Fanconi syndrome with karyomegalic interstitial nephritis after ifosfamide treatment for osteosarcoma: a case report.

Patients with ifosfamide-induced renal damage present with Fanconi syndrome. Karyomegalic nephropathy/interstitial nephritis (KNIN) is a rare form of chronic tubulo-interstitial nephritis that was initially considered a type of familial nephropathy. However, several reports of drug-induced KNIN, i.e., KNIN-like nephropathy, have been reported in recent years. We present the case of an 18-year-old man who presented with Fanconi syndrome and progressive renal dysfunction after receiving chemotherapy including ifosfamide and cisplatin for right femoral osteosarcoma. Renal biopsy revealed numerous atrophied tubular epithelial cells with large, polymorphic nuclei, and the definitive diagnosis was KNIN. Most patients with KNIN-like nephropathy who receive ifosfamide are concomitantly treated with cisplatin, indicating that ifosfamide and cisplatin might act synergistically to increase the risk for KNIN-like nephropathy. Further investigation in case series is warranted to reveal potential treatment approaches and to evaluate prognosis.

Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Acute tubulointerstitial nephritis possibly caused by vedolizumab for ulcerative colitis in a kidney transplant recipient: A case report.

Vedolizumab, which is used to effectively treat ulcerative colitis (UC), is a humanized monoclonal antibody that specifically inhibits α4ß7 integrin on lymphocytes and prevents lymphocyte migration into the intestinal tissues. Herein, we report a case of acute tubulointerstitial nephritis (ATIN) probably caused by vedolizumab in a kidney transplant recipient (KR) with UC. Approximately 4 years after kidney transplantation, the patient developed UC and was treated initially with mesalazine. Treatment continued with the addition of infliximab later; however, he was hospitalized because of poor symptom control and treated with vedolizumab. His graft function declined rapidly after vedolizumab was administered. Allograft biopsy revealed ATIN. Since no evidence of graft rejection was found, vedolizumab-associated ATIN was diagnosed. The patient was treated with steroids, and his graft function improved. Unfortunately, he finally underwent total colectomy considering that UC was refractory to medical treatment. Previously, cases of vedolizumab-induced acute interstitial nephritis have been reported; however, none were associated with KRs. This is the first report of ATIN in KR which was possibly induced by vedolizumab.

Prognostic factors of IgA nephropathy presenting with mild proteinuria at the time of diagnosis (a multicenter cohort study).

BACKGROUND: Clinical factors affecting renal prognosis in patients with immunoglobulin A nephropathy (IgAN) and low urinary protein excretion (U-Prot) remain unclear. This study evaluated such factors in patients with clinical grade I (CG-I) IgAN with U-Prot < 0.5 g/day. METHODS: This secondary analysis of a previous retrospective study included 394 patients with CG-I IgAN. The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine levels from baseline. Factors related to renal prognosis were examined using univariate and multivariate Cox regression analyses. CG-I was divided into C-Grade Ia (CG-Ia) (n = 330) with baseline eGFR ≥ 60 ml/min/1.73 m2, and C-Grade Ib (CG-Ib) (n = 64) with baseline eGFR < 60 ml/min/1.73 m2. Outcome incidence was compared between conservative and aggressive therapy (corticosteroids and/or tonsillectomy) groups. RESULTS: Overall outcome incidence was significantly higher in CG-Ib than in CG-Ia; the cumulative incidence was significantly higher in CG-Ib (hazard ratio, 9.67; 95% confidence interval, 2.90-32.23). Older age, higher IgA levels, eGFR < 60 mL/min/1.73 m2, lower eGFR at baseline were independent prognostic factors for CG-I. Older age, lower eGFR, higher IgA levels at baseline, and U-Prot remission at 1-year post-diagnosis were independent prognostic factors for CG-Ib. Aggressive therapy tended to suppress the cumulative outcome incidence compared with conservative therapy in CG-Ib (p = 0.087). CONCLUSION: An eGFR < 60 mL/min/1.73 m2 is a significant predictor of renal prognosis in patients with IgAN and U-Prot < 0.5 g/day.

Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report.

BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential inhibitory regulator of immune activation. CTLA-4 haploinsufficiency is known to be associated with dysregulation of FOXP3+ regulatory T cells, hyperactivation of effector T cells, and lymphocytic infiltration of multiple organs. However, there have only been a few reports of renal involvement with CTLA-4. Herein, we present a case of acute granulomatous tubulointerstitial nephritis (TIN) in a patient with CTLA-4 haploinsufficiency. CASE PRESENTATION: A 44-year-old man presented with a 3-week history of fever and malaise, and subsequently developed acute kidney injury (AKI) a few days after treatment with levofloxacin (LVFX). A kidney biopsy and immunohistochemical staining revealed granulomatous TIN with dominantly infiltrating CD4+ T cells. General symptoms and renal impairment showed improvement after discontinuation of LVFX and initiation of oral steroids. However, they worsened following steroid tapering. Further, a colon biopsy analysis showed similar findings to the renal tissue analysis. We suspected that granulomatous TIN was possibly associated with CTLA-4 haploinsufficiency. Therefore, the patient was transferred to another hospital for further treatment of CTLA-4 haploinsufficiency using immunosuppressive agents. CONCLUSIONS: There have been few reports regarding renal involvement of CTLA-4 haploinsufficiency. In the present case, granulomatous TIN could have arisen due to instability of immune regulatory functions, such as CTLA-4 haploinsufficiency, and treatment with LVFX could have triggered immunologic activation and severe inflammation as well as renal dysfunction.

Spontaneous remission in adult patients with IgA nephropathy treated with conservative therapy.

BACKGROUND: There are few studies describing the clinical course and spontaneous remission of IgA nephropathy (IgAN) in adult patients receiving conservative treatment. METHOD: Data from 62 adult patients with biopsy-diagnosed IgAN, who received conservative treatment at least 5 years prior, were retrospectively investigated. No patients received corticosteroids, other immunosuppressants, or tonsillectomy. Remission of proteinuria and hematuria were defined as proteinuria <0.3 g/gCr and urine red blood cells (RBC) <5 / high power field (HPF) on three consecutive urinalyses obtained during an observation period of ≥6 months. RESULT: Thirty-eight (61.3%) patients had remission of hematuria, 24 (38.7%) had remission of proteinuria, and 19 (30.6%) had remission of both. Remission rates increased in patients with proteinuria <0.5 g/g Cr at diagnosis. The median time to remission of hematuria was 2.8 years and that of proteinuria was 2.6 years. Patients who showed renal function decline (defined as 30% decline of estimated glomerular filtration rate [eGFR] from baseline) were older, had significantly lower eGFR, and higher proteinuria at diagnosis. Two patients with preserved renal function and normal proteinuria at diagnosis experienced renal function decline. Renal function did not decline within 3 years of diagnosis in patients with proteinuria <1 g/gCr at diagnosis. CONCLUSIONS: Relatively high rates of spontaneous remission were observed. Remission of both hematuria and proteinuria were frequent within 3 years after diagnosis, and renal function was well preserved during this period. These data indicate that it is rational to use conservative treatment for 3 years after the diagnosis instead of aggressive treatments.

Nephrotic syndrome due to preeclampsia before 20 weeks of gestation: a case report.

BACKGROUND: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period. CASE PRESENTATION: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely. CONCLUSIONS: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Morphological Features of Minimal Change Disease and Focal Segmental Glomerulosclerosis Using Repeat Biopsy and Parietal Epithelial Cell Marker.

INTRODUCTION: Minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS) are representative podocyte diseases. The clinical cause of MCD and FSGS has not been clearly elucidated yet. However, it is important to distinguish MCD and FSGS because their prognoses and responses to treatment are quite different. OBJECTIVE: This study aimed to examine whether parietal epithelial cell (PEC) marker and repeat biopsy are useful for diagnosing primary FSGS. METHODS: Clinicopathological features of 17 patients with the nephrotic syndrome, who underwent kidney biopsy ≥2 times from 1975 to 2017, and had MCD or FSGS were analyzed using PAX8. We defined patients with PAX8+ cells as PAX8+ and the remainder as PAX8- patients. Three cases of sample insufficiency and 1 non-steroid-resistant or frequently relapsing case indicated for repeat biopsy were excluded. RESULTS: Among the 13 patients studied, 4 were PAX8+ and 9 were PAX8- (median age: 41 and 46 years, -respectively, at first biopsy). PAX8+ and PAX8- patients showed no significant differences in clinical data and histological diagnosis except for a significant difference in histological diagnosis at the second biopsy. The number of PAX8+ patients increased to 6. Unlike the first biopsy results, FSGS was present in 5 of 6 (83.3%) PAX8+ patients; MCD occurred in all 7 (100%) PAX8- patients. Three of 6 (50.0%) PAX8+ patients undergoing repeat biopsy were steroid resistant; no (0%) PAX8- patient was steroid resistant. All cases of final FSGS diagnosis were PAX8+ at the first or second biopsy. Only 1 PAX8+ MCD patient was steroid resistant. All PAX8- MCD patients were frequently relapsing. CONCLUSIONS: More PAX8+ patients were diagnosed with FSGS than PAX8- patients. Clinical presentation of MCD in PAX8- patients was frequently relapsing. PEC marker staining in patients with the nephrotic syndrome, e.g., MCD, may help to diagnose FSGS.

Membranous nephropathy associated with thrombospondin type-1 domain-containing 7A (THSD7A) in an adult woman with eosinophilia.

A 30-year-old woman on steroid therapy for eosinophilia presented with nephrotic syndrome during steroid tapering. She was diagnosed with membranous nephropathy (MN) stage II-III (positive for IgG1 and IgG4) by renal biopsy. There was no evidence of secondary MN. Her urinary protein level was controlled to 0.5 g/day or less, and her eosinophil count in white blood cell differential was stabilized at less than 10% without increasing the steroid dosage. The renal specimen did not show any enhanced granular expression of PLA2R along the glomerular basement membrane, and PLA2R was not detected in the patient's serum. On retrospective analysis, enhanced granular staining for thrombospondin type-1 domain-containing 7A (THSD7A) in the glomeruli was detected in the biopsy, and anti-THSD7A IgG was detected in the serum using a commercial indirect immunofluorescence test (IFT). Based on these, the case was considered as THSD7A-associated MN with comorbid eosinophilia. The causal relationship between THSD7A-related MN and eosinophilia was unclear. However, a few cases of THSD7A-associated MN with eosinophilia have been reported, and further clarification on the relationship between THSD7A-related MN and eosinophilia is warranted.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: A single-centre retrospective study.

The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.

Lack of partial renal response by 12 weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV.

BACKGROUND: Lupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV. METHODS: Eighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years. RESULTS: Forty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3. CONCLUSIONS: Lack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI.

Asymptomatic post-transplant lymphoproliferative disorder diagnosed at one year protocol renal allograft biopsy.

Post-transplant lymphoproliferative disorder (PTLD) is a neoplastic complication with a potentially fatal outcome that develops as a consequence of immunosuppression, and is mainly associated with Epstein-Barr virus (EBV) infection. A 70-year-old woman underwent a live unrelated, ABO-incompatible renal transplant for end-stage renal disease. One year after transplantation, protocol biopsy revealed pathological changes indicative of the histological subtype of 'early lesions of PTLD' according to the World Health Organization classification, while the patient showed no clinical signs or symptoms. The patient was finally diagnosed with EBV-positive PTLD by in situ hybridization for EBER (EBV-encoded RNA), and was successfully treated based on the reduction of immunosuppression. Protocol biopsy within the first post-transplant year is the only diagnostic measure to detect asymptomatic early PTLD, which allows for early intervention and leads to better outcomes.

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy.

BACKGROUND: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). METHODS: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. RESULTS: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. CONCLUSIONS: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

Three cases of nephrotic syndrome associated with hematological malignancies characterized by glomerular endocapillary proliferation and massive inflammatory cel infiltration.

Nephrotic syndrome often emerges with malignancy. Membranous nephropathy is generally associated with solid tumors, and minimal change disease is associated with Hodgkin's disease. However, the complication of malignancy cannot be predicted by simply using renal histological findings. We report here three cases of nephrotic syndrome associated with hematological malignancy. On histology, Cases 1 and 2 were membranous nephropathy, and Case 3 was minimal change disease. Cases 1 and 2 were found to have B-cell non-Hodgkin's lymphoma, while Case 3 had Hodgkin's lymphoma. In Cases 1 and 2, proteinuria diminished as chemotherapy was started. All three cases were characterized by glomerular endocapillary proliferation and massive glomerular infiltration of inflammatory cells. These three cases are reported because their histologically atypical findings might be a feature of hematological malignancy- associated nephrotic syndrome and of any help for diagnosis.

Overestimation of the risk of progression to end-stage renal disease in the poor prognosis' group according to the 2002 Japanese histological classification for immunoglobulin A nephropathy.

BACKGROUND: The current (2012) histological classification of immunoglobulin A nephropathy was established using a case-control study of 287 patients. However, the risk of progression to end-stage renal disease (ESRD) has not been validated for the previous (2002) classification. This study aimed to determine whether the previous classification could identify the risk of long-term renal outcome through re-analysis of the 2012 cohort. METHODS: On the basis of the 2002 classification, namely 'good prognosis', 'relatively good prognosis', 'relatively poor prognosis', and 'poor prognosis', we examined the clinical data at the time of biopsy, the correlation between the 2002 classification and long-term renal outcomes, and a patient-by-patient correlation between the 2002 and 2012 classification systems. This was performed by analyzing samples from the 287 patients used to establish the 2012 classification. RESULTS: The rate of decline of estimated glomerular filtration rate was greater and the odds ratio of progression to ESRD was higher in the 'poor prognosis' group. In contrast, the odds ratio for renal death was comparable between the groups described as 'relatively poor prognosis' and 'relatively good prognosis' in the 2002 classification. Many patients in the 2002 classification were classified with a lower histological grade in the current classification, but none were classified with a higher grade. CONCLUSIONS: The 2002 classification could also identify the risk of progression to ESRD. However, it was overestimated for patients in the 'poor prognosis' group in the 2002 classification, as that group included patients with milder histological damage.