Clinical Neprology
Case Report
Peculiar Renal Endarteritis in a patient
with Acute Endocapillary Proliferative Glomerulonephritis
Takehiko Kawaguchi, Asami Takeda, Yoshiaki Ogiyama, Yukako Yamauchi,
Minako Murata, Taisei Suzuki, Yasuhiro Otsuka, Keiji Horike, Daijo Inaguma, Kunio Morozumi
Department of Nephrology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
Corresponding Author:
Takehiko Kawaguchi, MD, MPH, PhD
Department of Nephrology
Japanese Red Cross Nagoya Daini Hospital
Tel: +81-52-832-1121
Fax:+81-52-832-1130
kawatake45@gmail.com
Running Title: Renal Endarteritis with Acute Glomerulonephritis
Character Count: 12,179 (including spaces, limit 24,000)
ABSTRACT
Acute glomerulonephritis (AGN) is one of the most common renal diseases which are often
associated with infections, often resulting in diffuse proliferative glomerulonephritis (GN). This report
reviews an interesting case in which renal endarteritis coexisted in AGN with diffuse endocapillary
proliferation. The discussion highlights important pathological findings and clinical aspects in acute
endocapillary proliferative GN with renal endarteritis. Coexisting endarteritis should be in the
differential diagnosis of AGN in patients with persistent clinical courses.
Key Words: acute glomerulonerphritis (AGN) - diffuse proliferative glomerulonephritis (DPGN) renal endarteritis
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CASE REPORT
Clinical History
A previously healthy 41-year-old woman presented to a clinic with one week history of general
fatigue and slight fever after traveling to Hokkaido, the northern part of Japan. There was no history of
upper respiratory symptoms and gross hematuria. The patient denied rashes, arthralgia, myalgia, and
weight loss. Oral antibiotics (cefcapene, 3rd generation cephem) and non steroidal anti-inflammatory
drugs (NSAIDS) were prescribed at the clinic for a few days, but these drugs did not improve the
symptoms. She presented with the subsequent peripheral edema and 5 kg weight gain to the
emergency room of our hospital, and in view of acute kidney injury (AKI) with proteinuria and edema
she was admitted for workup. On physical examination, she was 1.57 meters tall (5 feet 2 inches) and
weighed 48.1kg (106 pounds) (43.1kg, 95 pounds, before the onset of symptoms) with body mass
index of 19.5 kg/m2. Heart rate was 73 beats/min and regular, and blood pressure was 107/64 mm Hg.
Body Temperature was 37.1℃. Except for pretibial pitting edema, the remaining physical examination
findings were unremarkable. She had normal heart sounds with no murmurs. Lungs were clear to
auscultation. Her abdomen was soft and non-tender. No lymphadenopathy or organomegaly was noted.
Neurological and musculoskeletal findings were unremarkable. There was no skin rash, erythema, or
purpura.
Electrocardiogram
and
chest
radiograph
showed
no
abnormalities.
Abdominal
ultrasonography showed normal-sized kidney without obstruction.
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Laboratory Data
Laboratory tests showed the following values: hemoglobin, 10.2 g/dL; white blood cell count,
3,900/μL; platelets, 107,000/μL; blood urea nitrogen, 35.6 mg/dL (12.7mmol/L); serum creatinine, 2.1
mg/dL (181 μmol/L), with an estimated glomerular filtration rate of 22 mL/min/1.73m2; albumin, 2.98
g/dL; total protein, 5.75 g/dL; and microscopic hematuria and proteinuria (protein, 1.6g/gCr);
C-Reactive protein (CRP), 1.04 mg/dL; erythrocyte sedimentation rate (ESR), 52 mm/h;
immunoglobulin G, 1,047 mg/dL; immunoglobulin A, 299 mg/dL; immunoglobulin M, 136 mg/dL;
complement components, C3, 66 mg/dL (normal, 69 to 128 mg/dL); C4, 25 mg/dL (normal, 14 to 36
mg/dL); CH50, <12 U/mL (normal, 25 to 48 U/mL); antistreptolysin-O (ASO) titer, 66 IU/mL (normal,
less than 166 IU/mL); antistreptokinase (ASK) titer, 5,120 (normal, less than 640); positive antinuclear
antibodies (×40); positive SSA titers 251 (range, 0 to 0.9); negative anti-SSB; negative
anti–double-stranded DNA antibody titers, negative antineutrophil cytoplasmic antibody (ANCA),
negative cryoglobulin. Serological tests for hepatitis B, C, and human immunodeficiency virus (HIV)
were negative. Serum immunoassays for Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human
herpes virus 6 (HHV6), Parvovirus B19, were negative, while Herpes Simplex virus (HSV) IgM/IgG
were positive (IgM 3.52, (normal, less than 0.80), IgG 52.5 (normal, less than 2.0)).
Kidney Biopsy
A percutaneous kidney biopsy was performed on admission day 4 to determine the cause of AKI
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with urinary abnormality and edema. On light microscopy, 73 glomeruli were present, of which 2 was
globally sclerosed. Any glomeruli show significant endocapillary proliferative features and marked
infiltration of mononuclear (MN) cells, not polymorphonuclear (PMN) leukocytes (Fig 1-A), some of
which presented mitotic changes (Fig 1-A, arrow head). They also showed mesangiolysis with loss of
tethering of the capillary walls of the glomerular basement membrane to mesangium (Fig 1-A, thin
arrow). There were no crescents or adhesions. Glomerular basement membranes did not show spikes
or pinholes, and capillary walls showed no double contours. There was no tubular atrophy and
interstitial fibrosis. Interlobular artery and its branch showed endarteritis mainly with MN leukocytes,
not PMN cells (Fig 1-B). In addition, fibrinoid necrosis was noted in the walls of the branch of the
artery (Fig 1-B, thin arrow). There was no evidence of thrombosis or emboli. In immunohistochemical
studies, KP1 positive cells, derived from monocytes, were dominant both in endocapillary proliferation and
in endarteritis, with minor CD3 positive cells, from T cells (Fig 1-C, D). Immunofluorescent (IF) studies
showed a “full house” deposition (positive for C3, C4, C1q, IgG, IgA, and IgM) with a fine granular
pattern both in the mesangium and in the peripheral capillary walls (Fig 2). No arteries or arterioles
showing vasculitis were included in the IF sample, while peroxidase antiperoxidase (PAP)
methods showed no deposition of any immunoglobulin in the same artery with endarteritis in the
LM sample, suggesting pauci-immune type with no immune complex. Electron microscopy (EM)
showed endocapillary proliferation, and many subendothelial deposits (Fig 3, arrow head), with no
subepithelial hump.
No organized structures of curved microtubular aggregates, typical of
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cryoglobulin deposits, were found at super high magnification (×27,000).
Diagnosis
Diffuse endocapillary proliferative glomerulonephritis (GN), immune complex mediated, with
focal endarteritis, pauci-immune type.
Clinical Follow-up
It was firstly decided to closely follow up the patient with symptomatic management of edema and
fever, and no immunosuppressive or antibiotic agents were added because the biopsy suggested acute
endocapillary proliferative GN, which was supposed to be self-limiting. One week after the biopsy,
serum creatinine and urinary protein level had decreased and peripheral edema had ameliorated.
Additionally, hypocomplementamia was improved. However, fever with headache continued and
serum inflammatory markers had gradually increased (CRP, 4.81 mg/dL; ESR, 104 mm/h). As blood,
urine and spinal fluid cultures ruled out the present bacterial infection, the subsequent elevated
inflammation may be attributed to vasculitis as observed on the biopsy specimen. The patient was
treated orally with prednisone 20mg per day. After the initiation of the treatment she made a
remarkable recovery with no fever and decreased inflammation (CRP, 0.37 mg/dL; ESR, 31 mm/h),
and discharged on day 15. During the outpatient follow-up, prednisone was tapered and off in 6 weeks,
with no relapsing the general and renal symptoms (Cr, 0.76 mg/dl; CRP, < 0.2mg/dl; C3, 81 mg/dL;
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C4, 19 mg/dL; CH50, 23.9 U/mL; ASK titer, 1,280).
DISCUSSION
We presented an interesting kidney biopsy case of acute endocapillary proliferative GN with renal
endarteritis. Based on the occurrence after a feverish event, hypocomplementemia, and its relatively
benign clinical course, this case was clinically expected to be post infectious acute GN (PIAGN),
although the pathogen or infectious site was not clearly identified by an extensive serological and
radiological workup. This case showed diffuse endocapillary proliferative change, one of the most
typical histological features of PIAGN. Not only streptococcus but also various pathogens are known
to cause AGN with diffuse endocapillary proliferation [1][2]. Glomerular subepithelial humps, often
seen in post streptococcal acute GN (PSAGN), were not found in this case, but glomerular humps may
be less prominent in non-PSAGN and more intramembranous or subendothelial deposits can be found
[3]. However, some pathological features in the case were inconsistent with typical PSAGN or
PIAGN; MN cells infiltration in endocapillary proliferative change and a “full house” deposition in IF
study. PMN leukocytes usually dominate in early stages of endocapillary proliferation in PSAGN or
PIAGN [4][5], but MN leukocytes were dominant in this case. A “full house” deposition in
immunofluorescence study was also inconsistent with typical PSAGN or PIAGN, characterized
mainly by IgG and C3 deposition. IF patterns vary enormously according to the causative antigens of
AGN, but full house deposition of PIAGN were previously described in a very few reports [6][7]. In
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spite of no typical clinical symptoms of oral or genital lesions, the serum immunoassay, positive HSV
IgM antibody, may suggest the possibility of the acute HSV infection, but the association between
HSV and the renal pathological changes was unclear. HSV-induced endocapillary proliferative GN
has never been described bibliographically, while the previous report suggested the relationship
between HSV infection and giant cell arteritis, not renal endarteritis [8].
Renal endarteritis itself is a rare finding coexisting in acute GN (AGN). Small arteritis or
endarteritis often coexists in the secondary GN associated with systemic disease, such as lupus
nephritis (LN) [9], cryoglobulinemic glomerulopathy [10], and hypocomlementemic urticarial
vasculitis. However, clinical examinations and laboratory findings ruled out these systemic
diseases. Though this case showed diffuse global endocapillary proliferation with a “full house”
deposition in IF study, resembling the pathology in LN class IV according to International
Society of Nephrology / Renal Pathology Society [ISN/RPS], the patient did not meet criteria for
systemic lupus erythematosus from the American College of Rheumatology. Cryoglobulinemic
glomerulopathy was also considered in the differential diagnosis of the endarteritis, but no
organized structure of cryoglobulin was found in the EM sample. Additionally, the endarteritis
was pauci-immune type with no immune deposit. Given the MNC infiltrates in endarteritis, the
same type of inflammatory infiltrates as those in endocapillary proliferative lesion, the
pathogenesis of the endarteritis and the endocapillary proliferation may possibly be identical.
However, it may be difficult to categorize this clinicopathology into any established type of GN.
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Further investigations are required to clarify the pathophysiological relationship between the
GN and its coexisting endarteritis.
The renal prognosis of this case was as excellent as that of typical PIAGN. An initial episode of
acute renal failure with PIAGN is not necessarily associated with a bad prognosis [11]. The
management is generally supportive, with salt restriction and diuretics to control of edema, and, if
necessary, treatment of high blood pressure and electrolyte abnormalities. Treatment of PIAGN
remains empirical because of the absence of therapeutic clinical trials, and immunosuppressive
treatment is rarely recommended. In this case, however, fever and elevated inflammation was not
self-limiting. This case was characterized by endarteritis coexisting in acute endocapillary proliferative
GN, and we may attribute the inflammation and the subsequent fever to the coexisting endarteritis
observed on the biopsy specimen. Some cases of clinically diagnosed PIAGN with a persistent course
should be recommended to undergo renal biopsy to confirm the diagnosis, in some of which
corticosteroids or other immunosupressants may be considered for coexisting vasculitis.
In summary, we described a peculiar renal endarteritis in a patient with AGN with endocapillary
proliferation. Renal endarteritis is a rare finding coexisting in AGN and not consistent with the typical
pathological feature of common PSAGN or PIAGN. Coexisting endarteritis should be in the
differential diagnosis of AGN in patients with persistent clinical courses. Further studies are needed to
identify the cause and the pathogenesis of renal endarteritis with endocapillary proliferative GN.
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ACKNOWLEDGEMENTS
Research Support: None
Financial Conflict of Interest: None
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REFERENCES
1. Schena FP. Renal manifestations in bacterial infections. Contrib Nephrol 1985;48:125.
2. Zarconi J, Smith MC. Glomerulonephritis: Bacterial, viral, and other infectious causes. Postgrad
Med 1988;84:239.
3. Nadasdy T, Silva FG. Acute postinfectious glomerulonephritis and glomerulonephritis caused by
persistent bacterial infection. In: Jennette JC, Olson JL, Schwartz MM, Silva FG ed. Heptinstall’s
Pathology of the Kidney. Philadelphia: Lippincott Williams & Wilkins, 2007:357.
4. Jones D. Inflammation and repair of the glomerulus. Am J Pathol 1951;27:991.
5. Jones DB. Glomerulonephritis. Am J Pathol 1953;29:33.
6. Smet AD, Kuypers D, Evenepoel P, et al. ‘Full house’ positive immunohistochemical
membranoproliferative glomerulonephritis in a patient with portosystematic shunt. Nephrol Dial
Transplant 2001;16:2258.
7. Lee LC, Lam KK, Lee CT, Chen JB, Tsai TH, Huang SC. “Full house” proliferative
glomerulonephritis: an unreported presentation of subacute infective endocarditis. J Nephrol
2007;20:745.
8. Powers JF, Bedri S, Hussein S, Salomon RN, Tischler AS. High prevalence of herpes simplex virus
DNA in temporal arteritis biopsy specimens. Am J Clin Pathol 2005;123:261.
9. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J
Am Soc Nephrol 1994;4:1499.
10. D’Amico G, Fornasieri A. Cryoglobulinemic glomerulonephritis; A membranoproliferative
glomerulonephritis induced by hepatitis C virus. Am J Kidney Dis 1995;25:361.
11. Ferrario F, Kourilsky O, Morel-Maroger L. Acute endocapillary glomerulonephritis in adults: A
histologic and clinical comparison between patients with and without initial acute renal failure. Clin
Nephrol 1983;19:17.
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Figure Legends
Figure 1. Light microscopy. (A) Endocapillary proliferation with mesangiolysis (arrow) and mitosis
(arrow head) (periodic acid-Schiff staining; original magnification ×200) (B) Endarteritis in the
interlobular artery, and fibrinoid necrosis (arrow) in the branch of the artery (Elastica-Masson
Staining; original magnification ×100) (C) (D) Expression of JC70a (a), KP1 (b), CD3 (c), L26 (d),
in glomeruli (C) and interlobular artery (D). KP1 positive cells, derived from monocytes, were
dominant both in endocapillary proliferation and in endarteritis, with minor CD3 positive cells, from
T cells. L26 cells, from B cells were rarely present. (immunohistochemical staining; original
magnification ×200 (C), ×100 (D) )
Figure 2. Immunofluorescence microscopy. A “full house” deposition (positive for C3, C4, C1q, IgG,
IgA, and IgM) with a fine granular pattern both in the mesangium and in the peripheral capillary
walls. (original magnification ×200 )
Figure 3. Electron microscopy. Electron dense deposits in subendothelial space, with no
subepithelial deposits or no organized structures (original magnification ×10,000 ).
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