Atypical Anti-Glomerular Basement Membrane Nephritis: A Case Series From the French Nephropathology Group.

RATIONALE & OBJECTIVE: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized by a bright linear immunoglobulin staining along the GBM by immunofluorescence without a diffuse crescentic glomerulonephritis nor serum anti-GBM antibodies by conventional enzyme-linked immunosorbent assay (ELISA). We characterized a series of patients with atypical anti-GBM disease. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients identified by the French Nephropathology Group as having atypical anti-GBM nephritis between 2003 and 2022. FINDINGS: Among 38 potential cases, 25 were included, of whom 14 (56%) were female and 23 (92%) had hematuria. The median serum creatinine at diagnosis was 150 (IQR, 102-203) µmol/L and median urine protein-creatinine ratio (UPCR) was 2.4 (IQR, 1.3-5.2) g/g. Nine patients (36%) had endocapillary proliferative glomerulonephritis (GN), 4 (16%) had mesangial proliferative GN, 4 (16%) had membranoproliferative GN, 2 (8%) had pure and focal crescentic GN, 1 (4%) had focal segmental glomerulosclerosis, and 5 had glomeruli that were unremarkable on histopathology. Nine patients (36%) had crescents, involving a median of 9% of glomeruli. Bright linear staining for IgG was seen in 22 cases (88%) and for IgA in 3 cases (12%). The 9 patients (38%) who had a monotypic staining pattern tended to be older with less proteinuria and rarely had crescents. Kidney survival rate at 1 year was 83% and did not appear to be associated with the light chain restriction. LIMITATIONS: Retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Compared with typical anti-GBM disease, atypical anti-GBM nephritis frequently presents with an endocapillary or mesangial proliferative glomerulonephritis pattern and appears to have a slower disease progression. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes. PLAIN-LANGUAGE SUMMARY: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized histologically by bright linear immunoglobulin staining along the GBM without diffuse crescentic glomerulonephritis or circulating anti-GBM antibodies. We report a case series of 25 atypical cases of anti-GBM nephritis in collaboration with the French Nephropathology Group. Compared with typical anti-GBM disease, we observed a slower disease progression. Patients frequently presented with heavy proteinuria and commonly had evidence of endocapillary or mesangial proliferative glomerulonephritis. About half of the patients displayed a monotypic immune staining pattern; they tended to be older, with less proteinuria, and commonly without glomerular crescents in biopsy specimens. No concomitant circulating monoclonal gammopathy was detected. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes.

Oxalate nephropathy after pancreaticoduodenectomy: a case report.

A 75-year-old male developed acute kidney injury KDIGO stage 3 a few weeks after Whipple surgery was performed for a distal cholangiocarcinoma. Kidney biopsy revealed oxalate nephropathy. This was attributed to post-Whipple malabsorption, poor compliance with pancreatic enzyme replacement therapy, and daily intake of vitamin C supplements. Pancreatic enzyme replacement therapy was resumed and calcium carbonate initiated, with an improvement in glomerular filtration rate. Unfortunately, due to oncological progression, best supportive care was initiated.We review the pathophysiology and conditions predisposing to secondary hyperoxaluria and oxalate nephropathy. This diagnosis should be considered among the main causes of acute kidney injury following pancreatectomy, with important therapeutic implications.

Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

Severe parental phenotype associates with hypertension in children with ADPKD.

BACKGROUND: Early detection of hypertension in children with autosomal polycystic kidney disease (ADPKD) may be beneficial, but screening children at risk of ADPKD remains controversial. We investigated determinants of hypertension in children with ADPKD to help identify a subgroup of children at risk of ADPKD for whom screening for the disease and/or its complications would be more relevant. METHODS: In a retrospective study including consecutive children with ADPKD aged 5-18 years and followed at Saint-Luc Hospital Brussels between 2006 and 2020, we investigated the potential association between genotype, clinical characteristics and parental phenotype, and presence of hypertension. Hypertension was defined as blood pressure > P95 during 24-h ambulatory monitoring or anti-hypertensive therapy use. Parental phenotype was considered severe based on age at kidney failure, Mayo Clinic Imaging Classification and rate of eGFR decline. RESULTS: The study enrolled 55 children with ADPKD (mean age 9.9 ± 2.2 years, 45% male), including 44 with a PKD1 mutation and 5 with no mutation identified. Nine (16%) children had hypertension. Hypertension in children was associated with parental phenotype severity (8/27 (30%) children with severe parental phenotype vs. 1/23 (4%) children with non-severe parental phenotype (p = 0.03)) and height-adjusted bilateral nephromegaly (6/9 (67%) children with bilateral nephromegaly vs. 3/44 (7%) children without bilateral nephromegaly (p < 0.001)). CONCLUSIONS: Severe parental phenotype is associated with higher prevalence of hypertension in children with ADPKD. Hence, children of parents with severe ADPKD phenotype may be those who will most benefit from screening of the disease and/or yearly BP measures. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review.

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

PKD1 mosaicism associated with severe renal, hepatic, and vascular phenotype.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in PKD1 or PKD2 genes. Mosaicism is characterized by a post-zygotic mutation resulting in the presence of two or more populations of cells with different genotypes in an individual. Mosaicism of PKD1, rarely identified by conventional Sanger sequencing, is more easily detected using next generation sequencing techniques (NGS). PKD1 mosaicism has classically been associated with either milder kidney disease, asymmetric kidney disease, and/or negative family history. We report the case of a patient presenting severe renal, hepatic, and vascular phenotype secondary to PKD1 mosaicism, with a surprisingly low percentage of mutant allele in the patient's kidney and liver tissue. We reviewed clinical presentations of reported cases of PKD1 mosaicism.

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

mTORC Pathway Activation and Effect of Sirolimus on Native Kidney Antiphospholipid Syndrome Nephropathy: A Case Report.

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.

Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis.

OBJECTIVES: In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. METHODS: Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. RESULTS: Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. CONCLUSION: Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.

Mechanisms of kidney disease in Sneddon's syndrome: Case report and literature review
.

Sneddon's syndrome is a rare, noninflammatory thrombotic vasculopathy characterized by the combination of livedo racemosa, recurrent stroke, and histopathological skin lesions of endarteritis obliterans. Although multiorgan involvement suggests its systemic nature, detailed pathological description of affected organs - including the kidney - is exceptional. We report a case of Sneddon's syndrome with chronic kidney disease, associated with features of endarteritis obliterans in the skin and the kidney. The clinical presentation of our patient is compared to previously reported cases of Sneddon's syndrome with biopsy-proven kidney disease. We also discuss the differential diagnosis, pathophysiological mechanisms, relationship with antiphospholipid syndrome, and management of patients with Sneddon's syndrome and kidney disease. This clinical observation supports the systemic nature of Sneddon's syndrome and provides insights into the mechanisms by which this rare but probably underdiagnosed disease alters kidney function.
.

Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis.

OBJECTIVES: Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN. METHODS: We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples. RESULTS: A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement. CONCLUSION: Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

TINU-associated Fanconi syndrome: a case report and review of literature.

BACKGROUND: Tubulo-interstitial Nephritis and Uveitis (TINU) syndrome is a rare oculo-renal inflammatory disease. Renal tubular defects are usually found, but full proximal tubular abnormalities have rarely been described. CASE PRESENTATION: We report the case of a 55-year old woman, native from Morocco, presenting with bilateral, non-granulomatous, anterior uveitis, mild renal insufficiency, leucocyturia and glycosuria. Further work-up showed hypophosphatemia and hyperphosphaturia, hypouricemia and hyperuricosuria, and hyper aminoaciduria, consistent with Fanconi syndrome. A kidney biopsy was obtained and showed diffuse interstitial infiltrates with tubular necrosis. The patient improved after the initiation of a corticosteroid therapy, with tapering dose. CONCLUSIONS: We reviewed the literature and found nine similar cases. This association mostly occurs in adult woman, without current evidence for an ethnic predilection, unlike previously reported. The renal prognosis seems favorable after corticosteroid therapy, even in case of severe renal injury. Nonetheless mild tubular defects may persist after treatment or spontaneous remission.

Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome.

BACKGROUND: Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. METHODS: Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. RESULTS: HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. CONCLUSIONS: We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.

Gitelman syndrome and glomerular proteinuria: a link between loss of sodium-chloride cotransporter and podocyte dysfunction?

We report on a 27-year-old patient presenting with chronic hypokalaemia, inappropriate kaliuresis, hypomagnesaemia and alkalosis, associated with moderate proteinuria. Genetic analysis evidenced a homozygous mutation (p.Arg399Cys) in the SLC12A3 gene coding for the sodium-chloride cotransporter (NCC), confirming the diagnosis of Gitelman syndrome. Further genetic testing did not show any mutation in NPHS2. A renal biopsy was performed in view of the unusual association with proteinuria. Light microscopy showed hypertrophy of the juxtaglomerular apparatus and discrete mesangial thickening. In addition to possible focal segmental glomerular sclerosis lesions, electron microscopy showed extensive segments of variably thickened glomerular basement membrane (GBM), contrasting with segments of regular GBM of low range thickness, and effacement of podocyte foot processes. Of interest, alterations of the GBM were also observed in a Slc12a3 knock-out mouse model for Gitelman syndrome. These data suggest that the association between Gitelman syndrome and secondary changes of the GBM is probably not coincidental. Possible mechanisms include angiotensin II- or renin-induced podocyte lesions, as well as chronic hypokalaemia.

Monogenic Kidney Diseases in Kidney Transplantation.

Monogenic kidney diseases are involved in up to 15% of end-stage kidney diseases (ESKDs) in adults, and in 70 % of pediatric patients. When these disorders lead to kidney failure (KF), kidney transplantation (KT) is the preferred mode of replacement therapy. KT requires specific considerations depending on the nature of the genetic disorder, the potential oncological risk, the risk of recurrence in the graft, the possibility of specific complications of immunosuppression, and the issue of living donation. The availability of genetic testing should play an increasing role in the evaluation of patients or related living donor candidates before transplantation, relevant for the pretransplantation and posttransplantation management.