Crescentic glomerulonephritis in a patient with advanced lung cancer during erlotinib therapy.

Sir,

Erlotinib (Tarceva®), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been shown to improve survival of previously treated non-small cell lung cancer (NSCLC) [1]. The common adverse effects of this agent include diarrhoea and anorexia [1], which may cause severe dehydration and renal failure, although their incidence has been low [2]. Here, we report a case of pauci-immune crescentic glomerulonephritis (CrGN) and acute renal failure in a patient with advanced NSCLC treated with erlotinib.

Case

In May 2009, a 72-year-old man with advanced NSCLC was admitted to our department because of acute renal failure. In July 2007, he underwent a pulmonary lobectomy for NSCLC. Because of intrapulmonary recurrence, he received multiple chemotherapies between November 2007 and December 2008, including carboplatin, docetaxel, paclitaxel, irinotecan and gemcitabine. In February 2009, erlotinib (150 mg daily) was started due to the progression of intrapulmonary lesions.

When erlotinib was started, serum creatinine (sCr) was 88 μmol/L and urinalysis showed only slight proteinuria without haematuria. During erlotinib treatment, diarrhoea and acneiform eruptions were transiently observed. Six weeks later, microhaematuria and 2+ proteinuria were detected. Over 1 month, proteinuria progressed to 3+ and sCr rose to 141 μmol/L.

On admission, he presented with anorexia, diarrhoea and severe dehydration. Although he was almost anuric, urine test revealed 3+ proteinuria and microscopic haematuria. Marked renal dysfunction and metabolic acidosis were noted (Table 1). The onset of microhaematuria and progressive renal failure and proteinuria suggested the possibility of rapidly progressive glomerulonephritis. However, he was critically ill and a renal biopsy was considered dangerous. In addition, acute tubular necrosis following pre-renal azotaemia was also probable. Thus, erlotinib was discontinued and supportive therapy with haemodialysis was started. Despite adequate fluid replacement, anuria persisted, and 1 month later, he died of pneumonia. By an autopsy, pauci-immune CrGN was diagnosed (Figure 1). No vasculitic lesion was found in other organs.

Table 1

Result of blood test on admission

White blood count	11.6 × 109/L
Haemoglobin	8.4 g/dL (84 g/L)
Platelets	156 × 109/L
Blood urea nitrogen	37.8 mmol/L
Serum creatinine	1,228 μmol/L
Serum protein, total	61 g/L
Serum albumin	21 g/L
Glycosylated haemoglobin A1c	5.4%
C-reactive protein	131 mg/L
Immunoglobulin (Ig)-G	12.8 g/L
IgA	8.7 g/L
IgM	0.5 g/L
C3	1.0 g/L
C4	0.4 g/L
Antinuclear antibody (ANA)	<1:40
Cryoglobulin	Negative
MPO-ANCA	Negative
PR3-ANCA	Negative
Anti-GBM antibody	Negative
pH	7.18
PaCO2	30.8 mmHg
Bicarbonate	11.3 mmol/L

Fig. 1

Microscopic renal findings of the postmortem examination. A quarter of glomeruli were globally sclerotic. Ninety percent of remaining glomeruli demonstrated crescents, mostly fibrocellular, without intracapillary proliferation. Immunostaining for IgG, IgA and IgM were negative. Focal interstitial lymphoplasmacytic infiltration was also noted (Periodic acid Schiff staining, original magnification ×200).

Discussion

Acute renal failure with nephritic urine sediment is an atypical manifestation during erlotinib therapy. As for renal complications, hepatorenal syndrome and acute renal failure have been reported, and both were considered to be associated with baseline hepatic impairment or severe dehydration [2]. Indeed, in the present case, pre-renal azotaemia due to dehydration was considered presumptively.

The mechanisms of CrGN are not clear. Microscopic polyangiitis and Wegener's granulomatosis were excluded because of negative findings on blood tests and the lack of extra-renal symptoms. EGFR was detected in glomerular parietal epithelial cells [3] and in the connective tissue of fibrocellular crescents in primary glomerulonephritis and lupus nephritis [3]. In addition, there have been several cases of leucocytoclastic vasculitis during treatment with erlotinib [4] or gefitinib, another EGFR tyrosine kinase inhibitor [5]. Pauci-immune CrGN is often observed with leucocytoclastic vasculitis; thus, it is possible that CrGN was induced by erlotinib. In fact, microscopic haematuria and renal function deterioration commenced during erlotinib therapy and no case of CrGN was reported for the other anticancer agents used in this case. Interstitial lymphoplasmacytic infiltration might be associated with erlotinib, because two cases of tubulointerstitial nephritis with gefitinib have been reported [6,7].

In summary, we describe a case of pauci-immune CrGN and acute renal failure, possibly induced by erlotinib. Further cases with renal complication during erlotinib therapy should be investigated.

Conflict of interest statement. None declared.