Heavy chain deposition disease presenting with raised anti-GBM antibody levels; a case report.

BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) is a rare condition accounting for < 1% of histopathological diagnoses made on kidney biopsy1. The best outcomes are seen in those diagnosed and treated promptly, but delay to diagnosis is common with the largest series reporting a median time from onset of renal impairment to diagnosis of 12 months2. Here, we report a case of the heavy chain subset of MIDD presenting with positive anti-glomerular basement membrane (anti-GBM) antibodies obscuring the true diagnosis. CASE PRESENTATION: Here, we present a challenging case presenting with oedema, haematoproteiuria, and new renal impairment. Anti-GBM antibodies were positive and prompted treatment as atypical anti-GBM disease. However, they were ultimately proven to be monoclonal and secondary to myeloma. The final diagnosis facilitated effective myeloma treatment which led to complete remission and independence from renal replacement therapy. CONCLUSIONS: This case reinforces the importance of comprehensive histopathological and haematological assessment in making the correct diagnosis. Here it facilitated effective treatment and recovery of renal function.

Long term outcomes in monoclonal gammopathy of renal significance.

Unlike AL amyloid and cast nephropathy, the long-term outcomes of monoclonal gammopathy of renal significance (MGRS) patients with other renal histopathologies remain unclear. It is uncertain if early intervention improves renal outcomes, because of a lack of evidence from prospective studies. In this retrospective study, we examined outcomes of 41 MGRS patients treated between 2004 and 2017 across five centres: four in the UK and one in the Republic of Ireland. The primary outcome measure was renal survival estimated by Kaplan-Meier product-limit method. Thirty-three patients (80·5%) were kappa light chain (LC) restricted. Twenty-seven patients (65·9%) presented with LC deposition disease on renal histology. At 24 months follow-up, estimated renal survival was 81·6% for the whole cohort. The estimated overall survival was 80·3% at 48 months. At 24 months, patients who had chronic kidney disease (CKD) stage 2-3b at diagnosis showed an estimated renal survival of 100% compared to 80·7% in those with CKD stage 4-5 at diagnosis (P = 0·04). Poorer outcomes in MGRS patients were historically attributed to delayed diagnosis due to small plasma cell clones, as well as the need for renal biopsy.

Predicting Outcome in Patients with Anti-GBM Glomerulonephritis.

BACKGROUND AND OBJECTIVES: Large studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses. RESULTS: The 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 (P=0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated (P<0.001). Only one of 15 patients with a focal class biopsy sample (≥50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (≥50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up. CONCLUSIONS: Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3.

Predictors of renal and patient outcomes in anti-GBM disease: clinicopathologic analysis of a two-centre cohort.

BACKGROUND: Patients with anti-glomerular basement membrane (GBM) disease are at increased risk of morbidity and mortality from renal failure, pulmonary haemorrhage or complications of treatment. One-third also have circulating anti-neutrophil cytoplasmic antibodies (ANCA). The aim of this study was to determine the clinicopathologic predictors of patient and renal outcomes in anti-GBM disease with or without ANCA. METHODS: Retrospective review of 43 patients diagnosed with anti-GBM disease over 20 years in two centres, including nine with dual anti-GBM and ANCA positivity. Renal biopsies from 27 patients were scored for the presence of active and chronic lesions. RESULTS: Dual-positive patients were almost 20 years older than those with anti-GBM positivity alone (P = 0.003). The overall 1-year patient and renal survivals were 88 and 16%, respectively. Oligoanuria at diagnosis was the strongest predictor of mortality; none of the 16 patients without oligoanuria died. In a Cox regression model excluding oligoanuria, age was the only other independent predictor of survival. Pulmonary haemorrhage and dialysis dependence did not influence mortality. Thirty-five of the forty-three (81%) patients required dialysis at presentation, including all nine dual-positive patients. Of them, only two (5.7%) regained renal function at 1 year. By logistic regression, oligoanuria at diagnosis and percentage of crescents were independent predictors of dialysis independence at 3 months. However, in biopsied patients, the presence of crescents (>75%) added little to the presence of oligoanuria in predicting dialysis independence. Histological activity and chronicity indices did not predict renal outcome. Two of the nine (22%) dual-positive patients relapsed compared with none of the anti-GBM alone patients. Seven patients received kidney transplants without disease recurrence. CONCLUSIONS: Oligoanuria is the strongest predictor of patient and renal survival while percentage of glomerular crescents is the only pathologic parameter associated with poor renal outcome in anti-GBM disease. Kidney biopsy may not be necessary in oligoanuric patients without pulmonary haemorrhage.

New advances in renal amyloidosis.

Renal amyloidosis is a rare and intractable disease that accounts for 0.2% of the original kidney diseases of dialysis patients in Japan. However, the number of patients with renal amyloidosis seems to be increasing in recent years. There have been some new concepts focusing on the mechanism of amyloidogenesis, such as molecular chaperones, seeding mechanism, and genetic polymorphisms of precursor protein. Clinical and histological features of renal amyloidosis vary according to the type. Significantly higher levels of urinary protein excretion are seen in the AL type, whereas microscopic haematuria is more prominent in the AA type. Histologically, amyloid deposition of AL type has stronger predilection for GBM than mesangium, and spicule formation is more frequently observed. In contrast, AA type has a higher affinity to TBM and interstitial area. For the histological diagnosis of renal amyloidosis, plural staining methods including Congo-red, Daylon and thioflavin-T stains are available. Combinations of these staining methods are necessary for establishing the precise diagnosis. The more recent and intensive treatments for renal amyloidosis are expected to improve patient outcome. For AL amyloidosis, high-dose melphalan plus high-dose dexamethasone or VAD, in conjunction with bone marrow stem cells transplantation, have shown a definitive effect on reducing urinary protein excretion. The biological agent, tumor necrosis factor (TNF alpha) blocker, improves the renal function in AA-type renal amyloidosis, as well as suppresses the inflammatory reactions in patients with rheumatoid arthritis. Clinical advances have been made in various aspects of renal amyloidosis.

Leiomyosarcoma of the abdominal aorta: a rare cause of renovascular hypertension.

We describe the case of a 44-year-old woman who presented with renovascular hypertension caused by primary leiomyosarcoma of the abdominal aorta that had metastasized into the renal arteries. Despite an extensive radiological evaluation, the diagnosis was mistaken first for Takayasu's arteritis and then for retroperitoneal hematoma or neoplasm. The patient developed renal failure due to bilateral renal infarction, and died 3 months after her initial presentation with ischemic colitis. Postmortem examination confirmed the diagnosis.

SM22alpha: the novel phenotype marker of injured glomerular epithelial cells in anti-glomerular basement membrane nephritis.

BACKGROUND/AIMS: Our previous comprehensive analysis of the genes expressed in kidneys with anti-glomerular basement membrane (GBM) nephritis using DNA microarrays showed that SM22alpha was one of the highly expressed genes. SM22alpha is a 22-kDa cytoskeletal protein that is exclusively expressed in smooth muscle cells. We investigated the localization of SM22alpha at mRNA and protein levels, and its pathological significance in anti-GBM nephritis kidneys. METHODS: Northern blot analysis, in situ hybridization, immunohistochemistry and double immunofluorescence studies were performed. The specific antibody (Ab) against SM22alpha was obtained by immunization of rabbits with recombinant rat SM22alpha protein. RESULTS: SM22alpha mRNA expression was upregulated in kidneys and inducibly expressed in the parietal and visceral glomerular epithelial cells in anti-GBM nephritis kidneys. Immunohistochemistry with anti-SM22alpha Ab showed that SM22alpha protein was localized in the same series of cells. Double immunofluorescence with anti-SM22alpha and anti-glomerular cell markers demonstrated that SM22alpha might be expressed in epithelial cells of injured glomeruli. In visceral epithelial cells, SM22alpha might be expressed in cells in which podocyte specific markers, podocalyxin and nephrin were lost. CONCLUSION: The injured glomerular epithelial cells in anti-GBM nephritis might undergo structural and functional alterations, including the expression of a smooth muscle marker, SM22alpha.

Renovascular hypertension: a unique cause of unilateral focal segmental glomerulosclerosis.

A 48-year-old man presented with malignant hypertension and massive proteinuria. Renal angiography showed complete obstruction of the left renal artery and 99mTc-mercaptoacetylglycine (MAG3) renography showed a nonfunctioning left kidney. Percutaneous transluminal renal angioplasty of the left renal artery was unsuccessful; hence, the patient underwent left nephrectomy because of uncontrolled hypertension and proteinuria. Histological examination of a right kidney specimen revealed lesions of focal segmental glomerulosclerosis with benign nephrosclerosis. In contrast, histology of the left kidney showed typical ischemic kidney with hypertrophy of arteriolar smooth muscle cells. The patient responded favorably to the nephrectomy, as his blood pressure and urinary protein dramatically decreased with no antihypertensive medication. This case illustrates the heterogeneous effect of the renin-angiotensin system on either kidney in patients with renovascular hypertension due to unilateral renal artery stenosis.

Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition.

BACKGROUND: Complement 4d (C4d) deposition in the peritubular capillary (PTC) in the kidney allograft is a useful diagnostic marker for humoral rejection. C4d is produced not only by the classical pathway but also by the lectin pathway of the complement activation cascade. We have recently reported the in situ role of the later phase of the complement cascade in renal allografts with C4d deposition; however, the initial process prior to C4d deposition is yet to be resolved. METHODS: To clarify the early phases of the complement activation cascade, we evaluated the deposition of initial proteins of the above two pathways; IgG, IgM, mannose-binding lectin (MBL), H-ficolin, L-ficolin, MBL-associated serine protease (MASP)-1 and MASP-2 in kidney allografts with PTC C4d deposition. RESULTS: Sixty kidney allograft specimens were divided into two groups on the basis of the presence of C4d deposition in PTC. The C4d-positive group (n = 18) included nine ABO-identical and nine ABO-incompatible cases, and the C4d-negative group (n = 42) had 34 ABO-identical and eight ABO-compatible (but not identical) cases. In the C4d-positive group, 16 of 18 cases showed diffuse H-ficolin and IgM deposition in PTC. In contrast, H-ficolin and IgM were not detected in PTC in the C4d-negative group. Other initial proteins were not detected in all cases. CONCLUSIONS: Our study suggested for the first time that the lectin pathway activated by H-ficolin may be involved in C4d deposition on PTC in the kidney allograft.

The morphological compensatory change of peritubular capillary network in chronic allograft rejection.

To clarify the compensatory hemodynamic alterations in the interstitium of renal allograft biopsies with chronic rejection, we evaluated the morphological changes in the peritubular capillary (PTC) network. Seven renal biopsy specimens from recipients with chronic rejection presenting with elevation of serum creatinine of 1.9 +/- 0.5 mg/dL were examined. Renal biopsy specimens from their counterpart donors were used as normal controls. In each specimen, non-pathological interstitial areas without fibrosis, tubular atrophy or cell infiltration were compared with pathological areas (PA) showing fibrosis and/or tubular atrophy using a computer image analysis. Morphological measurements revealed that the mean cut surface area of the PTC in the non-pathological and pathological interstitial areas in the recipient biopsies were significantly larger than that of the normal controls (p < 0.001 and 0.001, respectively). In the recipient biopsies, both of the mean cut surface areas of the tubules and PTC in the non-pathological areas were significantly higher than those in the PA (p < 0.001). The mean glomerular diameter in the recipient biopsies was also significantly higher than that of the donors (p < 0.01). In this study, we provided pathological evidence for the compensatory interstitial and glomerular hemodynamic alterations in kidney graft with chronic rejection and the condition as single kidney.

Osteopontin expression in acute renal allograft rejection.

BACKGROUND: Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown. METHODS: We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N= 22), protocol biopsies without rejection (N= 9), and perioperative donor biopsies (N= 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated. RESULTS: In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P < 0.05), CD68+ monocyte infiltration (P < 0.01), Ki-67+ regenerating tubular and interstitial cells (P < 0.05 and P < 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells. CONCLUSION: These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.

A clinicopathological study on the long-term efficacy of tonsillectomy in patients with IgA nephropathy.

Our study evaluated the clinical efficacy of tonsillectomy on the long-term renal survival in patients with primary IgA nephropathy (IgAN). Forty-six patients underwent tonsillectomy, and 74 patients did not. The mean of follow-up duration of all patients was 197.0+/-29.3 months (61-339 months). The baseline clinical and histological data at renal biopsy were not statistically different between the two groups with and without tonsillectomy. Five (10.9%) of the tonsillectomy group reached end stage renal failure (ESRF), whereas 19 (25.8%) of the non-tonsillectomy group did. The chi-square test between the two groups showed a significant difference (p <0.05). The renal survival of the tonsillectomy group was significantly higher than that of the non-tonsillectomy group by the Kaplan-Meier method with log-rank test (p <0.05). The Cox regression model also revealed that tonsillectomy had a significant favorable impact on the renal survival in long-term follow-up duration (p <0.05). Although our study was done by retrospective analyses, all the results proved that tonsillectomy had significant favorable effects on the long-term renal survival in patients with IgAN.