MYH9-related disease with a normal platelet count.

MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, progressive kidney failure, and sensorineural hearing loss. We describe a patient with MYH9-RD and a normal platelet count. A 13-year-old boy with a normal platelet count presented with proteinuria and hematuria and underwent a kidney biopsy. Light microscopy showed mild mesangial matrix expansion. Electron microscopy showed thinning of the glomerular basement membrane and splitting of the lamina densa. A tentative diagnosis of Alport syndrome was made. Unexpectedly, genetic analysis revealed a de novo MYH9 gene variant (p.Gln1068_Leu1074dup). A peripheral blood smear examination showed giant platelets and leukocyte inclusion bodies, confirming a diagnosis of MYH9-RD. In summary, we described a patient with MYH9-RD without thrombocytopenia who showed glomerular basement membrane abnormalities similar to Alport syndrome. Peripheral blood smear examinations may be helpful for an appropriate diagnosis of MYH9-RD, even in patients with proteinuria and a normal platelet count.

Primary Cilia Elongation in Early-Onset Polycystic Kidney Disease with 2 Hypomorphic PKD1 Alleles: A Case Report.

Recent studies have described several children with very early-onset polycystic kidney disease (PKD) that mimicked autosomal recessive polycystic kidney disease because of 2 hypomorphic PKD1 gene variants. However, no reports have described pathological changes in the primary cilia in these cases. We analyzed the primary cilia in the kidney tubules of an early elementary school child who had very early-onset PKD and a history of large, echogenic kidneys in utero. There was no family history of autosomal dominant PKD. The patient developed kidney failure and received a living-donor kidney transplant from his father. Genetic analysis revealed compound heterozygous variants in the PKD1 gene: c.3876C>A (p. Phe1292Leu) and c.5957C>T (p. Thr1986Met). These variants were likely pathogenic based on in silico analysis. The absence of kidney cysts in the parents suggested that these variants were hypomorphic alleles. Pathological examination of the patient's excised kidney showed prominent dilatation of the proximal and distal tubules. Immunofluorescence staining for α-tubulin showed pronounced elongation of the primary cilia. These findings suggest that the hypomorphic PKD1 variants expressed in this patient with very early-onset PKD were pathogenic.

Sella turcica and facial bones: Morphological integration in the human fetal cranium.

OBJECTIVES: The cranial base plays a significant role in facial growth, and closer analyses of the morphological relationship between these two regions are needed to understand the morphogenesis of the face. Here, we aimed to study morphological integration between the sella turcica (ST) and facial bones during the fetal period using geometric morphometrics. MATERIALS AND METHODS: Magnetic resonance images of 47 human fetuses in the Kyoto Collection, with crown-rump lengths of 29.8-225 mm, were included in this study. Anatomical homologous landmarks and semilandmarks were registered on the facial bones and the midsagittal contour of the ST, respectively. The shape variations in the craniofacial skeleton and the ST were statistically investigated by reducing dimensionality using principal component analysis (PCA). Subsequently, the morphological integration between the facial bones and ST was investigated using two-block partial least squares (2B-PLS) analysis. RESULTS: PCA showed that small specimens represented the concave facial profile, including the mandibular protrusion and maxillary retrusion. The 2B-PLS showed a strong integration (RV coefficient = 0.523, r = .79, p < .01) between the facial bones and ST. The curvature of the anterior wall of the ST was highly associated with immature facial morphology characterized by a concave profile. CONCLUSION: The strong integration between the two regions suggested that the anterior ST may be associated with facial morphology. This result quantitatively confirms previous studies reporting ST deformities in facial anomalies and induces further research using postnatal subjects.

A case of immunoglobulin G4-related kidney disease manifesting after dipeptidyl peptidase-4 inhibitor treatment.

A 68-year-old man with type 2 diabetes mellitus was admitted with decreased renal function. He had high IgG4 (1070 mg/dL) and hypocomplementemia (CH50, 25 U/mL). Kidney biopsy showed tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. Four years later, a second kidney biopsy revealed a new manifestation of membranous nephropathy and tubulointerstitial nephritis with exacerbated fibrosis formation. Six years later, the patient developed bullous pemphigoid, which was thought to be caused by DPP4 inhibitors, so DPP4 inhibitor treatment was discontinued. The use of DPP4 inhibitors correlated with changes in renal function, and the patient was diagnosed with IgG4-related kidney disease related to DPP4 inhibitors.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9 years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7 months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1 h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib.

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

Hepatitis B Virus-related Membranous Nephropathy with Crescentic Formation in an Inactive Carrier of Positive Hepatitis B Surface Antigen with Undetectable DNA under Anti-viral Treatment.

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

A case of bullous pemphigoid and renal disease after dipeptidyl peptidase 4 inhibitor administration.

A 62-year-old man with type 2 diabetes was admitted because of a decrease in estimated glomerular filtration rate from 72 to 17.5 mL/min/1.73 m2 in 10 years and development of widespread bullous skin lesions. His hemoglobin A1c level had been maintained at 6.0-7.0% for 10 years with a dipeptidyl peptidase (DPP)-4 inhibitor. Skin biopsy showed typical bullous pemphigoid, and kidney biopsy showed tubulointerstitial nephritis with eosinophilic infiltration and glomerular endothelial cell proliferation. After discontinuing the DPP-4 inhibitor, skin lesions improved, and renal decline slowed. This case indicates that DPP-4 inhibitors can cause not only skin lesions but also renal disease.

Dipeptidyl peptidase-4 inhibitor-related renal disease.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. METHODS: Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). RESULTS: Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of -11.2 (-17.6, -9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of -1.6 (-3.1, -0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. CONCLUSION: DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.

Apolipoprotein E-associated Lipoprotein Glomerulo-tubulopathy.

A 32-year-old man was admitted for the evaluation of proteinuria (5.69 g/day). A light microscopic examination showed markedly dilated glomerular capillary loops with vacuolated areas in many glomeruli, and vacuolated areas were seen on peritubular capillaries in the tubulointerstitium. When electron microscopy specimens prepared by pre-fixation with glutaraldehyde and post-fixation with osmium tetroxide were used for oil red staining, the deposition was confirmed on the affected areas. A genetic analysis of apoE showed that the lipoprotein glomerulopathy was due to apoE-Sendai (Arg145Pro, p.R163P) heterozygosity, which was found in not only the patient but also his mother and twin brother.

A Case of Acute Kidney Injury Caused by Myoglobin Cast Nephropathy With Sars-Cov-2 Infection in a Living-Donor Kidney Transplant Recipient.

When COVID-19 affects patients with risk factors such as chronic kidney disease or on immunosuppressive drugs, they often rapidly become seriously ill. We describe a 50-year-old man who was affected with SARS-CoV-2 and had undergone an ABO-compatible living-donor kidney transplantation from his father 14 years ago because of end-stage renal failure due to hypertensive nephrosclerosis. He had continued on immunosuppressive drugs and completed vaccination twice (9 months ago and 6 months ago) with messenger RNA (mRNA) vaccines against SARS-CoV-2. However, he was temporarily on a mechanical ventilator due to respiratory failure and hemodialysis due to acute kidney injury (AKI). He was finally weaned from the ventilator and hemodialysis by taking steroid and antiviral drugs. Echo-guided renal biopsy revealed myoglobin cast nephropathy. We experienced 14 outpatients after living-donor kidney transplantation infected with SARS-CoV-2, but only this case developed AKI.

Vesicoureteral Reflux Causes Interstitial Inflammation in Pediatric Kidney Allograft: A Clinicopathological Analysis of 1-Year Protocol Biopsies.

INTRODUCTION: At present, there is limited evidence of the histological impact of vesicoureteral reflux (VUR) on pediatric kidney allografts. In this study, we aimed to investigate the relationship between VUR diagnosed by voiding cystourethrography (VCUG) and 1-year protocol biopsy results. METHODS: One hundred thirty-eight pediatric kidney transplantations were performed in Toho University Omori Medical Center between 2009 and 2019. We included 87 pediatric transplant recipients who were evaluated for VUR by VCUG prior to or at the time of the 1-year protocol biopsy and underwent a 1-year protocol biopsy after transplantation. We evaluated the clinicopathological findings of the VUR and non-VUR groups, and histological scores were evaluated using the Banff score. Tamm-Horsfall protein (THP) within the interstitium was identified by light microscopy. RESULTS: Of the 87 transplant recipients, 18 cases (20.7%) were diagnosed with VUR by VCUG. The clinical background and findings were not significantly different between the VUR and non-VUR groups. The pathological findings revealed a significantly higher Banff total interstitial inflammation (ti) score in the VUR group than in the non-VUR group. Multivariate analysis indicated a significant relationship between the Banff ti score and THP within the interstitium, and VUR. The 3-year protocol biopsy results (n = 68) revealed a significantly higher Banff interstitial fibrosis (ci) score in the VUR group than in the non-VUR group. CONCLUSION: VUR caused interstitial fibrosis in the 1-year pediatric protocol biopsies, and interstitial inflammation at the 1-year protocol biopsy may affect interstitial fibrosis at the 3-year protocol biopsy.

Subclinical C1q Nephropathy Combined with Possible Donor-Derived IgA Deposition in a 1-Year Kidney Allograft Biopsy: A Case Report.

Few previous studies have reported immune-complex nephropathy that has not been classified as a specific phenotype in kidney allografts. We report a case of a de novo subclinical "full-house" pattern of deposition in a pediatric transplantation recipient with possible donor-derived IgA deposition. A five-year-old boy underwent living kidney transplantation due to congenital kidney and urinary tract anomalies. A one-hour implantation biopsy revealed IgA deposition. A four-month protocol biopsy finding showed less intense IgA deposition, in contrast with the one-hour biopsy, and trace para-mesangial deposits. A one-year protocol biopsy demonstrated a full-house deposition pattern and massive electron-dense deposits with minor glomerular changes. At the time of the one-year biopsy, kidney function was stable, with no urinalysis abnormalities. No evidence of systemic lupus erythematosus was observed in clinical and serologic examinations. Mesangial IgG, IgM, C3, and C1q deposition was codominant, and IgA deposition was weaker. We diagnosed this case as C1q nephropathy combined with remaining donor-derived IgA deposition. Few studies have reported C1q nephropathy in kidney allograft; further accumulation of cases is required. To distinguish between donor-derived and de novo glomerular lesions, it is important to assess the serial histologic findings of immunofluorescence and electron microscopy. Here, we report a rare case of subclinical C1q nephropathy with possible donor-derived IgA nephropathy.

Histiocytic Glomerulopathy With Noncrystalline Inclusion Associated With IgG-Kappa Plasma Cell Dyscrasia.

The kidney pathology of monoclonal gammopathy of renal significance varies greatly. In this report, we present a woman in her 20s with nephrotic syndrome and monoclonal immunoglobulin G kappa (serum and urine) without diabetes. She had a family history of nephrotic syndrome as well as hematologic and connective tissue disorders. A kidney biopsy showed nodular glomerulosclerosis, with the glomerular capillary full of histiocytes, which were strongly positive for kappa, not lambda. Immunoelectron microscopy revealed that histiocytes had infiltrated the glomerular subendothelial space, and enlarged lysosomes of histiocytes contained kappa light chains, without apparent crystalline formation. Bone marrow examination was negative for malignancy; thus, we diagnosed this case as histiocytic glomerulopathy with noncrystalline inclusion associated with immunoglobulin G-kappa plasma cell dyscrasia. Hematologic treatment with bortezomib and daratumumab decreased her level of serum kappa chain and proteinuria. Two years after diagnosis, her kidney function remained normal, urinary protein level decreased to 1 g/d, and free light-chain ratio decreased to 3.1.

Significance of Multinucleated Polyploidization of Tubular Epithelial Cells in Kidney Allografts.

INTRODUCTION: Multinucleated polyploidization (MNP) of tubular epithelial cells is occasionally observed in kidney allografts. The present study aimed to clarify the clinical and pathological significance of MNP of tubular epithelial cells in kidney allografts. METHODS: Fifty-eight 1-year biopsies from 58 patients who underwent kidney transplantation at our hospital from January 2016 to December 2017 were included. MNP was counted in each specimen, and the specimens were divided into two groups by the median value. The differences in clinical and pathological characteristics were compared. Ki67-positive cells were counted among tubular epithelial cells to explore the association between cell cycle and MNP. In an additional cohort, MNP was compared between biopsies after precedent T-cell-mediated rejection and precedent medullary ray injury. RESULTS: The 58 cases were divided into two groups by the median total amount of MNP: group A (MNP > 3) and group B (MNP ≤ 3). Maximum t-score before the 1-year biopsy was significantly higher in group A compared with group B. Other clinical or histological characteristics did not differ significantly. Total amount of Ki67-positive tubular epithelial cells was significantly correlated with total amount of MNP. Significantly higher amount of MNP was observed in cases with precedent T-cell-mediated rejection compared with precedent medullary ray injury. On receiver operating characteristic curve analysis, the cut-off value of MNP to predict precedent T-cell-mediated rejection was 8.5. CONCLUSIONS: MNP in tubular epithelial cells reflects prior tubular inflammation in kidney allografts. High amount of MNP indicates precedent T-cell-mediated rejection rather than precedent medullary ray injury caused by nonimmune etiologies.

Immunoglobulin G4-related Tubulointerstitial Nephritis with Simultaneous Resolution of Plasma Cell Infiltration and Fibrosis after Steroid Treatment.

We performed 3 kidney biopsies in a 71-year-old man. At the first biopsy, we made the diagnosis of immunoglobulin G4 (IgG4)-related interstitial nephritis characterized by the simultaneous presence of IgG4-positive plasma cells and characteristic fibrosis with a bird's-eye pattern. At the second biopsy, rather than finding fibrosis as a post-inflammatory scar, we noted that steroid treatment had caused the simultaneous disappearance of IgG4-positive plasma cells and fibrosis and had restored the normal tubular structure. The third biopsy showed the recurrence of the disease with inflammatory cells accompanied by fibrosis. These findings suggest that IgG4-positive plasma cells and fibrosis occur simultaneously.

Morphogenetic progression of thigh and lower leg muscles during human embryonic development.

Fetal musculoskeletal movements are first observed at approximately seven to 8 weeks of gestation. However, the separation and formation of skeletal muscles, especially the limbs, have not yet been described in detail. In this study, we elucidate the sequence of events leading to the formation of each thigh and lower leg muscle using serial sections. To observe muscle formation, 26 serial sections (50 legs) of human embryonic specimens ranging from Carnegie stages (CS) 19 to 23 were selected from the Kyoto collection stored at the Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine. As a result, we show the detailed formation and separation processes of the thigh and lower leg muscles. In the thigh, sartorius and tensor fasciae latae are separated at CS19, and the individual muscles observed in adults are identified after CS21. In the lower leg, the tibialis anterior exhibits early separation at CS20, and all muscles are identified at CS22. This study enables future research into the relationship between embryonic development and the evolution of muscle action from quadrupedal to erect bipedal walking.