Issues in etiology and diagnosis making of chyluria

Abstract

Chyluria, the passage of intestinal lymph in urine is common in the rural and economically weaker population of our country. Etiologically it has been classified as parasitic and nonparasitic (rare). By far the most important and most common cause effect relationship of chyluria is withWuchereria bancrofti.The issues in diagnosis making of chyluria include: confirmation of chyluria, localization of site of leakage in urinary tract, identifying the cause of chyluria and assessing as to how bad is the disease? A number of biochemical and radiological diagnostic tests are available for the same. Since this is 'a disease of the poor', there is a need to modify the approach of diagnostic evaluation and therapeutic protocols in order to curtail the overall cost of treatment.

Chyluria is the passage of intestinal lymph in urine, though an uncommon symptom has been recognized since the time of Charak (300 BC) who described it as 'shuklameha'. In our country, as the disease is rife in rural and economically weaker population, there is a need to modify the approach of diagnostic evaluation and therapeutic protocols. We have earlier published our endeavor to curtail the overall cost of treatment by judicious use of investigations.[¹] In this chapter we are retreating our approach of diagnosis making and also highlighting the etiology of this infirmity.

ETIOLOGY

Etiologically, chyluria has been classified into parasitic and nonparasitic forms:[²]

1. Parasitic (primary-tropical),

• Wuchereria bancrofti;
• Eustrongylus gigas;
• Taenia echinococcus;
• Taenia nana;
• Malarial parasites;
• Cereonomas hominis.

2. Nonparasitic (secondary: nontropical),

• Congenital;
• Lymphangiomas of urinary tract;
• Megalymphatics with urethral or vesical fistulae;
• Stenosis of thoracic duct;[²]
• Retro peritoneal lymphengicatasia;
• Traumatic lymphangiourinary fistulae;
• Lymphatic obstruction due to:
• Obstruction of thoracic duct by tumor;
• Granuloma glands, aortic aneurysm, and malformations;
• Obstruction of deep retroperitoneal lymphatics by same causes;
• Other causes;
• Pregnancy;
• Diabetes;
• Perniceous anaemia.

Parasitic chyluria

A numbers of parasites besides Wuchereria bancrofti have been incriminated by various workers as a cause of chyluria eg.Eustrongylus gigas, Taenia echinococcus, and malarial parasite. Taenia nana, Ascaris, S. Haematobium, and Ceronomas hominis. It is not clear, however, as to whether these parasites are actually responsible or whether their presence is merely coincidental. By far the most important and the most common cause-effect relationship of chyluria is with Wuchereria bancrofti. The endemic occurrence of chyluria in filaria infested regions and demonstration of parasites in the blood, lymph or urine of chyluric individuals by various workers supports this view.[²]

Nonparasitic chyluria

Nonparasitic conditions are rare causes of chyluria are usually associated with a process of stenosis or obstruction of the thoracic duct or retroperitoneal lymphatics.[³⁴] The common causes are tuberculosis, reteroperitioneal abscess and neoplastic infiltration of retroperitional lymphatics, trauma and pregnancy. A case of chyluria has been reported following an aortoiliac bypass graft and another in a patient following percutaneous nephrolithotomy.

PATHOPHYSIOLOGY

The anatomical basis of chyluria has been explained by many authors but has remained a subject of speculation till recently. The lymphatics of the kidney follow the renal vein and end in the lateral aortic glands. The efferents from the lateral aortic glands form the lumbar trunks. The intestinal trunks comprise the large vessels, which receive lymph from stomach, intestine, pancreas, spleen and from the lower and the anterior part of the liver. The lumbar trunks and the intestinal trunks drain into the cisterna chylii. The dilatation and varicosities of retroperitoneal, intestinal and renal lymphatics has long been recognized. This has been explained by two theories.

1. Obstructive theory

The parasitic infestation produces obliterative lymphangitis and lymphatic hypertension, which subsequently generate varicosity and collateral formation. Once lymphatics are dilated their valvular system fails adding to back flow and dilatation. This theory has been in vogue for nearly 100 years and appears partly contributory.

2. Regurgitative theory

The toxins released from dying filarial worms leads to some kind of weakness in the lymphatic wall ('ectasia'), which in turn leads to impairment of valvular mechanism. Direct inflammatory damage of valves may cause additional effect. Thus, regurgitation of chyle from cisterna chyli or large lymphatic trunk into the other may lead to varicosity and subsequently chyluria by rupture of these varicosities/dilated lymphatics into renal calyces or pelvis.

The route from the intestinal to the renal lymphatics has been the subject of much speculation but it is agreed that chyle must first travel from the lacteals to the cisterna chili or thoracic duct. Then because of obstruction and/or insufficiency of the valvular system of lymph channels there is a reterograde flow to the upper lumbar lymph glands, which drain the renal lymphatics. Definite inadequacy of the lymphatic vessel valves exist since retrograde flow is frequently seen extending down the prevertebral and paravertebral regions on reterograde pyelography. It has been clinically observed and experimentally demonstrated that congestion in the lymphatics resulting from inflammation produces varix of its afferent vessels. It is believed that chyluria occurs because of retroperitoneal lymphatics receiving lymph flow from the intestinal lymphatics become obstructed secondary to fibrosis produced by parasitic infestation thus short-circuiting chyle from the intestinal lacteals to renal lymphatics, which rupture subsequently.

Why chyluria is mostly unilateral?

The manifestation of chyluria depends upon the site of involvement and the anastomotic variation of lymphatic system in the individual patient. The anastomotic variation primarily occurs at the cisterna chyli where the lumbar trunks and the intestinal trunks join. The classical cisterna chylii as described above is seen in only about 47% of normal individuals, and the intestinal trunk in such cases drains in the lumbar trunks of one side or directly in the thoracic duct either as a single trunk or as multiple smaller ones. This may explain the presence of unilateral chylous oedema of only one extremity or unilateral chyluria. The unilateral findings are more common on the left side.[⁵⁶]

Investigations and diagnosis

In chyluria investigations are aimed at detection and confirmation of the presence of chyle in the urine and location of the lympho-urinary fistulae apart from other routine investigations for the general assessment of the patient Table 1. Unless complications are present renal function in usually unaffected. Microfilaria may or may not be demonstrated in urine and/or blood. Although eosinophilia is an accepted feature, most of investigators have not observed absolute eosinophilia in their patients. Leukocytosis has been reported in acute filarial manifestations.

Table 1: Diagnosis making

URINARY INVESTIGATIONS

Chylous urine is best studied immediately after it has been voided. A fatty diet a day or night before has been used to enhance chyluria. On gross inspection, classic chylous urine is like milk, frequently containing a semisolid gel. Blood and fibrin clots are frequently observed in most of the samples. When kept in the test tube, it usually settles down into three layers, the fat being lighter gets deposited as the top layer, the fibrin clots from the middle layer and cells together with debris settle in the bottom layer (Figure 1). [⁵⁶⁷]

Figure 1: Urinary investigations

When equal part of the milky urine and ether are vigorously shaken for a few minutes, there is almost complete clearing of opacity with slight turbidity remaining in the lower nonether zone. Under the microscope the sediment is found to contain variable number of erythrocytes and lymphocytes. The latter when stained fresh with one or two drops of 1:1500 aquous solution of methylene blue reveals small lymphocytes floating single or in clumps. Fat droplets of varying size can be seen. Casts and cylindroids are usually absent.[⁵⁷] Chylomicrons can be seen directly under microscope with dark ground illumination or stained with Sudan III. Oral ingestion of fat labelled with Sudan III (10 gm of butter with 100 mg of Sudan red III) causes orange pink colouration of urine in chylurics with in 2-6 h,[⁸] but Sudan III being expensive is not freely available. The urine examination at the hands of various pathologist has been found to inaccurate number of times, particularly if chyluria is mild. This is partly due to less sensitively of ether test where only subjective methods are employed to see the resolution of turbidity. Recently, focus is being shifted to biochemical as well as electrophoretic study to detect the lipid constituents of urine and recently urinary triglyceride have been demonstrated to be universally present even if the urine is clinically clear.[⁹] Whether chyluria is continuous/intermittent mild or severe, urinary triglycerides are invariably detected in morning samples. Patients of UTI or phosphaturia are negative for the same. Estimation of urinary triglycerides is 100% sensitive and specific test for chyluria. It is noninvasive and cost effective and is independent of manual error. The etimated values of chylomicrons, TGs and cholesterol in urine may point to the level of abnormal communication.

Similarly, urine albumin has been found in varying ranges from mild to nephrotic range[¹⁰] and immunoelectrophroresis has shown globulins of various types and apolipoprotein A 48 of intestinal origin in the urine.[¹¹] The urine may sometimes contain predominantly blood and sometimes, the severe haematochyluria in accompanied with a clot in bladder which is often confused as carcinoma bladder. We described the ultrasonographic appearance (Figure 2) of such clot where, in many echolucent areas are seen amidst the blood clot due to the coexistence of chylous component.

Figure 2: Ultrasound appearance of Chylous clot in bladder: note the heterogeneous character due to mixture of blood and chyle

Localization of lympho-urinary fistulae

Urologic investigations to localise site of lymphatico-urinary fistulae and obstruction should include, cystourethroscopy, retrograde pyelography (RGP) and lymphography, in some patients.Intravenous urography is mostly normal, hence its routine use is questionable. It may rarely demonstrate dilated para-calyceal lymphatics[²] particularly when ureteric pressure is applied. Renal size may appear larger in severe lymphatic disease. It has poor sensitivity and often proves to be a costwaste. It is recommended if higher concentration of (Ag No3) is being planned for instillation.

Cystourethroscopy and retrograde pyelography

Cystourethroscopy (CPE) is very useful and often shows milky efflux from one or both ureteric orifices.[¹²] Rarely, chylous efflux may be seen from bladder or even posterior urethra. Particularly when irrigant flow is stopped and bladder in semi-filled. In mild chyluria, ureteric catherization and split urinalysis for chyle may be done.[⁵¹²] Retrograde pyelography with fluoroscopic control and spot films often demonstrates pyelolymphatic backflow. Earlier studies demonstrated this in most of the cases and believed it to be diagnostic of chyluria. Later studies revealed that it is not specific of chyluria and may be seen in normal kidneys particularly if contrast is injected under pressure. However, it is more likely to occur in chyluria and should be differentiated from pyelovenous reflux, which is rather rare.[²]

We recommended some modifications in technique of RGP. Once localization of the laterality of chylous efflux is done cystoscopically a 5-6 0F ureteric catheter is gently introduced under fluoroscopic guidance until it reaches the renal pelvis. The RGP film is taken with the patient in 20° trendelenberg position. The contrast is gently instilled into the pelvis allowing gravity propagated filling of the pelvis instead of pressurized instillation. The films are checked for the presence of pyelolymphatic fistulae (Figures 3A, B, and C). We do not use force because sudden distension of renal collecting system is painful and may open up pyelovenous or pyelosinus channels, which may cause inadvertent reactions.

Figure 3: A, Retrograde pyelogram showing pyelolymphatic fistulae (mild). B, Retrograde pyelogram showing pyelolymphatic fistulae (moderate). C, Retrograde pyelogram showing pyelolymphatic fistulae (severe)

Lymphography

Lymphography shows lymphaticourinary fistulae (lymphaticocalyceal and lymphaticoelvic). Numerous torurous dilated lymphatics around hilar region (lymphangiectasia) communicating with paravertebral lymphatics and contrast outling major/minor calyx. Contrast may enter pelvicalyceal system in 40% and may be followed into bladder.[^13141516] Other associated findings may be; thoracic duct sometimes shows tortuosity and beading though mostly it is normal, round granular enlarged, nodes in para-aortic area, skipping of lymphatic chain in advance cases, dilated cisterna chylii may be demonstrated, abnormal lymphatics may be seen coursing down along line of ureter and transit of contrast medium from feet to thoracic duct is characteristically accelerated. Presently it is not recommended for routine use.

Lymphoscintigraphy

Recently, Radio-nuctide lymphoscintigraphy has been used to outline lymphatics in patients with various lymphatic disorders (Figure 4).[¹⁷¹⁸] A comparison is presented between the results of lymphangiography and lymphoscintigraphy in patients with chyluria (Table 2) and these are correlated well. Lymphoscintigraphy being less invasive has been promulgated as investigation of choice but is not available at all centers. A simple diagnosis-making algorithm is presented (Figure 5).

Figure 4: Lymphoscintigraphy showing pyelolymphatic fistulae

Table 2: Comparison between lymphangiography and lymphoscintigraphy

Figure 5: Algorithm for making diagnosis in chyluria

Elisa test for filariasis (fila test)

The ELISA test for filariasis is based on humoral immune response of the host to filarial antigen. The filarial ES antigen, immobilized on membrane is allowed to react with patients serum, followed by incubation with anti IgG enzyme conjugate. The presence of antibody is detected using a color change indicator system.[¹⁹] The specificity and sensitivity of this test has been reported to be 85 and 95%, respectively (Lymphatic filariasis fourth report of WHO expert committee of filariasis, 1984).

Renal biopsy

It is rarely done and mainly for research purpose. Light microscopic changes reported are; membranous nephropathy, mesangioproliferative nephropathy, endothelial cell proliferation; mild mononuclear cell interstitial infiltration. Ultrastructural changes reported are; immune complex type glomerulonephritis has been demonstrated in animal model, and also in human subjects.[²⁰] How far these changes affect course of chyluria is not know because they are just the result of filariasis not of chyluria perse. Slight increase in renal size has also been reported in chyluria (? due to lymphatic obstruction).

CONCLUSION

Since the available investigative options are myriad, there is a need to individualize their application in order to best suit the case so as to arrive at the diagnosis and plan the therapeutic intervention accordingly in a cost effective manner[²¹].