Medullary nephrocalcinosis associated with long-term furosemide abuse in adults

Yoon-Goo Kim1, Bohyun Kim2, Mi-Kyung Kim3, Shi-Jung Chung1, Hyeok-Jun Han1, Jeong-Ah Ryu2, Yoon-Ha Lee1, Kyu-Beck Lee1, Jee Yun Lee1, Wooseong Huh1 and Ha-Young Oh1,

1 Department of Nephrology, 2 Department of Diagnostic Radiology and 3 Department of Diagnostic Pathology, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Korea

Abstract

Background. The use of furosemide is well recognized as a predisposing factor of nephrocalcinosis in infants. Although furosemide is widely used for various medical conditions in adults, its association with nephrocalcinosis in adults is not well established.

Methods. We studied 18 consecutive adult patients (male:female ratio 1:17, age range 21–59 years) who habitually took furosemide to control weight or oedema for long periods of time (range 3–25 years). The daily dose of continuous intake of furosemide ranged from 40 to 2800 mg. Nephrocalcinosis was evaluated using renal ultrasonography (US), computed tomography (CT), or kidney biopsies.

Results. Renal US and CT revealed bilateral nephrocalcinosis of the medullary pyramids in 15 (83.3%) out of 18 patients. The duration of furosemide abuse was similar between nephrocalcinosis positive (NC(+)) and nephrocalcinosis negative (NC(-)) groups. The daily dose of furosemide was nearly 10 times higher in the NC(+) group (range 120–2800 mg, mean 538 mg) than the NC(-) group (range 40–80 mg, mean 67 mg). All patients showed variable degrees of renal insufficiency and there was no difference in creatinine clearance between the NC(+) and NC(-) groups (P>0.05). Kidney biopsies performed in three patients showed focal tubulo-interstitial fibrosis and atrophy and calcifications were observed in outer medullary tubulo-interstitium.

Conclusions. Long-term furosemide abuse can cause medullary nephrocalcinosis in adults, and the risk of developing of nephrocalcinosis seems to be correlated with the daily dose of furosemide. We suggest that long-term furosemide abuse should be suspected in adult patients when medullary nephrocalcinosis is incidentally detected by US or CT.

Keywords: adult; computed tomography; furosemide; nephrocalcinosis; ultrasonography

Introduction

Nephrocalcinosis associated with furosemide therapy in premature infants was first reported by Hufnagle et al. in 1982 [1]. Since then, other studies have confirmed the association in very-low-birth weight premature infants with bronchopulmonary dysplasia or hyaline membrane disease. The risk of developing nephrocalcinosis has been reported to be greatest in the more premature infants [26]. Recent reports, however, have suggested that long-term furosemide treatment carries a considerable risk of nephrocalcinosis even in older full-term infants with congestive heart failure, and that the risk is correlated with the dose of the drug [7,8]. A recent study in rats showed that nephrocalcinosis occurred in all age groups following 2 weeks of furosemide treatment [9]. These studies indicate that furosemide-related nephrocalcinosis can occur regardless of age, although the risk is higher in premature infants.

Furosemide is widely used by adults for various medical conditions and could be used without physician prescription for weight control or oedema [10,11]. In the latter condition, furosemide in excessive daily doses could be abused for long periods of time. It is not clear, however, whether nephrocalcinosis can occur under these circumstances in adults. With the advent of ultrasonography (US) and computed tomography (CT), nephrocalcinosis is more easily detected [12,13]. In order to determine the relationship between furosemide use and nephrocalcinosis in adults, we examined for nephrocalcinosis using imaging techniques and/or renal biopsies in patients with a history of long-term furosemide abuse.

Patients and methods

Patients
Between January 1995 and June 2000, we studied 18 consecutive patients with furosemide abuse in our nephrology division of Samsung Medical Center, a tertiary care hospital in Korea. The patients were referred to our nephrology division for the evaluation of hypokalaemia, oedema or incidental findings of nephrocalcinosis on abdominal ultrasound performed for unrelated reasons. All patients gave a history of intense concern about their weight and appearance. The most common motive for diuretic abuse was concern for their weight or oedema. Upon discontinuing diuretics they rapidly gained weight and became oedematous with abdominal distension, which eventually convinced them that diuretics were essential to prevent oedema. All patients were normotensive, and the presence of significant cardiac, hepatic, or renal diseases which could have caused oedema were excluded by clinical and laboratory examinations—including chest X-ray, thyroid function tests, routine urinalysis, and blood chemistry. Their oedema could be referred to as ‘idiopathic oedema’ or ‘diuretic-induced oedema’. Furosemide abuse was confirmed by the histories taken from 17 patients and by urine assay for diuretics in one patient who initially denied diuretics abuse. In order to detect diuretics in urine, we performed a simultaneous analysis for 13 diuretics by reverse-phase liquid chromatography with a diode-array detector using a gradient elution with acetonitrile and phosphate buffer on a Hypersil-ODS column. The detection limit of this test is 0.2 µg/ml of urine [14]. The duration of continuous abuse of furosemide ranged from 3 to 25 years. The patients gradually increased their daily dose to control oedema or weight, and the maximal daily dose varied from patient to patient ranging from 40 to 2800 mg. All patients denied taking diuretics other than furosemide. Four patients concurrently took the laxative Bisacodyl (Dulcolax®, bis-(p-ac-etoxyphenyl)-2-pyridylmethane) up to eight tablets per day.

The patients were instructed to discontinue furosemide intake or furosemide was switched to other diuretics (amiloride and/or indapamide) before or at the time of their referral. Fifteen out of 18 patients had discontinued furosemide intake at the time of our laboratory evaluation. Therefore, laboratory studies on furosemide intake were possible on only three patients.

Evaluation of nephrocalcinosis
Nephrocalcinosis was studied by plain abdominal radiograph, kidney US and CT. Renal ultrasonography was performed with Ultramark-9 HDI (Advanced Technology Laboratories, Bothell, USA) and Acuson 128 XP/10 (Acuson, Mountain View, USA) scanners using 2–4 or 2.5–3.5 MHz transducers. Transverse axial scans of upper, middle, and lower portions and two or three coronal scans were obtained of each kidney.

The pre-contrast CT scans of the kidneys were performed using GE High Speed Advantage (GE Medical System, Milwaukee, USA). Transverse scans of the whole kidney were obtained in 5-mm thicknesses and intervals. The US and CT findings were analysed by two radiologists (B.K. and J.R.) for the presence, location, and pattern of calcifications.

In US examinations, we used the specific criteria for nephrocalcinosis proposed by Myracle and coworkers [15], according to which echogenic foci in the renal pyramids must be at least 3 mm in diameter or produce shadowing and must be demonstrable in multiple planes. We classified hyperechoic pyramids into two different patterns: (i) diffuse increase throughout medullary pyramids (diffuse type) and (ii) hyperechoic rim in the periphery of the medullary pyramids (rim type). If both patterns were observed in a patient, the pattern was categorized as diffuse type if more than 50% of pyramids bilaterally showed diffuse increase in echogenicity and vice versa. CT findings were also categorized into diffuse and rim types using the same creteria applied to US findings.

To study the underlying histological changes, percutaneous renal biopsies were performed in three patients in whom nephrocalcinosis was detected by imaging methods. Routine immunofluorescent staining for immunoglobulins and complement as well as electron microscopic studies were done on the renal specimen.

Statistical methods
Values are expressed as mean±SE. Differences between two groups were evaluated with the Mann–Whitney U test.

Results

The renal US studies revealed medullary nephrocalcinosis in both kidneys in 15 (83.3%) out of 18 patients with furosemide abuse. Of these 15, nine patients showed diffuse increase in echogenicity throughout the pyramids (diffuse type) and six patients showed hyperechoic rim (rim type). Acoustic shadowing was demonstrated in three patients (Figure 1AGo and CGo).



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Fig. 1. Renal US and non-contrast CT showing medullary nephrocalcinosis in adult patients with furosemide abuse. (A) US shows diffuse increase in echogenicity throughout the medullary pyramids. Hyperechoic rim in the periphery of a pyramid is also observed. (B) CT of the same patient as in (A) shows rim-type calcification in the medulla. (C) US shows diffuse medullary hyperechogenicity with acoustic shadows. (D) CT of the same patient as in (C) shows dense calcification in the whole renal medulla.

 
On pre-contrast CT, bilateral medullary calcifications could be demonstrated in 12 (80%) out of 15 patients with hyperechogenic medullae (Figure 1BGo and DGo). In nine patients who had diffuse type on US, only four patients showed diffuse medullary calcifications on CT, while the remaining five patients showed peripheral rim-type calcifications on CT. Out of six rim-type patients on US, only three were rim type on CT and the remaining three patients had no evidence of calcifications on CT. The relationship between US and CT findings are summarized in Figure 2Go. Renal calcifications were observed on plain X-rays in only two out of 18 patients.



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Fig. 2. The relationship between renal US and CT findings.

 
The duration of furosemide abuse was similar between patients with or without nephrocalcinosis. However, the patients with nephrocalcinosis took a nearly 10-fold higher daily dose than the unaffected ones (Table 1Go). We studied the duration and dose of furosemide abuse vs the type of nephrocalcinosis on US. Patients with the diffuse type took higher daily doses of furosemide (range 160–2800 mg, mean 720 mg) than those with the rim type (range 120–480 mg, mean 280 mg).


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Table 1. Clinical characteristics of furosemide abusers with or without nephrocalcinosis

 
The clinical features of patients with and without nephrocalcinosis are summarized in Tables 1Go and 2Go. All patients were normotensive, normocalcaemic, and showed a variable degree of renal insufficiency. Because the status of furosemide intake at the time of evaluation could affect laboratory results, the data from 15 patients who were evaluated after cessation of furosemide intake (Table 1Go) and those of the three patients continuing furosemide (Table 2Go) were separated. In the former 15 patients, including three patients without nephrocalcinosis, there were no significant differences in creatinine clearance, daily urinary calcium excretion, serum potassium and bicarbonate, plasma aldosterone, and renin activity between patients with or without nephrocalcinosis. The three patients evaluated while taking furosemide all had nephrocalcinosis and typical features of Bartter's syndrome (Table 2Go). Hypercalciuria (>4 mg calcium/kg per 24 h or fasting urinary calcium/creatinine ratio >0.21) was present in one out of the three patients who took 2800 mg of furosemide per day at the time of study.


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Table 2. Clinical features of three patients with nephrocalcinosis who were taking furosemide when evaluated

 
The renal biopsies from three patients showed scattered discrete concretions, suggestive of calcification, apparently in the interstitium of the outer medulla (Figure 3AGo). The foci of calcifications were surrounded by interstitial fibrosis and adjacent tubules were atrophied with thickened and wrinkled basement membranes (Figure 3BGo). In addition, focal tubulo-interstitial fibrosis and atrophy with or without inflammatory cell infiltrates were observed in all three patients, involving from 10 to 30% of cortical area. The glomeruli showed no specific abnormalities and there was no evidence of immune deposits in immunofluorescent stains and electron microscopy (figures not shown).



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Fig. 3. Histological findings. (A) Renal biopsy shows foci of concretions, suggestive of calcifications, apparently in the interstitium of the outer medulla (arrows) (H&E, original x400). (B) The foci with tubular calcifications are surrounded by interstitial fibrosis (arrows). Scattered atrophic tubules with thickened and wrinkled basement membranes also are seen (PAS, original x200).

 

Discussion

Our results show that nephrocalcinosis may develop in adult patients when high doses of furosemide are used for long periods of time and that the risk of nephrocalcinosis seems to be correlated with the daily dose of the drug.

We employed high resolution US, which is now the recognized method for detecting and monitoring nephrocalcinosis. Hyperechogenic medullary pyramids in adults may not always indicate nephrocalcinosis and may also be seen on the US of patients with gouty kidney and primary hyperaldosteronism [16]. The pathologic cause in gout appears to be the deposition of urate crystals in the collecting tubules and associated interstitial nephritis. Hyperechogenic medullae in primary aldosteronism were thought to result from changes in the renal tubules and interstitium due to hypokalaemia [16]. Out of 18 patients, 15 showed hyperechogenic medullae. To confirm the presence of nephrocalcinosis, we performed non-contrast CT in those 15 patients, and medullary calcifications were confirmed in 12 (80%) patients. Although three patients with hyperechogenic medullae showed no calcification on CT results for calcification, we believe that these patients did have nephrocalcinosis. Although two out of those three had hyperuricaemia (data not shown), there was no clinical evidence of gout, and hyperuricosuria (>10 mg/kg/24 h) was not observed. Hyperuricaemia in these patients could be explained as furosemide-induced urate retention. Hyperaldosteronism could be excluded based on normal blood pressures, apparently normal appearance of adrenal gland on CT and low plasma aldosterone to renin ratios (data not shown).

We analysed and compared the patterns of nephrocalcinosis seen in US and CT (Figure 2Go). Our findings indicate that the echogenic rim is an early manifestation of nephrocalcinosis and US is a more sensitive imaging tool for the detection of nephrocalcinosis when compared with CT, as has previously been suggested [17,18].

An interesting finding in this study is that the risk of nephrocalcinosis seems to be correlated with the daily dose of furosemide (Table 1Go). Furosemide is widely used for the treatment of various conditions in adults and long-term use is not uncommon. To our knowledge, however, furosemide-associated nephrocalcinosis has not been recognized in adult patients, while it has been well known in premature infants. In our study, the daily dose of furosemide (range 120–2800 mg, mean 538 mg) taken by patients in whom nephrocalcinosis was detected far exceeds the usual prescribed dose. In contrast, nephrocalcinosis was not detected in patients who took relatively lower daily doses (range 40–80 mg, mean 67 mg) despite the fact that they took the drug for 14–17 years. Our data for dosage and the duration of furosemide abuse relied completely on histories taken from patients, which may not be reliable or accurate. Further study will be needed to confirm our observations and suspicions.

Furosemide intake may predispose to development of nephrocalcinosis by increasing urinary calcium excretion. We could measure urinary calcium excretion during high-dose furosemide intake only in three out of 18 patients, because the others had been instructed to stop taking furosemide at the time of referral. Nevertheless, hypercalciuria was observed only in one out of those three patients. A possible explanation may be that calciuria occurrs only during the first several hours following administration of furosemide following which calcium excretion decreases [19,20]. Nephrocalcinosis, therefore, may be attributed to a markedly fluctuant calciuretic effect of the drug. Another interesting finding is that the clinical features of furosemide abuse resemble Bartter's syndrome. Nephrocalcinosis has been reported in patients with Bartter's syndrome [2123], which may suggest that both conditions have similar pathogenesis. The pathogenesis of nephrocalcinosis in Bartter's syndrome remains unclear. Hypercalciuria is not a constant finding in Bartter's syndrome, as in patients with furosemide abuse. Persistent alkalosis and alkaline urine secondary to chloride deficiency could result in nephrocalcinosis in both Bartter's syndrome and patients with furosemide abuse [23,24].

Other factors may also have contributed to the development of nephrocalcinosis in our patients as suggested by previous studies on infants and animals, e.g. alterations in urinary excretion of oxalate and urinary levels of citrate and magnesium, which are known to inhibit crystal formation in the urine [5,12,25,26]. It also may be possible that the prolonged hypokalaemic metabolic alkalosis and high urine pH, which may occur in patients with furosemide abuse, may provoke precipitation of calcium phosphate [24]. In addition, long-term daily furosemide ingestion has been reported to cause chronic tubulo-interstitial changes with gradual impairment of renal function [27]. In our study, all patients, whether or not they had nephrocalcinosis, showed variable degrees of renal insufficiency (Table 1Go). Renal biopsies from three patients with hyperechogenic medullae also showed tubulo-interstitial fibrosis, tubular atrophy, and calcifications at the corticomedullary junction. These findings suggest that long-term use of furosemide could cause chronic tubulo-interstitial damage, with consequent alterations in tubular function promoting nephrocalcinosis, particularly when higher daily doses were used for long periods of time. In addition, chronic hypokalaemia produced by furosemide abuse could have provoked tubulo-interstitial injury in our patients [28,29]. Vacuolar lesions in the epithelial cells of the proximal tubules, known to be the characteristic change in chronic hypokalaemia [30], were not observed in our patients. It is possible that the prolonged hypokalaemia, which might have persisted for several years could cause more severe injuries to the tubular interstitium than vacuolization. In our study, there was age discrepancy between the patients with or without nephrocalcinosis and the mean age was higher in patients without nephrocalcinosis (Table 1Go). Because of the small number of patients, the clinical significance of this discrepancy could not be evaluated.

In this study, we did not demonstrate the reversibility of nephrocalcinosis after discontinuation of furosemide. Out of 15 patients in whom nephrocalcinosis was detected, eight patients were lost to follow up and four patients did not completely discontinue furosemide ingestion. Thus, long-term follow up US studies (>2 years) were possible only in three patients after discontinuation of furosemide. In these follow up examinations, resolution of nephrocalcinosis was observed in one patient.

In summary, this study shows that long-term furosemide abuse may cause medullary nephrocalcinosis in adults, and that the risk of developing of nephrocalcinosis seems to be correlated with the daily dose of furosemide. We suggest that long-term furosemide abuse should be suspected in adult patients when medullary nephrocalcinosis is incidentally detected by US or CT.

Acknowledgments

This work was supported by the Medical Research Fund of Samsung Medical Center, Sungkyunkwan University School of Medicine.

Notes

Correspondence and offprints requests to: Ha-Young Oh, MD, Department of Nephrology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon Dong, Kangnam Ku, Seoul, 135–710, Korea. Email: ygkim{at}smc.samsung.co.kr Back

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Received for publication: 6. 3.01
Revision received 7. 7.01.



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