Impact of initial steroid response on transplant outcomes in children with steroid-resistant nephrotic syndrome.

BACKGROUND: Limited data suggest children with secondary steroid-resistant nephrotic syndrome (secondary SRNS) have increased risk of recurrence post transplantation. There are no data on the association between secondary steroid resistance and risk of transplant loss. METHODS: Children who received kidney transplantation between 2000 and 2019 for either primary or secondary SRNS in Australia and New Zealand were included. Children presenting with nephrotic syndrome before 12 months were excluded. Data were gathered from chart reviews and ANZDATA. Transplant survival was estimated using the Kaplan-Meier estimator with Cox modelling used to explore predictors of survival. RESULTS: There were seventy children, 38 (55%) male, median age at presentation 4 years (IQR 2-7) and 46 (66%) Caucasian. Median age at transplant was 11 years (IQR 7-15) and 39 (55%) received living donor transplant. Secondary SRNS occurred in 20/70 (29%). For those with secondary SRNS, 18/20 (90%) had recurrence post-transplant, compared to 18/50 (36%) with primary SRNS (p = 0.001). Every child with history of atopy (n = 11) or with hypoalbuminaemia at time of transplant (n = 13) experienced immediate recurrence. For children with secondary SRNS, 8/18 (44%) with post-transplant recurrence had no response to therapy. For children with primary SRNS, 4/18 (22%) with recurrence had no response to therapy (p = 0.3). Overall, 10-year transplant survival was 47% (95%CI 29-77%) for those with secondary SRNS, compared to 71 (95%CI 57-88%) for those with primary SRNS (p = 0.05). CONCLUSIONS: Secondary steroid resistance is strongly associated with SRNS recurrence. Atopy and hypoalbuminaemia at transplant may be novel risk factors for recurrence. Further research is needed to assess if secondary steroid resistance is associated with poorer transplant outcomes. "A higher resolution version of the Graphical abstract is available as Supplementary information".

Long-term nephrotic syndrome recurrence risk of kidney transplantation in two siblings with ADCK4-associated glomerulopathy.

BACKGROUND: Mutations in the ADCK4 gene cause steroid-resistant nephrotic syndrome (NS), namely ADCK4-associated glomerulopathy. Reportedly, 38.5% of patients with ADCK4-associated glomerulopathy had end-stage renal disease (ESRD) at the time of diagnosis of ADCK4-associated glomerulopathy, requiring renal replacement therapy, such as dialysis and kidney transplantation. However, long-term NS recurrence risk of kidney transplantation in patients with ADCK4-associated glomerulopathy is unknown. METHODS: The clinical data and mutations in ADCK4 of two siblings with steroid-resistant NS were collected. The long-term prognosis of the two siblings who received kidney transplantation was evaluated. RESULTS: We describe two siblings with ADCK4-associated glomerulopathy who received deceased donor kidney transplantation and showed no clinical evidence of recurrence of NS during more than 10 years of follow-up. CONCLUSIONS: This suggests that long-term NS recurrence risk of kidney transplantation is low in patients with ADCK4-associated glomerulopathy who progress to ESRD.

Response to steroid and immunosuppressive therapies may predict post-transplant recurrence of steroid-resistant nephrotic syndrome.

BACKGROUND: Recurrence of SRNS is a major challenge in KT. Several clinical factors, including initial steroid sensitivity, have been associated with increased post-transplant SRNS recurrence risk. However, conflicting data have been reported, possibly due to the heterogeneous pathophysiology of SRNS and the lack of genetic testing of SRNS patients. Furthermore, the response to immunosuppressive therapies has not been evaluated. METHODS: Seventy patients aged 1-15 years at SRNS onset who underwent KT between 2002 and 2018 were enrolled. Patients with secondary, familial, syndromic, and genetic forms of SRNS and those who were not treated with steroid were excluded. This study aimed to assess the risk factors for post-transplant recurrence, including treatment responses to initial steroid therapy and additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A. RESULTS: Data from 36 kidney transplant recipients were analyzed. Twenty-two (61%) patients experienced post-transplant SRNS recurrence, while 14 patients did not. The proportion of patients who achieved complete or partial remission with initial steroid therapy and/or additional therapies with immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A was significantly higher in the SRNS recurrence group (19/22, 86%) than in the group without SRNS recurrence (6/14, 43%; p = .01). CONCLUSION: This study suggests that the response to steroid treatment, other immunosuppressive agents, rituximab, plasmapheresis, and/or LDL-A may predict post-transplant SRNS recurrence.

Five-Year Follow-Up and Successful Kidney Transplantation in a Girl with a Severe Phenotype of Pierson Syndrome.

Pierson syndrome (PIERSS) is a rare autosomal recessive disorder characterized by the combination of congenital nephrotic syndrome (CNS) and extrarenal symptoms including ocular malformations and neurodevelopmental deficits. PIERSS is caused by biallelic pathogenic variants in the LAMB2 gene leading to the defects of ß2-laminin, the protein mainly expressed in the glomerular basement membrane, ocular structures, and neuromuscular junctions. Severe complications of PIERSS lead to the fatal outcome in early childhood in majority of the cases. We report a case of 5-year-old girl with severe phenotype of PIERSS caused by biallelic functional null variants of the LAMB2 gene. Due to consequences of CNS, the patient required bilateral nephrectomy and peritoneal dialysis since early infancy. The course was additionally complicated by tubulopathy, life-threatening infections, severe hypertension, erythropoietin-resistant anemia, generalized muscular hypotonia, neurogenic bladder, profound neurodevelopmental delay, epilepsy, gastrointestinal problems, secondary hypothyroidism, and necessity of repeated ocular surgery due to microcoria, cataract, and nystagmus. Due to multidisciplinary efforts, at the age of 4 years, the kidney transplantation was possible. Currently, the renal graft has an excellent function; however, the girl presents severe neurodevelopmental delay. The report presents a unique long-term follow-up of severe PIERSS with a few new phenotypical findings. It highlights the clinical problems and challenges in management of this rare condition.

Successful kidney transplantation in a patient with neonatal-onset ILNEB.

BACKGROUND: ILNEB constitute an autosomal recessive disorder caused by homozygous or compound heterozygous mutation of the gene for the ITGA3. To date, 8 ILNEB patients have been reported, but all 6 neonatal-onset ILNEB patients suffered early death within 2 years. The most common cause of death among previously reported ILNEB patients was exacerbation of the respiratory condition. METHODS: In this study, we describe a case of ILNEB with neonatal onset in a female patient and the genetic and histopathological testing performed. RESULTS: Our patient had a compound heterozygous mutation in ITGA3. Compared to previously reported patients, this patient exhibited milder clinical and histopathological characteristics. After experiencing a life-threatening respiratory infection at 8 months old, the patient started periodic subcutaneous immunoglobulin treatment once every 1-2 weeks for nephrotic-range proteinuria-induced secondary hypogammaglobulinemia. At the age of 3 years, proteinuria gradually increased with severe edema despite strict internal management. Therefore, our patient underwent unilateral nephrectomy and insertion of a peritoneal dialysis catheter followed by another unilateral nephrectomy. One month later, she underwent an ABO-compatible living-donor kidney transplantation at the age of 4 years. CONCLUSIONS: Our patient is a neonatal-onset ILNEB patient who survived for more than 2 years and underwent successful kidney transplantation.

Access to Transplantation for Undocumented Pediatric Patients.

Clinicians in the United States today regularly face dilemmas about health disparities. Many patients and families cannot afford the medical care that doctors recommend. These problems are most stark when the medical care that is needed is lifesaving and expensive and involves scarce resources. Transplants are the best example of this. The most ethically disturbing situations occur when an undocumented immigrant child needs a transplant. We present such a case and analyze the ethical, legal, and policy issues that arise.

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. RESULTS: Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. CONCLUSIONS: Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.

Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome.

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single-center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non-steroidal anti-inflammatory drugs is a safe and non-invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.

Pre-emptive rituximab and plasma exchange does not prevent disease recurrence following living donor renal transplantation in high-risk idiopathic SRNS.

BACKGROUND: Children with non-genetic steroid-resistant nephrotic syndrome (SRNS) are at high risk of disease recurrence (DR) and graft loss following renal transplant (RT). Although pre-emptive plasma exchange (PE) and rituximab have been suggested to prevent DR, there is insufficient published data to support this practice. The aim is to study the role of pre-emptive PE and rituximab in the prevention of DR in children with non-genetic SRNS undergoing living donor (LD) RT. METHODS: Prospective single-centre study of four consecutive children (age 6-17 years) with non-genetic SRNS (including two with previous graft loss due to DR) who underwent LD RT between July 2014 and September 2016. All patients received a single dose of rituximab 375 mg/m2 2-4 weeks prior to the RT and four sessions of PE in the week prior to RT. All patients had previously undergone bilateral native nephrectomies. RESULTS: All children had early DR (2-26 days) following LD RT. Following early initiation of PE, three children achieved partial remission (PR) or complete remission (CR) 5-22 days after commencing treatment. One child continued to have heavy proteinuria along with graft dysfunction despite 52 sessions of PE and lost the graft 5 months after RT. At the latest follow-up of 36-60 months following RT, one child remains in CR and two are in PR. The latest eGFR was 45-104 ml/min/1.73m2. CONCLUSIONS: Pre-emptive rituximab and PE does not prevent DR in high-risk non-genetic SRNS. Prompt initiation of PE following DR appears to achieve PR or CR in the majority of patients.

A Rare and Extreme Case of Vulvar Swelling in the Setting of Nephrotic Syndrome in a Prepubertal Girl.

BACKGROUND: We present a rare case of severe vulvar edema secondary to steroid-refractory nephrotic syndrome in a prepubertal girl. CASE: The patient is an 8-year-old girl who presented during nephrotic syndrome relapse. She exhibited severe mons pubis and labial edema. She was treated with local symptomatic measures such as sitz baths, barrier ointment, and labial sling, with minimal relief. Improvement ultimately occurred after bilateral nephrectomy. SUMMARY AND CONCLUSION: Vulvar edema is rare in prepubertal girls. In this case, the edema was secondary to steroid-refractory nephrotic syndrome and was not responsive to local treatment measures. There is a paucity of data on effective treatment of vulvar edema in young girls. Our goal is to raise awareness of such pathology, which might lead to development of uniform guidelines for treatment of this condition.

Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics. RESULTS: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies. CONCLUSIONS: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

Point-of-Care Ultrasonography for Hernia Reduction: A Case of Incarcerated Umbilical Hernia.

BACKGROUND: Manual reduction of an incarcerated hernia is used to avoid emergency surgery, which comes with risks of complications and death, especially in patients with severe comorbidities. However, there are no established procedures for hernia reduction. CASE REPORT: We present the case of an 82-year-old man with refractory ascites due to nephrotic syndrome and chronic heart failure who developed an incarcerated umbilical hernia. Color Doppler ultrasonography allowed us to detect clearly visible blood-flow signals in the incarcerated bowel and rule out necrosis, which is a contraindication for reduction. Several attempts at manual reduction failed; ultrasonography-guided reduction revealed that fluid collection within the hernia sac was blocking the manual pressure directly on the incarcerated bowel toward the hernia orifice. After sac paracentesis (draining the fluid from the sac), the incarcerated bowel became palpable, leading to a successful reduction. Four days later, once the patient was in a stable condition, an elective surgery was performed to prevent the recurrence of incarceration. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We believe that this is a useful report on the use of point-of-care ultrasonography for incarcerated hernia from the initial assessment of bowel viability to reasonable hernia reduction through hernia sac paracentesis according to real-time observation. An approach based on visualization by ultrasonography, and not on the operator's experience, would be rational, and we believe that this approach will be feasible for emergency physicians, who are responsible for the initial treatment of incarcerated ventral hernia.

Using Electronic Health Record Data to Rapidly Identify Children with Glomerular Disease for Clinical Research.

BACKGROUND: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. METHODS: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (n=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (n=800) and nonglomerular cases (n=798). RESULTS: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months. CONCLUSIONS: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.

Pathologic tonsillar findings similar to IgA nephropathy and the role of tonsillectomy in a patient with nephrotic syndrome.

BACKGROUND: The pathological findings of tonsils in IgA nephropathy include the expansion of T-cell nodules around lymphoid follicles and abnormal reticulation of the crypt epithelium in contrast to chronic tonsillitis. Recently, several studies have reported that regulatory T cells play an important role in the maintenance of self-tolerance, an abnormality that is involved in the onset of nephrotic syndrome (NS). We encountered a patient of 28-year-old male with frequently relapsing nephrotic syndrome (FRNS) and chronic tonsillitis whose tonsils demonstrated pathological findings similar to those of IgA nephropathy. CASE PRESENTATION: A patient had developed NS at the age of 5 years, and was pathologically diagnosed with minimal change disease (MCD), for which he received various immunosuppressive agents as treatment for recurrence. Because tonsillitis often triggers the recurrence of NS, a tonsillectomy was performed for chronic tonsillitis at the age of 25 years. Immunohistochemical staining of his tonsils showed the expansion of CD4 positive lymphocytes around the lymphoid follicles and abnormal reticulation of the crypt epithelium. The number of peripheral blood CD4+CD25+ regulatory T cells increased, and the frequency of relapses decreased after tonsillectomy. CONCLUSION: A similar self-tolerance abnormality exists in NS and IgA nephropathy; therefore, tonsillectomy might become a novel therapeutic approach for FRNS to redress the unbalanced self-tolerance and to remove the tonsillar focal infection. Further studies are necessary to verify the clinical efficiency of tonsillectomy for FRNS with recurrent episodes triggered by tonsillitis.

Early or Late Transplantation in Congenital Nephrotic Syndrome: Which is Effective for Optimal Growth?

Congenital nephrotic syndrome (CNS) is a genetic disease that is present in the antenatal period or during the first 3 months of life. In this study, we aimed to compare growth parameters of patients with CNS who received kidney transplants and either (1) had a normal glomerular filtration rate (GFR) at the time of transplant or (2) chronic kidney disease (CKD) at the time of transplant. Patients with a diagnosis of CNS who had a minimum follow-up period of 6 months were evaluated retrospectively. Children at stages 4 or 5 CKD or patients receiving dialysis during the pretransplant period were defined as group 1; patients with normal GFR at the time of transplantation were classified as group 2. Short stature and low weight were defined as less than -2 standard deviation scores (SDS) for height and weight according to their age. A total of 17 patients were included in the study. Thirteen of 17 patients had NPHS1 gene mutations. Group 1 and group 2 consisted of 8 and 9 patients, respectively. Mean height SDS and mean weight SDS in group 2 were higher than group 1 in the pretransplant period (-4.34 ± 1.74 vs -2.84 ± 1.56; P = .011 and -3.54 ± 0.93 vs -1.83 ± 1.13; P = .008). In the post-transplant period, the significant difference in height SDS continued in favor of group 2 (-3.16 ± 1.11 vs -1.16 ± 0.87; P = .002). The short stature rate was 83% in group 1 and 72% in group 2 in the pretransplant period (P = .62), and 83% in group 1 and 27% in group 2 in the post-transplant period (P = .02). Early renal transplantation seems to be effective for optimal height gain in children with CNS.

Ofatumumab in post-transplantation recurrence of focal segmental glomerulosclerosis in a child.

FSGS is a potentially devastating form of nephrotic syndrome. Treatment of SRNS can be difficult, especially post-transplantation. The current therapy of post-transplant SRNS includes plasmapheresis, ACE-I, CNI, and monoclonal antibodies (rituximab). Patients who are refractory to these interventions have limited therapeutic alternatives. We present a case of a patient with SRNS secondary to FSGS. He did not respond to immunosuppressive medications prior to transplant, progressed to ESRD, and was started on chronic hemodialysis. He received a DDKT which was complicated by post-transplant FSGS recurrence. A course of plasmapheresis, rituximab, and CNI were administered with some response. Ofatumumab was then given to the patient. As a result, the patient achieved partial remission. Ofatumumab may be a safe and effective option for post-transplant recurrence of FSGS.