Autosomal Dominant Tubulointerstitial Disease Research Articles

#1061 Brucella infection in a patient with renal cystic disease and renal imaging changes before and after treatment: a case report

Abstract Background and Aims Brucellosis can affect nearly all systems. Genitourinary involvement is uncommon in patients with brucellosis, accounting for approximately 10% of cases. We diagnosed a rare case of renal cysts with brucellosis and reported renal imaging changes before and after treatment. Method A 38-year-old man was admitted to our hospital in September 2021 with complaints of elevated serum creatinine, proteinuria for more than 2 months, and intermittent fever for 2 weeks. In July 2020, the patient experienced fatigue, and a rash on all four extremities. He denied experiencing low back pain or joint swelling. Urine analysis revealed the following: BLD (+), Pro (+), 24-hour urine protein (24 h UP) 0.7 g; blood: Cr 11.88 mg/dL, UA 77.51 mg/dL, ALP 217 IU/L, and GGT 227 IU/L. MRI revealed multiple small punctate areas with short T1 signals in both kidneys and splenomegaly. Soon, he experienced persistent afternoon fever with a maximum temperature of 39.0°C, along with night sweats and left lumbar pain. There were no symptoms of cough, expectoration, or urinary tract irritation. The patient had diabetes mellitus and diabetic retinopathy. He has lived in the Inner Mongolia Autonomous Region. He denied having any contact with raw milk or mice. His father and sister had kidney disease and diabetes. In September 2021, the patient was admitted to our hospital. Urinalysis revealed BLD (-), Pro 0.3 g/L, and 24 hUP 1.39 g; blood: HGB 117 g/L, ALP 227 U/L, GGT 221 U/L, Cr 2.56 mg/dL, UA 88.79 mg/dL, and K 3.2 mEq/L. The infection indicators were as follows: the standard tube agglutination test (+) (Fig. 1), Brucella (+) in blood culture, a positive qualitative test for blood cryptococcal antigen and qualitative positive results for 6 Cryptococcus neoformans sequences in bronchoalveolar lavage fluid using next-generation sequencing. Ultrasound showed multiple cysts in both kidneys. It also showed uneven echogenicity in the left testis and visible lymph nodes in the left neck, bilateral axillae and groin. CT revealed cavitary nodules and ground-glass opacities in the right middle lobe, as well as splenomegaly. MRI revealed renal cysts (Fig. 2a, b, c) and abscesses (Fig. 2e, f, g). The patient was diagnosed with stage 3 chronic kidney disease (CKD), pulmonary cryptococcosis, and brucellosis associated with renal abscess, left orchitis, splenomegaly, multiple lymphadenopathies, rash, and hyperuricemia. Doxycycline, rifampicin, and fluconazole were administered. He had no fever, his low back pain had disappeared, and his rash were relieved. Results A reexamination after 2 months revealed the following: the urinalysis results revealed a BLD (-), Pro(-), and 24 hUP 0.15 g; blood: GGT 107 IU/L; ALP 72 IU/L; Cr 1.89 mg/dL; UA 0.22 mg/dL; and K 4.0 mEq/L. Ultrasound revealed a decrease in the size of the spleen. MRI revealed the liquefaction of renal abscesses. Brucella therapy has been found to be effective. Conclusion The patient was a young man who was infected with both Brucella and Cryptococcus. Although his hometown was in an area affected by an epidemic, his current residence was not affected. Namely, he was immunocompromised, which was associated with diabetes. After receiving anti-Brucella treatment, his symptoms disappeared, the renal abscess liquefied, but creatinine decreased to levels similar to those at onset without a decreasing trend. These findings suggest that the patient had underlying CKD that was not associated with Brucellosis. We believe that the CKD was diabetes and renal cysts. He had hyperuricemia, hypomagnesaemia, unexplained asymptomatic abnormal liver function, and mild proteinuria. Imaging indicated the presence of renal cysts. In addition to having diabetes, he had a family history of kidney disease and diabetes. We diagnosed the patient with CKD and as having autosomal dominant tubulointerstitial disease (ADTKD) associated with the HNF1B pathogenic gene mutation. This gene mutation is also rare in ADTKD patients. Genetic testing revealed that the causative genes include NM001303448. Potential causative genes included NM000128. The mutated genes mentioned above are not typical causative genes for HNF1B or other types of ADTKD.

#3320 GENETIC TESTING FOR MOLECULAR DIAGNOSIS OF NEPHROLITHIASIS AND NEPHROCALCINOSIS IN ADULT PATIENTS: A SINGLE-CENTER COHORT

Abstract Background and Aims Hereditary factors represent an important cause of nephrolithiasis which will generate stone disease in adult. Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) for a genetic mutation has become more accessible and the benefits are highlighted by an increasing number of publications. The aim of the paper was to study genetic screening for 36 NL and/or NC patients in order to identify the cases that can be confirmed by mutations in known kidney stone genes. Method Between 2020–2022 we included 35 adult patients with NL/NC with onset on pediatric age or in young adults, plus one of the following criteria: family history for NL/NC, indicative phenotype, recurrent NL. All the patients were diagnosed with NL and/or NC by ultrasound or computed tomography scan. Inform consent was signed and dated before blood samples and we performed genetic testing using nephrolithiasis panel (that include 45 genes) from 2 laboratories. In addition, we performed clinical assessment in a multidisciplinary team, underwent metabolic assessment, and caring out the genealogical tree. Results The study included 18 females and 17 males. The mean age of studied patients was 34.9 ± 10.3 years (range 18 – 54 years), although mean age of NL/NC diagnosis was 19.4 ± 12.0 years (range 0.5 – 34 years). 29 patients presented NL of any type, 12 patients presented both NL and NC, and 3 patients isolated NC. All the patients presented positive family history of NL/NC, 17 (48.5%) patients had pediatric age of onset, 17 (48.5%) patients presented indicative phenotype and 19 (54.2%) recurrent stone disease. Causative monogenic mutations were detected in 25 of 35 NL/NC. We identified 20 deleterious variants in 12 out of 45 analyzed genes. Genetic testing was positive with a definite diagnosis (had pathogenic variant) in 17 (48.6%) of cases, while 3 (8.6%) patients presented likely pathogenic variants, and 5 (14.3%) patients had variants of uncertain significance (VUS). In our cohort, the most common cause of kidney stone disease was cystine nephrolithiasis in 8 (22.8%) patients, followed by hereditary distal renal tubular acidosis in 4 patients, Dent disease in 3 patients, primary hyperoxaluria type 1 in 2 patients, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in 2 patients. Other causes of kidney stone disease included: renal hypouricemia type 1, hereditary hypophosphatemic rickets with hypercalciuria, primary mitochondrial disorders, autosomal dominant familial idiopathic hypercalciuria, Bartter syndrome type 3, and autosomal dominant tubulo-interstitial disease with hyperuricemia. Pathogenic mutations were detected in the following 5 dominant disease genes: SLC7A9 (4 patients), SLC4A1 (3 patients), ADCY10 (1 patient), HNF1B (2 patients), POLG (1 patient). Also, we identified pathogenic mutations in the following 7 recessive disease genes: CLCN5 (3 patients), AGXT (2 patients), CLDN16 (2 patients), SLC3A1 (3 patients), SLC34A3 (1 patient), WDR72 (1 patient), CLCNKB (1 patient). The mean eGFR for the study group was 71.2 ± 37.6 ml/min/1.72 m2. Seventeen patients presented eGFR < 60 ml/min/1.73 m2: seven patients CKD stage 3, four patients CKD stage 4, two patients CKD stage 5, and two patients were with renal replacement therapy. Conclusion Genetic kidney stone disease is an underdiagnosed condition. Although 48.5% of the patients had NL/NC onset on pediatric age, the molecular diagnosis was performed in adulthood, and, for some of them, when they suffer of advanced kidney disease. In our cohort, genetic testing had a high rate of positive molecular diagnosis of NL/NC due to selection criteria. Five of our patients presented VUS, but with disease-specific phenotype. We emphasize the importance of reporting these cases to generate additional evidence that could allow the reclassification of these variants. We conclude that the molecular diagnosis improves patient management, prevent or delay chronic kidney disease, offer possibility of genetic counseling and an extended screening to the family. Thus, our study showed the potential benefits of genetic testing, especially in high-risk groups for stone disease.

MO045THE APPLICATION OF A NGS KIDNEY PANEL REVEALED KEY CHALLENGES OF PKD1-2 ANALYSIS: INTERPRETATION OF MISSENSE VARIANTS, SIGNIFICANCE OF VARIANTS IN DUPLICATED REGIONS AND HIGH ALLELIC HETEROGENEITY

Abstract Background and Aims Genetic testing has changed the clinical management of inherited kidney diseases patients, improving prognosis, surveillance and therapy. On the other hand, it has put geneticists and clinicians in front of new challenges, as the heterogeneity of these disorders and the high number of variants, with no clear genotype-phenotype correlation. Method 108 patients underwent genetic analysis through a kidney focused NGS panel, named Nephroplex, containing 119 genetic loci associated with inherited kidney disorders. The study aimed to addressed the genetic landscape of cystic individuals and to analyze PKD1 and PKD2 variants in non-cystic individuals. Results Following diagnostic criteria, patients were divided as cystic kidney diseases (n=36) and non-cystic kidney diseases (n=72). Among the group of cystic patients, a causative mutation was detected in 51% of cases. We found thirty-seven PKD1 and PKD2 variants in 26 out of 35 individuals. In particular, 12 variants were shown to be damaging and nine of that were reported in public database, as CLINVAR and Mayo Clinic databases. Among pathogenic variants, twelve were truncating and the remaining were missense variants. Of note, 7 out of 12 damaging PKD1 mutations were located in duplicated regions. Moreover, in three cystic patients, we found a (i) a frameshift hemizygote OFD1 mutation (ii) compound heterozygote PKHD1 variants and (iii) a frameshift MUC1 variant, framing the diagnosis of oro-facio-digital type 1, autosomal recessive polycystic kidney disease and autosomal dominant tubulointerstitial disease, respectively. Interestingly, we detected 28 PKD1-2 rare variants in 21 out of 75 adult non cystic patients (28%). The most were observed in PKD1 genes (82% vs 18% in PKD2). Eighteen of 28 variants were described in the literature as likely benign or as mutations of uncertain significance, while we found 10 novel variants. In silico analysis revealed as pathogenic a frameshift mutation located in exon 15. Of note, the great part of these variations reside into the duplicated PKD1 regions. Conclusion Our data showed that genetic analysis of ADPKD retains unique challenges, given the high degree of homology of PKD1 with his pseudogenes and the high allelic heterogeneity in non-cystic individuals.

Autosomal dominant tubulointerstitial kidney disease: a new tool to guide genetic testing

Autosomal dominant tubulointerstitial disease (ADTKD) is a dominantly inherited progressive nonglomerular disease. Several factors, such as a nonspecific clinical presentation and relative rarity, impede the phenotyping of ADTKD into clinically relevant subtypes and impair the appropriate implementation of genetic testing. The study by Olinger etal. describes the largest multicenter ADTKD cohort, which is likely to become a key resource. The authors also provide a new clinical tool that could guide diagnosis and genetic testing.

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.