The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 ...years inter quartile range 51-64 years, median age of transplant 13 years 9-20 years, baseline eGFR 36.5 23-47.5) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days 15-19 from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal ...management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7–10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience ...of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, ...and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID‐19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D‐dimer, and lack of C‐reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS‐CoV‐2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.
Findings from an Italian cohort of kidney transplant patients with COVID‐19 support heterogenous disease courses with higher risks of acute respiratory distress syndrome and death in the subgroup with severe disease.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background and Aims
Alport Syndrome (AS), the most common genetic glomerular disease, due to pathogenic variants in COL4A3-COL4A5 genes, includes three main forms: X-linked AS (XLAS, ...COL4A5); autosomal recessive (ARAS, biallelic pathogenic variants in COL4A3 or COL4A4); autosomal dominant (ADAS; heterozygous COL4A3 or COL4A4 variant).
An expanded phenotypic spectrum of AS has been described, including recent reports of multiple kidney cysts in affected patients. The aim of the study was to evaluate the prevalence and characteristics of renal cysts in a cohort of adult patients with AS.
Method
This retrospective study included subjects with AS followed at the Outpatient Nephrogenetic Clinic of Spedali Civili di Brescia (Italy) from 2002 to 2022 and with at least one available renal imaging study (Ultrasonography/CT scan). Genetic testing was performed by using a next generation sequencing multi-gene panel for kidney disease.
Cystic phenotype was defined as the presence of ≥3 cysts in each kidney. The prevalence of renal cystic phenotype was compared between patients (pts) with AS and a group of age- and eGFR-matched pts with sporadic IgA nephropathy (IgA-N). Demographic and clinical features were compared between pts with or without cystic phenotype. Logistic regression was performed to test whether sex, age, type of variant and eGFR (CKD-EPI formula) were independently associated with the cystic phenotype.
Results
A total of 96 AS pts were studied. The pattern of inheritance was AD in the majority of the cohort (56%), XL in 25%, AR in 2% and unknown in the remaining 17%. The cystic phenotype was observed in 36 pts (38%). When compared to a matched IgA-N cohort (n = 79), the cystic phenotype was significantly more common in AS (42% in AS; 19% in IgA-N; p = 0,002). The majority of AS pts with cystic phenotype showed normal/reduced sized kidneys and multiple cortical and/or parapelvic renal cysts. Increased total kidney volume, in keeping with primary cystic kidney disease, was observed in three patients; however, pathogenic variants in known cysto-genes were excluded. At the time of renal imaging, AS pts with cystic phenotype were older and had a more marked reduction in kidney function than their non-cystic counterparts (Table 1). When stratifying patients based on age or eGFR, the prevalence of the cystic phenotype gradually increased in parallel with older age and declining eGFR (Figure 1). Independent predictors of the cystic phenotype were age (HR 1.96 95% CI 1.31-2.94 per 10 years; p = 0.001) and eGFR (HR 0.75 95% CI 0.64-0.89 per 10 ml/min/1.73m2;p = 0.001). Serial longitudinal ultrasounds were available for 15 cystic pts, among whom the cystic phenotype was first observed from 40 years of age onwards, at an overall median age of 59 (IQR 46–65).
Conclusion
Our data show that multiple bilateral kidney cysts, with no increase in kidney size, are frequently found in AS patients. The cystic phenotype is associated with older age and eGFR decline, suggesting that it can reflect the severity and/or duration of CKD. However, the higher frequency of cystic phenotype in AS than IgAN, the role of the collagen IV α3 to α5 chains in the basement membranes in the glomerulus and distal tubule, and the occurrence of kidney cysts in a canine model of ADAS, support a possible pathogenetic link between type IV collagen mutations and cystogenesis in AS. Finding kidney cysts should not discourage from considering the diagnosis of AS, particularly in adult patients and in the presence of familial CKD. Future prospective studies will be needed to shed light on the prognostic implications of the cystic phenotype and possible genotype-phenotype associations.
Abstract
Background and Aims
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder characterized by progressive bilateral renal cysts development and ...extrarenal phenotype, i.e. liver and/or pancreatic cysts, intracranial aneurism, hernias, mitral valve prolapse and diverticulosis. More than 90% of patients harbour heterozygous pathogenic variant in PKD1 or PKD2 genes, rarely in other cystogenes (e.g. GANAB, DNAJB11, ALG8, ALG9). Recently Senum et al. demonstrated that monoallelic loss of function (LoF) IFT140 variants are an important cause of ADPKD-like disease distinguished by large renal cysts, few liver cysts and mostly mild renal failure. The aim of our study was to define prevalence and phenotype of IFT140-ADPKD in an Italian ADPKD cohort.
Methods
The study included ADPKD patients, evaluated in 2021 and 2022, at Outpatient Clinic of Genetic Kidney Diseases of Brescia, Italy, that underwent in-depth clinical, laboratory, and instrumental assessments. ADPKD was clinically diagnosed according to Pei modified criteria, in patients with age-specific ultrasound criteria and family history consistent with autosomal dominant inheritance. From January 2022, NGS genetic testing protocol for ADPKD has been updated with IFT140 gene, thus the ADPKD gene panel included: ALG8, ALG9, ANKS6, DNAJB11, GANAB, IFT140, LRP5, PARN, PKD1, PKD2, PRKCSH, SEC61A1, SEC63. The new protocol has been offered to patients evaluated since January 2022 and to all genetically unresolved patients evaluated in 2021. All patients performed also multiple ligation probe amplification (MPLA) analysis of PKD1 or PKD2.
Results
In 2021 and 2022 ADPKD genes testing has been performed in 129 patients. Pathogenic variants in PKD1 or PKD2 genes were detected in 110/129 patients (85%); among the negative cases (19/129, 15%), 3 patients (P1,P2,P3) resulted heterozygous carrier of LoF variants in IFT140 gene: p.Arg307*, p.Lys1275Argfs*23 and p.Arg834* respectively. Overall 2,3% of ADPKD patients harboured IFT140 pathogenic variant; considering unresolved cases only, the prevalence was 15.7% (3/19). Segregation analysis identified the LoF variant in 3 daughters of P1 and in a son of P2. The 3 probands were diagnosed with renal disease in adulthood from fourth to sixth decade. In P1 eGFR (CKD-EPI formula) slowly declined from 104 ml/min/1.73 at onset (43 year-old) to 74.6 ml/min/1.73 at age 55. In P2 eGFR at first evaluation was 38 ml/min/1.73 (68 year-old); at last follow-up 32.9 ml/min/1.73 (73 year-old). In P3 eGFR declined from 51.7 ml/min/1.73 (55 year-old) to 42 ml/min/1.73 at age 67. Renal imaging in P1 at and P2 disclosed increased total kidney volume (TKV 1042 and 5520 cc respectively), large cysts and absence of cystic liver disease. P3 had slightly increased kidneys (TKV 447cc) with large renal cysts and few liver cysts. Hypertension was present in 4 patients, all with adult-onset (46-60 years). Two patients had an early diagnosis of kidney stones (age 24 and 18). No macroscopic hematuria or cyst infections were reported. In accordance with an ADPKD-like disease form, P1 presented inguinal hernia. Imaging data are summarized in Figure 1.
Conclusion
In this Italian cohort, heterozygous LoF variants in IFT140 gene is confirmed to be the third most common genetic cause of ADPKD-spectrum disease, the prevalence being 2,3%. The major features are late onset hypertension, increased kidney volume due to large cysts and slow progressive renal failure. IFT140 gene must be included in diagnostic protocol of ADPKD patients to better define renal prognosis, therapy and familial screening.
Alport syndrome (AS) is the most common genetic glomerular disease caused by mutations that affect type IV collagen. However, the clinical characteristics and significance of AS with kidney cysts are ...not well defined. This study investigated the prevalence and clinical significance of cystic kidney phenotype in AS.
Retrospective cohort study.
One hundred-eight patients with AS and a comparison cohort of 79 patients with IgA nephropathy (IgAN). Clinical, genetic, and imaging data were collected from medical records.
Cystic kidney phenotype evaluated by ultrasonography and defined as the presence of≥3 cysts in each kidney; demographic characteristics and estimated glomerular filtration rate (eGFR) at disease onset.
Cystic kidney phenotype in the AS and IgAN cohorts; time to chronic kidney disease (CKD) stage 3b and longitudinal changes in eGFR in the AS cohort.
Logistic regression analysis to test independent strengths of associations of clinical/demographic features with the binary outcome of cystic phenotype. Survival analysis for the outcome of reaching CKD stage 3b and linear mixed models for changes in eGFR over time in the AS cohort.
We studied 108 patients with AS; 76 (70%) had a genetic diagnosis. Autosomal dominant AS was prevalent, accounting for 68% of patients with a genetic diagnosis. Cystic kidney phenotype was observed in 38% of patients with AS and was associated with normal-sized kidneys in all but 3 patients, who showed increased total kidney volume, mimicking autosomal dominant polycystic kidney disease. The prevalence of cystic kidney phenotype was significantly higher in patients with AS when compared with the group of patients with IgAN (42% vs 19%; P=0.002). Patients with the cystic kidney phenotype were older and had more marked reduction in eGFR than patients without cystic changes. Among patients with AS, the cystic phenotype was associated with older age and a faster decline eGFR.
Retrospective, single-center study.
Cystic kidney phenotype is a common finding in AS. The cystic kidney phenotype is a common finding in AS, suggesting a possible role in cystogenesis for the genetic variants that cause this disease.
Hematuria is the classic renal presentation of Alport syndrome (AS), a hereditary glomerulopathy caused by pathogenic variants of the COL4A3-5 genes. An atypical kidney cystic phenotype has been rarely reported in individuals with these variants. To determine the prevalence of kidney cysts, we performed abdominal ultrasonography in a large group of patients with AS and a comparison group of patients with another glomerular kidney disease, IgA nephropathy (IgAN). Multiple kidney cysts, usually with normal kidney volume, were found in 38% of patients with AS. A few patients’ kidney volumes were large enough to mimic a different hereditary cystic kidney disease, autosomal dominant polycystic kidney disease. The overall prevalence of kidney cysts in AS was more than double that observed in the well-matched comparison group with IgAN. These findings emphasize the high prevalence of cystic kidney phenotype in AS, suggesting a likely association between the genetic variants that cause this disease and the development of kidney cysts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background and Aims
Discordant affected relative-pairs are seen in ∼10% of families with Autosomal Dominant Polycystic Kidney Disease (ADPKD); <1% of patients exhibit very early onset (VEO) ...disease. Complex genotypes may result in renal disease variability beyond that predicted by the sole effect of a single PKD mutant allele, leading to the discovery of biallelic or digenic disease. Here we illustrate such complexity in 6 ADPKD pedigrees.
Method
Among our single-center ADPKD cohort (186 index patients), we selected pedigrees (P) in which marked familial phenotypic variability or severe and early onset disease was investigated by NGS and MLPA analysis of PKD1 and PKD2 genes and NGS analysis of other cystogenes. Segregation analysis by Sanger sequencing of PKD variants was performed in available affected and unaffected family members.
Results
In P1 and P2, the index cases (IC), presented with very early onset (VEO) disease characterized by prenatal/neonatal enlarged and hyperechogenic kidneys mimicking autosomal recessive polycystic kidney disease (ARPKD). In P1, with neonatal onset, the ADPKD affected father transmitted a PKD1 PT variant p.Gln4231*, whereas the mother, without renal cystic phenotype, transmitted a PKD1 hypomorphic variant p.Asp1332Asn.
In P2, the ADPKD-PKD2 mother’s pregnancy was complicated by Potter sequence. Parent’s PKHD1 gene analysis was negative. Two missense NT variants in PKD1/PKD2 genes were detected in the healthy father, respectively p.Gly1944Arg and p.Thr203Ile. Therefore, a complex PKD inheritance was supposed in the fetus. Fetus DNA was not available.
In P3 early onset (EO) ADPKD in two monozygous twins was underpinned by a PKD1 NT variant (p.Arg1951Gln) inherited by the ADPKD mild affected father and worsened by a de novo PKD1 truncating variant p.Arg2402*.
In P4 and P5 a digenic ADPKD (PKD1 +PKD2 and PKD1 +PKHD1) was diagnosed in severe ADPKD IC. In P4 the two most severely affected siblings carried a PKD2 T variant (p.Ala365fs) and a PKD1 NT variant p-Cys259Tyr.
In P5 the IC presented with EO ADPKD, a de novo splicing variant c.2097 + 5_+6insT in PKD1 gene was discovered but the phenotype was probably worsened by the presence of biallelic variant in a second cystogene PKHD1: one paternally inherited: p.Gly1712Arg and one maternally inherited: p.Asp3088Asn .
Elderly parents in P6 had mild ADPKD with bilateral few kidney cysts and preserved eGFR, whereas IC showed moderate/severe CKD due to ADPKD biallelic variants. The IC carried a homozygous PKD1 NT variant (p.Arg4154Cys): each mutant allele inherited from the mild ADPKD affected parents.
Conclusion
Our study illustrates the genetic complexity in an otherwise “simple” Mendelian disorder, providing insights into the genetic basis of severity of ADPKD cases and into ADPKD intrafamilial disease variability. In our pedigree all cases with more severe clinical picture in the family presented at least two PKD variants. In P5 we found for the first time an EO ADPKD due to both PKD1 and PKHD1 variants.
PKD1 and PKD2 sequence analysis together with cystic kidney disease gene panel analysis is recommended in those patients with discordant phenotype compared to family members. Molecular study of PKD patients is expected to be a good prognostic tool together with clinical and renal imaging data to better manage disease therapy, follow-up and reproductive issues.
Figure:
Background
Causative mutations in the GANAB gene have been described in only 14 families, 9 diagnosed with late-onset Autosomal Dominant Polycystic Kidney Disease (ADPKD) and 5 with Autosomal ...Dominant Polycystic Liver Disease (ADPLD).
Case
Diagnosis of ADPKD was made in a 45-year old man during screening for hernia repair. CT scan showed enlarged cystic kidneys, nephrolithiasis and normal-sized liver with multiple cysts. Hematuria, hypertension and aortic root dilatation were also documented. Renal function was normal. Molecular analysis of PKD genes disclosed a heterozygous p.R839W GANAB variant inherited from the mother. Both his elderly parents presented normal-sized bilateral cystic kidneys but normal renal function. The GANAB-ADPKD mother had no liver cysts. The father was screened for PKD-related genes and no variant was found.
Genetic analysis
We describe a new family with late-onset ADPKD due to the p.R839W GANAB variant, previously reported in a severe ADPLD patient, requiring liver transplantation.
Discussion
Since ADPKD-GANAB is an ultrarare, recently described disease, reporting further patients may help unraveling gene-related phenotype. In our patients the p.R839W GANAB variant was not related to severe ADPLD, as previously reported, but with mild ADPKD and a plethora of renal and extrarenal manifestations, usually described in PKD1/PKD2 patients. The evidence that the GANAB variant may cause both ADPKD and ADPLD of variable severity supports that renal and hepatic cystogenesis are the result of a common defective polycystin-1 pathway.
Graphic abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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