Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common causes of advanced chronic kidney disease (CKD) in children. CAKUT should be diagnosed as early as possible to prevent the renal damage caused by urinary tract obstruction, vesicoureteral reflux and/or febrile urinary tract infection. Ultrasonography is the most useful and minimally invasive tool for diagnosing CAKUT and also essential for assessing treatment efficacy and evaluating outcomes in children with CAKUT. We also discuss the clinical guidelines on ureteropelvic junction obstruction (UPJo) and vesicoureteral reflux (VUR) published simultaneously by the Japanese Society of Pediatric Urology in 2016.
Recent advances in genetic analysis and development of national and international registries for rare diseases have unraveled genetic abnormalities and clinical characteristics in hereditary renal tubular disorders. In Dent disease and Lowe syndrome, large cohort studies revealed that nephrocalcinosis was not associated with progression of chronic kidney disease. In Bartter syndrome type 3, severe mutations and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. In Gitelman syndrome, gender and certain mutations were associated with larger required amount of potassium supplementation. In distal renal tubular acidosis, all three known genes of both autosomal dominant and autosomal recessive forms should be candidates for patients with onset in infancy and early childhood. Novel genes responsible for Fanconi syndrome were identified; sodium-phosphate cotransporter NaPi-IIa and an enzyme involved in peroxisomal oxidation. On the other hand, responsible genes have not been identified in substantial proportion of patients with renal tubular disorders, suggesting that factors modulating established molecules regulating water, electrolyte, and acid-base balance may be involved.
Idiopathic nephrotic syndrome is one of the major renal diseases that require aggressive therapy. Over the past 60 years,glucocorticoid has been employed as a first line agent to treat idiopathic nephrotic syndrome; however, the mechanism of its pharmacological action in the improvement of heavy proteinuria still remains unclear. Previously, we revealed that the human glomerulus expressed glucocorticoid receptor that was translocated from the cytoplasm to the nucleus after the binding to the dexamethasone. We also proved that the human glomerulus expressed glucocorticoid inactivating enzyme that indeed possessed the enzyme activity in podocytes. Based on these findings, we provided the novel concept suggesting the direct action of the glucocorticoid on the injured podocytes. Then, we subsequently revealed that the energy imbalance in podocytes underlay the pathomechanism of the proteinuria in the nephrotic syndrome, which was identified to be a target site of the immunosuppressants including glucocorticoid. In the near future, the compounds that could exert the effect on the energy pathway would be expected to be candidates for novel therapeutic agent to overcome glucocorticoid dependence and resistance.
Patients with idiopathic nephrotic syndrome (NS) receiving immunosuppressant often present with febrile infection, leading to a relapse of NS and/or hospitalization. We retrospectively studied a cohort compromising 83 children diagnosed with NS (203 cases of febrile infection) who were administered immunosuppressant between 2005 and 2016. We found that 15 patients (7.4%) presented with a relapse of NS associated with febrile infection. In patients presenting with a relapse use of mycophenolate mofetil (MMF) was significantly lower compared to those without a relapse (p<0.01). Mizoribine (MZR) use and mortality rate of influenza were significantly higher in patients showing a relapse compared to those without a relapse (p<0.05). Hospitalization was required in 15 patients (7.4%) and two of them developed a serious influenza infection. Among hospitalized patients, age at the onset of febrile infection and use of cyclosporine A were significantly lower compared to these parameters in non-hospitalized patients (p<0.05). MMF use was significantly higher in hospitalized patients compared to non-hospitalized ones (p<0.05). Our study found that MMF may be superior to high-dose-MZR to prevent relapsing NS associated with a febrile infection. However, MMF may be a risk factor for hospitalization at the time of febrile infection.
Seven girls (age, 4–13 years) with elevated serum creatinine (Cr) and presumed Mycoplasma pneumoniae infection were treated with 4–7 doses of tosufloxacin (TFLX) in a correct manner. Whereas four of the patients met the criteria for acute kidney injury, only one patient had elevated serum cystatin C. The elevated Cr normalized in all patients after TFLX withdrawal. Two patients had a history of treatment with TFLX; one had similar Cr elevation and abdominal pain two months previously and the other, who had received over 100 doses of TFLX over the past last five years, tended to have increased Cr even in the absence of TFLX. Four of the patients developed abdominal pain, nausea and loss of appetite that improved within two days. Computer tomography and magnetic resonance imaging revealed thickening of the small intestine and ascites accumulation. The pathophysiological mechanism of acute kidney damage under TFLX administration is thought to be cast nephropathy, but information about the adverse effects of TFLX is scant. We hope to resolve these issues and develop an optimal standard for TFLX administration.
We experienced a purpura nephritis case with histological findings of membranoproliferative glomerulonephritis of ISKDC grade VI, for which frequent steroid pulse therapy was effective. A 12-year-old boy experienced the complication of nephrotic syndrome at the time of developing purpura nephritis and showed histopathological findings of membranoproliferative glomerulonephritis. His prognosis was considered to be poor. When three courses of steroid pulse therapy, in addition to multidrug combination therapy, were administered, followed by two further courses, the patient experienced partial remission. Therefore, he was discharged from the hospital, and outpatient treatment was continued. Because both proteinuria and hematuria resolved, gradual tapering and eventual withdrawal of the steroid were performed. Administration of other drugs was also discontinued. To date, no recurrence of nephritis has been observed. Renal biopsy prior to drug withdrawal showed ISKDC grade II, indicating remission. The renal prognosis in cases of purpura nephritis complicated by nephrotic syndrome and/or with findings of membranoproliferative glomerulonephritis is considered to be poor. Though there are currently no appropriate treatments for these conditions, our current experience suggests frequent steroid pulse therapy to possibly be effective.
Branchio-oto-renal (BOR) syndrome is a condition associated with branchiogenic anomalies, deafness, and renourinary anomalies as a symptomatic triad, and abnormality of the EYA1 is considered to be a causative factor. We encountered a 1-year-and-10-month-old girl with BOR syndrome complicated by cerebral cavernous malformation (CCM) exhibiting novel mutation of the EYA1. She was diagnosed with BOR syndrome as she showed bilateral cervical fistulas, bilateral deafness, and bilateral hydronephrosis/hydroureter at birth. Her mother had preauricular pits and deafness. The child suddenly developed afebrile tonic-clonic convulsion. MRI disclosed CCM in the right parietal lobe, and gene analysis demonstrated novel heteromutation in exon 13 of EYA1. We report this case since there is no published report of BOR syndrome accompanied by EYA1 mutation and complicated by CCM.
In this case, oral prednisolone (PSL) treatment was initiated for immunoglobulin M nephropathy in a 7-year-old female patient; however, proteinuria increased. Urine protein to creatinine ratio prior to treatment was 1.1 g/gCr, but worsened to a maximum of 4.3 g/gCr. Serum albumin levels were also decreased and subsequently, the PSL dose was tapered. After 8 weeks of treatment, PSL was judged ineffective, and was discontinued. Following PSL discontinuation, urine protein levels quickly recovered to the pretreatment value. So it was diagnosed as drug-induced injury caused by PSL. In a drug-induced lymphocyte stimulation test, the result for Predonine® tablet was positive while the result for Medrol® tablet was negative. With hydroxypropyl cellulose (HPC), an additive present in Predonine® tablet only, the result was positive; therefore, HPC was judged as the causal substance. Thus, this case suggests that steroid drug-induced kidney injury must be considered if urinary protein level increases prior to treatment discontinuation, and additives should be evaluated even during the selection of other drugs. Notably, HPC was the causal substance here; thus, it is an additive for which caution is required.
Bevacizumab (BV), a humanized monoclonal antibody to the vascular endothelial growth factor (VEGF), is the molecular-targeted agent of inhibiting tumor angiogenesis. Proteinuria is known as one of the adverse effects of BV, but reported cases of renal histopathology are few. Here, we describe a patient, who developed proteinuria after BV monotherapy against optic glioma, presented pathological features of glomerular capillary endotheliosis and focal segmental glomerulosclerosis (FSGS). Previous reports showed the most typical histological findings in BV-related glomerular injury as thrombotic microangiopathy (TMA) and not with FSGS. Recently, an importance of the crosstalk mechanism between VEGF-producing podocytes and VEGF-receiving endothelial cells has been revealed in maintaining functional glomerular filtration barrier. Our case suggested that FSGS was resulted by BV therapy induced to damage the crosstalk mechanism of podocyte-endothelial VEGF axis signaling leading to the injury of glomerular filtration barrier.
We report a case of acute poststreptococcal glomerulonephritis (APSGN) diagnosed through renal biopsy in a patient with cirrhosis. A 13-year-old girl with biliary cirrhosis developed gross hematuria after surgery for biliary atresia. Serum anti-streptolysin O antibody (ASO) and anti-streptokinase antibody (ASK) levels were elevated, and the serum complement level was low. We strongly suspected APSGN but performed a renal biopsy to confirm the diagnosis because a urinalysis performed 6 months before this episode revealed occult blood (3+), which suggested a pre-existing comorbid chronic kidney disease. Glomerular staining for nephritis-associated plasmin receptor (NAPlr) and plasmin-like activity was positive, and a diagnosis of APSGN was established. Electron microscopic findings revealed subendothelial and mesangial deposits, splitting of the basement membrane, and mesangial interposition. Microscopic hematuria was present one year after the disappearance of proteinuria, so we surmised that hepatic glomerulosclerosis preceded the APSGN, based on the clinical course and pathological findings. For patients with cirrhosis, the differential diagnosis of acute renal disease should consider the coexisting disorder.