Recurrence of Anti-semaphorin-3B Mediated Membranous Nephropathy after Kidney Transplantation

Background: Membranous nephropathy (MN) is rare in pediatric patients, although its diagnosis may be underestimated in children who are responsive to corticosteroid therapy prescribed for a suspicion of minimal change disease. It is most often associated with an autoimmune disease, predominantly lupus. We previously reported the occurrence of early onset membranous nephropathy associated with Semaphorin 3B in 9 children and 2 adults. Methods: Biopsies were performed on native kidney and at 1 and 5 months after transplantation. Semaphorin 3B antigen was detected in immune deposits by immunohistochemistry and confocal microscopy on paraffin-embedded biopsies. Anti-Semaphorin antibodies were detected by Western blot and analyzed sequentially. Results: We report the first case of early recurrence after transplantation in a 7-year old boy who presented with severe nephrotic syndrome and advanced kidney failure. There was no evidence of hereditary or associated autoimmune disease. Abundant, almost coalescent deposits were seen by electron microscopy and bright granular, subepithelial staining was observed for Semaphorin 3B antigen. Western blot analysis of serum revealed antiSemaphorin 3B antibodies. Recurrence of MN occurred 25 days after transplantation and manifested as nephrotic range proteinuria despite conventional immunosuppressive therapy. Kidney biopsies confirmed histological MN recurrence with colocalization of Semaphorin 3B antigen and IgG (1). The patient was treated with rituximab. Anti-Semaphorin 3B antibodies, which were detected at transplantation, were not detected 40 days after rituximab. Conclusion: This case provides evidence that anti-Semaphorin 3B antibodies are pathogenic and should be monitored in patients with membranous nephropathy.

Case Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate consisting of the monoclonal antibody trastuzumab linked to the maytansinoid DM1 with potential antineoplastic activity and is approved for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified 124/1,243 (10%) renal adverse events for trastuzumab. However, there are no published case reports describing kidney biopsy findings related to nephrotoxicity of either trastuzumab or T-DM1. We report kidney biopsy findings in a case of nephrotic range proteinuria due to collapsing focal segmental glomerulosclerosis (FSGS) and tubular injury after initiation of T-DM1 therapy. After systematic exclusion of other causes, it is likely that the observed collapsing FSGS was associated with the prior initiation of T-DM1 therapy. This is further supported by the clinical course with improvement of proteinuria and kidney function 3 weeks after discontinuation of T-DM1 therapy without further specific treatment. In summary, we provide the first report of kidney biopsy findings in a case of nephrotic range proteinuria after initiation of T-DM1 therapy due to collapsing FSGS. This issue is especially relevant since T-DM1 is widely used, and nephrologists have to be aware of this potentially rare but severe complication.

Inferior vena cava thrombosis as a possible cause of nephrotic-range proteinuria: two case reports

Background Nephrotic-range proteinuria is a common reason for nephrological consultation in clinical practice. The differential diagnosis is wide, and generally focuses on different forms of glomerulonephritis, but other causes should not be overlooked, as illustrated in this article. Case presentations We report two female patients with nephrotic-range proteinuria. In the first case, a 46 year old Caucasian patient who suffered from extreme obesity (Body mass index (BMI) 77 kg/m2), acute kidney injury and nephrotic-range proteinuria were discovered during an emergency consultation for acute abdominal pain. The second patient (aged 52, also Caucasian) developed stage 4 chronic kidney disease and nephrotic proteinuria (protein/creatinine ratio 1821 g/mol) after accidental rupture of the inferior vena cava during a gastric bypass operation. On split-urine collection, both had a much higher degree of proteinuria during the day than during the night, compatible with orthostatic proteinuria. At further work-up, inferior vena cava thrombosis was diagnosed in both patients, whereas renal veins were patent. Discussion After simple anticoagulation in the first case, and anticoagulation plus endovascular recanalization in the second, there was almost complete resolution of the orthostatic proteinuria and a strong improvement of the estimated glomerular filtration rate in both patients. These cases highlight that nephrotic-range proteinuria can be linked to inferior vena cava thrombosis, and that a split-urine collection may also be very useful in the diagnostic work-up of proteinuria in adults.

Bursting the bubble: hereditary spherocytosis masking poor glycemic control

Hemoglobin A1c (HbA1c) is a very common measure utilized to diagnose diabetes and to monitor the level of glycemic control during the course of management. Despite the high utility of HbA1c, it has some limitations. Physiological conditions that affect the lifespan of red blood cells (RBCs) can falsely elevate or lower HbA1c results. In this case report, we present a case of a patient who was found to have hereditary spherocytosis (HS) after developing nephrotic range proteinuria. The patient had diabetes that was previously thought to be well controlled, but his HS was masking his poor glycemic control. This case highlights the importance of understanding the limitations of the HbA1c in managing patients with diabetes.

IgA Nephropathy Secondary to Ipilimumab Use

Ipilimumab is a human monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 approved for the treatment of non-small-cell lung cancer (NSCLC) and other malignancies. Despite a high prevalence of other immune-related adverse events (irAEs), checkpoint inhibitor (CPI)-related nephrotoxicity has been reported less frequently. In this clinical case report, we describe the evaluation of a 70-year-old female with stage IV NSCLC who presented with nephrotic range proteinuria 4 weeks after receiving her first cycle of ipilimumab. She underwent a renal biopsy and was found to have IgA nephropathy that was presumed to be secondary to ipilimumab use, given recent initiation of therapy and clinical history. Unfortunately, despite prompt initiation of corticosteroids, her acute kidney injury progressed and she required hemodialysis, later transitioning to hospice. To our knowledge, this is one of few reported cases of IgA nephropathy secondary to CPI use. With increasing use of CPIs, this case further emphasizes the need for continued surveillance for irAEs, which can occur at any point in a patient’s treatment course.

Tubuloglomerular Disease With Cone-Shaped Epiphyses Associated With Hypomorphic Variant and a Novel p.Cys14Arg in the TTC21B Gene: A Case Report

Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.

Tale of two nephropathies; co-occurring Alport syndrome and IgA nephropathy, a case report

Background Alport Syndrome and IgA Nephropathy (IgAN) are both disorders that can cause hematuria. Alport syndrome is most commonly an X-linked disease, caused by COL4A5 mutation. Mutations of COL4A3 and COL4A4 on chromosome two are also common causes of Alport syndrome. IgAN is the most common glomerulonephritis worldwide. Though IgAN is usually sporadic, an estimated 15% of cases have an inheritable component. These cases of Familal IgA Nephropathy (FIgAN) can have mutations on genes which are known to cause Alport Syndrome. Case presentation We report a case of a 27-year-old man with strong family history of renal disease, who presented with hematuria and new non-nephrotic range proteinuria. Physical exam showed no abnormalities. His creatinine remained persistently elevated, and renal ultrasound exhibited bilaterally increased echogenicity consistent with Chronic Kidney Disease. Twenty-four-hour urinary collection revealed non-nephrotic range proteinuria of 1.4 g, with otherwise negative workup. On biopsy, he had IgA positive immunofluorescent staining as well as moderate interstitial fibrosis and tubular atrophy. Electron microscopy showed a basket-weave pattern of thickening and splitting of the lamina densa-consistent with Alport Syndrome, as well as mesangial expansion with electron-dense deposits -consistent with IgAN. Conclusions Mutations of COL4A5 on the X chromosome, as well as mutations of COL4A3 and COL4A4 on chromosome 2, can cause both Alport Syndrome and FIgAN. Genome wide association studies identified certain Angiotensin Converting Enzyme gene polymorphisms as independent risk factors for progression of IgAN. Our Presentation with this co-occurring pathology suggests a new paradigm where Alport Syndrome and FIgAN may represent manifestations of a single disease spectrum rather than two disparate pathologies. Appreciating hematuria through this framework has implications for treatments and genetic counseling. Further genome wide association studies will likely increase our understanding of Alport Syndrome, FIgAN, and other causes of hematuria.

Premature birth carries a higher risk of nephrotic syndrome: a cohort study

The pathogenesis of nephrotic syndrome is unclear. We conducted a nationwide population-based cohort study to examine the associations between preterm births and subsequent development of NS. NS was defined as ≥ 3 records with ICD-9-CM codes for NS in hospital admission or outpatient clinic visits. To avoid secondary nephrotic syndrome or nephritis with nephrotic range proteinuria, especially IgA nephropathy, we excluded patients with associated codes. A total of 78,651 preterm infants (gestational age < 37 weeks) and 786,510 matched term infants born between 2004 and 2009 were enrolled and followed until 2016. In the unadjusted models, preterm births, maternal diabetes, and pregnancy induced hypertension were associated with subsequent NS. After adjustment, preterm births remained significantly associated with NS (p = 0.001). The risk of NS increased as the gestational age decreased (p for trend < 0.001). Among the NS population, preterm births were not associated with more complications (Hypertension: p = 0.19; Serious infections: p = 0.63, ESRD: p = 0.75) or a requirement for secondary immunosuppressants (p = 0.61). In conclusion, preterm births were associated with subsequent NS, where the risk increased as the gestational age decreased. Our study provides valuable information for future pathogenesis studies.