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.

Hypouricemia in the emergency department: A retrospective, single-center study.

Backgrounds: Few studies have reported the prevalence and characteristics of hypouricemia in the emergency department (ED). We investigated the prevalence and characteristics of hypouricemia in the ED of a university-affiliated hospital in Japan. Methods: This is a retrospective cross-sectional single-center study. All adult patients (18 years old or older) who had their serum uric acid (SUA) measured at the ED between 2011 and 2021 were included. Information collected included age, sex, SUA, and serum creatinine. Hypouricemia was defined as an SUA level ≦2.0 mg/dL. Results: A total of 10,551 patients were included in the study. Fifty-one percent were male. The median SUA levels were significantly higher in men than in women (6.0 [4.8-7.4] vs. 4.7 [3.7-6.1], p < 0.001). The prevalence of hypouricemia was higher in women than in men (2.0% vs. 0.9%, p < 0.001). A possible cause of hypouricemia was identified in 88 patients. Malignancy and diabetes were the major possible cause of hypouricemia (p < 0.001). Conclusion: The distribution of SUA levels and prevalence of hypouricemia differed significantly by sex and age in the ED. Malignancy was the leading cause of hypouricemia in the ED.

Impact of early initiation of renin-angiotensin blockade on renal function and clinical outcomes in patients with hypertensive emergency: a retrospective cohort study.

BACKGROUND: Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin-angiotensin-aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function. METHODS: This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years. RESULTS: Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1-5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m2) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m2) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77-1.0] vs. 0.63 [95%CI: 0.34-0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB. CONCLUSIONS: Early use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB.

Renal hypouricemia in a recipient of living-donor kidney transplantation: a case report and literature review.

Hypouricemia in kidney transplant (KT) recipients is rare since they usually have subnormal kidney function which raises serum uric acid level. Recently, interests in pathogenesis of hypouricemia have been increasing due to the understanding of the role of uric acid transporter in renal hypouricemia (RHUC). We herein report the case of RHUC consequently developed in a KT recipient from a living donor with RHUC diagnosed by the detailed urinary and genetic test. A 73-year-old Japanese man underwent KT, and the donor was his wife who had hypouricemia [serum uric acid (S-UA) 0.6 mg/dL]. Nine months after KT, the recipient's S-UA was low (1.5 mg/dL) with serum creatinine (S-Cr) of 1.56 mg/dL, and fractional excretion of UA (FEUA) was high (59.7%; normal < 10%), indicating RHUC. Regarding the donor's information, S-Cr, S-UA, and FEUA were 0.95 mg/dL, 1.0 mg/dL, and 54.5%, respectively. To investigate further on the pathogenesis of RHUC in both the recipient and the donor, we performed genetic tests. The donor had a homozygous mutation of W258X in the SLC22A12 gene and the recipient had a wild type of W258X. Finally, we reviewed the previous literature on RHUC among KT recipients and discussed the strategy of follow-up for these patients.

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia.

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes. Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients. Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (-45.05, 95% CI -48.90 to -41.24 mg/dL), TNFR1 (1.10, 95% CI-2.25 to 4.40), and TNFR2 (1.66, 95% CI -1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR. Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

Association between pill burden and interdialytic weight gain in patients with hemodialysis: A multi-center cross-sectional study.

High daily pill burden affects quality of life and mortality. High interdialytic weight gain (IDWG) is associated with increased mortality. We examined the association between pill burden and IDWG in hemodialysis patients. This cross-sectional study was conducted in six dialysis centers in Japan in June 2017. The exposure was the number of daily tablets, and outcome was defined as 1 day of relative IDWG divided by post-dialysis weight from the previous session. Among 188 outpatients (mean age, 68.7 [SD, 10.3] years; men, 67.0%; median dialysis vintage, 76.0 [interquartile range, 36.5, 131.5] months), the mean number of daily tablets was 19.7 ± 9.9, and mean relative weight gain was 3.5 ± 1.2%. Multiple linear regression analysis showed a regression coefficient of 0.021 (95% confidence interval: 0.004-0.039), indicating that one additional tablet prescription increased the IDWG by 0.021%. In hemodialysis patients, the daily pill burden was a significant, independent risk for increased relative IDWG.

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.

Arteriovenous fistulas after ultrasound-guided needle biopsy of kidney allografts and treatment outcomes after transcatheter embolization: A single-center experience in Japan.

BACKGROUND: Arteriovenous fistula (AVF) is one of the vascular complications after allograft biopsy, and their reported incidence rates range widely. Transcatheter embolization (TE) is a common AVF treatment in kidney allografts. However, information on AVF incidence and features and TE outcomes in Japanese kidney transplant (KT) recipients is lacking. METHODS: This study investigated 270 protocol or clinically indicated kidney allograft biopsies in 129 KT recipients during 2010-2016 at a single-center using standardized methods (16-gauge needle and ultrasound guidance). We recorded the incidence and clinical features of AVF using currently recommended standardized methods of allograft biopsy and TE outcomes regarding allograft function up to 12 months after the procedure in Japanese KT recipients. RESULTS: AVF incidence was 2.6% (seven cases). The time from biopsy to AVF diagnosis was 7 (median, interquartile range: 5-117, range: 1-318) days. The time from biopsy to AVF diagnosis was significantly shorter in symptomatic cases (gross hematuria) than in asymptomatic cases (median 6 vs. 117 days, p = 0.034). Symptomatic patients underwent TE within a shorter time (0-6 days) than asymptomatic patients (25-104 days). There were no complications, and allograft function was stable up to 12 months after TE despite using contrast media and partial renal infarction. CONCLUSIONS: AVF does occur in certain probabilities. AVF formation can occur without apparent bleeding and exist for a long time after allograft biopsy. TE is a safe and immediate treatment for AVF in kidney allograft.

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.

Encapsulating peritoneal sclerosis with steroid-resistant massive ascites successfully treated by peritoneal lavage.

Encapsulating peritoneal sclerosis (EPS) is the most serious complication of long-term peritoneal dialysis (PD). EPS is diagnosed by clinical symptoms (abdominal pain, nausea, vomiting, diarrhea, and anorexia.) and image study (intestinal expansion, peritoneal thickening and calcification, and ascites.). Steroid therapy and surgery are recommended as the treatment of EPS. Here, we report a case of EPS with steroid-resistant massive ascites successfully treated with peritoneal lavage. A 59-year-old female with end-stage kidney disease secondary to hypertension was started on PD in 2003. Due to recurrent exit-site infection and two episodes of peritonitis, she was transferred to hemodialysis (HD), and her PD catheter was removed in 2011. In February 2012, six months after discontinuation of PD, she was found to have massive ascites on abdominal computerized tomography (CT). The patient was diagnosed to have EPS and was started on prednisolone. Despite eight months of prednisolone therapy, the ascites did not decrease. Therefore, the PD catheter was inserted again, and she was started on daily peritoneal lavage from September 2012. After four months of daily peritoneal lavage, her ascites disappeared in January 2013. The PD catheter was removed in July 2013. Steroid treatment was completed in May 2014, and there has been no recurrence of ascites since then. The evaluation of ascites by abdominal CT is important in a patient on long-term PD. Since EPS may appear any time after the discontinuation of PD, it is important to start screening abdominal CT shortly after the discontinuation of PD. Steroid-resistant massive ascites can be successfully treated with peritoneal lavage.

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.

Cellular therapy of kidney diseases.

The understanding of cellular sources of kidney regeneration has rapidly evolved in the last decade. It is now believed that regeneration occurs predominantly from cells that reside within the injured kidney, with minimal contribution from extra-renal cells. We now know that improved kidney regeneration seen following exogenous administration of stem cells occur predominantly by noncellular paracrine mechanisms. Of all extra-renal stem cells, mesenchymal stem cells (MSC) are the most promising stem cell type for treating kidney diseases. There is an ongoing clinical trial evaluating safety and efficacy of MSC in treating acute kidney injury (AKI). Results of this trial are expected to bring use of MSC closer to the clinical realm. An improved understanding of the small molecules that facilitate kidney regeneration and are secreted by MSC will likely result in the development of new therapies for treating AKI. Identification of adult stem cell markers will result in improved understanding of pathophysiology of kidney diseases and could lead to the development of new cellular therapies. Directed differentiation of stem cells into desired cell types such as erythropoietin producing cells will allow selective replacement of lost kidney function. Cell-based therapies for patients with chronic kidney disease are presently in proof-of-principle stage and are expected to evolve in the coming years with improved understanding of stem cell biology. Technological advancement in cellular therapy is expected to provide improved therapeutic options for patients with kidney diseases in the near future.

Angiotensin II type 1 receptor blockade prevents decrease in adult stem-like cells in kidney after ureteral obstruction.

Infusion of renal side population (SP) cells, enriched with adult stem-like cells, can ameliorate acute renal failure. We investigated the effects of an angiotensin II type 1 (AT(1)) receptor antagonist, valsartan on SP cell changes in renal injury by ureteral obstruction. Renal SP fraction was reduced by 38%, and the number of cells expressing CD45, a marker of hematopoietic system, in renal SP cells was increased in obstructed kidneys. Valsartan attenuated renal injury and the associated SP profile changes. Angiotensin AT(1) receptor blockade may exert regenerative effect by preserving adult stem-like cells such as SP cells in the kidney.