Corrigendum: Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

[This corrects the article DOI: 10.3389/ti.2023.11589.].

Corrigendum: Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

[This corrects the article DOI: 10.3389/ti.2023.11590.].

Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with >3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation.

Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with >3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community.

Renal toxicity caused by diethylene glycol: an overview.

Diethylene glycol (DEG) is nephrotoxic, potentially resulting in high morbidity and mortality. Its main nephrotoxic by-product is diglycolic acid (DGA). This narrative overview summarizes selected literature with a focus on clinical findings, pathophysiology, diagnosis including morphological features of renal biopsies, and management. The kidney injury in DEG poisoning is secondary to proximal tubular necrosis caused by DGA. Marked vacuolization and edema of epithelial cells obstruct the lumen, reducing urine flow and, consequently, resulting in anuria and uremia. The clinical alterations due to DEG poisoning are dose-dependent. Patients may present with gastrointestinal symptoms and anion gap metabolic acidosis, followed by renal failure, and, later, encephalopathy and neuropathy. Although this three-phase pattern has been described, signs and symptoms may be overlapping. Data about DEG intoxication is scarce. Sometimes the diagnosis is challenging. The management includes supportive care, gastric decontamination, correction of acid-base disorders, and hemodialysis. The understanding of the metabolic processes related to DEG poisoning may contribute to its management, preventing death, serious sequels, or irreversible lesions.

Baseline characteristics and evolution of Brazilian patients with atypical hemolytic uremic syndrome: first report of the Brazilian aHUS Registry.

Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease. Therefore, studies involving large samples are scarce, making registries powerful tools to evaluate cases. We present herein the first analysis of the Brazilian aHUS Registry (BRaHUS). Methods: Analysis of clinical, laboratory, genetic and treatment data from patients inserted in the BRaHUS, from 2017 to 2020, as an initiative of the Rare Diseases Committee of the Brazilian Society of Nephrology. Results: The cohort consisted of 75 patients (40 adults and 35 pediatric). There was a predominance of women (56%), median age at diagnosis of 20.7 years and a positive family history in 8% of cases. Renal involvement was observed in all cases and 37% had low C3 levels. In the <2 years of age group, males were predominant. Children presented lower levels of hemoglobin (P = .01) and platelets (P = .003), and higher levels of lactate dehydrogenase (LDH) (P = .004) than adults. Genetic analysis performed in 44% of patients revealed pathogenic variants in 66.6% of them, mainly in CFH and the CFHR1-3 deletion. Plasmapheresis was performed more often in adults (P = .005) and 97.3% of patients were treated with eculizumab and its earlier administration was associated with dialysis-free after 3 months (P = .08). Conclusions: The cohort of BRaHUS was predominantly composed of female young adults, with renal involvement in all cases. Pediatric patients had lower hemoglobin and platelet levels and higher LDH levels than adults, and the most common genetic variants were identified in CFH and the CFHR1-3 deletion with no preference of age, a peculiar pattern of Brazilian patients.

Costus spiralis extract restores kidney function in cisplatin-induced nephrotoxicity model: Ethnopharmacological use, chemical and toxicological investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus spiralis (Jacq.). Roscoe (Costaceae) is traditionally used in Brazil for the treatment of kidney diseases such as pyelonephritis, urethra inflammation, kidney stones, and inflammatory conditions. There are reports of its use by Brazilian Indians since the 17th century when it was known as "pacocatinga." Currently, the use of the Costus species in Brazil is widespread, which was evidenced by the inclusion of the genus in the Brazilian National List of Medicinal Plants of Interest to the Unified Health System (RENISUS). AIM OF THE STUDY: This study aimed to confirm the ethnopharmacological use of Costus spiralis in the treatment of kidney diseases, toxicity study using animal models, and the phytochemistry of the species. MATERIALS AND METHODS: The chemical profile of Costus spiralis leaves extract (CSLE) was obtained for the hydroethanolic extract by ultra-performance liquid chromatography coupled to a mass spectrometer and ultraviolet detector with diode array (UPLC-UV/DAD-ESI-MS). The acute oral toxicity of the extract was predicted using the neutral red uptake cytotoxicity assay. Wistar rats were used in a model in vivo for confirmation of acute oral toxicity (2000 mg/kg p.o. for 14 days.) and determination of the effect on a cisplatin-induced nephrotoxicity model. RESULTS: The analysis by UPLC-UV/DAD-ESI-MS showed that the chemical composition of the extract is mostly di-glycosylated flavones of apigenin. In the extract were identified the flavones vicenin II and schaftoside. The quantification of total flavonoids by spectrometry showed 0.880%. CSLE proved to be safe for acute oral administration (2000 mg/kg) with an IC50 value of 222.9 µg/mL and predicted oral toxic dose of 523.82 µg/mL in a neutral red uptake cytotoxicity assay. The absence of death allows the classification of the extract in class 5 according to OECD 423 guidelines and therefore it can be considered as a high acute safety product, which is highly relevant, considering the wide popular use of the species. In the cisplatin-induced nephrotoxicity model, C. spiralis extract (5, 15, and 30 mg/kg) significantly improved renal function, reversing almost completely the effects on plasma creatinine levels and creatinine clearance (p < 0.001). CONCLUSIONS: This study demonstrates that oral administration of Costus spiralis extract leaves is safe and effective in restoring the renal function in rats in a cisplatin-induced nephrotoxicity. It is suggested that the observed activity is related to the flavonoids present. This hypothesis should be confirmed, and the participation of other secondary metabolites should be investigated in the future.

Antibrush Border Antibody Disease: A Case Report and Literature Review.

Anti-brush border antibody (ABBA) disease, also called anti-low-density lipoprotein receptor-related protein 2 (anti-LRP2) nephropathy, occurs due to the formation of antibodies against brush border antigens of the renal proximal convoluted tubule. We report a case of ABBA disease in a male farmer in his 30s who presented with 2 years of polyuria, dysuria, nocturia, and urinary urgency. He described a history of long-term occupational exposure to pesticides and silica, evolving into possible pneumoconiosis, and prior pulmonary tuberculosis. At presentation, he had reduced kidney function (serum creatinine 3.6 mg/dL) with hyponatremia, hypokalemia, hypophosphatemia, a normal anion gap, metabolic acidosis, and respiratory acidosis, and 2.2 g/day of urine proteinuria. The kidney biopsy was consistent with ABBA, showing amorphous immune-deposits in the tubular basement membrane and strong positivity on indirect immunofluorescence in the brush border of the proximal tubules. The trigger for production of ABBA is still unknown, but it may be associated with chronic conditions such as pulmonary tuberculosis and occupational exposures such as silica and pesticides, as seen in the patient in this report. Most cases do not respond to immunosuppression, and the prognosis is poor.

Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E. LPG mainly affects Asian individuals, however occasional cases have also been described in Americans and Europeans. Herein we report two unrelated Brazilian patients with LPG in whom genetic analyses revealed the APOE-Osaka/Kurashiki variant. CASE PRESENTATION - CASE 1: A 29-year-old Caucasian male sought medical attention with complaints of face swelling and foamy urine for the last 3 months. He denied a family history of kidney disease, consanguinity, or Asian ancestry. His tests showed proteinuria of 12.5 g/24 h, hematuria, serum creatinine 0.94 mg/dL, albumin 2.3 g/dl, total cholesterol 284 mg/dL, LDL 200 mg/dL, triglycerides 175 mg/dL, and negative screening for secondary causes of glomerulopathy. A kidney biopsy revealed intraluminal, laminated deposits of hyaline material in glomerular capillaries consistent with lipoprotein thrombi. These findings were confirmed by electron microscopy, establishing the diagnosis of LPG. His apolipoprotein E serum level was 72 mg/dL and genetic analysis revealed the APOE pathogenic variant c.527G > C, p.Arg176Pro in heterozygosis, known as the Osaka/Kurashiki mutation and positioned nearby the LDL receptor binding site. CASE 2: A 34-year-old Caucasian man sought medical assessment for renal dysfunction and hypertension. He reported intermittent episodes of lower-limb edema for 3 years and a family history of kidney disease, but denied Asian ancestry. Laboratorial tests showed BUN 99 mg/dL, creatinine 10.7 mg/dL, total cholesterol 155 mg/dL, LDL 79 mg/dL, triglycerides 277 mg/dL, albumin 3.1 g/dL, proteinuria 2.7 g/24 h, and negative screening for secondary causes of glomerulopathy. His kidney biopsy was consistent with advanced chronic nephropathy secondary to LPG. A genetic analysis also revealed the Osaka/Kurashiki variant. He was transplanted a year ago, displaying no signs of disease relapse. CONCLUSION: We report two unrelated cases of Brazilian patients with a diagnosis of lipoprotein glomerulopathy whose genetic assessment identified the APOE-Osaka/Kurashiki pathogenic variant, previously only described in eastern Asians. While this is the second report of LPG in Latin America, the identification of two unrelated cases by our medical team raises the possibility that LPG may be less rare in this part of the world than currently thought, and should definitely be considered when nephrotic syndrome is associated with suggestive kidney biopsy findings.

Therapeutic potential of human induced pluripotent stem cells and renal progenitor cells in experimental chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD. METHODS: We transplanted mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPC and hiPSC cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology, and immunohistochemistry were evaluated 45 days post-surgery. RESULTS: We successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups. CONCLUSIONS: In conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seem to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improves clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.

Evidences of histologic thrombotic microangiopathy and the impact in renal outcomes of patients with IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is the most common primary glomerulopathy worldwide. According to the Oxford Classification, changes in the kidney vascular compartment are not related with worse outcomes. This paper aims to assess the impact of thrombotic microangiopathy (TMA) in the outcomes of Brazilian patients with IgAN. MATERIALS AND METHODS: Analysis of clinical data and kidney biopsy findings from patients with IgAN to assess the impact of TMA on renal outcomes. RESULTS: The majority of the 118 patients included were females (54.3%); mean age of 33 years (25;43); hypertension and hematuria were observed in 67.8% and 89.8%, respectively. Median creatinine: 1.45mg/dL; eGFR: 48.8ml/min/1.73m2; 24-hour proteinuria: 2.01g; low serum C3: 12.5%. Regarding to Oxford Classification: M1: 76.3%; E1: 35.6%; S1: 70.3%; T1/T2: 38.3%; C1/C2: 28.8%. Average follow-up: 65 months. Histologic evidence of TMA were detected in 21 (17.8%) patients and those ones presented more frequently hypertension (100% vs. 61%, p <0.0001), hematuria (100% vs 87.6%, p = 0.0001), worse creatinine levels (3.8 vs. 1.38 mg/dL, p = 0.0001), eGFR (18 vs. 60 ml/min/1.73m2), p = 0.0001), low serum C3 (28.5% vs. 10.4%, p = 0.003), lower hemoglobin levels (10.6 vs. 12.7g/dL, p<0.001) and platelet counts (207,000 vs. 267,000, p = 0.001). Biopsy findings of individuals with TMA revealed only greater proportions of E1 (68% vs. 32%, p = 0.002). Individuals with TMA were followed for less time (7 vs. 65 months, p<0.0001) since they progressed more frequently to chronic kidney disease (CKD) requiring kidney replacement therapy (KRT) (71.4% vs. 21,6%, p<0.0001). Male sex, T1/T2, and TMA were independently associated with progression to CKD-KRT. CONCLUSIONS: In this study patients with TMA had worse clinical manifestations and outcomes. In terms of histologic evidence, E1 distinguished patients with TMA from other patients. Further studies are necessary to analyze the impact of vascular lesions on IgAN prognosis.

Is CD44 in glomerular parietal epithelial cells a pathological marker of renal function deterioration in primary focal segmental glomerulosclerosis?

BACKGROUND: The search for risk factors for chronic kidney disease in children with focal segmental glomerulosclerosis (FSGS) is important in defining prognosis and individualized treatment. This study preliminarily investigated whether CD44 immunostaining in glomerular parietal epithelial cells (PECs) is a prognostic marker in pediatric FSGS. METHODS: In this retrospective study, 26 patients with FSGS, biopsied from 1985 to 2010, were evaluated. Immunohistochemistry for CD44 was performed in all cases. For analysis purposes, patients were grouped according to whether or not they were positive for CD44 in PECs. The primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) of 50% or more. RESULTS: Median follow-up was 6.9 years. Median renal survival was 14.5 years and probability of a 50% decline of eGRF was 30% in 10 years. Nine children exhibited the primary outcome and 7 developed end-stage renal disease (ESRD). In comparison with PEC CD44-negative patients (n = 18), PEC CD44-positive patients (n = 8) presented lower baseline eGFR (99 ± 41 versus 141 ± 44 ml/min/1.73 m2, p = 0.035) and a significant decline in eGFR (-38.6 ± 39.5 versus -5.6 ± 25.3 ml/min/1.73 m2/year, p = 0.018). No difference was observed in FSGS subtypes or other glomerular features. Presence of CD44 staining in PECs was significantly associated with the decline in baseline eGFR of 50% or more. Renal survival was significantly reduced in PEC CD44-positive patients (3.8 vs 14.6 years in C4d-negative, p < 0.05). CONCLUSION: Our preliminary findings indicate, for the first time, that positivity for CD44 in PECs seems to be a pathological marker of renal function deterioration in pediatric patients with FSGS.

Biodegradable seeds of holmium don't change neurological function after implant in brain of rats.

AIM: To evaluate the surgical procedure and parenchymal abnormalities related to implantation of ceramic seeds with holmium-165 in rats' brain. BACKGROUND: An effective method of cancer treatment is brachytherapy in which radioactive seeds are implanted in the tumor, generating a high local dose of ionizing radiation that can eliminate tumor cells while protecting the surrounding healthy tissue. Biodegradable Ho166-ceramic-seeds have been addressed recently. METHODS AND MATERIALS: The experiments in this study were approved by the Ethics Committee on Animal Use at the Federal University of Ouro Preto, protocol number 2012/034. Twenty-one adult Fischer rats were divided into Naive Group, Sham Group and Group for seed implants (ISH). Surgical procedures for implantation of biodegradable seeds were done and 30 days after the implant radiographic examination and biopsy of the brain were performed. Neurological assays were also accomplished to exclude any injury resulting from either surgery or implantation of the seeds. RESULTS: Radiographic examination confirmed the location of the seeds in the brain. Neurological assays showed animals with regular spontaneous activity. The histological analysis showed an increase of inflammatory cells in the brain of the ISH group. Electron microscopy evidenced cytoplasmic organelles to be unchanged. Biochemical analyzes indicate there was neither oxidative stress nor oxidative damage in the ISH brain. CAT activity showed no difference between the groups as well as lipid peroxidation measured by TBARS. CONCLUSIONS: The analysis of the data pointed out that the performed procedure is safe as no animal showed alterations of the neurological parameters and the seeds did not promote histological architectural changes in the brain tissue.

Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy.

BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN. METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50% or more. RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50% decline in eGFR was 13% over 10 years. Nine children exhibited the primary outcome and 4 developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n = 37), C4d-positive patients (n = 10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, p < 0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 ml/min/1.73 m2/year; p = 0.045), and more frequently achieved the primary outcome (50.0 vs 10.8%, p = 0.013), and ESRD (30.0 vs 2.7%, p = 0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, p < 0.001). CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.

Immunoglobulin a nephropathy: Pathological markers of renal survival in paediatric patients.

IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end-stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.