For over a century, acute 'post-streptococcal glomerulonephritis' (APSGN) was the prototypical form of bacterial infection-associated glomerulonephritis, typically occurring after resolution of ...infection and a distinct infection-free latent period. Other less common forms of infection-associated glomerulonephritides resulted from persistent bacteraemia in association with subacute bacterial endocarditis and shunt nephritis. However, a major paradigm shift in the epidemiology and bacteriology of infection-associated glomerulonephritides has occurred over the past few decades. The incidence of APSGN has sharply declined in the Western world, whereas the number of Staphylococcus infection-associated glomerulonephritis (SAGN) cases increased owing to a surge in drug-resistant Staphylococcus aureus infections, both in the hospital and community settings. These Staphylococcus infections range from superficial skin infections to deep-seated invasive infections such as endocarditis, which is on the rise among young adults owing to the ongoing intravenous drug use epidemic. SAGN is markedly different from APSGN in terms of its demographic profile, temporal association with active infection and disease outcomes. The diagnosis and management of SAGN is challenging because of the lack of unique histological features, the frequently occult nature of the underlying infection and the older age and co-morbidities in the affected patients. The emergence of multi-drug-resistant bacterial strains further complicates patient treatment.
Small glomerular IgA deposits have been reported in patients with liver cirrhosis, mainly as an incidental finding in autopsy studies. We recently encountered nine cirrhotic patients who presented ...with acute proliferative glomerulonephritis with unusually large, exuberant glomerular immune complex deposits, in the absence of systemic lupus erythematosus (SLE) or monoclonal gammopathy-related kidney disease. Deposits were typically IgA dominant/codominant. Our aim was to further elucidate the etiology, diagnostic pitfalls, and clinical outcomes.
We present clinical features and kidney biopsy findings of nine cirrhotic patients with an unusual acute immune complex glomerulonephritis. We also identified native kidney biopsies from all patients with liver cirrhosis at our institution over a 13-year period (January 2004 to December 2016) to evaluate presence of glomerular IgA deposits in them (n = 118).
Six of nine cirrhotic patients with the large immune deposits had a recent/concurrent acute bacterial infection, prompting a diagnosis of infection-associated glomerulonephritis and treatment with antibiotics. In the remaining three patients, no infection was identified and corticosteroids were initiated. Three of nine patients recovered kidney function (one recovered kidney function after liver transplant); three patients developed chronic kidney disease but remained off dialysis; two patients became dialysis-dependent and one patient developed sepsis and expired shortly after biopsy. Within the total cohort of 118 patients with cirrhosis, 67 others also showed IgA deposits, albeit small; and 42 patients had no IgA deposits.
These cases provide support to the theory that liver dysfunction may compromise clearance of circulating immune complexes, enabling deposition in the kidney. At least in a subset of cirrhotic patients, a superimposed bacterial infection may serve as a "second-hit" and lead to acute glomerulonephritis with exuberant immune complex deposits. Therefore, a trial of antibiotics is recommended and caution is advised before immunosuppressive treatment is offered. Unfortunately, most of these patients have advanced liver failure; therefore both diagnosis and management remain a challenge.
Infection-related glomerulonephritis (IRGN) usually manifests as a proliferative immune-complex glomerulonephritis. The degree of renal dysfunction at presentation can vary. Association with ...histologic features on kidney biopsy remains unknown.
To study the correlation between renal function in IRGN at the time of biopsy and the severity of histologic features.
Culture-proven IRGN cases at our facility were included and divided based on estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m2. Patients' demographic and pathologic findings were obtained from electronic medical records and kidney biopsy reports.
In total, 104 cases were diagnosed with IRGN on biopsy (mean age, 55.6 ± 15.6 years; male, n = 79 76%; median eGFR, 14.5 mL/min/1.73 m2), and 51 of 104 showed eGFR <15 mL/min/1.73 m2. Among all the histologic features assessed, only percent tubules with red blood cell (RBC) casts showed statistical difference, being significantly higher in the lower-eGFR group (P = .004). Multivariable logistic regression analysis also showed that %tubules with RBC casts were associated with lower eGFR (odds ratio, 1.12; 95% CI, 1.01-1.24; P = .01). Patients with 5% or more RBC casts (n = 31) showed a lower eGFR (P = .02) and a higher %cellular crescent (P < .001) compared with those with less than 5% RBC casts. Patients with concomitant anticoagulant therapy (n = 11) showed higher percentages of RBC casts than those without anticoagulants (P = .02).
Particular attention to the extent of RBC casts on kidney biopsy is recommended in patients with IRGN because these portend worse renal dysfunction, more so in patients requiring anticoagulation (including for hemodialysis) because they are especially vulnerable to developing anticoagulant-related nephropathy.
Staphylococcus infection-associated GN (SAGN) is a well recognized disease entity, particularly because of the frequent IgA-dominant glomerular immunoglobulin staining on kidney biopsy. Biopsy ...features can resemble two other disease entities - primary IgA nephropathy and Henoch-Schönlein purpura nephritis - posing a diagnostic pitfall. This is clinically relevant because of the crucial difference in the therapeutic approach. The diagnosis of SAGN is further complicated by the variability in the degree of glomerular IgA (and C3) staining, the extent of electron dense immune-type deposits, and positive ANCA serology in some patients.
We performed a thorough histopathologic review of our single-center cohort of 78 culture-proven SAGN biopsies to assess the spectrum of IgA staining, prevalence of ANCA serology, prevalence of subepithelial "humps," and other histologic features to distinguish from primary IgA nephropathy.
Among the 78 SAGN biopsies, IgA staining was trace in 25%, mild in 19%, moderate in 44%, and strong in 12% of the cases. C3 was frequently moderate-to-strong but was trace in 14% of the biopsies. Concomitantly trace IgA, IgG, and C3 (pauci-immune pattern) was seen in 13%. Crescents were present in 35% of the SAGN biopsies. Out of 41 patients tested for ANCA, nine (22%) were positive, including patients with endocarditis and other infections. Subepithelial humps were identified in only 31% of the SAGN biopsies.
SAGN biopsies show marked variability in IgA immunofluorescence staining and low frequency of subepithelial humps compared with poststreptococcal GN. Occasional ANCA positivity is present in cases of SAGN, even in infections other than endocarditis. Therefore, biopsy diagnosis can be difficult particularly when clinical symptoms of infection are subtle. Both the pathologist and the nephrologist should be aware of these diagnostic pitfalls.
Abstract
Background
Primary immunoglobulin A nephropathy (IgAN) is characterized by IgA1-dominant or codominant glomerular deposits, postulated to be galactose deficient (Gd). However, glomerular IgA ...deposition can also occur in nonrenal diseases such as liver cirrhosis, psoriasis and inflammatory bowel disease (‘secondary IgAN’) or be an incidental finding in biopsies with other pathologies. A glomerulonephritis resembling IgAN can develop in patients with bacterial, mainly staphylococcal infections staphylococcal infection-associated glomerulonephritis (SAGN). There are no specific histological features to distinguish between these, but differentiation is critical for appropriate management. The aim of this study was to investigate whether a recently described antibody to Gd-IgA1 (KM-55) could aid in differentiating primary IgAN from other conditions with glomerular IgA deposition, especially SAGN.
Methods
We performed a retrospective cohort study of patients who underwent kidney biopsy for clinical indications and were found to have glomerular IgA deposits.
Results
We evaluated 100 biopsies, including primary IgAN (n = 44), secondary IgAN (n = 27), SAGN (n = 13), incidental IgA deposition (n = 8) and lupus nephritis (n = 8). There was no difference in Gd-IgA staining intensity or the proportion of positive cases between primary and secondary IgAN. SAGN and cases with incidental IgA deposits had significantly lower Gd-IgA staining intensity than primary IgAN, but up to 69% of SAGN cases were positive (albeit weaker).
Conclusions
Gd-IgA staining is present not only in primary IgAN, but also in biopsies with secondary IgAN, SAGN and incidental IgA. Weak or negative staining may favor SAGN, especially in the setting of infection, or incidental IgA in the absence of nephritic symptoms or in the presence of other unrelated glomerular pathologies. However, positive staining for Gd-IgA alone is not specific enough for a diagnosis of primary IgAN.
The interleukin-27 (IL-27)/T-cell cytokine receptor (TCCR) pathway plays an important role in development of protective immunity against cutaneous leishmaniasis caused by
Leishmania major.
In this ...study, we analyzed the role of IL-27/TCCR pathway in the host defense against visceral leishmaniasis (VL) by monitoring the course of
L. donovani
infection in TCCR-deficient C57BL/6 (TCCR−/−) mice. TCCR−/− mice mounted a robust inflammatory response, produced high levels of pro-inflammatory cytokines, and developed severe liver pathology after
L. donovani
infection that eventually resolved. Interestingly,
L. donovani
-infected TCCR−/− mice controlled the parasite growth in their organs significantly faster than similarly infected TCCR+/+ mice. Adoptive cell transfer and cell depletion studies revealed that CD4
+ T cells were involved in mediating liver immunopathology and controlling
L. donovani
growth in TCCR−/− mice. These results indicate that the IL-27/TCCR pathway is not essential for the induction of protective Th1 response during VL but is involved in mediating susceptibility to
L. donovani
. Additionally, the data demonstrate that although the IL-27/TCCR interaction limits the severity of liver inflammation during VL by controlling CD4
+ T-cell activity, it is not required for the resolution of hepatic immunopathology.
An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often ...associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear.
An acute increase in international normalized ratio (INR) to >3.0 in patients with chronic kidney disease (CKD) can associate with an unexplained acute increase in serum creatinine and accelerated ...progression of CKD. A subset of these patients have renal tubular obstruction by casts of red blood cells, presumably the dominant mechanism of the acute kidney injury described as warfarin-related nephropathy. Here, we developed an animal model of this acute kidney injury that is based on the 5/6-nephrectomy model to aid future investigation of the pathogenesis of this condition. We found that acute excessive anticoagulation with brodifacoum ("superwarfarin") increased serum creatinine levels and hematuria in 5/6-nephrectomized rats but not in controls. In addition, morphologic findings in 5/6-nephrectomized rats included glomerular hemorrhage, occlusive red blood cell casts, and acute tubular injury, similar to the biopsy findings among affected patients. Furthermore, in the rat model, we observed an increase in apoptosis of glomerular endothelial cells. In summary, the 5/6-nephrectomy model combined with excessive anticoagulation may be a useful tool to study the pathogenesis of warfarin-related nephropathy.
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