An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head.

Personalized Surgical Management Offers Full Restitution and Unimpaired Quality of Life to Patients with Duplex Kidneys and Associated Pathologies: 30-year Follow-up at a Tertiary Referral Center.

Background: Duplex kidneys may be associated with additional pathologies with an indication for surgery. Various surgical approaches have been described. However, little is known about long-term outcomes and quality of life (QoL) for these patients. Objective: To present long-term outcomes and QoL data up to 30 yr after surgical treatment of duplex kidneys and associated pathologies. Design setting and participants: We collected clinical and operative data for all patients who underwent surgery for complicated duplex kidney at our institution from 1990 to 2018. All patients were invited for a follow-up examination or telephone interview. Outcome measurements and statistical analysis: We evaluated renal function, clinical outcomes, residual dilation of the upper urinary tract, and health-related QoL. Results and limitations: Of the 176 patients included, 173 were available for follow-up (mean 140.5 mo). Surgical treatment involved an upper-tract, lower-tract, or combined approach in 11%, 56%, and 33% of cases, respectively. Rates of perioperative complications (8%) and secondary surgery (10%) were low. Overall, 95% of our patients achieved full restitution. Renal function was preserved in all cases, with recurrent urinary tract infections reported by just 2% and urinary incontinence by 1%. Good health-related QoL was reported by 98% of patients. Those without full restitution included six patients who underwent total nephrectomy and two boys who underwent multiple surgeries and urinary diversion. Our results are limited by their retrospective nature, including partly incomplete data sets. Conclusions: Management of duplex kidneys and associated pathologies is complex and highly individual. By planning a personal approach for each patient it is possible to achieve full bodily integrity and good QoL for most of these patients. Patient summary: Almost all patients undergoing surgery for duplex kidneys and associated pathologies will lead a life without body impairment and good quality of life.This trial is registered in the German Clinical Trials Register as DRKS00022542.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.

Severe metformin intoxication with lactic acidosis in an adolescent.

UNLABELLED: A 15-year-old healthy girl ingested 38.25 g (0.55 g/kg body weight) of metformin in a suicide attempt. Subsequently she developed lactic acidosis and moderate renal failure. An initial session of haemodialysis was able to treat the acidosis and reduce the toxic level of metformin. Nevertheless, a further increase in serum lactate was observed during and after the first dialysis treatment. A second session of haemodialysis was started 5 h after the end of the first session and resulted in a lowering of the lactate level and an almost total elimination of metformin. During the further clinical course, reversible acute renal failure with a maximum creatinine of 2.4 mg/dl was observed. CONCLUSION: Despite sufficient haemodialysis, the production of lactate can be greater than the elimination in the case of severe metformin intoxication. Therefore haemodialysis should be continued even in the situation of rising lactate levels during the treatment.