Early predictive factors for progression to kidney failure in infants with severe congenital anomalies of the kidney and urinary tract.

BACKGROUND: Severe congenital anomalies of the kidney and urinary tract (CAKUT) progress to infantile kidney failure with replacement therapy (KFRT). Although prompt and precise prediction of kidney outcomes is important, early predictive factors for its progression remain incompletely defined. METHODS: This retrospective cohort study included patients with CAKUT treated at 12 centers between 2009 and 2020. Patients with a maximum serum creatinine level ≤ 1.0 mg/dL during the first 3 days, patients who died of respiratory failure during the neonatal period, patients who progressed to KFRT within the first 3 days, and patients lacking sufficient data were excluded. RESULTS: Of 2187 patients with CAKUT, 92 were finally analyzed. Twenty-five patients (27%) progressed to KFRT and 24 (26%) had stage 3-5 chronic kidney disease without replacement therapy during the median observation period of 52.0 (interquartile range, 22.0-87.8) months. Among these, 22 (24%) progressed to infantile KFRT. The kidney survival rate during the infantile period was significantly lower in patients with a maximum serum creatinine level during the first 3 days (Cr-day3-max) ≥ 2.5 mg/dL (21.8%) compared with those with a Cr-day3-max < 2.5 mg/dL (95.2%) (log-rank, P < 0.001). Multivariate analysis demonstrated Cr-day3-max (P < 0.001) and oligohydramnios (P = 0.025) were associated with higher risk of infantile KFRT. Eighty-two patients (89%) were alive at the last follow-up. CONCLUSIONS: Neonatal kidney function, including Cr-day3-max, was associated with kidney outcomes in patients with severe CAKUT. Aggressive therapy for severe CAKUT may have good long-term life outcomes through infantile dialysis and kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

A case with somatic and germline mosaicism in COL4A5 detected by multiplex ligation-dependent probe amplification in X-linked Alport syndrome.

X-linked Alport syndrome (XLAS) is a progressive hereditary kidney disease caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain. To date, 11 cases having somatic mosaic variants in COL4A5 have been reported; however, all of them involved single-nucleotide variations (SNVs). Here, we report a female XLAS patient with somatic mosaicism identified by copy number variation (CNV) in COL4A5. The case was a 35-year-old female, the mother of the proband, whose only clinical symptom was hematuria. The proband, who was the son of this patient, was diagnosed with XLAS by gene testing, which showed a large hemizygous deletion from exon 3-51 in COL4A5 detected by next-generation sequencing and then confirmed by multiplex ligation-dependent probe amplification (MLPA). Then, MLPA analysis revealed that the female patient had the same deletion with only a 20% copy number reduction compared with a normal female control; she was thus diagnosed with XLAS with somatic mosaicism. CNVs in COL4A5 are relatively rare and, to the best of our knowledge, somatic mosaic variants with CNVs have never been reported. This case clearly featured a germline variant because the patient's son exhibited XLAS. This is thus the first case report on an XLAS patient having CNV in COL4A5 with somatic mosaicism. The obtained findings were very important for the genetic counseling of this family.

Successful Treatment of Anti-Factor H Antibody-Associated Atypical Hemolytic Uremic Syndrome.

Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis in terms of frequent relapses. Although eculizumab is an effective treatment for this type of aHUS, the method of eculizumab discontinuation is not yet established. Herein, we report a case of anti-CFH Ab-associated aHUS in a 6-year-old boy. Eculizumab induction therapy following plasma exchange improved his condition. After 14 months, eculizumab was discontinued because of meningococcal bacteremia. After 6 months of eculizumab cessation, prednisolone (20 mg/alternate days) and mycophenolate mofetil (500 mg/day) were initiated. There were no relapses or increases in anti-CFH Ab titers for 26 months after treatment initiation. We believe that eculizumab induction therapy, following plasma exchange and maintenance therapy with immunosuppressants after eculizumab discontinuation are effective treatments for anti-CFH Ab-related aHUS.

Invasive Bacterial Infection in Patients with Interleukin-1 Receptor-associated Kinase 4 Deficiency: Case Report.

Interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency (OMIM #607676) is a rare primary immunodeficiency of innate immune defect. We identified 10 patients from 6 families with IRAK4 deficiency in Japan, and analyzed the clinical characteristics of this disease. Nine patients had homozygous c.123_124insA mutation, and 1 patient had c.123_124insA and another nonsense mutation (547C>T). Umbilical cord separation occurred on the 14th day after birth or thereafter. Two patients had no severe infections owing to the prophylactic antibiotic treatment. Severe invasive bacterial infections occurred before the age of 3 in the other 8 patients. Among them, 7 patients had pneumococcal meningitis. Five patients died of invasive bacterial infection during infancy, although intravenous antibiotic treatment was started within 24 hours after onset in 4 patients among them. Analysis of cerebrospinal fluid of the patients who had fatal meningitis revealed very low glucose levels with only mild pleocytosis. The clinical courses of invasive bacterial infections were often rapidly progressive despite the early, appropriate antibiotic treatment in IRAK4 deficiency patients. The early diagnosis and appropriate prophylaxis of invasive bacterial infections are necessary for the patients.

Successful treatment with mycophenolate mofetil and tacrolimus in juvenile severe lupus nephritis.

Lupus nephritis (LN) of juvenile onset often has severe disease presentation. Despite aggressive induction therapy, up to 20% of patients with LN are resistant to initial therapy and up to 44% suffer a renal relapse. However, there is no consensus on an appropriate therapeutic regimen for refractory LN. We report a 13-year-old girl with recurrent LN who was not taking her medications. At age of 11 years, she was diagnosed with LN classified as International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV G (A) + V. She was treated with prednisolone and MMF after nine methylprednisolone pulses. Nineteen months later, she was admitted to the hospital with generalized edema. Her symptoms were nephrotic syndrome and acute renal dysfunction. She received three methylprednisolone pulses for 3 days, followed by oral prednisolone and MMF. Twenty-seven days after the three methylprednisolone pulses, her acute renal dysfunction was improved, but the nephrotic syndrome was not improved. A second biopsy showed diffuse lupus nephritis classified as the predominant finding of ISN/RPS class V. We added tacrolimus to the MMF. Four months after adding tacrolimus, the nephrotic syndrome improved. We conclude that adding tacrolimus to the treatment regimen for LN resistant to MMF is effective.

Efficacy and safety of darbepoetin alfa for anemia in children with chronic kidney disease: a multicenter prospective study in Japan.

BACKGROUND: We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND). METHODS: A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 µg DA for 200 IU rHuEPO. The initial DA dose for naïve patients was determined by body weight, and intended not to exceed 0.5 µg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks. RESULTS: Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA. CONCLUSION: These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD.

[Mycophenolate mofetil in induction and maintenance therapy for juvenile onset severe lupus nephritis].

OBJECTIVE: The aim of the present study was to evaluate the efficacy of mycophenolate mofetil (MMF) in the induction and maintenance therapy for juvenile onset severe lupus nephritis. METHODS: Children with severe focal, and diffuse proliferative lupus nephritis were treated with prednisolone (initial dose; 1 mg/kg/day, maximum dose; 60 mg/day) and MMF (initial dose; 300 mg/m2/day, increased to 1 g/m2/day) for 24 months after high-dose intravenous methylprednisolone (30 mg/kg/day). Urinalysis was performed, and renal function, and albumin were evaluated. Serum anti-double-stranded DNA antibody, and also serum C3 and C4 were measured. The duration of induction therapy was defined as the initial 6 months after treatment. The duration of maintenance therapy was defined as 18 months after induction therapy. RESULTS: Twelve children (mean age 12.6 +/- 1.7 years)were treated with induction therapy. With 6 months of induction therapy, urine protein, and serum anti-double-stranded DNA antibody, decreased significantly (p < 0.05), renal function improved, and albumin, serum C3 and C4 increased significantly (p < 0.05). Ten children received maintenance therapy. No patients had renal flares during maintenance therapy. The mean prednisolone dose was tapered to 9.2 +/- 2.3 mg/day. Among 5 patients who had a second biopsy after MMF therapy, 4 showed a significant reduction and one had no change in histology. Major infection episodes occurred in 5 patients: Herpes zoster in 3 patients, bacteremia in 2, and hair loss in 3, respectively. No patients discontinued MMF therapy. CONCLUSIONS: MMF is an effective induction and maintenance therapy for juvenile onset severe lupus nephritis.

Sporadic cases and an outbreak of leptospirosis probably associated with recreational activities in rivers in the northern part of Okinawa Main Island.

In the summer of 2003, sporadic cases and an outbreak of human leptospirosis probably related to recreation in rivers occurred in the northern part of Okinawa Main Island. Sixteen of 22 suspected cases were definitely diagnosed as leptospirosis by serological test or isolation. The infective leptospiral serovar in 14 cases was presumed to be Hebdomadis. Transmission was thought to occur by exposure to river water that was contaminated by the urine of infected animals. The findings indicate that recreation in rivers in this area is a significant risk factor for infection with leptospires.