Poststreptococcal acute glomerulonephritis in a girl with renal cell carcinoma: possible pathophysiological association

Abstract

The severity of the poststreptococcal acute glomerulonephritis is considered to be modulated by the immune response of each individual, although there had been few reports regarding specific factors. Renal cell carcinoma is a cancer frequently associated with paraneoplastic syndrome, characterized by fever, leukocytosis, elevated cytokines, and elevated hormone levels. All of these symptoms resolve after tumor resection. A girl with renal cell carcinoma developed renal failure rapidly, which resolved promptly right after nephrectomy for the carcinoma. She was diagnosed as having poststreptococcal acute glomerulonephritis according to the results of pathological and serological examinations. In addition, elevated serum interleukin-6 level before the surgery was detected. Six and a half years after the diagnosis, the patient’s renal function was within normal range and she was tumor free. Because of the quick resolution of her renal dysfunction after the nephrectomy, paraneoplastic syndrome induced by renal cell carcinoma seemed to play a key role in the accentuation of poststreptococcal acute glomerulonephritis.

Introduction

Various factors of immune responses affect the development of poststreptococcal acute glomerulonephritis (PSAGN). While immune complexes were reported to contribute partly to the development of nephritis, its pathogenesis has yet to be completely elucidated [1]. Only 5–10% of children with streptococcal pharyngitis develop PSAGN [2]. At present, predictive factors for PSAGN development after streptococcal infection are unavailable.

Paraneoplastic syndrome with hypercytokinemia is known to develop in 10–40% of patients with renal cell carcinoma (RCC) [3]. Increase in serum inflammatory cytokine levels has been reported to be useful markers of the disease’s status [3, 4]. Patients with RCC develop various symptoms related to paraneoplastic syndrome (PNS), such as fever, anemia, fatigue, hepatitis, and Cushing syndrome [3]. PNS associated with localized RCC usually resolves only by tumor resection.

We experienced a girl with renal cell carcinoma who developed renal failure due to PSAGN. The acute kidney injury symptoms rapidly exacerbated, but promptly resolved right after radical nephrectomy. Increased production of cytokines related to PNS might play a key role in the rapid development of PSAGN.

Case report

A 14-year-old girl was referred to our hospital because of microhematuria that was found at an annual school urine test. She had no upper respiratory inflammation and fever within six months. On physical examination, no abnormalities, including pedal edema, heart murmur, or rales, were detected. Ultrasonography revealed a 3.5-cm-wide mass in her right kidney with high blood flow indicating a malignant nature. And at this time, complements were normal (Table 1). So microhematuria was thought to be due to malignancy. When she was admitted 6 days after the first hospital visit, oliguria 200–250 mL/day, pedal edema, high blood pressure of 131/65 mmHg, and elevated serum creatinine of 0.52–1.20 mg/dL were noted. These symptoms had rapidly worsened during the 6 days before admission and she had gained 2.8 kg (from 46.5 to 49.3 kg) in weight. Her clinical course is shown in Fig. 1. She underwent right radical nephrectomy for the treatment of the tumor. Within an hour of the completion of the resection, her urine volume increased. And within a week, her blood pressure was normalized. On day14, her body weight recovered to her usual body weight of 44.3 kg (Fig. 1). Pathological analysis revealed renal cell carcinoma (RCC), stage I (T1aN0M0) without Xp11.2 rearrangement. The diagnostic imaging by computed tomography and the pathology data are shown in Fig. 2. In addition to the tumor, her kidney showed swollen glomeruli and endocapillary proliferation with neutrophil infiltration and mesangial cell proliferation, without crescent formation or sclerosis. Immunofluorescence microscopy revealed granular pattern C3 and IgG deposition in the capillary walls. Nephritis-associated plasmin receptor (NAPlr) and C3 were detected in the glomeruli. Serologic examination, retrospectively, confirmed elevated antistreptolysin-O (2880 IU/mL) and decreased complements (C3: 10 mg/dL; C4: 25 mg/dL; CH50: < 10.0 IU/mL). With all this information, she was diagnosed as having poststreptococcal acute glomerulonephritis (PSAGN) accompanied with RCC and after the first hospital visit, PSAGN was thought to have developed and progressed.

Table 1.

Blood and urinary analysis at first hospital visit

Complete blood count
White blood cells	14.6 × 109/L
Segmented	66.5%
Band	1.5%
Lymphocyte	28.5%
Monocyte	2.5%
Eosinophil	0%
Basophil	1%
Red blood cell	410 × 109/L
Hemoblobine	11.4 g/dL
Hematocrit	35.2%
MCV	85.9 fl
Platelet	341 × 109/L
Urinalysis
pH	7.0
Protein	–
Occult blood	3 +
Sugar sediment	–
RBC	20–99/HPF
WBC	0–1/HPF
Biochemical analysis
AST	19 U/L
ALT	10 U/L
LDH	169 U/L
BUN	14.0 mg/dL
Creatinine	0.52 mg/dL
Uric acid	4.4 mg/dL
Na	139 mEq/L
K	4.1 mEq/L
Cl	100 mEq/L
IP	10 mg/dL
Ca	4.2 mg/dL
CRP	0.46 mg/dL
IgG	2315 mg/dL
IgA	306 mg/dL
C3	135 mg/dL
C4	46 mg/dL
ASO	2880 IU/mL

MCV mean corpuscular volume, HPF high power field, ASO antistreptolysin-O

Fig. 1.

Clinical course, biochemistry, and urinalysis. (Upper: clinical course) The patient developed high blood pressure and oliguria rapidly. Just after surgical resection of the renal cell carcinoma, her urinary volume improved dramatically. Her blood pressure improved within 1 week of the operation. (Lower: biochemistry and urinalysis) Elevated ASO and low complement were present at the first hospital visit

Fig. 2.

Diagnostic images. a Computed tomography of the abdomen showed a tumor in her right kidney. b (× 40, hematoxylin and eosin staining): The finding is compatible with renal cell carcinoma, unclassified. c (× 40, periodic acid-methenamine silver), d (× 400, hematoxylin and eosin staining): Besides the tumor, microscopy showed swollen glomeruli and endocapillary proliferation with neutrophil infiltration and mesangial cell proliferation, without crescent formation or sclerosis. e, f (× 200, fluorescent antibody for (e): C3 and (f): IgG): C3 and IgG were deposited over the glomeruli. g (× 200, fluorescent antibody for nephritis-associated plasmin receptor), h (× 200, immunostaining for plasmin activity): the glomeruli were positive for plasmin

Her serum cytokine profile was evaluated. IL-6 levels were elevated (maximum 18.2 pg/mL) until the time of the tumor resection. Serum levels of other cytokines including neopterin, IL-18, soluble tumor necrosis factor receptor (sTNFR)-I, and sTNFR-II were not elevated (data not shown). The acute kidney injury promptly recovered right after nephrectomy. Her renal function remained within the normal range and the RCC was in complete remission 6.5 years after the initial diagnosis.

Discussion

This patient developed kidney injury within a short time. Her renal histologic examination revealed, other than RCC, intraductal proliferative lesions in the glomeruli showing acute glomerulonephritis and deposition of complement (C3), IgG, and NAPlr. NAPlr is considered a nephritogenic streptococcal antigen, and glomerular NAPlr deposition is detected in most patients with early-phase PSAGN [5]. Serologic examination revealed elevated ASO and decreased complement which was most prominent on the day of the surgery. Based on these findings, we diagnosed her as having acute renal failure due to PSAGN accompanied with RCC. This is the first report of PSAGN accompanied with RCC. There have been some case reports of membranoproliferative glomerulonephritis (MPGN) accompanied with RCC [6, 7]. One of these patients had been diagnosed as having nephrotic syndrome and renal failure, but was subsequently found to have a renal mass that proved to be renal cell carcinoma. Pathology of the noncancerous part of the kidney revealed MPGN [6]. The patients who developed an immune-complex disease similar in nature to the glomerulonephritis seen in the course of other chronic or persistent infection [8]. Its occurrence in malignancy may be the result of a similar pathologic mechanism [6]. PSAGN involves immune-complex disease similar to MPGN, probably PSAGN accompanied with RCC by a similar mechanism. In a short time of the completion of the resection, her urine volume increased. Maybe the cause of oligria was not only PSAGN, but also steal blood flow to the non-neoplastic kidney tissues associated with the very high blood flow to the tumor.

The paraneoplastic syndrome occurs in 10–40% of patients with RCC [3]. The symptoms include fever, anemia, hypertension, liver dysfunction, and amyloidosis. Various cytokines and hormones are elevated and play important roles in its pathogenesis. IL-6, which was elevated in our patient, has been reported as one of the major causes of the paraneoplastic syndrome in RCC. In addition, it was reported that leukocytosis which is usually observed in this condition was due to the overproduction of colony-stimulating factor from tumor cells [9]. Actually, leukocyte number was increased to 14,600/μL in our case. Thus, activated leukocytes might migrate to the renal glomeruli and contribute to the development of PSAGN. The quick resolution of her kidney injury just after the resection of the RCC indicated that its pathophysiology was closely related to RCC. Because renal dysfunction has not been reported as a paraneoplastic syndrome of RCC and because RCC of the patient did not seem to be directly causative in the development of renal dysfunction in terms of the size and location, we concluded that the patient’s renal dysfunction developed as a result of PSAGN, and paraneoplastic syndrome due to RCC possibly played an important role in the development of PSAGN.

Elevated IL-6 was reported among patients with PSAGN [10]. Cytokines from RCC and migration of inflammatory cells (leukocytes) could affect the immune response toward the development of PSAGN [10, 11].

RCC is the most frequent kidney cancer among adults and adolescents, mostly occurring in the sixth to eighth decade. On the other hand, it is very rare in children, consisting 3–4.3% of all pediatric renal tumors, which is almost 5% of all pediatric cancers [12]. In contrast, PSAGN occurs mostly in children (aged 5–12 years), the estimated incidence being 0.3/100,000 children [13]. Such difference in the susceptible age for PSAGN and RCC may be one of the reasons why no reports have previously been published on the development of PSAGN in patients with RCC.

In conclusion, the present case suggests that paraneoplastic syndrome associated with RCC accentuated the symptom of PSAGN.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national committee at which the studies were conducted and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. And we got consent form from her parent.