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Clinical Kidney Journal Advance Access published December 10, 2013
Clin Kidney J (2013) 0: 1–3doi: 10.1093/ckj/sft141 Renal phospholipidosis possibly induced by ranolazine Christoph Scheurle1, Maximilian Dämmrich2, Jan U. Becker2 and Martin W. Baumgärtel1 1Medizinische Abteilung, St. Franziskus-Hospital, Münster, Germany and 2Institute of Pathology, Hannover Medical School, Hannover,Germany Correspondence and offprint requests to: Martin W. Baumgärtel; E-mail: martin.baumgä[email protected] A 76-year-old male Caucasian patient was treated in our hospital for acutely decompensatedheart failure due to restrictive cardiomyopathy. Acute-on-chronic kidney failure developed withserum creatinine rising from 160 to 345 μmol/L (1.8–3.9 mg/dL); therefore, a kidney biopsy was per-formed. Besides secondary focal-segmental glomerulosclerosis and minimal amyloidosis, histo-logical analysis showed zebra bodies in the cytoplasm of some podocytes, suggesting renalphospholipidosis (PL). Possible causes for this storage disorder encompass Fabry’s disease, in rare cases silicosis, and an iatrogenic drug-induced aetiology. The main suspects are cationic amphiphi-lic drugs, such as amiodarone and chloroquine. The only cationic amphiphilic drug our patient hadtaken was the anti-anginal ranolazine, a compound not yet associated with PL. The patient hadtaken ranolazine for diastolic dysfunction over a period of 9 months until 6 weeks before renalbiopsy. In the absence of a hereditary disorder, silicosis and well-known pharmaceutical triggers, acausative role of ranolazine seems likely, and this drug should be considered in the differential di-agnosis of drug-induced PL.
Keywords: cationic amphiphilic drugs; myelin bodies; ranolazine; renal phospholipidosis; zebra bodies benign nephrosclerosis with moderate arteriolar hyalino-sis, fibrosis and kinking and ∼20% cortical tubular atrophy and interstitial fibrosis and minimal acute tubuloepithelial A 76-year-old male Caucasian patient was treated in our damage; Congo-red stains were negative. On ultra struc- hospital for acutely decompensated heart failure due to tural examination, podocyte foot process effacement of restrictive cardiomyopathy. A diagnosis of smouldering only 5% indicated secondary FSGS. Also, a few mesangial myeloma (IgG λ) had been made 2 months earlier (serum- fibrils were found—suspicious, but not diagnostic for IgG 30.8 g/L [normal range 7.5–15.6 g/L], serum-free light chain ratio κ/λ: 0.6 [normal range in renal insufficiency Surprisingly, the cytoplasm of a few podocytes was 0.37–3.1]). Because of the restrictive cardiomyopathy, sys- ladened with zebra and myelin bodies (see as temic amyloidosis with cardiac involvement was sus- described, these bodies are considered to represent an ex- cessive accumulation of phospholipids in the lysosome, The patient had chronic kidney disease stage G3bA1 and typically found in phospholipidosis (PL) [, ].
with stable renal function during the previous 12 months During the next few days after renal biopsy, the (MDRD-eGFR ∼40 mL/min per 1.73 m2, albuminuria 279 patient’s decompensated heart failure got worse in spite mg/24 h); his blood pressure was hypo- to normotensive of intensive diuretic therapy, and renal replacement (between 90/60 and 120/70 mmHg) and remained so therapy had to be initiated. After some weeks of dialysis, cardio-renal function recovered sufficiently to stop extra- A few days after hospital admission, the patient devel- oped acute-on-chronic kidney failure with serum creati-nine rising to 345 μmol/l (3.9 mg/dL) and progressive proteinuria (465 mg/g creatinine, mostly Bence Jones protein). Urinalysis did not show any casts or haematuria.
As renal involvement of the known gammopathy and Renal PL is an intracellular storage disease characterized the suspected amyloidosis was assumed, a kidney biopsy by accumulation of phospholipids within several types of renal cells, ranging from mesangial and glomerular endo- The major light microscopic findings were secondary thelial cells and podocytes to tubuloepithelial and intersti- focal and segmental glomerulosclerosis not otherwise specified (according to the classification proposed by Electron microscopic analysis shows intra-lysosomal D’Agati et al. []), affecting 2 of 31 glomeruli, moderate membranous lamellar inclusions, termed myelin or Zebra The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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or burning pain), and a normal α-galactosidase A activity Even though the patient had been exposed to silica over several years, we did not find any signs of silicosis in ahigh-resolution CAT scan of the chest.
Finally, a drug-induced PL had to be considered [As cationic amphiphilic drugs (i.e. amiodarone, chloroquine,aminoglycosides) are the main reasons for PL, we stronglysuspected such a drug as the cause. However, the patienthad never taken any of the drugs classically described tocause PL.
The only cationic amphiphilic drug the patient had taken was the anti-anginal ranolazine, a compound neverpreviously linked to PL. The patient had taken 375 mgranolazine twice daily for diastolic dysfunction over aperiod of 9 months until 6 weeks before renal biopsy.
His general physician had discontinued it in order to cutdown on the extensive medication the patient had beenprescribed.
Even though some cases of acute kidney injury have been attributed to PL induced by cationic amphiphilicdrugs [], PL is generally not believed to have any nega-tive consequences for renal function In our patient, GFR had remained stable while he was Fig. 1. Transmission electron micrograph of a podocyte with massive taking ranolazine, and only worsened 6 weeks after rano- accumulation of zebra bodies and myelin bodies (round structures) within the cytoplasm. The glomerular basement membrane (top right corner and lazine had been discontinued; therefore, the drug did not bottom edge) appears unremarkable, foot processes and glomerular seem to have any impact on kidney function; neither did endothelium on either side of the glomerular basement membrane are the other histological pathologies described above— well preserved. Original magnification ×6300.
except for the acute tubular damage.
Retrospectively, cardio-renal syndrome due to restrictive cardiomyopathy was the cause of the patient’s acute-on- bodies, as the ultra-structural correlate of the accumu- One can only speculate as to the reason why ranolazine A decreased activity of lysosomal phospholipase leads caused PL in this patient. The patient had been prescribed to an impaired elimination and hence accumulation of a rather low dose of the drug, and had not taken a larger phospholipids in the lysosomes. Several organs besides the kidney may be involved, i.e. lung, liver and heart [].
A dosage adjustment is recommended only when crea- Hereditary as well as acquired causes of reduced phos- tinine clearance falls below 30 mL/min and therefore did not seem necessary in our patient (initial MDRD-eGFR of Fabry’s syndrome is an X-linked disease. An inborn mutation results in a reduced activity of α-galactosidase A However, our patient had low muscle mass, so the real and consecutively in systemic PL []. Renal symptoms GFR may lie well under the creatinine-based estimated usually include a progressive loss of renal function and proteinuria; Fanconi syndrome has been described in Considering the (minimal) amyloidosis, it is tempting to some cases []. Angiokeratomas and neuropathic pain are draw an analogy to digitalis toxicity in this disease. As typical extra-renal manifestations [Cardiac involve- early as 1981, Rubinow et al. [] described that isolated ment (such as left ventricular hypertrophy, coronary amyloid fibrils bind digoxin and suggested this phenom- artery disease, conduction abnormalities) is common and enon as the reason for increased digitalis toxicity in amy- loidosis. It is beyond the scope of this report to test this Acquired PL is mostly iatrogenic and caused by a variety hypothesis, but one may well conjecture that a similar of drugs. Typically, cationic amphiphilic substances, such mechanism concerning ranolazine might play a role in as amiodarone, chloroquine and aminoglycosides, induce this case of renal PL. To the best of our knowledge, no PL [, , ], probably all except the latter without any association between monoclonal gammopathy or amyloi- dosis and PL has ever been described in the literature.
In rare instances, exposure to silica may lead to similar Thus, in the absence of any other likely causative histological changes and mimic Fabry’s disease [ factors, ranolazine should be considered in the differential Therefore, the histological finding of renal PL should lead to an extensive search for possible causes of thisstorage disorder.
Since it is virtually impossible to distinguish an iatro- Conflict of interest statement. None declared.
genic drug-induced PL from Fabry’s disease on ultra-struc- tural analysis of kidney tissue, the clinician has to use thepatient’s family history, extra-renal symptoms, and bio- chemical features, such as a reduced α-galactosidase A activity, to differentiate these two entities.
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