In this article, to express my gratitude for letting me host the 54th Annual Meeting of the Japanese Society for Pediatric Nephrology in the beginning of the new era of “Reiwa”, a message to the next generation of this great society is conveyed. First, the history of the etiology in idiopathic nephrotic syndrome, one of my lifeworks, will be summarized with my own data. Second, my precious lessons from several unforgettable patients will be introduced. To sum up the message: 1) Have a research mind and a research theme that will become a lifework, aiming to be a Physician Scientist; 2) Write case report papers actively; 3) Be aware that the patient at hand may give you a clue to solving clinical questions; 4) Ask yourself all the time why some patients respond well and others do not by the same standard treatments. Do not shut off your brain.
Renal ultrasonography is useful in the screening of pediatric chronic kidney disease (CKD), and studies on renal length have been used as a simple index. Renal length correlates with age and body height, the standard values of which can be obtained by calculations. In enlarged kidneys such as cystic or single kidney, and in atrophic kidneys, such as hypoplastic/dysplastic kidney or renal scarring, the renal length would help to distinguish the disease. In CKD, kidney size decreases with renal function decline. In cases with congenital anomalies of the kidney and urinary tract or low-birth-weight infants that cause CKD in children, the renal length should be evaluated. However, the standard value of the renal length may differ between countries and races. Therefore, studies are needed to identify more accurate standard values for the Japanese population to evaluate slight differences in renal length in the screening and follow-up for CKD.
The frequency of rituximab (RTX) use increases in complicated nephrotic syndrome (NS), raising concerns about infections associated with low IgG due to combination therapy with RTX and immunosuppressants. Between February 2008 and June 2017, we enrolled 74 children with complicated steroid-dependent NS (178 total RTX administrations, 13.8 years average patient age at time of administration) and retrospectively assessed prevalence of hypogammaglobulinemia (IgG level<500 mg/dl) and infection. Twenty doses (11%) were associated with hypogammaglobulinemia at 6 months after RTX administration. The average age (6.1 vs 14.4 years old, p<0.01) and serum IgG levels before administration of RTX (426 vs 656 mg/dl, p<0.01) were significantly lower in the hypogammaglobulinemia group. Among 15 patients we were able to observe for 1 more year, 8 patients had persistent hypogammaglobulinemia, and the use of mycophenolate mofetil (MMF) was significantly higher (78 vs 17%, p<0.05. IgG replacement therapy was performed in two patients whose IgG levels declined over time. In this study, only one varicella infection was noted. IgG replacement therapy should be considered on a case by case basis.
We investigated the clinical character of relapses of nephrotic syndrome during B-cell depletion in 137 patients with refractory steroid-dependent nephrotic syndrome who received 375 mg/m2 of single dose of rituximab. In 440 rituximab treatment, relapses during B-cell deletion were observed 25 times in 19 patients (5.7%). Forty-four percent of them were observed within 14 days after treatment of rituximab. Gender, age of onset of nephrotic syndrome, age at rituximab treatment, renal histology, past histories of steroid resistance showed no difference between patients who relapsed during Bcell depletion and others. Infusion reaction also was not calculated as a risk factor. Two third of patients who relapsed during B-cell depletion could discontinue steroid during B-cell depletion, which showed effectiveness of rituximab. According to the result of this study, we believe that we should maintain doses of steroid as relapse-preventable doses until two weeks after rituximab treatment. Even if patients suffered from relapse during B-cell depletion, rituximab might be effective and their disease character might be pathogenetically same as others. As we could not detect risk factors of relapse during B-cell depletion, prediction is difficult.
We describe a 7-month old infant who presented failure to thrive with metabolic acidosis. Ammonium chloride and bicarbonate ion load analyses demonstrated proximal renal tubular acidosis. Her serum zinc concentration was low, suggesting that her failure to thrive was a result of proximal renal tubular acidosis and zinc deficiency. Her 2 brothers also had short stature, and their serum zinc concentrations were also low. The infant was treated by high alkali therapy and zinc supplementation, and the 2 older brothers were treated by zinc supplementation. Genetic analyses did not identify any gene mutations in known causative genes of renal tubular acidosis. As the cause of failure to thrive is variable, it is important to make a differential diagnosis among several diseases.
The extreme dilatation of obstructive ectopic ureters makes diagnosis difficult. We report a case of an obstructive ectopic ureter difficult to distinguish from an ectopic ureterocele, causing urinary tract infection due to urinary stasis. A 3-month-old girl with fever of unknown origin was admitted and found to suffer from an upper urinary tract infection. Bilateral complete duplex kidneys and ureters were detected by contrast-enhanced CT. Left upper renal ureteral meandering and dilation were observed. A scan without contrast materials showed a cystic tumor in the bladder. We assumed an upper left renal ectopic ureterocele, and attempted to perform transurethral ureterotomy. However, the intraoperative cystoscope showed no cystic mass in the bladder, and the ureter derived from the left upper kidney was found to be connected to the posterior wall of the urethra near the bladder neck. We eventually confirmed an obstructive ectopic ureter connected to the left upper kidney and performed an upper-lower left renal ureteroureteral anastomosis. She has not had urinary tract infection since the surgery. When an intravesical cystic tumor is observed, it is necessary to examine the possibility of an obstructive ectopic ureter.
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive disease characterized by craniofacial and skeletal abnormalities and chronic kidney diseases, mainly nephronophthisis. We report sisters with heterozygous mutations in their WDR35 gene that caused their CED. Case 1 is the elder sister, and case 2 is the younger sister. Both have undergone surgery for craniosynostosis. Case 1 went to the hospital because she was pale at 3 years of age and was admitted with acute heart and renal failure. Case 2 visited our department at 1 year and 9 months of age, just after her sister was admitted. Both renal pathologies showed nephronophthisis and kidney alternative therapies were started. We checked their past blood tests and found that their chronic kidney diseases started from infancy. However, when we diagnosed renal failure, secondary heart failure had already developed. When skull, face, and skeletal abnormalities are observed, it is important to check renal function. Keeping CED in mind could prevent severe complications.
Although late-onset neutropenia (LON) is known as a late complication after administration of rituximab (RTX), there is no report for the bone-marrow findings in nephrotic syndrome. In addition, the pathogenic mechanism of LON or Rituximab-associated late-onset neutropenia (R-LON) still remains unknown. In this study, we conducted bone marrow examination for the case with LON three months after RTX administration for refractory nephrotic syndrome. Later, we discussed the pathogenic mechanism of R-LON by the bone marrow findings and the transition of peripheral blood CD20 cells. The case was for a 7-year-old girl who received RTX administration (375 mg/m2/administration) four times for FRNS/SDNS. Yet, she had fever and Grade 4 agranulocytosis two and a half months after the last administration. We also found differentiation arrest findings only for myelocyte series in the bone marrow examination. The percentage of CD20-positive cells in peripheral blood was 0.05%, but it was changed to 1.5% after one month and 7% after two months as normal. From the above-described results, LON has developed right before B-cell recovery. Thus, after RTX administration, it needs to pay attention to leucocyte and differential leukocyte count before B-cell recovery.