Relapse of minimal change nephrotic syndrome after initiation of sulfamethoxazole–trimethoprim combination therapy: a case report

Abstract

Minimal change nephrotic syndrome (MCNS) is characterized by podocyte injury leading to severe proteinuria, mainly mediated by T-cell activation and cytokine imbalance. Relapses are often triggered by immunological stimuli such as infections, vaccinations, or drugs; however, relapse following administration of sulfamethoxazole–trimethoprim (ST) combination therapy has not been reported previously. We report an extremely rare case of MCNS relapse triggered by ST combination therapy.A 55-year-old woman with a history of breast cancer treated with tamoxifen developed nephrotic syndrome and was diagnosed with MCNS by renal biopsy. After remission was achieved with prednisolone 50 mg/day, ST therapy was initiated for prophylaxis of Pneumocystis jirovecii pneumonia. Approximately 12 days after starting ST, she developed generalized erythema accompanied by relapse of nephrotic syndrome. Discontinuation of ST, atorvastatin, and esomeprazole while continuing prednisolone 40 mg/day led to a second remission. Drug-induced lymphocyte stimulation tests for all agents were negative, possibly due to concurrent corticosteroid therapy.Metabolites of sulfamethoxazole have been shown to activate CD4⁺ T cells and induce multiple cytokines including interleukin-13, interferon-γ, interleukin-22, and granzyme B. Such immune activation could explain the simultaneous occurrence of cutaneous manifestations (drug eruption) and renal relapse (MCNS).Relapse of drug-induced MCNS may occur through either direct podocyte injury or immune-mediated allergic mechanisms. Given the concurrent drug eruption, the latter mechanism appears most consistent with this case.When introducing new medications under immunosuppressive conditions, clinicians should consider the possibility of drug-induced relapse if proteinuria reappears.

Introduction

Minimal change nephrotic syndrome (MCNS) is characterized by podocyte injury leading to heavy proteinuria, primarily mediated by T-cell activation and cytokine imbalance [1, 2]. While spontaneous remission and steroid responsiveness are common in children, adult cases tend to relapse repeatedly [3]. Reported triggers for relapse include infections, vaccinations, medications, and severe physical stress, all of which may act as immunological stimuli [4–6].

Recent studies have suggested that, in some cases, autoimmune mechanisms such as the production of anti-nephrin antibodies may contribute to disease pathogenesis [7, 8], indicating that MCNS is a heterogeneous disorder with multiple immunologic pathways rather than a single disease entity.

However, relapse of MCNS following administration of sulfamethoxazole–trimethoprim (ST) combination therapy has not previously been reported. We describe a rare adult case in which MCNS relapse occurred shortly after ST administration for Pneumocystis jirovecii pneumonia (PJP) prophylaxis, accompanied by drug-induced skin eruption.

Case report

A 55-year-old woman with a history of breast cancer surgery at the age of 52, multiple uterine myomas, and chronic sinusitis was receiving tamoxifen 20 mg daily. Her regular medications also included clarithromycin 200 mg/day, carbocisteine 1500 mg/day, fexofenadine 120 mg/day, montelukast 10 mg/day, and flunitrazepam 1 mg at bedtime. She had no known drug allergies.

Approximately two weeks before presentation, she developed progressive leg edema and rapid weight gain of 3 kg. At her first nephrology visit (day 1), urinalysis revealed protein 4⁺ and microscopic hematuria (10–19 RBCs/HPF). Laboratory findings showed serum albumin 2.6 g/dL, total cholesterol 398 mg/dL, and a urinary protein–creatinine ratio (UPCR) of 13.9 g/gCr, leading to a diagnosis of nephrotic syndrome. (Table 1.) Atorvastatin 10 mg/day was initiated, and she was admitted for evaluation of suspected MCNS .

Table 1.

Laboratory findings on initial presentation

Parameter	Reference range	Result
CRP (mg/dL)	0.00–0.14	0.04
Total protein (g/dL)	6.5–8.0	5.8 ↓
Albumin (g/dL)	4.1–5.1	2.6 ↓
AST (IU/L)	13–33	41 ↑
ALT (IU/L)	8–42	40
LDH (IU/L)	124–222	257 ↑
CK (IU/L)	41–153	142
γ-GTP (IU/L)	9–32	23
Na (mEq/L)	138–145	141
K (mEq/L)	3.6–4.8	4.0
Cl (mEq/L)	101–108	106
Ca (mg/dL)	8.8–10.1	8.8
IP (mg/dL)	2.5–4.5	3.9
Mg (mg/dL)	1.7–2.6	2.0
BUN (mg/dL)	8–20	9
UA (mg/dL)	2.3–7.0	4.4
Creatinine (mg/dL)	0.46–0.79	0.60
eGFR (mL/min/1.73 m2)	≥ 60	79.4
Total cholesterol (mg/dL)	128–219	398 ↑
Triglycerides (mg/dL)	30–149	258 ↑
HDL-cholesterol (mg/dL)	40–96	111 ↑
LDL-cholesterol (mg/dL)	0–139	222 ↑
Glucose (mg/dL)	73–200	91
Transferrin (mg/dL)	200–360	210
Urinary Na (mEq/L)	–	66
Urinary K (mEq/L)	–	14
Urinary Cl (mEq/L)	–	67
Urinary urea nitrogen (mg/dL)	–	159
Urinary uric acid (mg/dL)	–	12.8
Urinary creatinine (mg/dL)	–	20.9
Urinary NAG (U/L)	–	5.2
Urinary IgG (mg/L)	–	20
Urinary IgA (mg/L)	–	2
Urinary IgM (mg/L)	–	0
Urinary transferrin (mg/L)	–	270
Urine protein-to-creatinine ratio (g/g Cr)	< 0.15	13.9
Urine RBC (/HPF)	–	10–19
WBC (/μL)	3300–8600	6800
Neutrophils (%)	40–70	66.1
Lymphocytes (%)	20–45	25.0
Monocytes (%)	2–10	7.9
Eosinophils (%)	0–8.5	0.5
Basophils (%)	0–1	0.5
Hemoglobin (g/dL)	11.6–14.8	13.3
Platelets (× 104/μL)	15.8–34.8	12.8↓
IgG (mg/dL)	861–1747	1065
IgA (mg/dL)	93–393	212
IgM (mg/dL)	33–183	61
C3 (mg/dL)	86–160	126
C4 (mg/dL)	17–45	38
Anti-GBM antibody (U/mL)	< 3.0	< 2.0
ANA	(−)	(−)
ANCA (MPO, PR3) (U/mL)	< 3.5, < 2.0	< 0.2, < 0.6
HbA1c (%)	4.9–6.0 (approx.)	5.8

A renal biopsy on day 9 demonstrated 23 glomeruli, of which one showed global sclerosis and one contained erythrocytes in Bowman’s space. No mesangial proliferation or matrix expansion was observed.

Immunofluorescence microscopy performed on deparaffinized formalin-fixed sections showed mild, nonspecific mesangial deposition of IgM and C1q, without findings suggestive of anti-nephrin antibody–mediated injury (Fig.1A ). Electron microscopy demonstrated diffuse effacement of podocyte foot processes without electron-dense deposits in the glomeruli (Fig. 1B), supporting the diagnosis of minimal change nephrotic syndrome. Prednisolone 50 mg/day and esomeprazole 20 mg/day were started on day 7. On day 17, ST combination therapy (sulfamethoxazole 800 mg/trimethoprim 160 mg once daily) was added for PJP prophylaxis. By day 18, the UPCR had fallen below 0.3 g/gCr, indicating complete remission, and the patient was discharged on day 19.

Fig. 1.

Clinical course of the patient. Changes in urinary protein-to-creatinine ratio (UPCR, blue bars) and serum creatinine (sCr, orange line) are shown during hospitalization and relapse. The green bars indicate prednisolone (PSL) dosage, and the red band represents the TMP–SMX administration period. A transient sharp increase in UPCR (92.9 g/gCr) occurred during TMP–SMX use, followed by remission after drug discontinuation

After discharge, prednisolone was tapered to 40 mg/day on day 26. On day 29, erythematous rashes appeared on the trunk, and she revisited the outpatient clinic on day 31. Laboratory tests revealed relapse of nephrotic syndrome (serum albumin 1.8 g/dL, UPCR 92.9 g/gCr). Considering a drug-induced eruption, ST combination therapy, atorvastatin, and esomeprazole were discontinued, and a drug-induced lymphocyte stimulation test (DLST) was performed on the same day. The DLST was negative for all agents (stimulation indices: ST 105%, esomeprazole 86%, and atorvastatin 92%).

On day 33, she developed marked edema and hyponatremia (serum Na 113 mEq/L) and was readmitted to the hospital, where she was initially managed in the intensive care unit (ICU).

With intravenous 3% saline, albumin infusion, and furosemide, both edema and electrolyte abnormalities improved. She was transferred to the general ward on day 37. By day 40, UPCR had again decreased to  < 0.3 g/gCr, and she was discharged on day 47 in complete remission.(Fig. 2)

Fig. 2.

Renal biopsy findings. A Immunofluorescence microscopy performed on deparaffinized formalin-fixed sections showing mesangial deposition of IgM and C1q. B Electron microscopy images of the glomerulus showing severe effacement of podocyte foot processes. Representative images are shown at original magnifications of × 1500 (left) and × 3000 (right). No electron-dense deposits are observed in the glomeruli

During the second hospitalization, rituximab therapy was considered but ultimately withheld because renal pathology showed no evidence of anti-nephrin antibody-mediated injury. In addition, since rituximab is generally indicated for frequently relapsing or steroid-dependent MCNS in adults, its use was deemed unnecessary in this single, drug-related relapse. The addition of another immunosuppressive agent could also have complicated the clinical picture, making it more difficult to clarify the causal relationship among the drug, the skin eruption, and the nephrotic relapse.Clinical improvement was achieved with corticosteroid monotherapy, and prednisolone was gradually tapered and discontinued five months after onset, with no further relapses during follow-up.

Discussion

This case represents a rare instance of relapse of MCNS temporally associated with ST combination therapy. Renal biopsy findings were consistent with MCNS: immunofluorescence on deparaffinized sections showed mild, nonspecific mesangial IgM and C1q deposition, and electron microscopy demonstrated diffuse podocyte foot-process effacement without electron-dense deposits. These findings argue against immune complex–mediated glomerulonephritis, including C1q nephropathy or virus-related disease.

In this case, several potential factors coincided with the relapse of MCNS, including the initiation of ST combination therapy, tapering of prednisolone (from 50 to 40 mg/day), and the concomitant use of atorvastatin and esomeprazole. However, both atorvastatin and esomeprazole had been initiated several days before the introduction of ST combination therapy (on days 1 and 7, respectively), making them less likely to be the triggers of relapse. Considering the timing of administration and the onset of the rash, as well as the reported frequencies of cutaneous adverse reactions (0.1–1% for atorvastatin and 0.01–0.02% for proton pump inhibitors, compared with approximately 3–4% for ST combination therapy) [9–11], ST combination therapy was therefore regarded as the most likely causative agent for both the drug eruption and the nephrotic relapse. Moreover, remission was achieved despite maintaining prednisolone at 40 mg/day, suggesting that the relapse was not simply due to steroid tapering but more plausibly associated with immune activation induced by ST combination therapy.

The sulfamethoxazole metabolite, nitroso-SMX, has been shown to strongly activate CD4⁺ T cells, inducing multiple cytokines such as IL-13, IFN-γ, IL-22, and granzyme B [12]. Such immune activation may stimulate not only cellular immunity but also B-cell–mediated antibody production, potentially leading to concurrent manifestations of drug eruption and nephrotic relapse. In this case, the drug-induced lymphocyte stimulation test (DLST) was negative for all agents, but this result was likely influenced by ongoing corticosteroid therapy, which may have suppressed the in vitro immune response.

It should be noted that this case represents a relapse of pre-existing MCNS rather than a de novo, drug-induced onset. In drug-induced de novo MCNS, the drug or its metabolites may act as novel antigens, triggering initial sensitization and immune activation. In contrast, relapse-type cases may reflect partial reactivation of pre-existing immune memory, where nonspecific immune stimulation—such as infection or exposure to medications like ST combination therapy—appears to trigger T-cell–mediated podocyte injury without true de novo sensitization.

Recent studies have also highlighted that a subset of MCNS cases involve autoantibodies against nephrin, implicating humoral immune mechanisms in disease pathogenesis [7, 8]. However, in this patient, immunofluorescence findings revealed no podocyte-associated punctate IgG deposition, which argues against an anti-nephrin antibody–mediated process. Taken together, the close temporal relationship between ST administration, the onset of rash, and nephrotic relapse, together with the known T-cell–activating properties of sulfamethoxazole, supports a T-cell–driven, non-antibody-mediated immunoallergic mechanism.

While immune-mediated injury appears most consistent with this case, other mechanisms of drug-induced MCNS have been described. Some agents may directly damage podocytes without immune involvement. For instance, relapse of MCNS following intravitreal administration of bevacizumab has been attributed to disruption of podocyte integrity caused by VEGF pathway inhibition [13, 14]. These observations suggest that drug-induced MCNS relapse may occur through multiple, mechanistically distinct pathways.

Taken together, the pathogenic mechanisms of drug-induced MCNS can be broadly classified into three categories.

One possible mechanism is direct podocyte injury, in which the drug or its metabolites interfere with podocyte structure or signaling pathways.

Another involves T-cell activation and cytokine-mediated injury, representing a non–antibody-mediated immunoallergic response.

A third mechanism entails immune activation that stimulates B cells and promotes the production of autoantibodies, such as anti-nephrin antibodies, leading to podocyte damage.

Based on the clinical and pathological findings, the present case most likely reflects the second mechanism. Nevertheless, this association remains circumstantial, and the possibility that the relapse was related to the natural course of MCNS or other unrecognized factors cannot be completely excluded.

Although extremely rare, clinicians should be aware that ST combination therapy can provoke immune activation potent enough to trigger relapse of MCNS, particularly in patients receiving immunosuppressive treatment.

Abbreviations

Alb

Albumin

TP

Total protein

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

LDH

Lactate dehydrogenase

CK

Creatine kinase

γ-GTP

γ-Glutamyl transpeptidase

Na

Sodium

K

Potassium

Cl

Chloride

Ca

Calcium

IP

Inorganic phosphate

Mg

Magnesium

BUN

Blood urea nitrogen

UA

Uric acid

Cre

Creatinine

eGFR

Estimated glomerular filtration rate

TChol

Total cholesterol

TG

Triglycerides

HDL-C

High-density lipoprotein cholesterol

LDL-C

Low-density lipoprotein cholesterol

Glu

Glucose

Tf

Transferrin

NAG

N-acetyl-β-D-glucosaminidase

Ig

Immunoglobulin

RBC

Red blood cell

WBC

White blood cell

Hb

Hemoglobin

Plt

Platelet

ANA

Antinuclear antibody

ANCA

Anti-neutrophil cytoplasmic antibody

GBM

Glomerular basement membrane

Declarations

Conflict of interest

Dr. Shoichi Maruyama has received honoraria and research support from several pharmaceutical companies, as disclosed in the ICMJE COI form.All other authors declare no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

During the preparation of this work, the author(s) used ChatGPT (OpenAI) to assist in language editing and improving readability. After using this tool, the author(s) reviewed and edited the content as needed and take full responsibility for the content of the publication.

Informed consent

Informed consent was obtained from the patient.