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.

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.

An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD.

Introduction: Accurate tools to inform individual prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Here, we report an artificial intelligence (AI)-generated method for routinely measuring total kidney volume (TKV). Methods: An ensemble U-net algorithm was created using the nnUNet approach. The training and internal cross-validation cohort consisted of all 1.5T magnetic resonance imaging (MRI) data acquired using 5 different MRI scanners (454 kidneys, 227 scans) in the CYSTic consortium, which was first manually segmented by a single human operator. As an independent validation cohort, we utilized 48 sequential clinical MRI scans with reference results of manual segmentation acquired by 6 individual analysts at a single center. The tool was then implemented for clinical use and its performance analyzed. Results: The training or internal validation cohort was younger (mean age 44.0 vs. 51.5 years) and the female-to-male ratio higher (1.2 vs. 0.94) compared to the clinical validation cohort. The majority of CYSTic patients had PKD1 mutations (79%) and typical disease (Mayo Imaging class 1, 86%). The median DICE score on the clinical validation data set between the algorithm and human analysts was 0.96 for left and right kidneys with a median TKV error of -1.8%. The time taken to manually segment kidneys in the CYSTic data set was 56 (±28) minutes, whereas manual corrections of the algorithm output took 8.5 (±9.2) minutes per scan. Conclusion: Our AI-based algorithm demonstrates performance comparable to manual segmentation. Its rapidity and precision in real-world clinical cases demonstrate its suitability for clinical application.

HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. METHODS: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. OUTCOMES: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. CONCLUSION: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

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.

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.

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.

Idiopathic nephrotic syndrome relapse following COVID-19 vaccination: a series of 25 cases.

Background: Several cases of idiopathic nephrotic syndrome (INS) relapse following the administration of coronavirus disease 2019 (COVID-19) vaccines have recently been reported, raising questions about the potential relationship between the immune response to COVID-19 vaccination and INS pathogenesis. Methods: We performed a retrospective multicentre survey describing the clinical and biological characteristics of patients presenting a relapse of INS after COVID-19 vaccination, with an assessment of outcome under treatment. Results: We identified 25 patients (16 men and 9 women) presenting a relapse within 1 month of a COVID-19 vaccine injection. The glomerular disease was of childhood onset in half of the patients and most patients (21/25) had received at least one immunosuppressive drug in addition to steroids for frequently relapsing or steroid-dependent nephrotic syndrome (NS). All patients were in a stable condition at the time of injection and 11 had no specific treatment. In five patients, the last relapse was reported >5 years before vaccine injection. The Pfizer-BioNTech (BNT162b2) vaccine was used in 80% of the patients. In 18 cases, INS relapse occurred after the first injection, a mean of 17.5 days after vaccination. A second injection was nevertheless administered in 14 of these patients. Five relapses occurred after administration of the second dose and two relapses after the administration of the third dose. All but one of the patients received steroids as first-line treatment, with an additional immunosuppressive agent in nine cases. During follow-up, complete remission was achieved in 21 patients, within 1 month in 17 cases. Only one patient had not achieved at least partial remission after 3 months of follow-up. Conclusions: This case series suggests that, in rare patients, COVID-19 vaccination may trigger INS relapse that is generally easy to control. These findings should encourage physicians to persuade their patients to complete the COVID-19 vaccination schedule.

Sino-Orbital Aspergillosis in a Kidney Transplant Recipient.

Sino-orbital aspergillosis is a rare and severe infection mostly seen in immunocompromised individuals in which diagnosis may be challenging with potentially life-threatening consequences. Infection usually starts in the paranasal sinuses with secondary spreading to the adjacent orbits. Here, we report the case of a kidney transplant recipient who presented with proven invasive sino-orbital aspergillosis resulting in irreversible loss of vision despite surgical management and antifungal therapy. We review the literature with a focus on clinical presentation, diagnostic tools, and recommended treatment in the context of kidney transplantation.

Crystalglobulin-Associated Kidney Disease: A Case Report and Literature Review.

The kidney is commonly involved in multiple myeloma and other disorders producing monoclonal immunoglobulins. Crystalglobulinemia is a rare condition characterized by spontaneous crystallization and deposition of monoclonal immunoglobulins within the microvasculature of the kidney and other organs, leading to inflammation, ischemia, and end-organ damage. The present case and literature review highlight the clinical spectrum, diagnostic challenges, management, and outcomes of this underrecognized complication of monoclonal gammopathy. Crystalglobulin-associated kidney disease should be suspected in patients with rapidly progressive kidney disease associated with hematuria, proteinuria, extrarenal lesions (ie, skin and joints), and monoclonal gammopathy. Kidney biopsy is critical to the diagnosis, which relies on the identification by ultrastructural analysis of electron-dense crystalline structures composed of a monoclonal immunoglobulin within the kidney microvasculature. Conventional immunofluorescence on frozen tissue frequently fails to detect monoclonal protein deposits, and pronase-based antigen retrieval on paraffin-embedded material or immunoelectron microscopy is required to unmask antigenic epitopes located within crystalline inclusions. Early intervention combining treatment of clonal cell proliferation and plasma exchanges is warranted to reduce the burden of this rare but dramatic complication of monoclonal gammopathy.

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.

Inhibition of sodium-glucose cotransporter 2 to slow the progression of chronic kidney disease.

Chronic kidney disease (CKD) is a major public health problem, increasing the risk of cardiovascular events and death and potentially leading to kidney failure. Novel drugs that slow the progression of this non-communicable disease are therefore urgently needed. Initially developed as glucose-lowering drugs, inhibitors of the sodium-glucose cotransporter 2 (SGLT2) drastically reduce the overall mortality and cardiovascular events and slow the progression of CKD. Kidney protection conferred by SGLT2 inhibitors is independent from the presence of diabetes, observed on top of renin-angiotensin system inhibition and consistent across a wide range of categories of glomerular filtration rate and albuminuria. The mechanisms through which SGLT2 inhibitors improve kidney outcomes are likely multifactorial. Inhibition of SGLT2 in the kidney proximal tubule results in natriuresis and glucosuria, with beneficial effects on metabolic control, blood pressure and body weight. In addition, SGLT2 inhibitors also improve intraglomerular hemodynamics, podocyte integrity, cell metabolism, and erythropoiesis and reduce hypoxia, oxidative stress, sympathetic nervous activity, inflammation and fibrosis. The major impact of SGLT2 inhibitors on kidney outcomes, along with the excellent safety profile of this new class of drugs, open novel avenues for the treatment of CKD in patients with and without diabetes.

Flank pain has a significant adverse impact on quality of life in ADPKD: the CYSTic-QoL study.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored. Methods: The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations. Results: The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain. Conclusion: ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain.

Limited Performance of Estimated Total Kidney Volume for Follow-up of ADPKD.

INTRODUCTION: Total kidney volume (TKV) is a qualified biomarker for disease progression in autosomal dominant polycystic kidney disease (ADPKD). Recent studies suggest that TKV estimated using ellipsoid formula correlates well with TKV measured by manual planimetry (gold standard). We investigated whether the ellipsoid formula could replace manual planimetry for follow-up of ADPKD patients. METHODS: Abdominal magnetic resonance images of patients with ADPKD performed between January 1, 2013, and June 31, 2019, in Saint-Luc Hospital, Brussels, were used. Two radiologists independently performed manual TKV (mTKV) measures and kidney axial measures necessary for estimating TKV (eTKV) using ellipsoid equation. Repeatability and reproducibility of axial measures, mTKV and eTKV, and agreement between mTKV and eTKV were assessed (Bland-Altman). Intraclass correlation coefficient (ICC) was used to assess agreement on Mayo Clinic Imaging Classification (MCIC) scores. RESULTS: 140 patients were included with mean age 45±13 years, estimated glomerular filtration rate (eGFR) 71±31 ml/min per 1.73 m2, and mTKV 1697±1538 ml. Repeatability and reproducibility were superior for mTKV versus eTKV (repeatability coefficient 2.4% vs. 14% in senior reader, and reproducibility coefficient 6.7% vs. 15%). Intertechnique reproducibility coefficient (95% confidence interval [CI]) was 19% (17%, 21%) in senior reader. Intertechnique agreement on derived MCIC scores was very good (ICC = 0.924 [0.884, 0.949]). CONCLUSION: TKV estimated using ellipsoid equation demonstrates poor repeatability and reproducibility compared with that of mTKV. Intertechnique agreement is also limited, even when measurements are performed by an experienced radiologist. Estimated TKV, however, accurately determines MCIC score.