renal parenchyma. LVhile nonerythrocytic animals showed marked renal atrophy, erythrocytic animals showed only moderate thinning of the renal parenchyma. While most animal studies”.” point to erythropoietin as the mediator between polycythemia and ureteral obstruction, Melby, Murphy, and Mirand”: failed to show an!’ significant response in plasma erythropoietin activity in rhesus monkeys following production of experimental hydronephrosis. Their study, however, remains an exception to the general observation that a true state of erythroqrtosis exists in most experimentally induced unilateral hydronephrosis since the rise in hemoglobin and hematocrit is associated with increased total red cell volume, accelerated incorporation ofFvi!’ into the red blood cell (RBC) precursor, and an enhanced bone marrow erythroid activit),. In obstructive nephrogenic pol!q+hemia we postulate the concept of “pressure stimulatiol;” of the kiclne!. to accelerate erythropoietin production by a mechanism depicted in Figure effects of both intra2.’ ’ The superimposed parenchymal and intrapelvic pressure in h,zdronephrosis cause a circulator~~ disturbance at the level of the efferent arterioles and vasa recta change with tubular that translates into ischeniic atrophy. lllav

This schema was arrived at after microscopic examination of the renal parenchyma following ureteral ligation in rabbits. Indeed, angiographic

stud>- of h~.droIlephrotic rabbit liidne!~s shows marked dilninution in renal blood flo~v within t\venty-.fbur hours after ureteral ligation. I: The result is ischemic pressure necrosis of the tub& cells and subsequent c\-tolysis which, by inducing a \.asomotor disturbance, ma!. further compromise renal arterial supplv. I’; In addition, the causal effect of renal ischemia and hastened erl-thropoietin production can be inferred from \zarious other experimental obser\~ations. For example, the association of an intact juxtaglomerul;r apparatus (JGA) and glomerulus and the preservation oferythropoietic function in the setting of advanced hydronephrosis have led to specldation that the JGA ma)’ be a major site of erythropoietill production. Also. experimental renal hypoxia produced b>, renal arter\. constriction in animals results in a significant increase in plasma erythropoietin levels and erythroq,tosis. I7 Moreover, both renal arteq- c:onstriction’” and ureteral ligation” have been associated with elevated erythropoietin levels and altered granularit)(a reflection of ll~pel-“(~ti\.it!,) of the JGA. One might infer, theref;)re. the existence of a corresponding clinical triad of pol!qthemia, renal arteq. stenosis, and 11)pertension. In f&t, such a rare triad has been reported. I!’ The mechanism by which h>.dronep hrosis results in polycythemia is, therefore, probabl). attributable to the microangiopathic effects of‘renal parenchymal ischemia. This serves :LSthe stimulus to excessive erythropoietin elaboration and sllbsequent pol>~cythemia. In this fashion. the pressure stimulus of h!,droneptir(~sis

is translated production.

into

Clinical

accelerated

rr!~thropoietin

Hydronephrosis

Clinically observed polycythemia associated u.ith hydronephrosis was first reported by Cooper and Tuttle in 1958,‘” and sporadic reports have appeared since then.“’ Oi Table I summarizes the experience in 11 such patients in whom a primar), puhnonaq causation as well as pal\-cythcmia vera were I-tiled out. Cases of tumor-associated h,,dronephrosis have also been excluded. All of these patients presented with simultaneous poll,cythemia and hydronephrosis with resollltion of the former by elimination of the h>,dronephrosis, usuall!, b,r nephrectoln!.. Theil henratologic profile is compared pre- and postnephrectonr!. and allows for preoperative phlebotomy in most. Case 8 is particularly interesting in that he had preliminar! lueteral drainage prior to nephrectomy. t’rographic, gross, and microscopic findings as well as an assessment of the presence or absence of residual \,iable renal parenchyma are also tabulated. All patients were men between the ages of twenty-one and sixty-five years. whose preoperati1.e hemoglobins ranged front 1X.X to 23.5 Gm/ 100 ml, and whose hematocrits ranged from 57 to 71% (means 20.8/64.5). Postoperativel?. these levels fell to a mean of 14.1 Cm/100 ml and 45% , respecti\,el!.. The onset of remission of er)throcytosis ranged from one week to fifteen months. Earl!, resolution was not attributr~d to

T.UX.E I. Case No.

Reference

Age. Sex

Reported Ilemoglobi” PreIPost

Hematocrit Pm/Post

19/1.3

.S. \1

cases of resolution

of polycythemia

RBC ( x 10”) Onset of Remission PrelPost

after

EPA*

treatment

Program

Gross Findings

of hydronephrosis hlicropatholoa

Etiology

Residual Viable Parrnchyma

w/4.1

; 6X/?

S.P

2

Gardner and Fre! mannZ’

(is, \I

3

Lwxnce and Donald”

:3;, \I

21/1Ti

62,X1

23.5/15.i

71 /-lri

w2, \I

23.5/15.2

71/46

N.A

:>

:i

51/G

A.E

i

‘?

5

Donati.

?/P

Congcnital hand across ureter Idiopathic

6.45/4.46

?

et al.‘” 6

Ihid.

7

Narayana

‘/‘i

42, \I

6.75/P

N.P

6.90/P

r. P

‘J

\onc

et al.=” fi

Ibid.

13.51

9

Jaworski and Wo2anz”

21.11

Jones,

s7. I1

10

19/12

P

‘> z/16$

N.A.

$1498

2l.H/13

62/40

6 M/P

lH.8/1.5

57/45

?

et al:”

11

Ibid.

*EPA = erythropoietin activity: tBaseline values. :Values after 12 days of ureteral $Postnephrectomy values.

N.P.

= not performed:

S.A.

= no activity;

A.E.

= active

erythropoieti”;

N = normal.

drainage.

YROLOC’I

:

APRII.

1983

VOLL’XIE

XXI.

NUMBER

4

blood loss. Erythropoietin assays, unfortunatel>; were performed in onl~r 5 patients preoperative]): Unfortunately, in none of these 5 was the postoperative level of erythropoietin studied. A pronounced erythropoietic activit\, was noted in 3 ofthese patients preoperati\sely. df 11 kidneys studied, 5 were nonfunctioning b>r urographic criteria. In none of these cases was renal fllnction assessed by such studies as selecti1.e catheterization, phenolsulfonphthalein excretion, or renal scan. Two showed segmental obstruction of the collecting system (calyceal and infundibular), and 3 showed hydronephrosis with renal function present, albeit probably delayed. In the cases of nonsegmental hydronephrosis the gross findings were those of advanced cystic atrophy of the collecting system with renal pelvis capacities ranging from 1.5 to 6 L, and presumably total replacement ofrenal parenchyma (except in Case 9). The 2 cases of segmental obstruction showed significant amounts of normal residual renal tissue. Microscopic findings generally included chronic inflammation and tubular atrophy. Microangiopathic changes were noted in 3 of 7 microscopic descriptions. The primary causes of the obstruction included stone disease, extrinsic ureteral compression by congenital band, ureteropelvic junction narrowing, and “idiopathic.” Case 9 showed comparable rates of resolution of polycythemia both during a twelve-day interval of ureteral catheter drainage as well as after nephrectomy. operative

Comment Clinicall?; polycythemia-associated hydronephrosis Ioccurs in either segmental or total collecting system obstruction. It has been reported in hydronephrosis of diverse etiology-intrinsic or extrinsic, stones, ureteropelvic function obstruction, or congenital bands. In contrast to the situation in animals it has appeared consistently in cases of,advanced cystic dilatation ofthe collecting system as well as with marked parenchymal atrophy. In experimental hydronephrosis the erythrocytosis, once elicited, is self-limiting.> The initial stimulus to erythropoietin production is, over overtaken by ultimate parenthe long term, chymal destruction. That accelerated erythropoiesis may not develop in the case of rapidly produced high-pressure hydronephrosis emphasizes the observation that the stimulation of renal erythropoiesis by back pressure must be set into motion prior to the onset of advanced renal atrophy.” The question of how much atrophy is needed to reverse erythropoiesis is difficult to

determine since there appears to be JM) absolute correlation between the degree of parenchymal failure and the rate of erythropoietin production. In fact, normal erythropoiesis has been noted in animals even in the face of 80-per cent renal destruction. 2H renal tissue reAssuming that 110 functional mained in the cases of advanced atrophic hydronephrosis, we must clarify the source of the polycythemia consistently noted in these patients. Either erythropoietin was being produced in an extrarenal site “!’or there was unrecognized viable renal parenchyma in these kidneys. Where renal cortical tissue is still preserved (as in cases of segmental hydronephrosis and Case 9), erythrocytosis can be reversed either by renal pelvic decompression or by nephrectomy. Both methods showed similar characteristics of remission of polycythemia. These findings conform to the experimental model proposed in Figure 2. Small vessel derangement has been noted in some microscopic descriptions. These changes consisted of endothelial proliferation, glomerular sclerosis, and blood vessel dilatation. Similar microangiopathy may well have been present in the other cases, but they are not specifically mentioned. Therefore, despite the fact that past uncertainties regarding the source of erythrocytosis in hydronephrosis have led some to postulate chronic hematuria or products of bacterial degeneration as the cause,“’ it appears that the most likely direct stimulus is a microangiopathic event. The results of erythropoietin assays, when performed, have been variable. Plasma erythropoietic activity was elevated to eight times normal in Case 10, a patient with a markedly atrophic, 6-L, in a hydronephrotic sac, and yet not detected patient with considerable parenchymal residuum (Case 9). While the reason for the first of these observations is unclear, the absence of detectable erythropoietic activity in the second instance may be attributed to either technical factors in the assay or to the assay being insufficiently sensitive to detect small elevations in erythropoietin.“”

Polycythemia is consistently produced in animals undergoing experimental hydronephrosis. This hematologic response is thought to be mediated by microcirculatory insult and a more accelerated elaboration of erythropoietin by the hy\Vhile an association bedronephrotic kidney. and polycythemia has tween hyclronephrosis been reported in humans, it is a relati\.ely rare

event. Further studies are necessary - particularly a more consistent search for erythropoietin levels in patients both before and after treatment of hydronephrosis to explain why this should be so, as well as to confirm that the polycythemia in humans is secondary to an increased production of erythropoietin. 10 Nathan D. Perlman Place New York, New York 10003 (DR. LEITER)

1. Carnot P, and Deflandre G: Sur l’activite hematopoietique du serum au tours de la regeneration due sang, Compt rend Acad Sci 143: 384 (1906). 2. Naets, JP: Er)thropoiesis in nephrectomized dogs, Nature 181: 1134 (1958). 3. Reissman KR, et u/: Erythropoietic response to anemia or erythropoietin injection in uremic rats with or without functioning renal tissue, Blood 16: 1411 (1960). 4. Jacobson LO, et al: Role of the kidney io erythropoiesis, Nature 179: 633 (1957). 5. Mitus WJ, and Toyama K: Experimental renal er)throcytosis. Role of the juxtaglomerular apparatus, Arch Pathol 78: 658 (1965). 6. Oliver WJ, and Brody GL: Effect of prolonged hypoxia upon granularity of renal juxtaglomerular cells, Circu Res 16: 83 (1965). 7. Donati RM, Lange RD, and Gallagher NI: Nephrogenic erythrocytosis, Arch Intern 14ed 112: 960 (1963). 8. Jones NF, Payne RW, Hyde RD, and Price TM: Renal polycythemia, Lancet 1: 299 (1960). 9. Volzhskaya AM: Erythropoietic properties of plasma and changes in the blood composition in experimental hydronephrosis, Bull Exper Biol Med 69: 131 (1970). 10. Toyama K, and Mitus J: Experimental renal erythrocytosis. Relationship between the degree of hydronephrotic pressure and the production oferythrocytosis, J Clin Lab Med 68: 740 (1966). 11. Mirand EA, and Prentice TC: Presence of plasma erythropoietin in hypoxic rats with or without kidneys and/or spleen, Proc Exper Biol Med 96: 49 (1957).

12. Naets JP: The role of the kidney in erythropoiesis in the dog, in Williams PC (Ed): Hormones and Kidneys (Memoirs of the Society for Endocrinolog): No. 13). London. Academic Press, 1964, p 176. 13. Melby EC, Murphy GP, and Mirand EA: Enthropoietin levels in response to ureteral occlusion or reinsertion in the rhesus monkey, Invest Urol3: 92 (1965). 14. Lee-Brown RK: The circulatory changes in progressive hydronephrosis, J Ural 12: 1 (1924). 15. Herdman JP, and Jaco NT: The renal circulation in experimental hydronephrosis, Br J Urol 22: 52 (1950). 16. Sheehan HL, and Davis JC: Experimental hydronephrosis. Arch Pathol68: 185 (1959). 17. Fisher lW, Schofield R, and Porteous DD: Effects of renal hypoxia on eqthropoietin production, Br J Haemat 11: 382 (1965). 18. Hirashima K, and Takaku F: Experimental studies on crythropoietin: 11 The relationship between the juxtaglomerularcells and erythropoietin. Blood 20: 1 (1962). 19. Hudgson P et al: Renal artery stenosis with hypertension and high haematocrit, Br Med J 1: 18 (1967). 20. Cooper WM, and Tuttle WB: Polyqthemia associated with a benign kidney lesion: report of a case of erythrocytosis, with remission of polycythemia following nephrectom); Ann Intern Med 47: 1008 (1958). 21. Gardner FH, and Freymann JG: Erythrocythemia (polycythemia) and hydronephrosis, N Engi J Med 259: 323 (1958). 22. Lawrence JH, and Donald WG: Polycythemia and hydronephroais or renal tumors, Ann Intern Med 50: 959 (1959). 23. Martt JM, et al: Polycythemia and hydronephrosis. ibid 54: 790 (1961). 24. Donati RM, et al: Nephrogenic eqthrocytosis, Arch Intern Med 112: 960 (1963). 25. Narayana AJ, et al: Hydronephrosis and pol)cythaernia, Br J Ural 48: 175 (1976). 26. Jaworski ZF, and Wolan CT: Hydronephrosis and polycythemia. A case of erythrocytosis relieved by decompression of unilateral hydronephrosis andcured by nephrectomy, Am J \led 34: 523 (1963). 27. Jones NF, et al: Renal polycythemia, Lancet 1: 299 (1960). 28. Osnes S: Experimental study of an erythropoietic principle produced by the kidney, Br Med J 2: 650 (1959). 29. Mallick NP, and GeaF CG: Renal disease, in Israels MCG, and Delamore IW (eds): Haematological Aspects of Systemic Disease, London. M’B Saunders, 1976. p 265.

CROLOGY

I) APRIL 1983

; VOI.UhlE

XXI. NLMBEH

-1