In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: COL4A3 , COL4A4 , and COL4A5 encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome.

Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4. Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant “severity,” and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α3α4α5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.

We report the case of a seven-yr-old Caucasian girl who presented with progressive deterioration of renal function 13 months after HSCT for myelodysplastic syndrome. BK virus nephropathy was suspected and confirmed. After reduction of immunosuppression and treatment with IVIG, leflunomide, ciprofloxacin, and cidofovir, clearance of BK virus from blood was achieved, and further progression or renal failure was prevented. We believe that BK virus nephropathy should be considered in cases of renal function deterioration in all immunocompromised patients.

BackgroundAcute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN.Patients, design and settingWe collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate.ResultsThirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3–6 months later (p<0.001). After 3–6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3–6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil.ConclusionsDespite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3–6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.

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Background Chronic heart failure (CHF) affects approximately 26 million people worldwide. Nearly half of CHF patients develop heart failure with preserved ejection fraction (HFpEF), which is associated with myocardial hypertrophy and fibrosis. Although chronic inflammation was suggested as a critical factor contributing to fibrosis development, a new hypothesis of CHF pathogenesis suggested that altered gut microbiota contributes to leaky gut phenotype development and promotes a systemic inflammatory state. CHF patients have an altered gut microbiome. However, the effect of gut microbiota on fibrosis development in HFpEF patients is not yet known. Thus, this clinical study involving HFpEF patients (n = 47) and healthy volunteers (n = 43) intended to identify the correlations between microbiota changes and fibrosis markers in HFpEF patients. Methods We used 16S rRNA metagenomic sequencing to identify the microbiota changes in HFpEF patients. Myocardial fibrosis was quantified using T1 myocardial mapping by using cardiac magnetic resonance. We also assessed the levels of microbial metabolites—trimethylamin N-oxide (TMAO) and short-chain fatty acids (SCFAs)—and measured bloodstream miRNAs and cytokines. The gut microbiome functions were simulated using PICRUSt algorithm. Results The gut microbial communities of HFpEF patients were markedly different from those of healthy individuals. The abundance of Faecalibacterium, Prevotella, and Pseudomonas was significantly decreased, whereas that of Lachnoclostridium, Blautia, Haemophilus, Dorea, Peptococcus, and Tyzzerella was increased in HFpEF patients. These changes could have affected TMAO metabolism and SCFA production: TMAO and hydroxypyruvate levels were significantly higher, whereas isovaleric, methylbutyric, and propionic acids were significantly lower in HFpEF patients than in healthy individuals. The simulation with PICRUSt revealed that genes responsible for starch fermentation, SCFA production, and secondary bile acid metabolism were downregulated. Correlation analysis identified the involvement of microbiota changes and miRNAs 183-3p and 193b-3p. Conclusions Gut microbiome composition shifts in HFpEF patients impair biochemical functions, increase TMAO production, and decrease SCFA biosynthesis. The significant decrease in Faecalibacterium could have the most prominent effect on the host physiology. However, this needs to be determined by conducting experiments on animal models, because the mechanism by which the microbiota is associated with cardiac fibrosis development is not yet known.

Background: Transplant-associated thrombotic microangiopathy (TAM) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). There is some evidence of endothelial injury playing a significant role in TAM development. The efficacy of defibrotide was demonstrated for prophylaxis and treatment of another HSCT-associated endothelial damage syndrome-liver veno-occlusive disease. The data for defibrotide usage in TAM are limited. Case Description: A 9-year old boy underwent HSCT from a matched unrelated donor for monosomy seven-associated myelodysplastic syndrome treatment. A myeloablative preparative regimen and post-transplant immunosuppression with cyclophosphamide on days +3 and +4 and a combination of tacrolimus with mycophenolate mofetil from day +5 were used. From day +61, sustained fever with progressive neurologic impairment and no evidence of infection was observed. On day +68, the patient developed severe TAM with acute kidney injury requiring renal replacement therapy (RRT). Defibrotide therapy 25 mg/kg/day was administered for 7 days with resolution of TAM symptoms. It was followed by multiple hemorrhagic episodes-epistaxis, hemorrhagic cystitis, and renal hemorrhage, which are presumed to be the complications of defibrotide therapy. Conclusion:Defibrotide could be an effective therapy for TAM, but adequate doses, duration of therapy, and drug safety profile both for pediatric and adult patients need to be evaluated by randomized prospective studies.