J Atherosclerosis Prev Treat. 2021 May-Aug;12(2):55-60 | doi:10.53590/japt.02.1024
Georgia Anastasiou1, Evangelia Dounousi2, Αnila Duni2, George Liapis3, Evangelos Liberopoulos1
1Department of Internal Medicine, Faculty of Medicine, University of Ioannina, Ioannina, Greece
2Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
31st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Background: Staphylococcus aureus is a non-typical cause of glomerulonephritis. Aim: We present a case of Staphylococcus-related glomerulonephritis secondary to osteomyelitis in a patient with diabetes and very high cardiovascular risk. Case summary: A 63-year-old man with diabetic foot ulcer presented to the Emergency Department complaining of right lower limb swelling and vasculitic rash on both lower limbs. He had a history of 2nd right metatarsal joint osteomyelitis due to methicillin-sensitive Staphylococcus aureus and had been receiving ciprofloxacin and clindamycin during the last 7 days before presentation. Urine analysis revealed proteinuria and hematuria and 24-hour urine protein of 5 g/day. Renal biopsy showed Staphylococcus-related glomerulonephritis with IgA deposits, mostly in the mesangium. Conclusion: Although post-infectious glomerulonephritis is well documented, its relationship with Staphylococcus aureus osteomyelitis has been rarely reported.
Key words: Staphylococcus-associated glomerulonephritis, osteomyelitis, diabetic foot, vasculitic rash, high cardiovascular risk
Corresponding author: Dr Evangelos N Liberopoulos, MD Associate Professor of Medicine Department of Internal Medicine, Faculty of Medicine, University of Ioannina 45 110 Ioannina, Greece Tel: +302651007502, Fax: +302651007016, E-mail: firstname.lastname@example.org
Submission: 28.05.2021, Acceptance: 09.07.2021
The term post-infectious glomerulonephritis has primarily referred to post-streptococcal glomerulonephritis. Immunocompromised background, most commonly diabetes or malignancy and aging have emerged as risk factors of staphylococcus-associated glomerulonephritis1,2. Staphylococcus-associated glomerulonephritis develops with a concurrent staphylococcal infection, such as endocarditis, cellulitis, pneumonia, visceral abscesses, urinary tract infection, and less commonly osteomyelitis3. Staphylococcus-associated glomerulonephritis has been reported in 7 diabetic patients with foot ulcer and osteomyelitis4,5-8. Of note, only in 2 patients (1 with diabetes and cervical osteomyelitis and 1 non-diabetic with wrist osteomyelitis) vasculitis rash was evident9,10. We report here the case of staphylococcus-associated glomerulonephritis in a patient with diabetic foot ulcer and osteomyelitis.
A 63-year-old man at very high cardiovascular risk due to a history of type 2 diabetes, dyslipidemia, atrial fibrillation, smoking (40 pack-years) and diabetic foot ulcer on the right foot presented to the Emergency Department complaining of right lower limb swelling and rash on both lower limbs. He had a history of diabetic foot ulcer (Figure 1) and 2nd right metatarsal joint osteomyelitis (Figure 2) due to methicillin-sensitive Staphylococcus aureus. He had been receiving ciprofloxacin and clindamycin during the last 7 days before presentation. Furthermore, he was on stable doses of alogliptin 25 mg, metformin 1000 mg twice daily, rosuvastatin 40 mg, ezetimibe 10 mg, apixaban 5 mg twice daily and nebivolol 5 mg.
FIGURE 1. Diabetic foot ulcer on right foot.
On physical examination, the patient was hemodynamically stable and afebrile. The right lower limb was swollen, and vasculitic rash was evident on both lower limbs. Laboratory results are shown in Tables 1 –2 –3
FIGURE 2. Magnetic resonance imaging shows 2nd right metatarsal joint osteomyelitis.
Renal ultrasonography showed normal findings. Due to lab results (Tables 1 –2 –3) and especially proteinuria [protein-creatinine ratio (PCR) = 5390.0 mg/g] and urine sediment, kidney biopsy was performed. Renal biopsy showed diffuse proliferative glomerulonephritis whereas co-dominant IgA and C3 deposits in the mesangium as well along the glomerular basement membranes were observed in immunofluorescence staining (Figure 3).
FIGURE 3. IgA deposits, mostly in mesangium in immunofluorescence examination (IgA x 400).
During hospitalization, patient was administered meropenem and tigecycline. After 14 days of hospitalization, right lower limb edema was improved and vasculitic rash had abated. Inflammatory markers were also improved, and most recent lab tests are shown in the Tables 1 –2 –3.
We report here a case of staphylococcus-associated glomerulonephritis in a patient at very high cardiovascular risk, diabetic foot ulcer and osteomyelitis. As of 24 February 2021, staphylococcus-associated glomerulonephritis has been described in 7 patients with diabetes and foot ulcer and osteomyelitis, 2 patients with diabetes and vertebral osteomyelitis, and 1 patient with diabetes and olecranon osteomyelitis9,11-12. IgA and C3 mesangial deposits are common among cases with reported biopsy findings. However, vasculitis rash is referred in only 2 patients with staphylococcus-associated glomerulonephritis and concurrent osteomyelitis9-10.
Staphylococcus-associated glomerulonephritis is an immune complex-mediated disease; staphylococcal antigens are planted in glomeruli and activate T cells, which results in polyclonal B-cell activation and production of polyclonal immunoglobulin (Ig) A, IgG, IgM and complement activation10,13. IgA antibodies often react with staphylococcal antigens14. This may partly explain why glomerular immune deposits in patients with staphylococcus-associated glomerulonephritis usually show abundant IgA deposits with IgG. Patients with staphylococcus-associated glomerulonephritis manifest hematuria, proteinuria of varying degrees, a rising serum creatinine, and/or peripheral edema. Cutaneous vasculitis can occur in patients with staphylococcus-associated glomerulonephritis, mimicking IgA vasculitis (Henoch-Schönlein purpura) or antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis4.
Staphylococcal antigens may activate T cells and polyclonal B cells, and thus induce the production of IgA, IgM and IgG. Staphylococcal antigens and IgA coexist in the circulation for prolonged time10. This prolonged antigenemia increases immune complexes formation and tissue deposition causing glomerulonephritis with IgA dominant or codominant deposits and less frequently vasculitis1,10,14.
Staphylococcus-related glomerulonephritis after osteomyelitis is a rare clinical entity. Diabetes, alcoholism, cancer, or intravenous drug addiction predispose to staphylococcal infection1,2. Renal disease can manifest 5-30 days after staphylococcal infection. Long-term kidney outcomes vary from complete recovery to persistent kidney function impairment, and end-stage kidney disease (ESKD)2. In our case, glomerulonephritis was diagnosed following one week of osteomyelitis treatment. One year later the patient has chronic kidney disease (eGFR= 51 mL/ mL/min/1.73m2) and microalbuminuria.
Diagnosis of staphylococcus-associated glomerulonephritis should be taken into consideration when at least two of the following criteria are present: 1) hypocomplementemia (primarily low C3), 2) endocapillary proliferation and exudative glomerulonephritis on light microscopy, 3) C3 (with IgA or IgG) dominant or codominant glomerular staining on immunofluorescence microscopy, and 4) hump-shaped subepithelial deposits on electron microscopy15. Treatment of the disease is based on antibiotics, control of hypertension, and edema and symptom relief1,10. Patients should be monitored for resolution of active infection, remission of hematuria, reduction in serum creatinine to baseline value, reduction in proteinuria, and if present, resolution of hypocomplementemia.
Staphylococcus-associated glomerulonephritis can be misdiagnosed as C3 glomerulonephritis. In patients with C3 glomerulonephritis, persistent or recurrent active glomerulonephritis over a prolonged period is common and renal disease follows an upper respiratory infection16. Staphylococcus-associated glomerulonephritis can also be misdiagnosed as primary IgA nephropathy as both entities may be triggered by infection. Although hematuria, palpable purpura or acute kidney injury might both occur with Staphylococcus-associated glomerulonephritis and IgA nephropathy, initial presentation at an older age or in a patient with diabetes favor the diagnosis of post-infectious glomerulonephritis. In addition, the histological pattern of the kidney biopsy provides significant clues for the differential diagnosis, such as the presence of diffuse exudative glomerulonephritis on light microscopy rather than a mesangial proliferative pattern are suggestive of post-infectious glomerulonephritis rather than IgA nephropathy. Serum ANCA was negative and therefore ANCA-associated vasculitis was unlikely.
In conclusion, we present a patient at very high cardiovascular risk, diabetic foot ulcer and osteomyelitis who developed staphylococcus-related glomerulonephritis with nephrotic-range proteinuria, edema, palpable purpura and acute kidney injury.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
INSTITUTIONAL REVIEW BOARD STATEMENT
Considering the non-interventional design of a case-report and the anonymity of the presented data, ethical review and approval were waived for this study.
INFORMED CONSENT STATEMENT
Written informed consent has been obtained from the patient to publish this paper.
DATA AVAILABILITY STATEMENT
Data not available on request due to restrictions of privacy.
CONFLICT OF INTEREST
None to declare.
1. Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D’Agati VD. Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore). 2008 Jan;87(1):21-32.
2. Nasr SH, Fidler ME, Valeri AM, Cornell LD, Sethi S, Zoller A, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol. 2011 Jan;22(1):187-95.
3. Satoskar AA, Parikh SV, Nadasdy T. Epidemiology, pathogenesis, treatment and outcomes of infection-associated glomerulonephritis. Nat Rev Nephrol. 2020 Jan;16(1):32-50.
4. Riley AM, Wall BM, Cooke CR. Favorable outcome after aggressive treatment of infection in a diabetic patient with MRSA-related IgA nephropathy. Am J Med Sci. 2009 Mar;337(3):221-3.
5. Wen YK. The spectrum of adult postinfectious glomerulonephritis in the new millennium. Ren Fail. 2009;31(8):676-82.
6. Nasr SH, Markowitz GS, Whelan JD, Albanese JJ, Rosen RM, Fein DA, et al. IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Human Pathology. 2003 Dec;34(12):1235-41.
7. Lewis A, Ng MK, Lacey M, Pensiero AL. Anuric Acute Kidney Injury Due to Infection-related Glomerulonephritis Secondary to Foot Osteomyelitis. Cureus [Internet]. 2019 Apr [cited 2021 Apr 20];11(4):e4476. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579338/
8. Spital A, Sterns RH, Panner BJ. Glomerulonephritis and reversible renal failure resulting from osteomyelitis in a diabetic patient. Am J Med. 1988 Aug;85(2):235-6.
9. Zeledon JI, McKelvey RL, Servilla KS, Hofinger D, Konstantinov KN, Kellie S, et al. Glomerulonephritis causing acute renal failure during the course of bacterial infections. Histological varieties, potential pathogenetic pathways and treatment. Int Urol Nephrol. 2008;40(2):461-70.
10. Nadasdy T, Hebert LA. Infection-related glomerulonephritis: understanding mechanisms. Semin Nephrol. 2011 Jul;31(4):369-75.
11. Aliyeva N, Demir E, Caliskan Y, Yazici H, Yildiz A. A Rare Clinical Entity: Staphylococcus-Related Glomerulonephritis. Exp Clin Transplant. 2017 Mar. Available from: https://pubmed.ncbi.nlm.nih.gov/28350291/ DOI: 10.6002/ect.2016.0066
12. Ho C-I, Wen Y-K, Chen M-L. Glomerulonephritis with Acute Renal Failure Related to Osteomyelitis. Journal of the Chinese Medical Association. 2008 Jun;71(6):315-7.
13. Koyama A, Sharmin S, Sakurai H, Shimizu Y, Hirayama K, Usui J, et al. Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy. Kidney Int. 2004 Jul;66(1):121-32.
14. Shimizu Y SH, Hirayama K, Seki M, Yoh K, Yamagata K, Koyama A. Staphylococcal cell membrane antigen, a possible antigen in post-methicillin resistant Staphylococcus aureus (MRSA) infection nephritis and IgA nephropathy, exhibits high immunogenic activity that is enhanced by superantigen. Nephrol. 2005 May-Jun;18(3):249-56.
15. Nasr S, Radhakrishnan J, D’Agati V. Staphylococcus-associated glomerulonephritis in adults. In: UpToDate, Post, TW (Ed), UpToDate, 23 Nov 20.
16. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. The Lancet [Internet]. 2010 Sep [cited 2021 Apr 20];376(9743):794-801. Available from: https://pubmed.ncbi.nlm.nih.gov/20800271/