American Journal of Kidney Diseases最新文献

Rationale & objective: Monoallelic predicted loss-of-function (pLoF) variants in IFT140 have recently been associated with an autosomal dominant polycystic kidney disease (ADPKD)-like phenotype. This study enhanced the characterization of this phenotype.

Study design: Case series.

Setting & participants: Seventy-five among 2,797 European individuals with ADPKD-like phenotypes who underwent genetic testing that revealed pLoF IFT140-variants.

Findings: The 75 individuals (median age 56 years, 53.3% females) were from 61 families and were found to have 41 different monoallelic pLoF IFT140-variants. The majority of individuals presented with large, exophytic kidney cysts (median total kidney volume, 688mL [IQR, 201-4,139]), and 90.2% were classified using the Mayo Imaging Classification as Mayo Class 2A. Arterial hypertension was present in 50.7% of the individuals (median age at diagnosis, 59 years [IQR, 29-73]). Only 1 patient developed kidney failure (at age 69 years). A significant difference was observed in the age-adjusted estimated glomerular filtration rate (eGFR) between the male and female patients (P<0.001), and 56.3% of the individuals over the age of 60 years had an eGFR of<60mL/min/1.73m². The estimated genetic prevalence of monoallelic pLoF IFT140 variants was 19.76 (95% CI, 18.8-20.7) and 27.89 (95% CI, 23.8-31.9) per 10,000 in the Genome Aggregation Database and the 100,000 Genomes Project (100kG), respectively. Only cystic kidney disease (ICD-10 Q61) was associated with pLoF IFT140 variants (P = 2.9 × 10^-9, odds ratio = 5.6 (95% CI, 3.3-9.2) in 100kG.

Study limitations: Retrospective study; IFT140-related cystic kidney disease may not be diagnosed in younger patients or patients with milder forms.

Conclusions: Individuals with monoallelic IFT140 pLoF variants are likely to develop kidney cysts atypical of classic ADPKD and generally have a favorable kidney prognosis.

Plain-language summary: Monoallelic pathogenic variants in IFT140 have been linked to a spectrum of kidney disease clinically similar to autosomal dominant polycystic kidney disease (ADPKD). This article describes a case series of 75 individuals with ADPKD-IFT140. Affected individuals typically presented with an atypical imaging pattern, had fewer but larger kidney cysts compared with classic ADPKD, and rarely developed liver cysts. Although the kidney prognosis appeared better than in classic ADPKD, 56.3% of individuals over 60 years of age had stage 3 or more severe CKD. Individuals with ADPKD-IFT140 variants are likely to develop kidney cyst patterns atypical of ADPKD. Their kidney prognosis appears favorable.

Renal tubular acidoses (RTAs) are a subset of non-anion gap metabolic acidoses that result from complex disturbances in renal acid excretion. Net acid excretion is primarily accomplished through the reclamation of sodium bicarbonate and the buffering of secreted protons with ammonia or dibasic phosphate, all of which require a series of highly complex and coordinated processes along the renal tubule. Flaws in any of these components lead to the development of metabolic acidosis and/or a failure to compensate fully for other systemic acidoses. Identification and diagnosis of RTA can be challenging, and the consequences of untreated RTA can be life-threatening. The use of serum and urinary indices can help elucidate the kidney's capacity to respond to acidemia, characterize these disturbances further, and guide treatment.

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are inherited disorders that share many features such as kidney cysts, hypertension, urinary concentrating defects, and progressive chronic kidney disease. Underlying pathogenic mechanisms for both include cilia dysfunction and dysregulated intracellular signaling. ADPKD has been traditionally regarded as an adult-onset disease, whereas ARPKD has been classically described as an infantile or childhood condition. However, clinicians must recognize that both disorders can present across all age groups ranging from fetal life and infancy to childhood and adolescence, as well as adulthood. Here we highlight the points of overlap and distinct features for these disorders with respect to pathogenesis, diagnostic modalities (radiological and genetic), clinical assessment, and early therapeutic management. In particular, we consider key issues at two critical points for transition of care, i.e., fetal life to infancy and adolescence to adulthood. These timepoints are poorly covered in the extant literature. Therefore, we recommend guiding principles for transitions of clinical care at these critical junctures in the lifespan. While there is no cure for polycystic kidney disease (PKD), recent insights into pathogenic mechanisms have identified promising therapeutic targets that are currently being evaluated in a growing portfolio of clinical trials. We summarize the key findings from these largely adult-based trials and discuss the implications for designing child-focused studies. Finally, we look forward to the next horizon for childhood PKD, highlighting gaps in our current knowledge, and discussing future directions and strategies to attenuate the full burden of disease for children affected with PKD.