Atypical Polycystic Kidney Disease as defined by Imaging.

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P < 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P < 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P < 0.001), or progression to CKD stage 3 or stage 5 (P < 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD.

Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD.

BACKGROUND AND OBJECTIVES: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. RESULTS: Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. CONCLUSIONS: Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3.

Intrafamilial Variability of ADPKD.

INTRODUCTION: Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD. METHODS: The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients. RESULTS: Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types. CONCLUSION: Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD.

Prognostic Performance of Kidney Volume Measurement for Polycystic Kidney Disease: A Comparative Study of Ellipsoid vs. Manual Segmentation.

Total kidney volume (TKV) is a validated prognostic biomarker for risk assessment in autosomal dominant polycystic kidney disease (ADPKD). TKV by manual segmentation (MS) is the "gold standard" but is time-consuming and requires expertise. The purpose of this study was to compare TKV-based prognostic performance by ellipsoid (EL) vs. MS in a large cohort of patients. Cross-sectional study of 308 patients seen at a tertiary referral center; all had a standardized MRI with typical imaging of ADPKD. An experienced radiologist blinded to patient clinical results performed all TKV measurements by EL and MS. We assessed the agreement of TKV measurements by intraclass correlation(ICC) and Bland-Altman plot and also how the disagreement of the two methods impact the prognostic performance of the Mayo Clinic Imaging Classification (MCIC). We found a high ICC of TKV measurements (0.991, p < 0.001) between EL vs. MS; however, 5.5% of the cases displayed disagreement of TKV measurements >20%. We also found a high degree of agreement of the individual MCIC risk classes (i.e. 1A to 1E) with a Cohen's weighted-kappa of 0.89; but 42 cases (13.6%) were misclassified by EL with no misclassification spanning more than one risk class. The sensitivity and specificity of EL in distinguishing low-risk (1A-B) from high-risk (1C-E) MCIC prognostic grouping were 96.6% and 96.1%, respectively. Overall, we found an excellent agreement of TKV-based risk assessment between EL and MS. However, caution is warranted for patients with MCIC 1B and 1C, as misclassification can have therapeutic consequence.

Impact of Early Acute Kidney Injury on Management and Outcome in Patients With Acute Respiratory Distress Syndrome: A Secondary Analysis of a Multicenter Observational Study.

OBJECTIVES: To understand the impact of mild-moderate and severe acute kidney injury in patients with acute respiratory distress syndrome. DESIGN: Secondary analysis of the "Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure", an international prospective cohort study of patients with severe respiratory failure. SETTING: Four-hundred fifty-nine ICUs from 50 countries across five continents. SUBJECTS: Patients with a glomerular filtration rate greater than 60 mL/min/1.73 m prior to admission who fulfilled criteria of acute respiratory distress syndrome on day 1 and day 2 of acute hypoxemic respiratory failure. INTERVENTIONS: Patients were categorized based on worst serum creatinine or urine output into: 1) no acute kidney injury (serum creatinine < 132 µmol/L or urine output ≥ 0.5 mL/kg/hr), 2) mild-moderate acute kidney injury (serum creatinine 132-354 µmol/L or minimum urine output between 0.3 and 0.5mL/kg/hr), or 3) severe acute kidney injury (serum creatinine > 354 µmol/L or renal replacement therapy or minimum urine output < 0.3 mL/kg/hr). MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital mortality, whereas secondary outcomes included prevalence of acute kidney injury and characterization of acute respiratory distress syndrome risk factors and illness severity patterns, in patients with acute kidney injury versus no acute kidney injury. One-thousand nine-hundred seventy-four patients met inclusion criteria: 1,209 (61%) with no acute kidney injury, 468 (24%) with mild-moderate acute kidney injury, and 297 (15%) with severe acute kidney injury. The impact of acute kidney injury on the ventilatory management of patients with acute respiratory distress syndrome was relatively limited, with no differences in arterial CO2 tension or in tidal or minute ventilation between the groups. Hospital mortality increased from 31% in acute respiratory distress syndrome patients with no acute kidney injury to 50% in mild-moderate acute kidney injury (p ≤ 0.001 vs no acute kidney injury) and 58% in severe acute kidney injury (p ≤ 0.001 vs no acute kidney injury and mild-moderate acute kidney injury). In multivariate analyses, both mild-moderate (odds ratio, 1.61; 95% CI, 1.24-2.09; p < 0.001) and severe (odds ratio, 2.13; 95% CI, 1.55-2.94; p < 0.001) acute kidney injury were independently associated with mortality. CONCLUSIONS: The development of acute kidney injury, even when mild-moderate in severity, is associated with a substantial increase in mortality in patients with acute respiratory distress syndrome.

Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing.

BACKGROUND: Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population. METHODS: To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity. RESULTS: Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively. CONCLUSIONS: Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.

[Granulomatosis with polyangiitis (Wegener's granulomatosis)]. / Granulomatose avec polyangéite (maladie de Wegener).

Granulomatosis with polyangiitis (GPA), is the recently proposed, new alternative name for Wegener's granulomatosis. It defines a systemic small-vessels vasculitis, characterized by frequent involvement of upper and lower respiratory tract. The presence of cytoplasmic-type ANCA with anti-proteinase 3 specificity is observed in more than 90% of patients with GPA but is not mandatory for the definition of the disease, which is based on clinical criteria and presence of granulomas on the tissue biopsy. Necrotizing glomerulonephritis is observed in more than 50% of patients, and has important prognostic value, requiring urgent therapeutic intervention. Classical immunosuppressive schemes used in GPA combine high-dose corticosteroids and cyclophosphamide, but recent trials have shown that rituximab offers a similar efficacy with probably less cytotoxic side-effects. The best maintenance treatment is not yet defined, but the prevention of relapses remains the main therapeutic challenge in this vasculitis.

Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab.

BACKGROUND AND OBJECTIVES: Several different entities have recently been described among glomerular diseases associated with monoclonal IgG deposits. The aim of this study was to describe the distribution of the different pathologic subtypes of IgG-associated glomerulopathy and to evaluate the IgG isotype involved in these diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study including all patients with glomerular deposits of monoclonal IgG referred to three nephrology departments between 1980 and 2008. RESULTS: Twenty-six patients were included. Nephrotic syndrome was almost constantly associated with a renal dysfunction in 14 of 26 patients. The presence of M-spike was detected in only 30% of the patients, and an overt hematologic malignancy (myeloma, lymphoma) was identified in 9 of 26 patients. Patients were almost equally divided into two distinct histologic patterns: membranous nephropathy (MN) or membranoproliferative glomerulonephritis (MPGN). IgG3 deposits were identified in 80% of patients with MPGN, whereas IgG1 deposits were present in 64% of patients with MN. Ultrastructural study showed that immune deposits were nonorganized in most patients. Seven patients were treated with rituximab with excellent results: five of seven had a complete remission of the nephrotic syndrome and two of seven had a partial response. After a mean 24-month follow-up, only one patient experienced relapse of the nephropathy. CONCLUSIONS: GN with monoclonal Ig deposits can be associated with MPGN or MN, which are correlated with IgG3 and IgG1 isotypes, respectively. Rituximab appears to have a very favorable benefit-to-risk ratio for patients with no overt hematologic malignancy.

Excessive interleukin-15 transpresentation endows NKG2D+CD4+ T cells with innate-like capacity to lyse vascular endothelium in granulomatosis with polyangiitis (Wegener's).

OBJECTIVE: Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell-mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease. METHODS: We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age-matched controls. RESULTS: We observed circulating innate-like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX-associated molecule 1, and some killer cell Ig-like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin-15 (IL-15) transpresentation through increased expression of IL-15 receptor α (IL-15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain-related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC-independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors. CONCLUSION: Our results suggest that NK cell-like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL-15 as an important mediator in the progression of GPA toward generalized vasculitis. IL-15/IL-15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor-positive CD4+ T cells in selected GPA patients.

Severe renal failure in acute bacterial pyelonephritis: do not forget corticosteroids.

Acute renal failure (ARF) is a rare complication of acute pyelonephritis in adult immunocompetent patients. Recovery of renal function usually occurs if antibiotics are promptly initiated. However, long-term consequences of renal scarring due to acute pyelonephritis are probably underestimated, and some patients present with prolonged renal failure despite adequate antibiotic therapy. We report two cases of severe ARF complicating bacterial pyelonephritis successfully treated with corticosteroids in association with conventional antibiotics.