Primary oxalosis

Primary Oxalosis

LENNART

BOWIST,

BENGT LINDQVIST, YNGVE

&TBERG,

LAW

STEEN,

Umeil,

Sweden

M.D. M.D. M.D.

M.D.

From the Departments of Pathology and Internal Medicine, University of Ume& Ume& Sweden. Requests for reprints should be addressed to Dr. L. Boquist, Department of Pathology, University of Umeb, S-901 87 UmeA 6, Sweden. Manuscript accepted December 17.1971.

This man with primary oxalosis had a familial history of the disease, onset of symptoms in adult age and elevated levels of serum and urinary oxalic acid, as well as increased urinary excretion of glycolic and glyoxylic acid. Uremia developed and dialysis was tried but the disease progressed, with the appearance of polyneuropathy and peripheral ischemic alterations leading to atrophy and gangrene. He died in uremia after 14 months of hemodialysis. It is suggested that hemodialysis should not be utilized in patients with primary oxalosis. Postmortem examinations included light microscopy, and transmission and scanning electron microscopy. Calcium oxalate deposits were found in kidneys (glomeruli, interstitium, and tubular epithelial cells and lumens), myocardium, spongy bone, prostate, testes, striated muscles, aorta, inferior vena caval vein and in numerous arteries and arterioles. The oxalate crystals are believed to be primarily formed intracellularly in the various organs. Additional findings were chronic pyelonephritis, degeneration of peripheral nerve fibers and perineural fibrosis. Oxalosis is a rare disease, especially with the onset of symptoms in adult age. It leads to progressive renal failure and death in uremia. The definition of oxalosis and the closely related hyperoxaluria varies, but usually oxalosis is described as a condition of calcium oxalate nephrolithiasis and nephrocalcinosis with associated extrarenal deposition of calcium oxalate. Hyperoxaluria differs from oxalosis mainly in the absence of extrarenal deposits [l]. Distinction is made between a hereditary, primary (idiopathic or endogenous) and a secondary (symptomatic or exogenous) type of oxalosis. A variant of primary hyperoxaluria-L-glyceric aciduria-has recently been described [2]. Gasser and Wuketich [3] have suggested a classification of oxalosis into two types: type I being characterized by early appearing and protracted signs of renal disease because of stone formation, and type II being characterized by absence of symptoms until renal insufficiency appears, after which a progression is rapid. Several reviews of oxalosis have appeared, but up to now only slightly more than 100 cases have been reported. We describe a patient with primary oxalosis, which lead to uremia and death, who presented with symptoms of peripheral neuropathy and peripheral gangrene in the lower extremities, and who was subjected to morphologic investigations (transmission and scanning electron microscopy) which have not been previously undertaken in patients with this disease.

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PRIMARY

OXALOSIS-BOOUIST

MATERIALS Autopsy

and the following

alkaline

Congo von

and red,

eosin,

and

Kossa,

Polarization

morphologic

after death. The following

hematoxylin

Gieson,

the

routine

were

periodic

acid-Schiff,

and

staining

methods

McMahon

was

were

stains

Ladewig,

microscopy

procedures

employed

for

cortical

were

and

fixed

medullary

by

dehyde

in 0.34

pH

7.4,

followed

tetroxide

in the

regions

immersion

in

M Verona1

acetate

2.5

by postfixation same

of

Perdrau.

the

in 1 per

buffer.

After

rinsing

dration the specimens were embedded and sections were cut on an Ultrotome stained

with

amined

in a Siemens

Scanning

uranyl

acetate

and

Elmiskop

Electron

lead

citrate

mens

were

Dryer

freeze-dried

Model

I.

with

gold

to

were

viewed

in a Cambridge

man

two

was has

brothers

and

73, 17, 27 and known whether

in

1925

reported one

into

white

sister

died

13 years of age, or not the father

he was

found

cells

in the

of

in The

2,605

of

Serum

and a maximum mg/24

hours

uri-

(normal

creatinine

was

13 to

17

1,328

and

476,

1.345

and

908

beginning

of 1970

which

verified

was 1970

almost

a rapidly

observed by

the patient totally

in

progressing

both

arms

poly-

and

legs,

electromyography.

From

was

in the legs

paretic

totally

paretic

in the arms,

and

from

NoJune

1970 on he was bound to bed or wheel chair. He was mentally lucid but sometimes depressed. In January progressive

ischemic

changes

were

noted

arms and legs, especially in the feet, and severe pain in various locations. He died 1971, in uremia and circulatory insufficiency. At autopsy

at

the body

was that

of a man

in the

he suffered on April 2, with

atrophic

muscles, gangrene of toes number 2 and 3 on the left foot, and discoloration of all other toes. There were

It is not The pa-

red

416,

was

and

which

disease

and

small

yellow-white

hesions

and

on

seen

the in

crystalline pericardial the

left

and

a low blood dis-

100 ml of yellowish fluid. mainly in the left portion.

sediment

of 3.6

urinary

(normal

hours).

clearance. Nonprotein nitrogen and were normal. Intravenous urography

urinary

(normal

ml, respectively.

vember

of pulmonary

proteinuria,

hours

and 7 to 10 mg/lOO ml after dialythe serum concentration of oxalic

neuropathy

also

to have

hours)

value

instituted.

ml before May 1970

In the

father,

respectively. had oxalosis. because

uri-

mg/24

hours), a maximum 56.4 mg/24 hours

mg/24

acid

0.7 to 4.7 mg/24

was

776,

Tissue

renal

to 45.0

transverse liver and

blood

creatinine pressure

11.1 glyoxylic

pg/lOO

IV scanning

[6].

to 49.8 mg/24 acid value of

140

August, September, November and December 1970 and in January 1971 were 1,532 and 751, 961 and

in 10 per the speci-

a family

previously

tient was hospitalized in 1931 and peritoneal tuberculosis. In 1951

8.4

1971

born

been

range

of

the

CASE REPORT This

value

(nor-

a maximum

from

microscope.

oxalosis

acid

ml),

oxalic

ml

acid had increased to 850 c(g/lOO ml before and 450 pg/lOO ml after dialysis. The corresponding figures in

a thickness

Stereoscan

oxalic

pg/lOO

serum

pg/lOO

ex-

about 150 A was performed in an Edward Vacuum Coating Unit, Model E 12 E after which the specimens electron

nary

included

180 to 290

were

in a Speedivac-Pearse

Coating

to 289

mg/lOO sis. In

of both kidneys were the dissection micro-

scope or ripped with forceps. After fixation cent formalin and rinsing in redistilled water

182

filter)

dehy-

101.

Specimens

cortical and medullary regions either cut with a scalpel under

to

osmium

and

range,

1969

from

In January 1970 deterioration was recorded. The urine volumes diminished and uremia was more marked. Hemodialysis (16 hours/week with a Gambro-

in Epone 812 III. Sections

I A and/or

Microscopy.

cent

mal

range,

glutaral-

adjusted

ranging

nary

from

during

values

range,

kidneys

cent

buffer

findings

the right caused complete obpyelolithotomy was performed.

acid

glycolic

detec-

both

per

Laboratory

of van

and

tion of crystalline structures and amyloid. Transmission Electron Microscopy. Specimens the

both sides; those on struction and bilateral

AND METHODS

started immediately Light Microscopy. used:

ET AL.

deposits

and

surfaces. pleural

cavity,

colon and peritoneum, diaphragm. The peritoneal

fibrous

Adhesions

adwere

between

the

and between the cavity contained

The heart was hypertrophic, There were numerous hard,

closed dilated renal pelves with numerous calculi of varying size. A high fluid intake was recommended, and he had large urine volumes. During the subsequent years the course was rather uncomplicated.

yellow-white patches on the coronary arteries. Similar patches, sometimes with white crystalline streaks, were found in the aorta, main arteries, mesenteric arteries and peripheral arteries in the feet. Vascular oc-

In 1969 he was admitted to the hospital because of cystitis. The urinary sediment contained a moderate amount of red and white blood cells. No bacteria were

clusion were

ropoiesis without oxalate crystals. Liver biopsy was normal, and renal biopsy disclosed changes suggestive of pyelonephritis but no oxalate crystals. Intravenous urography showed numerous calculi in the renal pelves. Percutaneous puncture of the renal pelves was carried out in September 1969. Calculi were found on

May 1973

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Journal of Medicine

Volume

not

noted, obliterated.

but

both

dorsal

The tracheal

pedis

arteries

cartilage

con-

tained scattered foci of hard, white crystalline material. The lungs were slightly fibrotic and possessed basal bronchopneumonias. Acute splenitis was seen, and the lymph nodes were occasionally enlarged. The kidneys (Figure 1) were slightly contracted and the capsules focally thickened and adherent. Their surface was finely and coarsely granulated and on cutting the kidneys, a gritty sensation was obtained. There was a marked reduction of the renal parenchyma to a thickness of about 0.5 cm. Scattered deposits of crystalline material were found in both kidneys. The renal pelves were dilated and contained

found in the urine. Serum and urinary calcium values were normal. Serum creatinine was 2.4 mg/lOO ml. The patient was sent to the University Hospital in Umea for further examinations and treatment. A sternal bone marrow aspirate showed normoblastic eryth-

674

was markedly

54

PRIMARY OXALOSIS-BOOUIST

Figure 1. Specimen of left kidney showing reduced thickness hydronephrosis and numerous concrements of varying size.

about the

40 concrements left

side.

Most

smooth

contours

surface.

The

with

on the

right

concrements

and onion-skin

largest

a diameter

measured

of 2 mm

was

side

and

were

a few

faceted

appearance 2 by found

concrements,

exhibited

slight

concrements. as, central

mainly

hyperplasia

in the and

rete.

deposition

tubules

of the cut

tained

epithelial of

glomerular

hyalinization,

roid and suprarenal glands were On light microscopy crystals tex and medulla were birefringent,

prostate pancreparathy-

grossly normal. were found in the cor-

(Figure 2A) of both kidneys. did not stain with hematoxylin

They and

eosin, gave a positive von Kossa reaction (Figure 26), showed often a radial rosette-like pattern and were interpreted as calcium oxalate deposits. Sometimes a fibroblastic reaction occurred around the crystals. They were mainly confined to the tubular lumens and interstitium but were and occasionally

also seen in glomeruli.

in tubular epithelial cells There were also depos-

and

renal

remnants.

thickening tion

and medullary

atrophic

ureter,

of calcified

The gastrointestinal tract, liver, nervous system, pituitary, thyroid,

of small were

A stone

left

The

media

Many

close to the ureteral orifice. The urinary bladder was moderately hypertrophic. The testes contained yellowwhite

its in the

with

3 cm. in the

on

of both the cortical

the

arteries and

Other

glomerular

renal

arterioles.

tumens

con-

changes

basement

chronic

periglomerular,

regions,

and

their

ET AL.

were

membranes,

inflammatory

peritubular

and

brosis, suggesting chronic pyelonephritis. Extrarenal calcium oxalate crystals

reac-

interstitial

were

fi-

present

in

the myocardial muscle fibers (Figure 2C), spongy bone, prostate, seminiferous tubules and striated muscle fibers (Figure 2D). Scattered, sometimes extensive deposits were found in the muscle media in aorta and inferior vena cava, the muscle fibers of numerous arterioles in various locations. sometimes

observed

crystals. The peripheral focal

degeneration

in

nerves

arteries (Figure 3) and Subintimal fibrosis was

areas in the

of the nerve

fibers of the as well as in

with

calcium

extremities fibers

with

oxalate exhibited

the appear-

ance of amorphous masses (Figure 4) and perineural fibrosis. There were no crystalline deposits in the peripheral nerves. Other essential microscopic findings

May 1973

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PRIMARY

OXALOSIS-BOQUIST

ET AL

D

C calcium oxalate crystals in renal tubules and interstitium. Van Gieson stain, polarization microscopy; magnification X 720. 6, calcium oxalate deposits in tubules, interstitium and glomeruli. Periglomerular fibrosis and diffuse infiltration of lymphocytes are also seen. Von Kossa stain; magnification X 460. C, crystals of calcium oxalate in myocardial muscle fibers. Van Gieson stain, polarization microscopy; magnification X 720. D, atrophic skeletal muscle fibers containing calcium oxalate crystals. Van Gieson stain, polarization microscopy; magnification X 740. Figure

676

2. A, birefringent

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PRIMARY

OXALOSIS--8OOtJlST

ET AL.

Figure 3. Do&l pedis artery showing subintimal fibrosis and cakium oxaiate deposits’ in the media.; cl01 the partly disrupted internal elastic lamina. Van Gieson-elastin stain, polarization microscopy; magnific; X 220. Figure 4. Peripheral nerve showing focal degeneration masses. Van Gieson stain, magnification X 560.

of the nerve fibers which are replaced

Figure 5. Electron micrograph showing cytoplasm of tubular epithelial particles, often in parallel arrangement. Magnification X 48,000.

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cell with needle-shaped

The American Journal of Medicine

by amorphous electron

dense

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677

PRIMARY

OXALOSIS-BOQUIST

ET AL.

Figure 6. Scanning electron micrograph showing a tubular radial rosette-like pattern and portion of surrounding epithelial

were

atrophy

and a small The

of striated healed

muscles,

myocardial

specimens

gangrene

in the toes

under

and the

transmission

electron microscope were obtained after the preservation of the kidney parenchyma ceptable. The findings, however, are limited

death, but was acto the ap-

pearance

were

pres-

of varying

size

ent.

of the

Electron

crystalloid

dense,

Under

infarction.

examined

structures

crystalloid

that

bodies

and shape were seen in tubular lumens, thelium, interstitium, occasional glomeruli

structures

tral

of

the of

cytoplasm, degeneration it was often

sometimes

tubular epiand smooth

within

were

May 1973

The American

Journal

tubular which

from the loof the ‘latter crystals.

of Medicine

Volume

be seen

microscope

identified, in the tubular

and

glomeruli crystalline

lumens

The subunits

the foot slightly

processes

widened

(Figure

sometimes particles.

7) had

slightly

covered by very The interspaces

on the glomerular

(Figure

(Figure often a cenirregusmall be-

capillaries

8).

There is no doubt that our patient actually represents a case of primary oxalosis. He was a member of a family with a high incidence of the disease, and he had nephrocalcinosis, nephrolithiasis and extrarenal crystalline deposits. Signs of renal disease, including the presence of nephrolithiasis, were first recorded when he was 26 years old. In this respect the case is less common, since in about 65 per cent of the patients with oxalosis the onset of symptoms occurs before the age of five [5]. Progression of the disease was rather slow; no signs of renal insufficiency were found until 1969. Thus, this patient cannot be considered as

particles most often were confined to the proximal convoluted tubules. Although it was not possible to prove identity between the crystals observed in the light microscopic sections and the electron dense

678

could

electron easily

with a

COMMENTS

portion of the tubular system was affected. It seemed, however, that cytoplasmic deposits of electron dense

structures in the ultrastructural material, calization and the general appearance they appeared to represent calcium oxalate

were

structures

crystals were composed of subunits, appearance of spicules radiating from

focus.

tween

lysosomes.

and atrophy in the difficult to determine

scanning

lar surface and were rounded or irregular

shaped particles of varying length, often in parallel arrangement (Figure 5). They could be found in any porBecause epithelium

the

tubules

6). The with the

muscle fibers of arteries and arterioles. Those occurring in the tubular epithelial cells consisted of needle-

tion

lumen that contains crystalline cells. Magnification X 75,700.

54

PRIMARY

line structures

in a tubular

lumen. Magnification

OXALOSIS-BOQUIST

ET AL.

X-37,600.

8. Scanning electron micrograph of glomerular with slightly dilated interspaces. Magnification X 62,000.

Figure

having either type I or II oxalosis according to Gasser and Wuketich’s classification [3]. Over 80 per cent of the patients with oxalosis die before the age of 20 [2]; many die in renal failure in a decade or less [7]. Survival into the fourth to sixth decade is rare [8,9]. In oxalosis excessive amounts of oxalic, glycolic and glyoxylic acid are excreted. In the variant L-glyceric aciduria, glycolic acid excretion is normal. Increased levels of urinary oxalate in the absence of pyridoxine deficiency have been suggested to be diagnostic for primary hyperoxaluria [5]. However, in the presence of renal insufficiency, the urinary excretion of oxalate is decreased and in the late stages of the disease it may be normal. The oxalic acid to creatinine ratio remains elevated to 0.05 to 0.07 also under such circumstances [4]. Normal levels of urinary oxalate may also be found in patients with rapid deposition of oxalate [7]. Hyperuricemia and hypercalcemia have been recorded in some cases of oxalosis [4]. In our patient both serum and urinary oxalic acid levels were elevated and urinary excretion of glycolic and glyoxylic acid was increased. The direct effect of renal failure on the excretion of oxalic acid

capillary

showing

interdigitating

podocyte

processes

was difficult to study because dialysis was instituted at the onset of renal failure. After the dialyses urinary oxalate excretion markedly decreased. Physical findings are sparse in patients with oxalosis. The clinical features most commonly encountered are renal colic, asymptomatic gross hematuria, recurrent urinary tract infections and hydronephrosis. Less commonly encountered are joint manifestations [9], Raynaud’s disease [lo], intermittent claudication [ll] and gangrene of the fingers. Hypertension may appear in association with renal failure, and secondary hyperparathyroidism has been observed in a few cases [5,12]. Apart from signs of renal disease, the most conspicuous clinical findings in our patient were polyneuropathy and ischemic alterations in the extremities leading to gangrene in the toes. The ischemia was apparently caused by calcium oxalate deposits in the arterial smooth muscle fibers and secondary subintimal fibrosis. There were no crystalline structures in the peripheral nerves, but nerve fiber degeneration and perineural fibrosis were found. The pathogenesis of these alterations is not clearly known, but vascular changes with impaired blood supply might have played a role.

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PRIMARY

OXALOSIS-BOQUIST

ETAL.

Calcium oxalate deposits were found in the myocardial muscle fibers, without associated clinical signs of cardiac involvement. Arrhythmias may occur in oxalosis [13], probably because of deposits in the conduction system [14]. So-called fibroplastic myocarditis has also been reported in this disease [15]. A fibrotic area probably representing a healed myocardial infarction, but no signs of myocarditis, was found in our patient. The fibrosis might have been caused by crystalline vascular deposits and associated subintimal fibrosis and by heart muscle fiber deposits leading to cellular necrosis. Rather uncommon sites for deposition of calcium oxalate are synovial membranes, central nervous system, testes, esophagus [lo], lymph nodes [16], thymus and adipose tissue [17]. The widespread involvement can be due to the presence of oxalate in the arterial walls in various organs [5,10]. The recognition of crystals of calcium oxalate in biopsy or autopsy specimens of kidneys, liver or bone marrow is essential for the diagnosis of oxalosis. The crystals may be identified as calcium oxalate by optical examination [4]. They do not stain with the routine stains and are disclosed with special technics, such as von Kossa, only in the presence of calcium carbonate or phosphate [18]. The crystalloid structures found under the light microscope and under the transmission and scanning electron microscopes were similar in distribution and crystalline composition. Because of this an identity seems probable between the crystals observed with the various technics. We have been unable to find any previous report on the ultrastructural appearance of the kidneys in cases of primary oxalosis or of the fine structural alterations after experimental administration of calcium oxalate. Renal morphology, however, has been studied after experimental sodium oxalate administration [19,20] which, it has been suggested, increases the production of basement membranous substances and results in an uptake of crystalline particles from the urine into lysosomes of tubular epithelial cells [21]. Such uptake may also occur in primary oxalosis, but since the crystals in the epithelial cells in our patient often lacked an obvious relationship to lysosomes, the oxalate crystals might well have been produced in the tubular epithelial cells (because of altered metabolism?) in which they evoked reactive and degenerative alterations, possibly leading to disintegration and atrophy of these cells and liberation of the crystalline material into the tubular lumens. A similar mechanism could be working in smooth and striated muscle fibers, as has been proposed

680

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also by Mohr and Hey [lo]. The deposits in the glomeruli might be due to increased excretion of oxalate present in the blood. In approximately two thirds of all kidney stones oxalate is a major constituent. Increased concentration of oxalate in the urine may be found in experimentally induced pyridoxine deficiency, whereas large doses of pyridoxine hydrochloride reduce the urinary excretion of oxalate [22]. Hyperoxalemia has been reported in uncontrolled diabetes [23], and oxalate may increase in the urine and renal parenchyma after ethylene glycol intoxication, in various parasitic infections [4], following ingestion of some foods in excess [I], in renal disorders such as chronic glomerulonephritis, chronic pyelonephritis and renal tubular acidosis, as well as in uremia. The frequent occurrence of calcium oxalate nephrolithiasis in the presence of only moderately elevated serum oxalate levels denotes that the oxalic acid clearance in the kidneys is probably high. The treatment of primary oxalosis represents a great problem. An increase in fluid intake in order to decrease the concentration of sol&es in the urine, the administration of phosphate in large doses to inhibit crystal formation and the administration of pyridoxine in doses of 150 mg/day have been recommended [8]. Hemodialysis decreases the concentration of oxalate but, although it is effective in controlling uremia, it is insufficient to remove adequate amounts of oxalate [12]. Success has been reported in one patient with hyperoxaluria who received a homotransplant in combination with calcium carbamide administration [24]. In another patient, who received renal transplants on two separate occasions, the treatment was unsuccessful; at autopsy both kidneys showed oxalate deposition [25]. Klauwers et al. [16], who also observed a case in which renal transplantation was unsuccessful, state that transplantation should not be performed in primary oxalosis. In our patient both clinical and laboratory evidence of progression of the disease was obtained during the 14 months of hemodialysis. Thus, it appears that this treatment is of little or no value in cases of oxalosis. From 1951 to 1969 our patient adhered to a high fluid intake, and during these years his general condition was rather good. We believe that it is urgent for patients with oxalosis to consume large volumes of fluid (4 liters or more a day) during long periods. Diagnosis of the disease at an early stage, when treatment possibly is most effective, might be achieved by determining urinary oxalate excretion in patients with calcium oxalate nephrolithiasis.

PRIMARY OXALOSIS--BOQUIST ET AL.

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regular haemodialysis therapy. Brit J Urol 41: 546, 1969. Coltart DJ, Hudson RED: Primary oxalosis of the heart: a cause of heart-block. Brit Heart J 33: 315, 1971. Beil E, Seibel K, Riecker G: Herzerkrankung bei primarer Oxalose. Klin Wschr 47: 513, 1969. Orf S: Kasuistischer Beitrag zum Krankheitsbild der Oxalose. Med Welt p 2603, 1965 I I. Klauwers J, Wolf PL, Cohn R: Failure of renal transplantation in primary oxalosis. JAMA 209: 551 1969. Lindholm J: Intra-vitam diagnosis of oxalosis. Acta Med Stand 178: 155,1965. Pizzolato P: Histochemical recognition of calcium oxalate. J Histochem Cytochem 12: 333, 1964. Galle P: Oxalose renal experimentale. Etude au microscope electronique et par spectrographic des rayons X. Nephron 1: 158, 1964. Pitha J: Elektronenmikroskopie der Nieren bei experimenteller exogener Oxalose. Zbl Path 109: 546, 1966. David H, Uerlings I: Feinmikroskopische Strukturveranderungen der Niere nach chronischer Applikation von Natriumoxalat. Beitr Path Anat 136: 284, 1968. Gibbs DA, Watts RWE: The action of pyridoxine in primary hyperoxaluria. Clin Sci 38: 277, 1970. Jurgens R, Spehr G: Zur Physiologie und Pathologie des Oxalsaurestoffwechsels. Deutsch Arch Klin Med 174: 456, 1933. Solomons CC, Goodman SI, Riley CM: Calcium carbamide in the treatment of hyperoxaluria. New Eng J Med 276: 207, 1967. Deodhar SD, Tung KSK, Zuhlke V, Nakamoto S: Renal homotransplantation in a patient with primary familial oxalosis. Arch Path 87: 118. 1969.

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