Clinical and Experimental Nephrology

, Volume 14, Issue 4, pp 385–388

Complete remission of non-HIV collapsing glomerulopathy with deflazacort and lisinopril in an adult patient

  • Jorge Vega
  • Francisco Javier Guarda
  • Helmuth Goecke
  • Gonzalo P. Méndez
Case Report

DOI: 10.1007/s10157-010-0284-1

Cite this article as:
Vega, J., Guarda, F.J., Goecke, H. et al. Clin Exp Nephrol (2010) 14: 385. doi:10.1007/s10157-010-0284-1
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Abstract

Collapsing glomerulopathy is a form of focal segmental glomerulosclerosis that is usually associated with HIV-1 infection, and is characterized by its poor prognosis and almost inevitable progression to end-stage renal disease. Its pathological features include collapsed glomeruli, podocyte hypertrophy and hyperplasia, and pseudocrescents. This case report shows the evolution of a 58-year-old patient with non-HIV idiopathic collapsing glomerulopathy who presented with severe nephrotic syndrome and renal insufficiency and was treated with lisinopril and deflazacort, a synthetic corticosteroid that has shown fewer cosmetic effects and glucose and bone metabolism complications than prednisone. The patient responded with full recovery of renal function and normal range of protein excreted in urine after less than two years of treatment. The patient has not suffered a recurrence of his nephrotic syndrome after three years of steroid withdrawal. There is no proven therapy for collapsing glomerulopathy, and this case highlights an alternative for treating this disease with few secondary effects.

Keywords

Collapsing glomerulopathy Nephrotic syndrome Deflazacort Lisinopril Focal segmental glomerulosclerosis Chronic kidney diseases Renal insufficiency 

Introduction

Collapsing glomerulopathy (CG), first described in 1986 by Weiss et al. [1], is a variant of focal segmental glomerulosclerosis (FSGS) with a poor prognosis [2, 3]. It is usually seen in patients with HIV infection [4]. There are also idiopathic and other secondary forms, the latter associated with other infections, drugs, autoimmune diseases, organ transplants and malignancies [5, 6]. Clinical manifestations are rapid impairment in renal function, massive proteinuria (as part of nephrotic syndrome) and specific changes in the renal biopsy, such as podocyte hyperplasia and hypertrophy, microcystic changes in renal tubules and collapse of glomerular loops [7]. Reports of full recovery from CG are scarce [5, 8, 9]. In this article, we report a case of an adult patient presenting with severe nephrotic syndrome secondary to an idiopathic CG, who was successfully treated with lisinopril and deflazacort (DEF), a synthetic glucocorticoid that has shown fewer adverse effects than other steroids [10, 11].

Case report

A 58-year-old Caucasian man with mild hypertension was admitted due to the sudden onset of a severe edematous state. His blood pressure was 140/100 mmHg, height 165 cm and weight 101 kg. The patient had never used illicit drugs and had only received 5 mg lisinopril in recent years. Laboratory tests showed proteinuria in the nephrotic range (22.9 g/day), impairment of renal function (blood urea nitrogen 16 mmol/L, serum creatinine 216.6 µmol/L, creatinine clearance 0.87 mL/s), hyperlipidemia (total cholesterol 10.9 mmol/L, triglycerides 6.6 mmol/L) and severe hypoproteinemia (22.0 g/L) and hypoalbuminemia (16.0 g/L). Hematocrit was 0.47, hemoglobin 9.8 mmol/L, leukocytes 9.7 × 109/L, platelets 204 × 109/L, ESR 62 mm/h, uric acid 232 µmol/L, glucose 6.5 mmol/L, sodium 140 mmol/L, potassium 4.2 mmol/L, chloride 108 mmol/L, prostate-specific antigen 1.0 µg/L, IgG 2.58 g/L, IgA 2.0 g/L, and IgM 0.61 g/L. Serum electrophoresis showed hypoalbuminemia and hypogammaglobulinemia without monoclonal peak. Urinalysis showed hematuria (20–30 h.p.f.), leukocyturia (10–20 h.p.f.) and hyaline, granular and white cell casts. Serology for HIV, HBV, HCV, parvovirus B19 (IgM antibodies), ANA, anti-DNA antibodies, anti-ENA antibodies and ANCA was negative, and serum levels of C′3 and C′4 were in their normal ranges (1.10, 0.25 g/L, respectively). Chest X-ray showed a normal cardiac silhouette, bilateral pleural effusion and aortic elongation. The ultrasound showed two kidneys of normal size and appearance.

The patient underwent a renal biopsy that showed characteristic features of collapsing glomerulopathy (Fig. 1). The sample included sixteen glomeruli on light microscopy examination; three of them presented hypercellular proliferation in Bowman’s space with shrinkage of capillary loops of the glomerular tuft, representing evident collapsing lesions (Figs. 12a, b). Another five glomeruli had focal segmental glomerulosclerosis, three with nonspecific segmental sclerosis lesions (NOS) and two with tip lesion-like features. One glomerulus was globally sclerosed. The tubulointerstitial compartment presented no significant atrophy or fibrous changes (<3%). Microcystic changes in isolated distal tubules containing PAS-positive casts were noted (Fig. 2c). Arterioles had mild to moderate hyaline changes of the intima with mild hyperplasia of the smooth muscle cells of their walls. Immunofluorescence did not show immune complex deposition. Electron microscopy analysis confirmed a diffuse epithelial cell injury, with complete effacement of foot processes and other degenerative changes (Fig. 2d). Tubuloreticular inclusions were not observed in the glomerular capillary endothelial cells.
Fig. 1

Cortical zone of the kidney biopsy. On the upper left side of the micrograph there is a tubule with microcystic transformation. In the middle right the tubules show prominent resorption droplets. Three glomeruli show changes consistent with segmental collapsing lesions (upper right, upper left and bottom). (Silver methenamine stain, ×100)

Fig. 2

a Bowman’s space of the glomerulus is almost entirely occupied by hyperplastic podocytes (arrows) that cause the collapse of several capillary loops of the glomerular tuft (arrowheads). (Silver methenamine stain, ×400). b The glomerulus on the right presents a severely collapsing lesion with hypertrophy of the visceral epithelial cells (arrows) and prominent resorption droplets in the cytoplasm of the abnormal podocytes (arrowhead). (Silver methenamine stain, ×400). c The tubulointerstitial alterations of the collapsing glomerulopathy included focal tubular microcystic transformation containing PAS-positive casts (asterisks). Other tubules show protein resorption droplets (arrows). (Periodic acid-Schiff stain, ×200). d Ultramicrograph of a glomerulus showing diffuse effacement of the visceral epithelial cell foot processes (arrows). There are also other degenerative changes of the podocyte, including many cytoplasmic vacuoles (asterisks). (Uranil acetate-lead citrate, ×1,900)

The patient was started on deflazacort at a dose of 60 mg/day due to his desire to avoid the cosmetic effects associated with the long-term use of prednisone. Lisinopril 10 mg/day, atorvastatin 10 mg/day, furosemide and hydrochlorothiazide were also started. After ten weeks, diuretic therapy was withdrawn because of the complete remission of the edema together with an improvement in the albumin level to 37 g/L and a reduction in the proteinuria to 5.6 g/day. His weight was 77.5 kg. By the end of the first six months of treatment, in which the dosage of DEF was maintained at 60 mg/day and lisinopril was progressively increased to 40 mg/day, the level of proteinuria had decreased to 1.7 g/day (Fig. 3). During this period, the blood pressure was always lower than 140/100 mmHg, and serum glucose was lower than 5.5 mmol/L. The only side effects of the steroids were the appearance of thrush after four months of treatment, which was successfully treated with topical nystatin, as well as slight fattening of the face. Over the next six months, DEF was gradually reduced to 6 mg/day, and the proteinuria reduced to 0.70 g/day. During the second year of treatment, after gradually reducing DEF, normal levels of creatinine clearance (2.0 mL/s) and protein excretion (0.106 g/day) were reached. DEF was withdrawn by the 24th month of treatment. Sixty-five months after beginning the therapy, the CG was still in complete remission (proteinuria 0.102 g/day), with normal renal function regained (creatinine clearance 2.3 mL/s) and no evidence of cosmetic Cushingoid effects in the patient.
Fig. 3

Evolution of proteinuria and creatinine clearance throughout the treatment with deflazacort (DEF) (black arrow, DEF withdrawal)

Discussion

The incidence and prevalence of idiopathic CG is not known, although there has been a significant rise in the number of cases reported in the last few years [5]. This variant of FSGS occurs predominantly in black people [12]. Clinical manifestations of CG are severe nephrotic syndrome and rapid progression to renal failure. Some patients relate that the onset was preceded by febrile episodes. Upon comparing the evolution of CG patients with those affected by other variants of FSGS, it seems that the former evolves more frequently to renal failure and has a greater mortality rate [9, 13].

The pathophysiology involved in CG is not yet known. Researchers propose that some factors associated with the onset of CG include expression of viral proteins in the renal parenchyma, the release of cytokines and growth factors in glomeruli and renal vessels, and dysregulation of mitochondrial activity that prevents the affected cells from undergoing apoptosis [8]. In addition, the trans-dedifferentiation of podocytes and cells of Bowman’s capsule into macrophage-like cells, which could be involved in the inflammatory response and in epithelial proliferation with the formation of pseudocrescents, is also described [5, 9].

There is no specific treatment for idiopathic CG. Drugs used in other variants of FSGS are prescribed, such as high-dose steroids and immunosuppressor agents like cyclosporine or mycophenolate in association with antiproteinuric drugs (ACE inhibitors or angiotensin II receptor blockers), statins and diuretics [12]. Despite these approaches, no therapeutic combination of drugs has yielded a significant clinical response in patients suffering CG, and in most cases such combinations are unable to prevent the progression to end-stage renal disease [13]. This issue makes it necessary to continue with research aimed at finding new drugs or new therapeutic schemes that can facilitate remission of this poor-prognosis variant of FSGS.

Deflazacort is an oxazoline derivative of prednisolone, and a pro-drug whose metabolite (21-desacetyl-deflazacort) has a greater anti-inflammatory activity than its metabolic effects on bone and glucose [11, 14]. Its half-life is shorter than those of prednisone and methylprednisolone, which also reduces its pharmacodynamic properties [15]. It has been shown by several groups that the anti-inflammatory effects of DEF are comparable to those of commonly used steroids, but with fewer effects on bone mineral content [14]. Moreover, research on animals has proven that DEF produces less neuronal damage than prednisone at an equivalent dosage, but that it generates a greater immunosuppressant effect [16].

In this patient with severe nephrotic syndrome, it was decided that high-dose corticoids should be employed, based on published recommendations for other variants of FSGS. The patient rejected this therapy, arguing he was not willing to suffer Cushingoid’s symptoms, which long-term use of prednisone would provoke, and so the patient requested an alternative treatment with fewer adverse effects. Because DEF had shown a good response in patients with other forms of nephrotic syndrome [14], it was recommended in this case, even though there was no published evidence of its benefit for CG in adults. The patient presented complete remission of nephrotic syndrome and full recovery of renal function after using high-dose DEF for six months. The drug was administered in association with lisinopril and atorvastatin, and so the severe cosmetic effects resulting from the use of high-dose prednisone were not experienced by the patient.

Based on this case, we propose that DEF associated with lisinopril could be a therapeutic alternative for CG in adults. Undoubtedly, prospective controlled trials are needed to validate its effectiveness towards a pathology that has shown a very poor response to other available therapies.

Conflict of interest statement

None.

Copyright information

© Japanese Society of Nephrology 2010

Authors and Affiliations

  • Jorge Vega
    • 1
    • 2
  • Francisco Javier Guarda
    • 3
  • Helmuth Goecke
    • 1
    • 2
  • Gonzalo P. Méndez
    • 4
  1. 1.Departamento de NefrologíaDiálisis y Trasplante, Hospital Naval A. NefViña del MarChile
  2. 2.Departamento de Medicina, Sección de Nefrología, Escuela de MedicinaUniversidad de ValparaísoValparaísoChile
  3. 3.Escuela de MedicinaUniversidad Católica de ChileSantiagoChile
  4. 4.Departamento de Anatomía Patológica, Escuela de MedicinaPontificia Universidad Católica de ChileSantiagoChile

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