Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

INTRODUCTION: The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. METHODS: Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH >1× and >2× the URL 1 year after transplantation. RESULTS: We included 325 KTRs (56% female, age 38 ± 13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of >25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53% vs. 62%, P = .16, HR.94 [95% CI:.67-1.32]) and KDOQI (60% vs. 60%, P = 1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs > 88 pg/mL (58% vs. 64%, P = .33) and > 176 pg/mL (55% vs. 62%, P = .19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. CONCLUSION: In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

Urinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis.

We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with response to therapy in patients with proliferative LN. The observational longitudinal study included 60 Mexican adults with proliferative LN followed during the first year after LN flare. uSerpA3 was detected by Western blot analysis at flare and after 3, 6, and 12 mo. The response to therapy was determined 1 yr after the LN flare. We evaluated the correlation between uSerpA3 and histological parameters at LN flare. The temporal association between uSerpA3 and response to therapy was analyzed with linear mixed models. uSerpA3 prognostic performance for response was evaluated with receiver-operating characteristic curves. Among the 60 patients studied, 21 patients (35%) were class III and 39 patients (65%) were class IV. uSerpA3 was higher in class IV than in class III LN (6.98 vs. 2.89 dots per in./mg creatinine, P = 0.01). Furthermore, uSerpA3 correlated with the histological activity index (r = 0.29, P = 0.02). There was a significant association between the temporal course of uSerpA3 and response to therapy. Responders showed a significant drop in uSerpA3 at 6 mo compared with LN flare (P < 0.001), whereas nonresponders persisted with elevated uSerpA3. Moreover, uSerpA3 was significantly lower at flare in responders compared with nonresponders (2.69 vs. 6.98 dots per in./mg creatinine, P < 0.05). Furthermore, uSerpA3 was able to identify nonresponders since 3 mo after LN flare (area under the curve: 0.77). In conclusion, uSerpA3 is an early indicator of kidney inflammation and predictor of the clinical response to therapy in patients with proliferative LN.NEW & NOTEWORTHY LN requires aggressive immunosuppression to improve long-term outcomes. Current indicators of remission take several months to normalize, prolonging treatment regiments in some cases. Serpin-A3 is present in urine of patients with proliferative LN. We evaluated the excretion of serpin-A3 in serial samples of patients with proliferative LN during the first year after flare. We found that uSerpA3 correlates with kidney inflammation and its decline at early points predicts the response to therapy 1 yr after flare.

Systemic BK Virus Infection in a Pediatric Patient With Severe Combined Immunodeficiency.

Human BK virus (BKV) infection is known to occur mostly during childhood with the establishment of latent infection with no tissue damage or clinical manifestations. However, conditions causing immunosuppression can lead to increased virus replication and tissue damage. Although the tissues most commonly involved are the kidneys, bladder, ureters and, to some extent, brain tissue, there are some reports that suggest that BKV may cause multisystemic infections. In this case, a 12-month-old child was seen to suffer from multiple gastrointestinal infections. This prompted a search for immunodeficiencies, which revealed the presence of severe combined immunodeficiency. The child was eventually hospitalized and continued showing recurrent bouts of gastroenteritis as well as lower respiratory infection. After multiple antibiotic courses, he developed acute kidney injury, a hemophagocytic syndrome, and eventually respiratory failure, which led to his death a year later. Autopsy findings revealed the presence of a disseminated BKV infection involving the kidneys, ureters, leptomeninges, and pancreas. Analysis of the literature failed to show any previous case of BKV pancreatitis. The present case suggests that BKV can damage more tissues than previously reported and may be responsible for systemic infections in immunosuppressed patients.

Nephrotic syndrome in the setting of LECT2 amyloidosis: Take a look at the podocyte.

Amyloid light-chain (AL) amyloidosis represents the most common type of amyloid affecting the kidneys. As AL amyloidosis is frequently clinically manifested as nephrotic syndrome, this glomerular syndrome has been improperly linked to all other types of kidney amyloidosis. In this report, we highlight the importance of amyloid typing, as the deposition of several amyloidotic proteins in the kidneys is not associated with heavy proteinuria. We present two cases of patients who presented with sudden-onset nephrotic syndrome and kidney biopsies showing interstitial, vascular, and/or mesangial LECT2 amyloidosis. Further examination by electron microscopy demonstrated diffuse foot process effacement consistent with minimal change disease and no amyloid deposition in the glomerular basement membrane. Both patients had complete remission after glucocorticoid treatment. We conclude that the presence of nephrotic syndrome in a patient with LECT2 amyloidosis must alert for a potential concurrent podocytopathy.

Reduced endothelial nitric oxide synthase activation contributes to cardiovascular injury during chronic kidney disease progression.

Major cardiovascular events are a common complication in patients with chronic kidney disease (CKD). Endothelial dysfunction can contribute to the cardiovascular injury observed in CKD. Here, we used a rat model of acute kidney injury to CKD transition to investigate heart alterations in the pathway activating endothelial nitric oxide synthase (eNOS) and its impact on the cardiac injury observed during CKD progression. Fifty male Wistar rats were subjected to sham surgery (n = 25) or bilateral renal ischemia-reperfusion (IR-CKD) for 45 min (n = 25). Rats were studied on a monthly basis up to 5 mo (n = 5). In another set of sham and IR-CKD rats, l-arginine was administered starting on the third month after renal ischemia. CKD development and cardiac alterations were monitored in all groups. CKD was characterized by a progressive increase in proteinuria and renal dysfunction that was evident after the fifth month of followup. Heart hypertrophy was observed starting on the fourth month after ischemia-reperfusion. There was a significant increase in brain natriuretic peptide levels. In the heart, IR-CKD rats had increased eNOS phosphorylation at threonine 495 and reduced eNOS-heat shock protein-90α interactions. l-Arginine administration prevented the heart alterations observed during CKD and increased eNOS coupling/dimerization and activation. In summary, CKD progression is accompanied by cardiac hypertrophy, fibrosis, oxidative stress, and increased brain natriuretic peptide levels. These alterations were associated with limited eNOS activation in the heart, which may result in reduced nitric oxide bioavailability and contribute to cardiac injury during CKD.

LECT2 Amyloidosis in Kidney Transplantation: A Report of 5 Cases.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis is a recently recognized entity that often affects the kidneys. Little information is available regarding kidney transplant outcomes in patients with LECT2 amyloidosis or who received kidney allografts containing LECT2 amyloid. We present clinical findings and allograft outcomes of 5 patients who received kidneys with donor-derived LECT2 amyloidosis. In all 5, LECT2 amyloidosis was discovered during protocol biopsies or in evaluation of suspected rejection. Less than 10% of kidney parenchyma was involved, with mostly interstitial and vascular deposits. Allograft function was not impaired and the amyloid deposits persisted for up to 8 years of follow-up. We conclude that kidneys with limited and localized LECT2 amyloid deposits that are otherwise suitable for transplantation need not be automatically discarded.

Delayed spironolactone administration prevents the transition from acute kidney injury to chronic kidney disease through improving renal inflammation.

BACKGROUND: Acute kidney injury (AKI) is not as harmless as previously thought since it may lead to chronic kidney disease (CKD). Because most of the time ischemic AKI occurs unexpectedly, it is difficult to prevent its occurrence and there are no specific therapeutic approaches to prevent the AKI to CKD transition. We aimed to determine whether mineralocorticoid receptor blockade (MRB) in the first days after ischemia/reperfusion (IR) can prevent progression to CKD. METHODS: Four groups of male Wistar rats were included: sham and three groups of bilateral renal ischemia for 45 min, one without treatment and the other two receiving spironolactone for 5 or 10 days, starting 24 h after IR. The rats were studied at 10 days or 5 months after ischemia induction. RESULTS: After 5 months of follow-up, the untreated group exhibited clear evidence of AKI to CKD progression, such as proteinuria, reduced renal blood flow, tubulointerstitial fibrosis, glomerulosclerosis and glomerular hypertrophy. All these alterations were prevented by both spironolactone treatments initiated 24 h after IR, the 10-day treatment being more effective. Within the early mechanisms of the MRB protective effect are the reduction of inflammation and increased endothelin-B-receptor expression and endothelial nitric oxide synthase activation in the first 10 days after IR. CONCLUSIONS: We propose that MRB, administered 24 h after the ischemic injury that leads to AKI, reduces inflammation and promotes efficient tissue repair that avoids the AKI to CKD transition. These data highlight a therapeutic window to preclude CKD development after AKI.

Immune gene expression in kidney biopsies of lupus nephritis patients at diagnosis and at renal flare.

BACKGROUND: Up to 50% of lupus nephritis (LN) patients experience renal flares after their initial episode of LN. These flares contribute to poor renal outcomes. We postulated that intrarenal immune gene expression is different in flares compared with de novo LN, and conducted these studies to test this hypothesis. METHODS: Glomerular and tubulointerstitial immune gene expression was evaluated in 14 patients who had a kidney biopsy to diagnose LN and another biopsy at their first LN flare. Ten healthy living kidney donors were included as controls. RNA was extracted from laser microdissected formalin-fixed paraffin-embedded kidney biopsies. Gene expression was analyzed using the Nanostring nCounter® platform and validated by quantitative real-time polymerase chain reaction. Differentially expressed genes were analyzed by the Ingenuity Pathway Analysis and Panther Gene Ontology tools. RESULTS: Over 110 genes were differentially expressed between LN and healthy control kidney biopsies. Although there was considerable molecular heterogeneity between LN biopsies at diagnosis and flare, for about half the LN patients gene expression from the first LN biopsy clustered with the repeated LN biopsy. However, in all patients, a set of eight interferon alpha-controlled genes had a significantly higher expression in the diagnostic biopsy compared with the flare biopsy. In contrast, nine tumor necrosis factor alpha-controlled genes had higher expression in flare biopsies. CONCLUSIONS: There is significant heterogeneity in immune-gene expression of kidney tissue from LN patients. There are limited but important differences in gene expression between LN flares, which may influence treatment decisions.

Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity.

The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular chloride concentration [Cl-]i, and transepithelial salt transport. Modulation of SPAK kinase activity may have an impact on hypertension and obesity, as STK39, the gene encoding SPAK, has been suggested as a hypertension and obesity susceptibility gene. In fact, the absence of SPAK activity in mice in which the activating threonine in the T loop was substituted by alanine (SPAK-KI mice) is associated with decreased blood pressure; however its consequences in metabolism have not been explored. Here, we fed wild-type and homozygous SPAK-KI mice a high-fat diet for 17 wk to evaluate weight gain, circulating substrates and hormones, energy expenditure, glucose tolerance, and insulin sensitivity. SPAK-KI mice exhibit resistance to HFD-induced obesity and hepatic steatosis associated with increased energy expenditure, higher thermogenic activity in brown adipose tissue, increased mitochondrial activity in skeletal muscle, and reduced white adipose tissue hypertrophy mediated by augmented whole body insulin sensitivity and glucose tolerance. Our data reveal a previously unrecognized role for the SPAK kinase in the regulation of energy balance, thermogenesis, and insulin sensitivity, suggesting that this kinase could be a new drug target for the treatment of obesity and the metabolic syndrome.

Effect of Pinocembrin Isolated from Mexican Brown Propolis on Diabetic Nephropathy.

Propolis is a resinous beehive product that has been used worldwide in traditional medicine to prevent and treat colds, wounds, rheumatism, heart disease and diabetes. Diabetic nephropathy is the final stage of renal complications caused by diabetes and for its treatment there are few alternatives. The present study aimed to determine the chemical composition of three propolis samples collected in Chihuahua, Durango and Zacatecas and to evaluate the effect of pinocembrin in a model of diabetic nephropathy in vivo. Previous research demonstrated that propolis of Chihuahua possesses hypoglycemic and antioxidant activities. Two different schemes were assessed, preventive (before renal damage) and corrective (once renal damage is established). In the preventive scheme, pinocembrin treatment avoids death of the rats, improves lipid profile, glomerular filtration rate, urinary protein, avoid increases in urinary biomarkers, oxidative stress and glomerular basement membrane thickness. Whereas, in the corrective scheme, pinocembrin only improves lipid profile without showing improvement in any other parameters, even pinocembrin exacerbated the damage. In conclusion, pinocembrin ameliorates diabetic nephropathy when there is no kidney damage but when it is already present, pinocembrin accelerates kidney damage.

HSP72 is an early biomarker to detect cisplatin and acetaminophen nephrotoxicity.

OBJECTIVE: To evaluate whether the urinary HSP72 levels (uHSP72) are a useful biomarker for early diagnosis of acute kidney injury (AKI) induced by two widely used drugs: cisplatin and acetaminophen. MATERIALS AND METHODS: To analyze the time-course of nephrotoxic injury and uHSP72 levels, male Wistar rats were administered a single high dose of cisplatin (7 mg/kg) or acetaminophen (750 mg/kg) and were assessed at 6, 12, 24, 48, 72, 96 and 120 h. RESULTS: AKI induced by cisplatin was characterized by tubular injury that started at 6 h and was enhanced after 48 h. Plasma creatinine was increased only after 72 h. In contrast, uHSP72 levels were augmented after 6 h and were enhanced after 48 h of cisplatin administration, which was consistent with the tubular injury. In acetaminophen-induced AKI, the tubular lesions were less severe and predominantly characterized by tubular cell detachment. Interestingly, uHSP72 levels were increased after 6 h of acetaminophen injection and remained elevated at the following time points, reflecting the tubular injury, even in the absence of major functional changes. CONCLUSIONS: In two models of renal injury induced by nephrotoxic drugs, we showed that uHSP72 could be used as an early biomarker to detect subtle to severe tubular injury.

AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease.

Despite clinical recovery of patients from an episode of acute kidney injury (AKI), progression to chronic kidney disease (CKD) is possible on long-term follow-up. However, mechanisms of this are poorly understood. Here, we determine whether activation of angiotensin-II type 1 receptors during AKI triggers maladaptive mechanisms that lead to CKD. Nine months after AKI, male Wistar rats develop CKD characterized by renal dysfunction, proteinuria, renal hypertrophy, glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis. Renal injury was associated with increased oxidative stress, inflammation, α-smooth muscle actin expression, and activation of transforming growth factor ß; the latter mainly found in epithelial cells. Although administration of losartan prior to the initial ischemic insult did not prevent or reduce AKI severity, it effectively prevented eventual CKD. Three days after AKI, renal dysfunction, tubular structural injury, and elevation of urinary biomarkers were present. While the losartan group had similar early renal injury, renal perfusion was completely restored as early as day 3 postischemia. Further, there was increased vascular endothelial growth factor expression and an early activation of hypoxia-inducible factor 1 α, a transcription factor that regulates expression of many genes that help reduce renal injury. Thus, AT1 receptor antagonism prior to ischemia prevented AKI to CKD transition by improving early renal blood flow recovery, lesser inflammation, and increased hypoxia-inducible factor 1 α activity.

Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies.

BACKGROUND: Angiotensin II type 1 receptor antibodies (AT1Rabs) have been associated with significantly reduced graft survival. Earlier graft loss has been observed in patients who had pretransplant AT1Rabs and posttransplant donor-specific antibodies (DSA). METHODS: The main goal of this retrospective cohort study was to examine the association between AT1Rabs and the time period to detection of de novo human leukocyte antigen (HLA-DSA) posttransplantation in living donor kidney transplant recipients (KTR). The analysis included 141 KTRs. Pretransplant frozen serum samples were tested for AT1Rabs by ELISA and HLA-DSA by SAB (Luminex) at both the pre- and post-KT time points. RESULTS: The median AT1Rab level was 9.13 U (interquartile range 5.22-14.33). After a mean follow-up period of 3.55 years, 48 patients were found to harbour de novo HLA-DSAs. The presence of AT1Rabs [hazard ratio (HR) 1.009, 95% confidence interval (CI) 1.002-1.01, P = 0.010], male-to-male transplantation (HR 2.57, 95% CI 1.42-4.67, P = 0.002) and antecedent borderline changes or acute cellular rejection (ACR) (HR 2.47, 95% CI 1.29-4.75, P = 0.006) were significantly associated with de novo DSA detection. A dose-dependent association between AT1Rab levels (<10 U, 10.1-16.9 U, 17-29.9 U and >30 U) and de novo DSA detection was observed (log-rank P = 0.0031). After multivariate analysis of AT1Rab levels (continuous variable), AT1Rabs >30 U, male-to-male transplantation, donor age, higher class I percentage of Panel Reactive Antibody and antecedent borderline changes or ACR remained as independent significant risk factors for the detection of de novo DSAs. CONCLUSIONS: The findings suggest that higher levels of pretransplant circulating antibodies against AT1R (>30 U) in kidney graft recipients constitute an independent risk factor for earlier de novo HLA-DSA detection during the posttransplant period.

Thrombotic microangiopathy and poor renal outcome in lupus patients with or without antiphospholipid syndrome.

OBJECTIVES: To assess the presence of acute thrombotic microangiopathy (aTMA) and chronic vascular lesions (cTMA) in lupus nephropathy, and to evaluate their association with extrarrenal lupus features, aPL positivity, antiphospholipid syndrome (APS) and renal survival. METHODS: We studied lupus patients with renal biopsy, ≥1 year of post-biopsy follow-up and at least two aCL (IgG-IgM), anti-ß2GP-I (IgG-IgM) and/or lupus anticoagulant (LAC) determinations. A blinded nephropathologist evaluated all biopsies. We retrospectively collected clinical, serological, treatment and renal survival data. We plotted survival curves and used Cox regression analysis. RESULTS: A total of 90 biopsies were included with a median disease duration 5.9 years and median follow-up 2.4 years. Eleven patients (12.2%) had cTMA and 3 (3%) aTMA. There was no difference in age, lupus duration, hypertension, drugs, APS, non-renal lupus features, low C3 or C4 aCL IgG, anti-ß2GP1-IgG or IgM and LAC between cTMA and non-cTMA groups. The cTMA group had aCL-IgM less frequently (27% vs. 66%, p=0.02), more class IV nephropathy (100% vs. 40%, p=0.01), higher activity index scores (7.5 vs. 2, p=0.03) and a tendency to need chronic dialysis (54.5% vs. 24% p=0.06). At four years of follow-up, 28% of the cTMA group and 62% of the non-cTMA group were free of dialysis (log rank p=0.03). cTMA was associated with chronic dialysis (RR 2.9, CI 95% 1.1-8.1, p=0.03). CONCLUSIONS: cTMA conferred a poor renal outcome. We found a low frequency of TMA that was not associated with with APL positivity or APS, suggesting that other factors hitherto not studied are involved in its pathogenesis.

Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.

Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na(+)Cl(-) cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K(+) secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4(-/-)). WNK4 mRNA and protein expression were absent in WNK4(-/-) mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4(+/+) but not WNK4(-/-) mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K(+) diet, was impaired in WNK4(-/-) mice.

Intra-renal transfection of heat shock protein 90 alpha or beta (Hsp90α or Hsp90ß) protects against ischemia/reperfusion injury.

BACKGROUND: We previously reported that radicicol (Hsp90 inhibitor) induced a reduction in the renal blood flow and glomerular filtration rate, in part due to a reduction in urinary NO2/NO3 excretion, suggesting that Hsp90 regulates renal vascular tone in physiological conditions. However, there is a lack of information concerning Hsp90α or Hsp90ß role on eNOS activity and their association with acute kidney injury (AKI) characterized by an inadequate NO production. This study evaluated the effects of Hsp90α or Hsp90ß intra-renal transfection under ischemia/reperfusion (IR) injury. METHODS: Uninephrectomized (Nx) rats were intra-renally transfected through injections with Hsp90α or Hsp90ß cloned into pcDNA3.1(+) or empty vector (EV) at 48 h before inducing IR, as indicated in the following groups: (i) Nx+sham, (ii) Nx+IR, (iii) Nx+IR+EV, (iv) Nx+IR+Hsp90α and (v) Nx+IR+Hsp90ß. After 24 h, physiological, histopathological, biochemical and molecular studies were performed. RESULTS: IR-induced renal dysfunction, structural injury, tubular proliferation, the elevation of urinary Hsp72 and the reduction of urinary NO2/NO3 excretion. These alterations were associated with reduced eNOS-Hsp90 coupling and changes in the eNOS phosphorylation state mediated through a reduction in PKCα and increased Rho kinase expression. In contrast, intra-renal transfection of Hsp90α or Hsp90ß prevented IR injury that was associated with the restoration of eNOS-Hsp90 coupling, eNOS activating phosphorylation and PKCα and Rho kinase levels. CONCLUSIONS: Here we showed that eNOS-Hsp90 uncoupling plays a critical role in promoting NO reduction during IR. This effect was effectively reversed through Hsp90α or Hsp90ß intra-renal transfection, suggesting their implication in regulating NO/eNOS pathway and the renal vascular tone.

Exostosin-1/exostosin-2 expression and favorable kidney outcomes in lupus nephritis: a retrospective cohort study.

INTRODUCTION/OBJECTIVES: The heterodimer exostosin-1/exostosin-2 (EXO-1/2) is a novel antigen observed in membranous nephropathy associated with systemic lupus erythematosus. This study aimed to evaluate the association between EXO-1/2 positivity in kidney biopsy and kidney outcomes. METHODS: The kidney biopsy tissue from 50 class 5 lupus nephritis (LN) and 55 mixed class 3/4 + 5 LN patients was stained for EXO-1/2. Baseline clinical and histological characteristics were compared between EXO-1/2 positive and EXO-1/2 negative patients. Time-to-event analyses were performed to compare rates of response to therapy, kidney flares, and progression to a 40% decline of the glomerular filtration rate (eGFR), doubling of serum creatinine, and kidney failure. RESULTS: Fourteen out of 50 (28%) of class 5 and 5 out of 55 (9%) of mixed class 3/4 + 5 LN stained positive for EXO-1/2. Patients with class 5 LN and EXO-1/2 positive stain were younger, with better kidney function at presentation, and lower scarring in the kidney biopsy analysis. Over a median follow-up of 100 months, patients with positive EXO-1/2 staining had significantly lower rates of progression in the full cohort. When analyzed separately in class 5 and mixed class LN subgroups, there were significantly lower rates of progression to a 40% decline of the eGFR and non-statistically significant trends for doubling of serum creatinine and kidney failure. CONCLUSION: EXO-1/2 is a novel antigen detected in class 5 LN and associated with a good prognosis of kidney function. The incorporation of EXO-1/2 staining in clinical practice can potentially modify the management of LN due to its prognostic implications. Key Points • Exostosin-1/exostosin-2 antigen has been found in cases of membranous nephropathy associated with autoimmune diseases such as systemic lupus erythematosus. • Exostosin-1/exostosin-2 staining in the kidney biopsy of class 5 or mixed class 3/4 + 5 lupus nephritis is associated with a good long-term prognosis of kidney function. • The incorporation of exostosin-1/exostosin-2 staining into clinical practice can potentially modify management due to its prognostic implications.