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Background Dermatologic diseases with autoantibodies were recognized early as autoimmunity became accepted as a pathogenic immunologic concept. Laboratory testing to identify disease-defining autoantibodies and investigate their role in pathophysiology has evolved since. Content Blistering dermatologic diseases, profiled by autoantibody production, target epithelial components critical in cell–cell and cell–matrix adhesion, resulting in epithelial separation and other characteristic features of the disorders. This review covers the clinical indications for dermatologic disease-related autoantibody testing, the specifics of procuring specimens to test, the available diagnostic tests, and information provided by the testing. Atypical, uncharacteristic, and less well-known clinical and autoantibody profiles as well as several of the many future prospects for expansion of the testing applications are elaborated on in the online Data Supplement. Summary Autoantibody-associated dermatologic diseases are acquired immunologic disorders that have considerable clinical implications affecting essential barrier functions of skin and mucous membranes and causing discomfort, including pain and pruritus. Certain of the diseases can have life-threatening manifestations, and treatments can have significant side-effects. The skin diseases may presage other clinical associations that are important to recognize and treat. Laboratory testing aids in the diagnosis of these diseases through identification of the autoantibodies and is essential for prompt and precise knowledge of the disease type for prognosis, further clinical evaluations, and treatment decisions.

Background: There has been a long, storied relationship between various bacterial infections and glomerular injury, which is now encompassed under the term of infection-related glomerulonephritis (GN). The clinical and pathologic manifestations vary depending on the duration, magnitude, and underlying pathogen associated with the inciting infectious process. A brief and acute episode may lead to a self-limiting glomerular manifestation while a chronic or repetitive infection can result in persistent and irreversible injury. In this review, we will discuss the clinical and pathologic findings associated with the infection-related glomerulonephritides. Summary: An acute exudative GN with an influx of neutrophils is the most characteristic morphologic alteration associated with infection-related glomerular injury. The immunofluorescence staining pattern often reveals prominent complement component C3 deposition in both capillary walls and mesangial regions with or without accompanying immunoglobulin. Large subepithelial electron-dense deposits known as “humps” are the hallmark ultrastructural finding; however, these features can also be present in C3 glomerulopathies, which are often triggered by infections and may have similar underlying abnormalities in alternative pathway complement activation. In addition, other glomerular injuries can simultaneously be present along with infection-related GN, such as diabetic nephropathy, lupus nephritis, or immunoglobulin A nephropathy, constituting a true diagnostic challenge for the pathologist. Key Messages: Bacterial infection-related GN represents a spectrum of glomerular injury with variable clinical and pathologic presentations. The pathologic findings can show overlap with other glomerular diseases, and different forms of infection-related GN vary in terms of prognosis and treatment approach.

Programmed cell death receptor-1 blocking antibodies and cytotoxic T-lymphocyte–associated antigen-4 blocking antibodies are referred to as checkpoint inhibitors and are used in cancer immunotherapy. While enhancing T-cell antitumor immunity, checkpoint inhibitors can also cause immune-mediated nephrotoxicities, manifesting mostly in acute kidney injury. Cytotoxic T-lymphocyte–associated antigen-4 blockade was associated with acute interstitial nephritis with variable degrees of podocyte effacement, minimal change disease, and membranous nephropathy. Conversely, programmed cell death receptor-1 blockade has mostly been associated with acute interstitial nephritis, with or without various glomerular diseases. In particular, cases of minimal change disease were reported with programmed cell death receptor-1 blockade, including two cases of minimal change disease reported in Hodgkin’s lymphoma and one with mesothelioma, in addition to one case of focal segmental glomerulosclerosis after treatment of renal cell carcinoma. We report a case of acute interstitial nephritis and minimal change disease in a patient with Hodgkin’s lymphoma treated with nivolumab and discuss pathophysiological hypotheses. The association of minimal change disease with Hodgkin’s lymphoma is well-recognized and may be related to c-mip protein and/or CD80. The checkpoint pathway likely triggers the auto-immune, T-cell-mediated, minimal change disease associated with Hodgkin’s lymphoma; however, this pathogenic process may also involve a programmed cell death receptor-1– fyn-c-mip interaction or a PD-L1–CD80 cross-talk at both T-cell and podocyte level.

Introduction Staphylococcal infection–related glomerulonephritis (GN) has been shown to represent a unique form of infection-related GN that contains IgA-dominant deposits and is often seen concurrently with the bacterial infection. Biopsies commonly reveal an endocapillary proliferative and/or exudative or mesangial proliferative GN. Rare cases have been reported to show cryoglobulin-like features, including hyaline pseudothrombi and wireloop deposits; however, detailed characterization of these cases is lacking. Methods The pathology archives from the University of Utah and Sharp Memorial Hospital were reviewed from January 2016 to September 2017 in search of cases with GN containing IgA-dominant deposits and features of cryoglobulinemia. Results Of 1965 native kidney biopsies, 5 showed IgA-dominant GN with cryoglobulinemic features. All patients had active staphylococcal infections at the time of biopsy. All presented with acute kidney injury (serum creatinine range: 1.7−6 mg/dl), and all had proteinuria and hematuria. All biopsies showed exudative GN, and 4 biopsies had focal crescents. All had focally prominent hyaline pseudothrombi with or without wireloop deposits, and all showed co-dominant staining for IgA and C3 on immunofluorescence microscopy. Serologic testing for cryoglobulinemia was performed in 3 patients and was transiently positive in 1 patient. Four patients required hemodialysis at last follow-up, whereas 1 patient returned to baseline kidney function. Conclusion IgA-dominant GN with cryoglobulinemic features is an uncommon but severe form of glomerular injury in patients with staphylococcal infections. Four of 5 patients had crescentic glomerular injuries, all of whom required hemodialysis at last follow-up. Patients with IgA-dominant GN with features of cryoglobulinemia should be evaluated for active staphylococcal infection.

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation.

Kidney injury related to paraproteinemia is common and typically occurs after the fourth decade of life in association with an underlying plasma cell dyscrasia or other lymphoproliferative disease. Kidney transplantation in paraprotein-related kidney disease can be successful in conjunction with treatment of the underlying hematopoietic process; however, when hematologic response to therapy is not achieved, recurrent kidney injury is frequently seen. We describe a young male patient who presented at the age of 23 years with end-stage kidney disease thought to be secondary to focal segmental glomerulosclerosis; this patient ultimately received two kidney allografts. He experienced recurrent proteinuria in both kidneys, with a biopsy from his second allograft showing kappa-restricted crystalline light chain podocytopathy, which was identified in both his native and first allograft kidneys upon retrospective review. Recurrent light chain podocytopathy has not been previously reported but poses a diagnostic challenge as it can mimic focal segmental glomerulosclerosis, particularly in young patients in whom paraprotein-related kidney injury is usually not suspected.

Background C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen. Methods Fourteen biopsies from 12 patients meeting diagnostic criteria for C3G were identified in patients > 49 years of age from 2005 to 2015 after exclusion of cases containing masked monotypic immunoglobulin deposits. Pathologic and clinical features were reviewed. Results The median age was 63.5 years and 75% of patients were male. All had renal insufficiency at presentation. Kidney biopsy showed DDD in three patients and C3GN in the remainder. Serum protein electrophoresis revealed a paraprotein in 10 patients, 8 of which had a plasma cell dyscrasia on bone marrow biopsy. A membranoproliferative pattern of glomerular injury was seen in 64% of biopsies, while mesangial proliferative and endocapillary proliferative patterns were seen less frequently. Among patients with at least 1 year of follow-up (n = 9), five were on renal replacement therapy, three showed stable (but impaired) kidney function and one demonstrated improvement. Conclusions C3G is an uncommon but important cause of kidney injury in older adults and associates with a high prevalence of paraproteinemia. In adult patients with C3G, prognosis is guarded as most patients showed either progression to end-stage kidney disease or stable but impaired kidney function.

Background Post-infectious glomerulonephritis (PIGN) is an immune complex-mediated glomerular injury that typically resolves. Dominant C3 deposition is characteristic of PIGN, but with the emergence of C3 glomerulonephritis (C3GN) as a distinct entity, it is unclear how the pathologic similarities between PIGN and C3GN should be reconciled. Therefore, nephrologists and nephropathologists need additional guidance at the time of biopsy. Methods We studied 23 pediatric and young adult patients diagnosed with PIGN. Patients were divided into two groups, one with co-dominance between C3 and immunoglobulins and the other meeting proposed diagnostic criteria for C3GN. Clinical and pathological features were compared. Results No clinical and/or pathological features could distinguish between those with C3-co-dominant deposits and those with C3 dominance. Nearly all patients in both groups regained their baseline renal function without clinical intervention. Conclusions Although the identification of abnormalities of the alternative pathway of complement is characteristic of C3GN, testing is not widely available and the turnaround time often exceeds 1 month. Our study found that PIGN with either co-dominant or dominant C3 deposition in a cohort of young patients has excellent short-term outcomes. Close clinical observation for persistent abnormalities, such as hypocomplementemia, prolonged hematuria or proteinuria, is recommended to single out patients that may harbor intrinsic complement abnormalities.

In older adults, the most common kidney biopsy diagnoses include pauci-immune crescentic glomerulonephritis, membranous nephropathy, and focal segmental glomerulosclerosis. Recently, investigators described a small series of older patients (aged 66-80 years) with acute kidney injury and a kidney biopsy demonstrating tubular basement membrane (TBM) immune deposits of polytypic immunoglobulin G (IgG) and C3, acute tubular injury, and tubulointerstitial inflammation. They identified a circulating antibody against kidney tubular low-density lipoprotein (LDL) receptor-related protein 2 (LRP2; also known as megalin) in patients' sera and colocalization of LRP2 with IgG in TBM deposits. We present a rare case of anti-LRP2 nephropathy/anti–brush border antibody disease and describe the novel feature of abundant IgG4-positive interstitial plasma cells. Along with the combination of TBM deposits, tubulointerstitial nephritis (TIN), and segmental glomerular subepithelial immune deposits seen in both entities, this newly described feature adds to the morphologic overlap with IgG4-related TIN. Identification of large TBM deposits using light microscopy and IgG staining of apical aspects of proximal tubules using immunofluorescence microscopy can point to the correct diagnosis of anti-LRP2 nephropathy and prompt confirmatory studies. Particularly in older patients with immune complex–mediated TIN who lack clinical, laboratory, radiographic, and/or characteristic histologic features of IgG4-TIN or other autoimmune, infectious, or drug-related injury, a diagnosis of anti-LRP2 nephropathy should be considered.

Soft tissue sarcomas are a rare group of mesenchymal malignancies which can range from low to high grade. These tumors have different clinical, radiographic, and histopathological characteristics. Beta human chorionic gonadotropin is a naturally secreted hormone by placental syncytiotrophoblast cells during pregnancy. On very rare occasions, sarcomas can develop the ability to ectopically produce human chorionic gonadotropin. Very few cases exist in the literature of soft tissue sarcomas expressing this hormone. We report the case of a 55-year-old female who presented with a posterior thigh soft tissue sarcoma who on the day of surgical resection was found to have an unusually elevated serum human chorionic gonadotropin. Positive immunohistochemical staining of the resected mass confirmed the sarcoma as the source of the beta human chorionic gonadotropin.

Amyloid nephropathy is an uncommon disease that frequently presents with reduced kidney function and proteinuria and, in developed nations, is most often associated with underlying paraproteinemia. The histologic appearance of glomerular amyloid deposition includes mesangial and capillary wall infiltration by an amorphous eosinophilic material, and features of endo- or extracapillary proliferation are not typically seen. Rare cases of crescentic injury have been reported in a subset of patients with amyloid nephropathy, particularly those with amyloid derived from serum amyloid A protein. Collapsing glomerulopathy, which like crescentic injury is associated with an extracapillary proliferation, has not to our knowledge been reported in the setting of amyloid nephropathy. We report 2 patients presenting with acute kidney injury and nephrotic syndrome found to have amyloid nephropathy with prominent epithelial cell hyperplasia and glomerular collapse on biopsy. This injury is likely multifactorial and related to direct podocyte injury and vascular compromise and expands further the spectrum of paraprotein-associated renal injury.

Pauci-immune glomerulonephritis (GN) represents a severe form of glomerular injury and is the most common cause of crescentic GN in adults. To date, the clinicopathologic features of pauci-immune GN are not well characterized in the pediatric population.Twenty-six biopsies from 21 pediatric patients with pauci-immune GN were identified retrospectively from the pathology archives of the University of Chicago (biopsy incidence 5 % among pediatric patients).There was distinct female predominance (2.5:1) among the patient cohort. Serologic studies identified anti-neutrophil cytoplasmic antibodies (ANCA) in 85 % of patients, and 80 % had systemic manifestations of vasculitis. The median estimated glomerular filtration rate (eGFR) at presentation was 43 ml/min/1.73 m(2). Based on a previously proposed classification of ANCA-associated GN, we identified a spectrum of injury, including crescentic (n = 9), focal (n = 7), mixed (n = 5) and sclerotic GN (n = 5). Necrotizing arteritis was identified in a minority of patients (n = 3). The majority of those patients for whom data were available had been treated with cyclophosphamide and corticosteroids, with or without rituximab. Of the 21 pediatric patients, 58 % had developed chronic kidney disease at follow-up (eGFR90 ml/min/1.73 m(2)), of whom 85 % of those had crescentic, mixed or sclerotic GN.Pediatric patients with pauci-immune GN are similar to their adult counterparts in terms of clinical manifestations and histopathologic findings. Among the 21 patients in our study, those with focal GN had the best outcomes while patients with crescentic, mixed or sclerotic GN overwhelmingly had a poor long-term outcome for kidney function.

Kidney injury is a complication of intravascular hemolysis associated with many forms of hemolytic disease. Reports of kidney biopsy findings in patients with hemolysis-related kidney injury have focused primarily on the accumulation of hemosiderin pigment within proximal tubular epithelial cells (hemosiderosis), a feature of chronic hemolysis. The nephrotoxic effects of hemoglobin include direct cytotoxicity to tubular cells, but hemoglobin also can precipitate in distal nephron segments, forming obstructive casts. We present a case of hemolysis-associated tubular injury, characterized by acute onset of intravascular hemolysis followed by acute kidney injury with acute tubular injury and abundant intratubular casts containing hemoglobin.

Prior studies demonstrate poor agreement among pathologists' interpretation of kidney biopsy slides. Reliability of representative images of these slides uploaded to the United Network of Organ Sharing (UNOS) web portal for clinician review has not been studied. We hypothesized high agreement among pathologists' image interpretation, since static images eliminate variation induced by viewing different areas of movable slides. To test our hypothesis, we compared the assessments of UNOS-uploaded images recorded in standardized forms by three pathologists. We selected 100 image sets, each having at least two images from kidneys of deceased donors. Weighted Cohen's kappa was used for inter-rater agreement. Mean (SD) donor age was 50 (13). Acute tubular injury had kappas of 0.12, 0.14, and 0.19; arteriolar hyalinosis 0.16, 0.27, and 0.38; interstitial inflammation 0.30, 0.33, and 0.49; interstitial fibrosis 0.28, 0.32, and 0.67; arterial intimal fibrosis 0.34, 0.42, and 0.59; tubular atrophy 0.35, 0.41, and 0.52; glomeruli thrombi 0.32, 0.53, and 0.85; and global glomerulosclerosis 0.68, 0.70, and 0.77. Pathologists' agreement demonstrated kappas of 0.12 to 0.77. The lower values raise concern about the reliability of using images. Although further research is needed to understand how uploaded images are used clinically, the field may consider higher-quality standards for biopsy photomicrographs.

Infection with hepatitis C virus has been associated with a number of extrahepatic manifestations, including kidney disease. Of the glomerular pathologic states described with hepatitis C virus infection, cryoglobulinemic glomerulonephritis is the most prevalent. On kidney biopsy, cryoglobulinemic glomerulonephritis has a variable appearance, with a membranoproliferative pattern of injury as the most common light microscopic finding. Ultrastructurally, curved and paired microtubules are the most characteristic finding, but these also can be variable. We present a case of cryoglobulinemic glomerulonephritis with distinct and highly unusual ultrastructural findings.

Kidney injury can be a complication of hematopoietic neoplasia by both direct and indirect mechanisms. Virtually all lymphomas and plasma cell dyscrasias can show kidney involvement, including parenchymal infiltration and by secondary injury. Recently, a unique form of glomerulonephritis with masked monotypic immunoglobulin deposits has been reported, which shows frequent association with hematopoietic neoplasia and a propensity for progressive kidney disease. In many instances, these cases are likely diagnosed as glomerulonephritis with dominant C3 due to the absence of immunoglobulin staining by routine immunofluorescence microscopy. The patient reported here showed lymphomatous infiltration on kidney biopsy and mesangial proliferative glomerulonephritis with dominant staining for C3 without immunoglobulins on initial immunofluorescence; however, monotypic immunoglobulin G κ light chain was revealed after additional immunofluorescence staining was performed on the paraffin-embedded tissue. This patient's case highlights the evolving state of kidney biopsy interpretation and the expanding spectrum of kidney disease in the setting of hematopoietic neoplasia.

In the United States, approximately 35% of adults with Systemic Lupus Erythematosus (SLE) have clinical evidence of nephritis at the time of diagnosis; with an estimated total of 50–60% developing nephritis during the first 10 years of disease [1–4]. The prevalence of nephritis is significantly higher in African Americans and Hispanics than in Caucasians, and is higher in men than in women. Renal damage is more likely to develop in non-Caucasian groups [2–4]. Overall survival in patients with SLE is approximately 95% at 5 years after diagnosis and 92% at 10 years [5, 6]. The presence of lupus nephritis significantly reduces survival, to approximately 88% at 10 years, with even lower survival in African Americans [5, 6]. The American College of Rheumatology (ACR) last published guidelines for management of systemic lupus erythematosus (SLE) in 1999 [7]. That publication was designed primarily for education of primary care physicians and recommended therapeutic and management approaches for many manifestations of SLE. Recommendations for management of lupus nephritis (LN) consisted of pulse glucocorticoids followed by high dose daily glucocorticoids in addition to an immunosuppressive medication, with cyclophosphamide viewed as the most effective immunosuppressive medication for diffuse proliferative glomerulonephritis. Mycophenolate mofetil was not yet in use for lupus nephritis and was not mentioned. Since that time, many clinical trials of glucocorticoids-plus-immunosuppressive interventions have been published, some of which are high quality prospective trials, and some not only prospective but also randomized. Thus, the ACR determined that a new set of management recommendations was in order. A combination of extensive literature review and the opinions of highly qualified experts, including rheumatologists, nephrologists and pathologists, has been used to reach the recommendations. The management strategies discussed here apply to lupus nephritis in adults, particularly to those receiving care in the United States of America, and include interventions that were available in the United States as of April 2011. While these recommendations were developed using rigorous methodology, guidelines do have inherent limitations in informing individual patient care; hence the selection of the term “recommendations.” While they should not supplant clinical judgment or limit clinical judgment, they do provide expert advice to the practicing physician managing patients with lupus nephritis.

The diagnosis of acute rejection is suspected by clinical presentation and confirmed by biopsy. Serum creatinine levels increase during allograft dysfunction, but this measure is neither sensitive nor specific for acute rejection (1, 2). The gold standard for diagnosing rejection is needle biopsy, which is invasive, painful, and as sociated with patient morbidity (1–4). It would be advantageous to develop a noninvasive test that could detect rejection, improve transplant outcomes, and reduce the cost of care. The use of human plasma for biomarker discovery provides a means to monitor disease states in a relatively noninvasive manner (5, 6). Plasma comes in contact with tissues which are apt to release protein components that reflect the disease-altered state of the tissue (6). The SELDI ProteinChip System (Bio-Rad, Hercules, CA) uses solid phase extraction of proteins and peptides from biological mixtures followed by detection using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. ProteinChip arrays use a variety of chromatographic and biological surfaces to bind subsets of proteins from complex biological samples (7). The bound proteins are used to generate protein profiles used for biomarker discovery (7, 8). Urine protein profiles from renal allograft rejection patients have identified potential biomarker candidates and generated valuable insight into the biology of graft injury (9–15). The utilization of plasma for finding candidate bio-markers of renal allograft rejection holds promise as a biological fluid that can provide informative proteomic signatures of renal allograft rejection (16). This study analyzes the plasma proteomes of renal transplant patients by SELDI. Twenty-two proteins/peptides had significant differences when comparing plasma during rejection with postrejection. The combination of two candidate proteins had a high discriminatory value for detecting rejection. Two of the 22 candidates were identified and one, apolipoprotein A1 (Apo A1), was validated by enzyme-linked immunosorbent assay (ELISA) in the original and a larger independent cohort.

A previously healthy, 14-year-old African-American female presented with a 1-week history of fatigue, scleral icterus, and darkened urine. Transaminases were elevated with an aspartate transaminase of 1258 U/l and an alanine aminotransferase of 1636 U/l. Serologic work-up was negative for hepatitis A, B, and C viral infection but positive for antinuclear antibody (1:1280) and anti-smooth muscle antibody (200, reference

Infectious diseases are a major cause of morbidity and mortality in humans throughout the world. Renal involvement by a variety of infectious etiologies either in isolation or during widespread dissemination can result in significant organ dysfunction. Viruses, such as human polyomavirus or adenovirus, can directly infect kidney tubular epithelial cells and induce tubulointerstitial inflammatory responses. Alternatively, the immune response of the host to offending viruses, such as hepatitis B, hepatitis C virus, or human immunodeficiency virus, can lead to immune complex formation resulting in a variety of glomerular patterns of injury. Fungal and mycobacterial infections injure primarily through direct colonization of the kidney, which may be exacerbated by the associated inflammatory response to the initial infection. The kidney has a limited number of ways to respond to the wide array of infectious agents. Therefore, there are many overlapping histopathologic features, and definitive identification of the offending microorganism based on a kidney biopsy can be a diagnostic challenge. The wide spectrum of renal diseases in humans caused by common viral, fungal, and mycobacterial pathogens will be reviewed. Bacterial infections involving the kidney will be discussed elsewhere.

Infectious endocarditis is associated with a number of systemic manifestations, including kidney disease. Kidney manifestations, including hematuria, parenchymal infarction, and glomerulonephritis, may affect as many as 40%-50% of patients with infective endocarditis. In a minority of cases of infective endocarditis, routine bacterial cultures do not yield an offending organism. Bartonella species are a known and relatively common cause of culture-negative endocarditis and have been associated with the development of endocarditis-associated glomerulonephritis. We present a case of Bartonella endocarditis–associated glomerulonephritis in which recognition of a characteristic immunofluorescent pattern and thorough investigation of the clinical history led to this uncommon diagnosis.

Leukocyte chemotactic factor-2 (LECT2) amyloidosis has been described as being associated with kidney disease; however, no clinical manifestations outside of the kidney have been previously reported. We describe a patient presenting with pulmonary-renal syndrome found to have deposition of amyloidogenic LECT2 (ALECT2) within both the lung and the kidney. This case is unique in regard to both the patient's clinical presentation of pulmonary-renal syndrome in the setting of amyloidosis and the biopsy finding of ALECT2 deposition within the lung. It also emphasizes the importance of tissue diagnosis in such cases, given that amyloidosis was not initially considered in the differential diagnosis.

A previously healthy 17-year-old African-American male presented with acute kidney injury after playing basketball without rest for 5–6 h. At presentation, his serum creatinine was 468.5 µmol/L (5.3 mg/dL) with an estimated glomerular filtration rate (eGFR) of 17 mL/min/1.73 m2 calculated by the four-variable modification of diet in renal disease study equation. He had no history of kidney disease and was not taking any medications. Serum creatine kinase was elevated at 2277 U/L (reference range: 9–185 U/L) and his unconjugated bilirubin was 75.2 µmol/L (4.4 mg/dL). Hemoglobin was 133 g/L (13.3 g/dL) and a direct agglutination test was negative. Serum haptoglobin and hemoglobin electrophoresis studies were not done. Due to concern for rhabdomyolysis-associated acute tubular injury/necrosis, a kidney biopsy was performed. Seventeen glomeruli were sampled and were histologically unremarkable. Proximal tubules showed marked attenuation of brush borders and epithelial cell flattening. Granular cast material was identified within distal tubular lumina, which stained weakly by periodic acid–Schiff (PAS) reagent (Figure 1A) and eosinophilic on the hematoxylin and eosin stain (Figure 1B). Immunohistochemical staining for myoglobin was negative (Figure 1C); however, hemoglobin A diffusely and strongly stained the cast material (Figure 1D). A Prussian blue histochemical stain was negative for hemosiderin deposition. No glomerular, tubular basement membrane or interstitial deposits were seen by immunofluorescence or electron microscopy. The biopsy was interpreted as acute tubular injury/necrosis with hemoglobin casts, suggestive of hemolysis-associated acute kidney injury. Fig. 1. By light microscopy, distal tubules show granular cast material, which stains weakly by PAS reagent (A), and eosinophilic on the hematoxylin and eosin-stained section (B). The granular casts were negative upon immunohistochemical staining for myoglobin ... The patient was treated supportively with return to normal kidney function (eGFR > 90 mL/min/1.73 m2) 1 month after presentation. Due to the rapid recovery and absence of persistent hemolysis, it was felt that the hemoglobinuria was a result of exertion-related hemolysis. Renal exposure to excess heme is a known cause of kidney injury and can occur in the setting of intravascular hemolysis (hemoglobinuria) and rhabdomyolysis (myoglobinuria) [1]. Uncommonly, hemoglobinuria can occur as a consequence of physical exertion and subsequent mechanical injury to erythrocytes. This phenomenon, referred to as ‘march hemoglobinuria,’ was first observed in military personnel in the nineteenth century and has since been reported in patients participating in activities with repetitive impact, including runners and percussionists [2–4]. Reports of hemolysis-associated kidney injury have almost exclusively focused on the accumulation of intracytoplasmic hemosiderin (hemosiderosis) within tubular cells, [5] which was absent in our case and is a feature of persistent and/or recurrent bouts of hemolysis and hemoglobinuria. The differential diagnosis of acute tubular injury in the setting of excessive physical exertion includes hypovolemic acute tubular injury, rhabdomyolysis-associated acute tubular injury and hemolysis-associated injury. Hypovolemic acute tubular injury can show intratubular casts formed by the sloughing of cell cytoplasm into the tubular lumina; however, these casts fail to stain for both myoglobin and hemoglobin A. Rhabdomyolysis and hemolysis-associated tubular injury can both demonstrate intratubular hyaline and granular casts, which appear identical on light microscopy. Immunohistochemical staining for myoglobin and hemoglobin A is required to separate these entities pathologically. In summary, acute intravascular hemolysis can rarely occur in the setting of physical exertion and can result in toxic tubular injury with intratubular cast formation.