Background
Oxford classification of Immunoglobulin A Nephropathy (IgAN) identifies four pathological features as predictors of renal outcome (MEST‐score): mesangial proliferation (M); endocapillary ...proliferation (E); segmental glomerulosclerosis (S); tubular atrophy/interstitial fibrosis (T). In particular extracapillary proliferation (Ex) was not considered as an independent histological variable predicting renal outcome. Recently the VALIGA study provided a validation of the Oxford classification in a large European cohort of IgAN patients and re‐stated that Ex is not associated with a worse renal prognosis. We propose a retrospective study to evaluate the predictive value of the MEST‐score in a multi‐centre, single region group of patients from central Italy and in addition, to investigate Ex as a marker predicting renal outcome.
Methods
One hundred and seven patients were enrolled in this study. Clinical data of each patient were available at diagnosis and follow‐up. The median age at diagnosis was 36.7 years; 72% of the patients were males. Histological parameters were those included in the MEST‐score of the Oxford classification; in addition, Ex was also assessed.
Results
Multiple linear regression models for survey were used. Statistical analysis showed a correlation between the progression of renal decline, in terms of estimated glomerular filtration rate (slope eGFR), and M, S, T. Differently from Oxford and VALIGA studies, no correlation was found with E, while Ex correlated with a decline of eGFR.
Conclusions
Our results suggest that Ex represents an additional independent variable associated with a faster decline of renal function in IgAN.
Summary at a Glance
In this manuscript, the authors evaluated the predictive value of the Oxford classification of IgA nephropathy in a multi‐centre, single region group of patients from central Italy and showed that extracapillary proliferation was an independent predictive factor of IgA nephropathy.
Abstract
Background and Aims
ADPKD is the most common form of inherited renal disease worldwide. ADPKD care has advanced over the past decade by the identification of several clinical/genetic risk ...factors of progression and approval of first disease-modifying drug. Further clinical outcomes research is needed to improve patient-centered clinical care; in addition new disease-modifying therapies are in pipeline, requiring a growing need for patient enrolment in clinical trials. To advance these goals, the Italian Society of Nephrology, supported by the Italian PKD Foundation (AIRP) established in 2020 the creation of a National web-based ADPKD Registry. Here we present the design of this Registry and the preliminary results.
Method
Adult patients with clinical or genetically confirmed diagnosis of ADPKD have been enrolled in the Registry, hosted by a secure online platform including both a clinical and genetic database. Databases have modular design collecting clinical features, including demographic data, type of diagnosis, e-GFR at onset and at time of first and last nephrological referral, age at onset of hypertension (HTN) and major urological complications (UC), Total Kidney Volume (hTKV) and Mayo Imaging Classification of ADPKD, age at ESRD, use of aspecific renal-protective and disease-modifying drugs, additional risk factors for CKD progression (smoke, diabetes, NSAID), extra-renal manifestations. Genetic data collected include type of PKD1/2 variant with ACMG classification and pathogenic prediction tools, testing method, results of segregation analysis. Statistics included estimation of eGFR slope using linear-mixed modelling.
Results
By January 2023, the Registry had recruited 985 ADPKD patients across 21 Italian Nephrology Unit; 513 (52,1%) were females; 967 (98,2%) Caucasians. Familiar history of ADPKD was reported in 738 patients (79%). All CKD stages were represented and 105 (14,1%) patients reached ESRD (median age 57y ± 11,5). hTKV was available for 353 (35,9%) patients, with a median value of 1100 ± 996 ml/m; a Mayo class of 1C or higher was found in 221 (70,4%). PROPKD score was evaluated in 162 patients, and in 50% of them it was associated with low risk of progression. A total of 191 (21,6%) were receiving Tolvaptan. Demographic and clinical characteristics are summarized in Table 1.
Genetic testing was performed in 288 patients; 111 (38,5%) had PKD1 truncating (T) variants; 67 (23,3%) PKD1 non truncating variants; 69 (24%) PKD2 variants. In 41 patients (14,2%) no pathogenic variants were detected.
In our cohort deterioration of renal function over time, estimated using eGFR slope was significantly associated with Mayo Imaging classes, high-medium PROPKD score, PKD1-T variant, HTN onset before 35 yo (Figure) and early UC (−2,3 vs. −1,9 ml/min/1.73m2/y, p = 0.014).
Conclusion
The Italian ADPKD National Registry is an important research tool collecting clinical and genetic information. Our preliminary data confirm that in the Italian population genotype, early onset HTN or UC, Mayo Imaging classification and PROPKD score are able to predict deterioration of GFR in ADPKD. The future empowerment of the Registry will provide a comprehensive description of clinical features and genetic variants related to ADPKD in a large cohort of Italian patients, enabling us to better understand genotype-phenotype correlation. Furthermore, the Registry could be an opportunity to identify patients suitable for future clinical trials or observational studies concerning specific aspects of the disease.
Abstract
Background and Aims
The natural history of ADPKD has been defined in numerous studies in various countries and in various genetic and environmental contexts but the problem has not yet been ...studied in sufficiently large studies in the Italian population. We have studied the evolution of ADPKD in a cohort of 445 incident patients enrolled in a time span between 2012 and 2016 in 28 nephrological centers in 3 regions of central Italy. The main demographic and clinical characteristics of this cohort are reported below.
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Method
The analysis was carried out on a sample of 296 patients with at least 2 creatinine measurements prior to ESKD and with eGFR at onset ≥45 ml/min/1.73m2. The median follow-up was 15 years (range 1-42 years). The analysis of the data was carried out with the Joint model, an approach that allows the simultaneous modeling of longitudinal (repeated over time) and time to event ESKD or GFR<45 ml/min/1.73m2 data. This approach produces two sub-models: a longitudinal model (mixed linear model, sub-model A in the table) and a time to event model (Cox model, survival sub-model B in the Table). The two models are mutually associated through an analytical structure that quantifies the relationship between the variables of interest.
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Results
The average eGFR decline in the entire population was -2.13 ml/min/1.73m2/year. In males the decline in GFR was significantly higher than in females (M: -2.63 ml/min/1.73m2; in F -1.74 ml/min/1.73m2/year, p <0.005) while it was not significant differences are observed for the different age groups considered separately in the two sexes (p = 0.158 in the M; p = 0.625 in the F).
In the longitudinal model the age at diagnosis >30 years and the presence of hypertension were significantly associated with an accelerated decline in GFR and patients older than 50 years exhibited a reduction by 35 ml/min/1.73m2 greater than those younger than 30 years. In the survival model the GFR trend and sex were associated with the risk of renal survival. For each incremental baseline unit of GFR the risk for ESKD decreased by 16% (HR: 0.84) and in females the risk was about one third compared to males (HR: 0.31).
Conclusion
This study, the first to apply the joint model in the analysis of the evolution of renal function in ADPKD and the first in a sizeable cohort in Italy, provides important information on the progression of polycystic kidney disease in an incident series of Italian patients with ADPKD.
Abstract
Background and Aims
In recent years, treatment of ADPKD (Autosomal Dominant Polycystic Kidney of the Adult) has been based on the antisecretive and antiproliferative effect of several drugs. ...Tolvaptan, a vasopressin receptor antagonist, has been shown to slow disease progression in the face of side effects such as aquaresis and liver damage. Currently, the drug's reimbursability is allowed in patients aged up to 55 years, CKD 2-4 (GFR ≥ 25 ml/min) with evidence of rapid disease progression.
Method
We report the experience with Tolvaptan in 62 patients with ADPKD who were recruited from 11 Nephrology Units in Lazio (Italy).
Baseline characteristics of patients are reported in Table 1.
Renal volume was evaluated by MRI (26 patients), CT scan (3 patients), or ultrasonography (28 patients).
Rapid progression’s criteria were the following: Mayo Clinic classification, PRO-PKD score and the annual loss of GFR. Mean duration of Tolvaptan’s treatment was 522 days (range 56-867).
The Tolvaptan dosage used at the beginning of therapy was 60 mg/day in 95% of patients; at the end of follow-up, 37% were still taking 60 mg/day, while 38.7% were taking 90 mg/day and 16.1% were taking 120 mg/day.
Results
Median diuresis was 5-6 liters over 24 hours. A mean reduction in GFR of 12.5% (which was maintained for the next 12 months) was observed after initiation of therapy as a likely effect of tubulo-glomerular feedback.
Monthly blood tests were performed to monitor side effects (hyper/hyponatremia, increased bilirubin and/or transaminases, etc.).
Therapy was withdrawn by 2 patients (3.2%) due to aquaresis, while it was discontinued in 3 patients (4.8%) according to clinicians’ decision due to hepatic damage (3-fold increase in transaminases and/or bilirubin normal values). No significant alteration in natremia was observed in any patient. An increase in CK was observed in one patient, leading to momentary discontinuation of therapy. One patient withdraw therapy because of CKD’s progression to stage 5 after 2 years of therapy.
Conclusion
Results of this observational study show that Tolvaptan therapy was well tolerated and the incidence of liver damage was superimposed on that described in the literature.
It will be necessary to continue clinical observation over the time and apply Tolvaptan’s therapy to a larger population in order to assess its effects on disease progression.
Pregnancy on dialysis is increasingly being reported. This study evaluates the behavioural profile of the children of mothers on dialysis and the parental stress their mothers undergo when compared ...with a group of mothers affected by a different chronic disease (microcythaemia) and a group of healthy control mothers.
Between 2000 and 2012, 23 on-dialysis mothers gave birth to 24 live-born children in Italy (23 pregnancies, 1 twin pregnancy, one of the twins deceased soon after delivery); of these, 16 mothers and 1 father (whose wife died before the inquiry) were included in the study (1 mother had died and the father was unavailable; 2 were not asked to participate because their children had died and 3 were unavailable; children: median age: 8.5, min-max: 2-13 years). Twenty-three mothers affected by transfusion-dependent microcythaemia or drepanocitosis (31 pregnancies, 32 children) and 35 healthy mothers (35 pregnancies, 35 children; median age of the children: 7, min-max: 1-13 years) were recruited as controls. All filled in the validated questionnaires: 'Child Behaviour Checklist' (CBCL) and the 'Parental Stress Index-Short Form' (PSI-SF).
The results of the CBCL questionnaire were similar for mothers on dialysis and healthy controls except for pervasive developmental problems, which were significantly higher in the dialysis group, while microcythaemia mothers reported higher emotional and behavioural problems in their children in 8 CBCL sub-scales. Two/16 children in the dialysis and 3/32 in the microcythaemia group had pathological profiles, as assessed by T-scores (p: ns). PSI-SF indicated a normal degree of parental stress in microcythaemia subjects and healthy controls, while mothers on dialysis declared significantly lower stress, suggesting a defensive response in order to minimize problems, stress or negativity in their relationship with their child.
According to the present analysis, the emotional and behavioural outcome is normal in most of the children from on-dialysis mothers. A 'positive defence' in the dialysis mothers should be kept in mind when tailoring psychological support for this medical miracle.
ADPKD treatment: Tolvaptan and Octreotide Galliani, Marco; Chicca, Silvana; Vitaliano, Elio ...
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia,
2019-Dec-09, Letnik:
36, Številka:
6
Journal Article
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent monogenic hereditary disease as well as the most studied inherited kidney disease. Two drugs have recently been authorized ...that can slow down the progression of the disease: Tolvaptan (vasopressin receptor antagonist) and Octreotide-LAR (long-acting somatostatin analogue); they both are able to reduce the activity of cyclic adenosine monophosphate (cAMP) and therefore have anti-proliferative and anti-secretory effects. This review analyzes the main trials published to date demonstrating the effects on disease progression in patients with ADPKD and illustrates the indications for identifying subjects eligible for therapy.
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