Are there any factors affecting the outcome of endoscopic sclerotherapy in filarial chyluria? A prospective study.

INTRODUCTION: Filarial chyluria is a frequent problem in India. While endoscopic therapy is the mainstay of treatment, it is not always successful. We aimed to determine parameters that affect outcomes of endoscopic sclerotherapy for filarial chyluria (FC).
METHODS: Prospectively maintained data of FC patients who received endoscopic sclerotherapy between June 2011 and March 2015 were analyzed. Sclerotherapy included either povidone-iodine (0.1%) or silver nitrate (1%). The parameters recorded included clinical evaluation, urinary triglyceride (TG)/cholesterol, sclerotherapy treatment, and follow-up.
RESULTS: One hundred and fifty-seven patients (male: female, 104:53) with a mean age (± standard deviation [SD]) 41.12 ± 13.68 years underwent endoscopic sclerotherapy. Grade II (68.88%) chyluria was a most common presentation followed by Grade III (25.69%). One hundred and forty-four patients responded whereas six patients failed to respond; another seven were lost to follow up, and twenty patients had recurrence. Overall success rate was 86.11%. Baseline urinary TG (mean ± SD) between success and recurrence group was 195.51 ± 164.73 mg/dl and 652.65 ± 62.55 mg/dl and cholesterol (mean ± SD) was 16.99 ± 10.08 mg/dl and 89.07 ± 39.87 mg/dl, respectively. Patient with urinary TGs >300 mg/dl and urinary cholesterol >30 mg/dl had 3.2 and 1.3 times higher chance to have recurrence after endoscopic sclerotherapy, respectively. Choice of sclerosing agent (silver nitrate 1% versus povidone-iodine 0.1%) had no difference in success rate, but silver nitrate had slightly higher complications rate (25% vs. 20%). A higher number of instillations (>3) was associated with better success rate. Majority of the complications were either Clavien Grade 1 or 2.
CONCLUSIONS: The factors predicting recurrence were higher clinical grade, higher number of pretreatment courses, and high urinary TG and cholesterol.

INTRODUCTION

Filarial chyluria (FC) is not an uncommon problem in tropical countries. Chyluria is clinically classified into Grade I (milky white urine), Grade II (whitish clots or episodes of clot retention), and Grade III (hematochyluria).[1] The initial management includes dietary modification with medical treatment. Medical therapy has a success rate of about 50%–65%.[2345] Patients who fail or do not respond to conservative medical treatment are managed by endoscopic sclerotherapy. Instillation therapy has variable success rates ranging between 65% and 80%.[167] Commonly used agents for sclerotherapy include povidone-iodine (0.1%–0.3%) and silver nitrate (1%) as these agents have more successful outcomes with fewer complications.[17] Patients who do not respond to instillation therapy may choose to undergo either repeat instillation or pyelolymphatic disconnection surgery. However, instillation therapy remains the mainstay of management for this disease with pyelolymphatic dissection being an uncommon surgery.

To the best of our knowledge, predictors for success or failure to instillation therapy have not been investigated. This information would be useful as this would help us in understanding the pathophysiological basis of endoscopic therapy and also in planning therapy. Previously, we reported factors that predict successful medical therapy in patients with chyluria.[3] In the present study, we determined different parameters that affect outcomes of endoscopic sclerotherapy for FC.

METHODS

After Institutional Ethical Board clearance, we prospectively collected data of FC patients who were subjected to endoscopic sclerotherapy for the first time between June 2011 and March 2015. Chyluria was diagnosed by the presence of chyle and/or triglycerides (TGs) (>10 mg/dl) in urine sample, and filarial etiology was confirmed using blood immunochromatography test which has good sensitivity and specificity (Binax-Alere, USA) and IgG/IgM Combo Rapid Test.[8] Patients were excluded if they did not give consent for inclusion, milky urine not because of chyluria, non-FC, patients found to have urinary tract or any other malignancy, pregnancy, known medical renal disease/compromised renal function (serum creatinine >1.5 mg/dl), uncontrolled diabetes, tuberculosis, and history of contrast allergy. Furthermore, patients in whom the therapy had to be stopped before completion of sclerotherapy treatment due to complications or had received endoscopic sclerotherapy before were excluded from the study. The indications for instillation therapy included patients who failed multiple courses of antifilarial treatment (diethylcarbamazine – 6 mg/kg into three divided doses for 3 weeks with doxycycline 100 mg twice for 4 weeks and single dose of albendazole 400 mg + ivermectin 200 μg/kg), nonresponders to medical therapy, and patients with chylous clots giving rise to difficulty in voiding or clot retention with or without hematochyluria.

The parameters recorded included history (such as total disease duration and details of past medication), clinical examination, serum albumin, urinary TG/cholesterol (enzymatic kit method), details of sclerotherapy treatment (sclerosing agent, dose, duration, complications, response to therapy, and time of recurrence), and follow-up.[89] All included patients completed at least 1-year of follow-up.

Sclerotherapy instillation was done under local anesthesia combined with sedation.[6] The ureteric catheter was placed under fluoroscopic guidance to ensure proper placement. We routinely instilled the first dose of sclerosing agent at the time of ureteric catheterization except when there was gross hematuria or patients were having discomfort or flank pain. The sclerosing solution used was either povidone-iodine (0.1%) or silver nitrate (1%) depending on the choice of the surgeon. Silver nitrate powder (2 g) was dissolved in 200 ml of water in a glass bottle to prepare 1% concentration. The bottle was wrapped in a black paper to avoid exposure to light, kept in a dark room, and sterilized by autoclaving. To prepare 0.1% povidone-iodine, we used 10% (w/v) povidone-iodine in distilled water with 1:100 dilutions. Freshly prepared drug was instilled 8 hourly, and the instilled volume was determined at the time of ureteric catheterization.[6] The contrast agent (urografin – 76%, Schering Pharma, Germany) was instilled to completely fill the pelvicalyceal system without overdistension under fluoroscopy guidance. The amount of contrast agent instilled to fill the pelvicalyceal system completely was defined as instillation volume. The patients received either three, six, or nine doses. This decision for the number of doses was based on gross clearance of chylous urine and was also based on the patient's tolerance and/or complications. The decision to continue another three doses was taken in the morning, and if the urine was milky, then another three doses were given. This flexible protocol was followed to reduce the risk of complications from extra doses after the urine became clear.

Responders to therapy were defined as those patients where the urine became clear on gross examination at the end of instillations. Recurrence was defined as relapse of gross chyluria after an initial response. Success was defined when the patients did not have any episode of gross chyluria with minimum 12-months follow-up or at last follow-up. All patients were advised fat-restricted diet in the postinstillation period and were asked to avoid further exposure to mosquito bite.[3] Follow-up was done at 2 weeks, 3 months, 9 months, and thereafter if needed or if the patient developed recurrence. At each follow-up visit, patients were enquired about episodes of milky urine, and urine examination was done for evidence of chyle or TGs. Dietary compliance was checked at each visit. Telephonic interview was obtained if the patient failed to attend the clinic.

Statistical analysis

The data were analyzed using SPSS (SPSS version 16.0, SPSS Inc., Chicago, Illinois, USA). Continuous variables were analyzed by independent t-test and discrete variable are analyzed by Chi-square test. P < 0.5 was considered statistically significant. The odds ratio to determine the cutoff values of urinary TGs and urinary cholesterol (using mean values) to differentiate between patients who responded to treatment versus those who experienced recurrence was calculated. Factors found significant (P < 0.05) on univariate analysis were subjected to multivariate analysis.

RESULTS

One hundred and fifty-seven patients fulfilled the inclusion criteria. Ninety-nine patients received povidone-iodine whereas 58 received silver nitrate instillation. One hundred and forty-four (144; 96%) patients responded to instillation therapy whereas 6 (4%) failed to respond (nonresponders). These six patients (four men) had a mean age of 38.65 years. Of these, five patients had Grade III chyluria at presentation whereas three patients had a recurrence after previous medical therapy with baseline high mean urinary TG level (673.16 ± 65.23 mg/dL). They were subsequently managed by either repeat renal pelvic instillation therapy (RPIS) within 6 weeks with a different sclerosing agent (three patients) or underwent pyelolymphatic disconnection (three patients). Nonresponding patients having persistent high-grade chyluria after initial RPIS opted for surgical disconnection. No patient in this group recurred after pyelolymphatic disconnection surgery after an average follow-up of 15.4 months. Another seven patients were lost to follow-up. These 13 patients were excluded from further analysis.

The success rate was 86.11% with the average follow-up being 21 months (range: 12–31). Twenty patients experienced recurrence of chyluria at a mean follow-up period of 21 months (range: 12–27). Patients with higher clinical grade, higher number of pretreatment drug courses (mean ± standard deviation, 2.32 ± 1.4), and high urinary TG and cholesterol had poor outcome to sclerotherapy. The serum albumin levels and absolute eosinophil counts were not significantly different between success and recurrence groups. Demographic, historical, biochemical, and operative data are shown in Table 1. If the patient consented, recurrence was managed with either second session of RPIS or laparoscopic chylolymphatic disconnection. The difference in the clinical and biochemical parameters between successful group and recurrence group is shown in Table 1. Multivariate logistic regression analysis (success versus recurrence) with factors affecting outcomes of endoscopic sclerotherapy is shown in Table 2. On calculating the odds ratio to predict the chances of recurrence, it was found that patients with urinary TGs >300 mg/dl and urinary cholesterol > 30 mg/dl had 3.2 and 1.3 times higher chance to develop recurrence following endoscopic sclerotherapy (confidence interval – 95%, P < 0.04).

Table 1

Overall clinical, historical, biochemical, and operative data of the entire group and according to response to therapy

Table 2

Multivariate logistic regression analysis of factors affecting the responses to instillation therapy (success vs. recurrence)

The complications in silver nitrate and povidone-iodine groups are depicted in Table 3. Thirteen patients (13/52, 25%) in the silver nitrate group and 18 patients (18/92, 20%) in the povidone-iodine group had various complications. According to modified Clavien-Dindo grading system, the complications seen were a transient postoperative fever in nine cases (Grade I), hematuria managed with hydration in four cases (Grade I), and flank pain in 13 cases (Grade I). These were managed with oral and intravenous analgesic. Infectious complication was seen in 5 patients. Four patients developed acute pyelonephritis (Grade II) which was managed with intravenous antibiotics. One patient needed Intensive Care Unit care for sepsis due to acute pyelonephritis (Grade III) and was managed conservatively.

Table 3

Complications according to modified Clavien-Dindo grading

DISCUSSION

Chyluria is one of the chronic manifestations of filariasis. Lymphatic filariasis is a parasitic disease transmitted by mosquito affecting around 120 million people in eighty tropical and subtropical countries.[10] About 23 million people suffer from filarial disease in India with high endemicity in our province, Uttar Pradesh (14.6%).[11] Approximately 2% of filariasis patients develop chyluria.[12] About 30%–40% of patients do not respond or respond partially to medical therapy or recur after the initial response.[3513] Most recurrences are treated by repeat course of conservative medical treatment.[5] However, some of these patients need endoscopic sclerotherapy or chlylolymphatic disconnection.

It is believed that chyluria is a consequence of retroperitoneal lymphatic blockage or lymph regurgitation due to infection by filarial parasites. This leads to increased pressure within the lymphatic channels that rupture within the pelvicalyceal system leading to abnormal communication and chyluria.[514] The rationale for sclerotherapy is that the sclerosing agent enters the pyelo-lymphatic fistulae causing chemical lymphangitis with resulting inflammation and fibrosis. This fibrosis causes obliteration of abnormal communication and relief from chyluria.[15]

On univariate analysis, we found that the recurrence was higher in certain group of patients. These include patients with higher grade at presentation, multiple prior treatments, and patients with higher urinary TG and cholesterol levels. On multivariate logistic regression analysis, our data showed that patients with Grade II/III disease, high urinary TG/cholesterol levels at presentation, multiple prior conservative treatment courses, and lower number of instillation doses (<3) were associated with higher chances of recurrence.

The pathophysiological basis of recurrence after sclerotherapy has not been investigated and fully understood. The possible reasons of recurrence could include either inadequate treatment or the disease biology itself. The possible causes of inadequate treatment may be slippage of ureteric catheter during patients' mobilization, blockage of ureteric catheter (especially with silver nitrate), incomplete doses because of persistent or intolerable pain during instillation, or due to complications from instillation such as hematuria, acute pyelonephritis, or sepsis or dietary noncompliance.[161718] Another reason for poor response could be the concentration of the sclerosing agent. To reduce the incidence of side effects, the sclerosants are used in a very dilute form compromising efficacy.[1920] We place the ureteral catheter under fluoroscopic guidance to ensure that the catheter is placed in the middle of renal pelvis. Blind insertion may lead to placement of ureteral catheter into the superior calyx or other unfavorable location.

The sclerosing agents cause fibrosis and obliteration of chylolymphatic fistulae with resolution of chyluria. However, as the retroperitoneal blockage persists some patients either fail to respond or develop recurrence. In our study, six patients did not respond to sclerotherapy even after nine doses of instillation. Recurrence could be explained by increase in the degree of obstruction due to either fresh bite by infected mosquito or some other unknown reasons. Those who recur may have opening up of the previously obliterated communication, formation of new communications, or leak from some another source (like ureter).[21] New lymphatic communication may occur both after sclerotherapy as well as after surgical disconnection. Traditionally, surgical chylolymphatic disconnection has higher success (95%–100%) as well as lower recurrence rate than endoscopic sclerotherapy.[2223]

Nonadherence to dietary restriction may also lead to recurrence. In the postinstillation therapy, we advised all patients to continue fat-restricted diet and to use cooking oil containing medium chain TGs (MCT, <12 carbon atom) fat.[3] MCT oil is commercially available and can be started 5 ml three times a day (TDS) and can be increased to 15 ml TDS; however, it is costly. Some authors recommend using coconut oil (rich source of MCT), but it is not advisable because it contains other fatty acids also.[2] Dietary modification includes the use of minimum amount of oil for cooking (preferably in nonstick pans), skimmed milk, restrict ghee/butter, and avoid adding extra ghee on dal or spreading butter on bread/roti, restrict sweets, prefer fish and chicken than mutton for nonvegetarian, taking regular diet like dal, roti, rice, bread, and cornflakes.[2] However, it is difficult to ensure dietary compliance in economically poor and rural population. This needs further evaluation, as there is no study available for dietary restriction versus no restriction affecting the outcome after endoscopic sclerotherapy.

We found that there was no difference between silver nitrate and povidone-iodine instillation as per efficacy (84.78% vs. 88.46%, respectively). Various sclerosing agents are available in different concentrations.[2425] Serious complications of instillation therapy may result from the use of higher concentration of sclerosing agents or simultaneous bilateral instillation. There are reports of higher complications such as sepsis, ureteric stricture, or even death following the use of 3%–5% silver nitrate.[26] To decrease the complications, 1% silver nitrate is usually used nowadays. However, it is possible that this lower concentration may lead to higher chance of recurrence and/or nonresponse to therapy.[27]

There is debate about the ideal number of instillations doses. Traditional instillation protocol is 8 hourly for 3 days with total nine doses.[728] There are some studies show that three doses may have similar efficacy to that with nine doses.[29] Sparse data also suggest that even single dose may have similar efficacy, but these studies have not mentioned the outcomes according to grade or severity of disease.[2230] We tailor the dose according to the response and offer three, six, or nine doses. This approach reduces the risk of overtreatment and reduces complications. However, we noticed that patients who received three doses had higher chances of recurrence (2 out of 9) as compared to nine doses (86 out of 89), P < 0.04. On multivariate analysis, there was a significant difference in response between patients receiving <3 versus >3 doses (P = 0.02).

Complications were graded according to modified Clavien grading scores. Silver nitrate had slightly higher complications rate than povidone-iodine (25% versus 20%, P = 0.12). Most of the complications were minor in nature. Urine culture must be sterile before instillation therapy to avoid infectious complication such as pyelonephritis.

There were some limitations in this study. First, the problem for analyzing result in chyluria patient is difficult because natural remissions are known. Therefore, it is difficult to differentiate between natural remission and cure of the disease.[13] Second, it is a general recommendation to tell the patients to take precautions such as avoiding further mosquito bites. However, this advice may be difficult to comply. It may be possible that the medical management/sclerotherapy was effective, but because of repeated exposure, the patient developed recurrence. However, documenting this cause as the reason for treatment failure is impossible. Hence, it is possible that recurrence of chyluria could be either because of treatment failure or possibly related to some unidentified factors.

Another problem in the study was the variable sclerosing agents used (either povidone-iodine or silver nitrate) and variable dosage protocol. The follow-up was also short. Chyluria often recurs after many years. A randomized control trial involving larger sample size will be required to better understand this issue.

There are certain strengths of this study. There are no studies with such large number of endoscopic sclerotherapy-treatment-naive patients being treated. Moreover, predictors for response to endoscopic sclerotherapy have never been studied before.

CONCLUSIONS

Higher clinical grade, higher number of pretreatment courses of drug therapy, high urinary TG and cholesterol level, predict failure of endoscopic therapy in filarial chyluria.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.