Tohoku

J. exp.

Renal

Med.,

1975,

116, 267-275

Impairment

Nocturnal

in Patients

with

Paroxysmal

Hemoglobinuria

TAKAO SAITO, TAKASHI FURUYAMA, SEIJU ONODERA, HIROSHI SAITO, RYUJI SHIOJI, YOTARO HURUKAWA, YASUHIKO SASAKI, ISAO SATO and KAORU YOSHINAGA

The Second Department of Internal University School of Medicine, Sendai

SAITO, Y.,

T.,

SASAKI,

with

SATO,

Paroxysmal Three

chronic

hemolytic kidney

of

glucosuria, tubular suggesting

renal

lesions and

two

were

paroxysmal

1 and

Case

may

cases

nocturnal

showed

3)

had

be

the

responsible

hemoglobinuria;

histories

of

(Case

2)

Case

nephrological

and 2

hemolysis

interstitial

severe

nephritis;

reduced

and

Case of

and renal

the

Renal

point

the

(3),

of

nephritis.

in

for

116

specimen

interstitial

revealed

Patients

1975,

accompanied

biopsy

intravascular

primarily

HURUKAWA, in

Med.,

clearance

were

From from

exp.

The

urate

(Case

R.,

hemoglobinuria

the

2)

increased

phosphate

resulting

anemia

nocturnal All

SHIOJI, Impairment

J.

hemoglobinuria.

impairment.

alteration chronic

H., Renal

Tohoku

studied.

proteinuria,

tubular

SAITO, K.

paroxysmal

repeated

of

renal

with

(Case

reabsorption

S.,

YOSHINAGA,

Hemoglobinuria.

patients

tubular

ONODERA,

and

patients

anemia

hemodynamic persistent

T., I.

Nocturnal

267-275 „Ÿ by

FURTYAMA, Y.,

Medicine, Tohoku

3,

view, severe

impairment.•\ tubular

dysfunction

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disease characterized by bemolytic anemia and hemoglobinuria occurring at night or early in the morning. Many studies about this disease have disclosed that histological examination of kidney specimen obtained by biopsy or necropsy reveals a large amount of hemosiderin deposits in the proximal convoluted tubules and the Henle's loops. In spite of these findings renal function has been considered to be almost normal unless acute renal failure or pyelonephritis is complicated (Crosby 1953; Berliner 1962; Rubin 1971). We have encountered three cases of PNH in which chronic renal lesions without the history of acute renal failure and of urethral infection were recognized by means of several nephrological examinations. One of the cases was accompanied by diabetic nephropathy. In these cases, however, the renal lesions were supposed to be related to hemodynamic changes due to repeated intravascular hemolysis and chronic anemia. CASE REPORT

Case 1( M.U.): A 69-year-old farmer visited Tohoku University Hospital in Received

for publication,

April

22, 1975. 267

268

T. Saito

September

1965

suffered

from or

Raynaud's to

our

conjunctivae

soft.

The

data

no

examination revealed In and

our

was

of the

a

on

83.7

after

and

film

showed

not

the

slightly

breadth

the

beneath

The

the

right 164/90.

and

studies

abnormalities.

remarkable.

No was

was

function

function

his

bulbar

abdomen

pressure liver

kidney

no

of

anemic.

The

blood

1;

gave

a strongly

Administration

of

other

in

On

Table

funduscopic

intravenous

for

But

it

10

days

was

pyelography

per

The

day.

of

the

of

The

In

he

sodium

at the

of was and

that

time

result to

was

and

therapy

diminished

1966,

for

of

which

steroid

from

blood,

blood

performed

was

April

g

glucose,

different

glucose

therapy.

30

the

test

distinctly

ocoult

prednisolone

alkalizing

during

tolerance

urinary

for

of

urinary

increased

was The

mg

anemia.

expectation

glucose

which 2).

in

result

30

and

ineffective.

gradually

cessation

positive daily

hemosiderinurina

daily

(Table

the

urinalysis

for

curve,

therapy

finger

Table

time The

chest.

The

in

admission,

g

one

palpable.

always

effective

diabetic

steroid

positive

before

be

slightly

discharged

from

hospital. Case

2

Hospital

(S.M.):

in

1969,

from

in

blastic

and

was

total

improved

wine-colored

He

nose He

where

22-year-old

1971.

104/mm3.

anemia

A

March

bleeding

159 •~

14

every

farmer

had

no

gingiva

admitted liters

little.

in

admitted

of

renal

February

Izawa

blood

November

Bone

was

history

to of

In

day.

marrow

to

1969.

Hospital

were

transfused

1970

he

that

Iwate

aware RBC

prefecture

in

March

that

showed

became time

until

noted

University

He

At

in

aspiration

Tohoku

disease.

was April

1970.

morning

But

urine

tendency

to

was

erythro

hyperplasia. At

the

time

of

well-nourished.

abdomen

were

are

summarized abnormalities.

hemosiderin. therapy

hospital

in and

admission

to

the

was

normal. in

our

hospital,

conjunctivae

Gynecomastia

no

this

his

Palpebral

observed.

data

urine

given

palpable

anemic.

the

calyces.

persisted.

day

to

disclosed

our

change

not

g per

amounted

the

diabetic blunting

hemolysis.

3

the

At

had

atmospheric

well-nourished.

the

he

remarkably

conjunctivae of

1959,

with

be

present.

examination

not

affected

and

palpebral

Since

to

not build

summarized

2;

not

found

average

was

X-ray

was

preventing

the

chest

was

bicarbonate

only

Table

anemia

days

and

was

are

the

hospital,

severe

36

in and

of

edge

spleen data

ECG

was

anemia.

was was

were

physical

liver

The

hematological

The

on

he

purpura

he

noted

margin.

laboratory

of

and

and

which

1964,

subicteric,

was

and

costal

3.

In

hospital,

were

abnormality

jaundice

jaundice,

season.

phenomenon

admission

The

hemoglobinuria,

persistent

temperature

flat

for

et al.

present.

The

Tables

blood

1, 2

The

and

morning

6

g of

sodium

did

not

result

pressure 3.

bicarbonate in

without

renal

functions

in

The

our

120/40.

ECG

and

always

response.

outpatient

average

of

the

The the

for

He

was

improvement

chest

was

film

showed

glucose

3

.

months discharged The

the

findings

X-ray

April

fairly

and

protein,

. in

and

jaundice

laboratory

chest

daily

clinic

build

No

contained

given

marked

of

findings

was

was

favorable

1971

was

anemic.

Physical

urine

September

he were

and

However, from

our

hematological 1974

were

not

Renal

Impairment TABLE 1.

TABLE 2.

different

from

those

in Patients Hematological

with

PNH

269

studies

Other laboratory ,findings

on his admission.

Case 3 (A.T.): A 62-year-old single woman without occupation was admitted to Tohoku University Hospital in January 1974 for hemolytic anemia. She was divorced at the age of 32. She had no history of pregnancy, of glomerulonephritis and of urethral infection. In 1961, she was admitted to a certain hospital

270

T. Saito

TABLE 3.

* specific

gravity; •õosmolality

et al.

Kidney function studies

.

because of fatigue and the discoloration of her nails. A diagnosis of aplastic anemia was made and stored blood was transfused. In 1963, when thyroidectomy was done at the Department of Surgery of our hospital with a diagnosis of nodular goiter, pancytopenia was detected and 2.5 liter of fresh blood were transfused. Thereafter she became to be often troubled by common cold and jaundice. In 1973, she was admitted to Ishinomaki Red Cross Hospital with nausea and tiredness of the knee joints, where Ham test was found positive. At the time of her admission to our hospital she was slender and averagely nourished. The conjunctivae and the face showed no anemia and no icterus. Petechiae was revealed on the mucous membrane of the mouth. The chest and the abdomen were normal physically. The laboratory data are given in Tables 1, 2 and 3. The chest X-ray films and the ECG showed no abnormalities. Funduscopic examination revealed no hypertensive changes. Culture of the urine was sterile. In March 1974, she was discharged with improvement of the subjective symptoms. RESULTS OF SPECIAL EXAMINATIONS

In these three cases, RBC and hemoglobin concentration were decreased in the peripheral blood, and erythroid hyperplasia was revealed in the bone marrow. Ham test, sugar water test and/or Hegglin test were positive. Morning urine specimens showed a large number of hemosiderin crystals. Alkaline phosphatase in neutrophile leucocytes was decreased. Erythrocyte osmotic fragility was normal. LDH was highly elevated. All these data support the diagnosis of PNH. Kidney function studies in these cases are shown in Table 3. In Case 1, dysfunction of the kidney seemed definite because creatinine clearance and

Fig.

1.

Renal

Impairment

gel

electrophoretic

Polyacrylamide

in Patients

with

PNH

of

urinary

patterns

271

proteins.

A,

typical

glomerular proteinuria in chronic glomerulonephritis; B, Case 2; C, Case 3; D, typical tubular proteinuria in transplantation kidney. L.M.W. protein, low molecular weight protein;

Tf., transferrin.

maximum and

concentration

maximum

glucosuria

was

Moreover, a

and ƒÀ

constantly

fractions are

Case

the

failure. 1).

glucosuria

was

Renal Case

2.

The

Case

1

thickening material

are are

diabetic

change

2):

the

In

revealed,

is the

data

the

but

make of

of

cellular

four the

changes

renal

high

value.

bands

in

the

findings

are Fanconi

and of

the

syndrome.

excretion

diagnosis

was

reduced

chronic

tubular

renal

proteinuria

decreased,

and

renal

dysfunction.

in

Case

the

1,

and

following glomeruli

mesangial

proliferation

excepting

PSP

(TRP)

twenty

and

These

showed

1966

a

a few

like

the

tubular

April

majority

1).

urine

disclosed

Nevertheless, glomerular

(Fig.

clearance

However,

revealed

decreased

to

suggested in

membrane

intact seen.

the

creatinine

revealed

disorders

phosphate

examinations

basement

relatively

to

of

performed

histological

band

enough

2,

normal.

urine

tubular

electrophoresis

These were

(Fig.

lumina

contrast

present.

of

were

reabsorption

biopsies

albumin

Case

clearance of

clearance,

urine gel

Tubular

nearly

urate

proximal

creatinine of

In

were

and

to in

Polyacrylamide

(Fig.

in

of

ability

reduced.

urine

electrophoresis

addition

observed fall

concentrating

were

observed gel

in

often

3,

urine of

polyacrylamide

which In

of

concentration

in

taken,

deposition is

scarcely

hyalinized

most

surrounding

just

mentioned.

May

1971

in

findings. mild of seen,

glomeruli.

A

and

capillary

No

tubules large

diffuse

PAS-positive

are

nodular atrophic

number

of

272

Fig.

T. Saito

2. rular cristals cell

Histological basement

picture

of

membrane

are

deposited

in

infiltration

are

present.

the

kidney

and

increased

atrophic

et al.

biopsy

tubular

(Azan-Mallory

specimen

mesangial

in matrix

epithelia. stain, •~

Case can

Interstitial

2. be

Thickened seen. fibrosis

glome

Hemosiderin and

round

200)

hemosiderin deposits are seen in the surviving epithelia of convoluted tubules. There is an increase of interstitial tissue accompanied by diffuse infiltration of round cells. Case 2 (Fig. 3) : All the obtained glomeruli appear normal. On more detailed examination, there is mild interstitial fibrosis around these glomeruli, and some of convoluted tubules are atrophic. A large number of hemosiderin crystals are deposited in proximal convoluted tubules and Henle's loops. Round cell infiltration in interstitium is not so remarkable. In case 3 renal biopsy was not performed. DISCUSSION

In case 1, diabetes mellitus became manifest in consequence of the steroid therapy for hemolytic anemia. The renal histological finding of this case shows an early diabetic glomerulosclerosis (Kimmelstiel et al. 1966). However, the tubular atrophy and the interstitial fibrosis in this case are more severe than the changes expected in this stage of diabetic nephropathy (Gellman et al. 1959). Furthermore, funduscopic examination of this case showed little diabetic change. This may confirm the mildness of diabetic nephropathy of this case since it is generally found that diabetic nephropathy and retinopathy progress with similar pace. Blaisdell et al. (1958) reported on the renal lesions of PNH complicated with

Renal

Fig.

3.

Histological

normal. interstitium

picture

Atrophic can

of

tubular be

seen.

Impairment

the

kidney

epithelia (Trichrome

in Patients

biopsy with

with

specimen

massive

deposits

PNH

in

Case of

273

3.

Glomerulus

hemosiderin

and

appears extended

stain, •~200)

diabetes mellitus. Although it was evident that the case was complicated by pyelonephritis, they supposed that the changes on tubules and interstitium may be at least in part a consequence of the massive deposition of iron. In our case, the patient's history, intravenous pyelography and urinalysis did not suggest complication of pyelonephritis. It may be regarded that these changes on tubules and interstitium seen in our case are due to PNH itself. It is of common knowledge that renal glucosuria, increased urate clearance and a few low molecular weight protein bands seen in urinary protein electrophoresis were the indicators to tubular dysfunction (Revillard et al. 1970; Ramsdell and Kelley 1973). Accordingly, tubular dysfunction may be apparent in Case 2, cor -responding to the histological change. All of these changes seem to be closely related to PNH because no other disorder was present. In Case 3, tubular dysfunction appears more distinct from decline of %TRP and presence of renal glucosuria and tubular proteinuria. Histological confirmation was lacking in this patient. But, she had no history of urethral infection, and the culture of the urine was sterile. Consequently, it is likely that the tubular dysfunction was due to PNH, too. When PNH is accompanied by lesions of kidney, mainly those of tubules and interstitium, it is the subject of discussion whether the lesions are directly due to hemoglobinuria or not. Crosby (1953) mentioned that in PNH there was no scarring of the kidney or destruction of nephrons unless infection supervened.

274

T. Saito

et al.

Similar opinions have been published by several investigators afterwards (Berliner 1962; Rubin 1971). On the other hand, Heitzman et al. (1953) and Blaisdell et al. (1958) suggested that these changes of kidney were significantly affected by iron deposits resulting from reabsorption of large amounts of hemoglobin in tubules. However, we do not know if iron is nephrotoxic as copper , cadmium, lead or mercury. Meanwhile, several reports have suggested that tubular function may be impaired with reabsorption of massive protein in proximal convoluted tubules like albumin in patients with nephrotic syndrome (Sebastian et al . 1968), BenceJones protein in myeloma (Harrison and Blainey 1967) and lysozyme in monocytic leukemia (Muggia et al . 1969). According to this concept it is likely that reabsorption of hemoglobin in proximal convoluted tubules inflicts damage upon kidney, for hemoglobin is a protein of molecular weight nearly equal to albumin (M.W. 68000). On the contrary, in most instances of disorders associated with renal hemosiderosis, functional and histological impairment of the kidney has not been revealed how massive hemosiderin deposits may have been (Leonardi and Ruol 1960; Hutt et al. 1961; Roberts and Morrow 1966). We cannot conclude, therefore, that only hemoglobinuria was the cause of the renal impairment in our patients. Shioji et al. (1974) asserted that alteration in renal hemodynamics may be a predisposing factor as the cause of tubular dysfunction in patients with nephrotic syndrome. The observation about paroxysmal cold hemoglobinuria with renal insufficiency by Sussman and Kayden (1948) suggested diminished renal blood flow with vasoconstriction as one of the mechanism of renal damage . On the other hand, Bradley and Bradley (1947) mentioned that renal vasoconstriction with great reduction of effective blood flow occurred in severe chronic anemia. Some by-products of the hemolytic process also may produce a significant circulatory depression resulting in renal ischemia , although the change may be temporary (Burwell et al. 1947; Conn et al. 1956). Consequently, since the patients reported here have a history of repeated hemolytic crisis and of a severe anemia with one million level of RBC per cubic millimeter in the peripheral blood , there have possibly been continuous renal vasoconstriction, and reabsorption of massive hemoglobin may have accelerated anoxia of tubular cells in the ischemic stat e to cause chronic tubular dysfunction . References

1) Berliner, G.B. (1962) On the effect of prolonged hemoglobinuria and hemosiderinuria on the renal function and urinary tracts in paroxysmal noct urnal hemoglobinuria (M archiafava-Micheli disease). Ter. Arkh ., 11, 34-38. 2) Blaisdell, R.K., Priest , R.E. & Beutler, E. (1958) Paroxysmal nocturnal hemoglob inuria: A case report with a negative Ham presumptiv e test associated with serum properdin deficiency. Blood, 13, 1074-1084. 3) Bradley, S.E. & Bradley, G.P. (1947) Renal function during chr onic anemia in man. Bl ood, 2, 192-202. 4) Burwell, E.L., Kinney, T.D. & Finch . C.A. (1947) Renal damage following intravas cular hemolysis. New Eng . J. Med., 237, 657-665.

Renal

Impairment

in Patients

with PNH

275

5)

Conn, H.L., Jr., Wood, J.C. & Rose, J.C. (1956) Circulatory and renal effects following transfusion of human blood and its components to dogs. Circulat. Res., 5, 18-24. 6) Crosby, W.H. (1953) Paroxysmal nocturnal hemoglobinuira: Relation of the clinical manifestations to underlying pathogenic mechanisms. Blood, 8, 769-812. 7). Gellman, D.D., Pirani, C.L., Soothill, J.F., Muehreke, R.C. & Kark, R.M. (1959) Diabetic nephropathy: A clinical and pathologic study based on renal biopsies. Medicine, 38, 321-367. 8) Harrison, J.F. & Blainey, J.D. (1967) Adult Fanconi syndrome with monoclonal abnormality of immunoglobulin light chain. J. clin. Path., 20, 42-48. 9) Heitzman, E.J., Combell, J.S. & Stefanini, M. (1953) Paroxysmal nocturnal hemoglobinuria with hemosiderin nephrosis. Amer. J. clin. Path., 23, 975-986. 10) Hutt, M.P., Reger, J.F. & Neustein, H.B. (1961) Renal pathology in paroxysmal nocturnal hemoglobinuria: An electron microscopic illustration of the formation and disposition of ferritin in the nephron. Amer. J. Med., 31, 736-747. 11) Kimmelstiel, P., Osawa, G. & Beres, J. (1966) Glomerular basement membrane in diabetics. Amer. J. clin. Path., 45, 21-31. 12) Leonardi, L. & Ruol, A. (1960) Renal hemosiderosis in the hemolytic anemias: Diagnosis by means of needle biopsy. Blood, 16, 1029-1036. 13) Muggia, F.M., Heinemann, H.O., Farhangi, M. & Osserman, E.F. (1969) Lysozymuria and renal tubular dysfunction in monocytic and myelomonocytic leukemia. Amer. J. Med., 47, 351-366. 14) Ramsdell, C.M. & Kelley, W.N. (1973) The clinical significance of hypouricemia. Ann, intern. Med., 78, 239-242. 15) Revillard, J.P., Manuel, Y., Francois, R. & Traeger, J. (1970) Renal diseases associated with tubular proteinuria. In: Proteins in Normal and Pathological Urine, edited by Y. Manuel, J.P. Revillard & H. Betuel, S. Karger, Basel, pp. 209-219. 16) Roberts, W.C. & Morrow, A.G. (1966) Renal hemosiderosis in patients with prosthetic aortic valves. Circulation, 33, 390-398. 17) Rubin, H. (1971) Paroxysmal nocturnal hemoglobinuria with renal failure. J. Amer. med. Ass., 215, 433-436. 18) Sebastian, A., Mcsherry, E., Ueki, I. & Morris, R.C. (1968) Renal amyloidosis, nephrotic syndrome and impaired renal tubular reabsorption of bicarbonate. Ann. intern. Med., 69, 541-548. 19) Shioji, R., Sasaki, Y., Saito, H. & Furuyama, T. (1974) Reversible tubular dysfunction associated with chronic renal failure in an adult patient with the nephrotic syndrome. Clin. Nephrol., 2, 76-80. 20) Sussman, R.M. & Kayden, H.J. (1948) Renal insufficiency due to paroxysmal cold hemoglobinuria. Arch. intern. Med., 82, 598-610.