Pegylated-liposomal Doxorubicin-induced Glomerular Thrombotic Microangiopathy.

Pegylated liposomal doxorubicin (PLD) has emerged as a recent innovation within the realm of antineoplastic agents, distinguished by its incorporation of doxorubicin within the liposomal bilayer. Given the low risk of cardiotoxicity, the clinical use of PLD has been expanding. We encountered a patient who underwent extended PLD therapy for recurrent malignancy and subsequently developed PLD-associated thrombotic microangiopathy, which was diagnosed by a detailed pathophysiological assessment. This case underscores the importance of considering thrombotic microangiopathy as a potential differential diagnosis in patients presenting with unexplained hypertension and renal impairment during prolonged PLD monotherapy.

Pembrolizumab-induced Acute Tubulointerstitial Nephritis Accompanying Fanconi Syndrome and Type 1 Renal Tubular Acidosis.

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Nephrotic syndrome induced by aortic regurgitation with Takayasu arteritis: an autopsy case with long-term clinical follow-up.

Takayasu arteritis is a rare, chronic, and large-vessel vasculitis involving the aorta and its branches in a complex autoimmune reaction. Takayasu arteritis sometimes complicates aortic regurgitation and chronic kidney disease, but rarely accompanies nephrotic syndrome. We had a patient with Takayasu arteritis and concomitant aortic regurgitation. She had nephrotic syndrome that was refractory to immunosuppressive therapy but was promptly improved after surgical aortic valve replacement. In her kidney biopsy, glomeruli had mild mesangial proliferative changes without immune complex deposition. Her proteinuria remained negative until the recurrence of aortic regurgitation due to perivalvular leakage. Seventeen years after the surgery, she died suddenly. In her kidney autopsy, the arteriolar showed severe hyalinosis and the glomerulus showed mesangial proliferative changes with segmental mesangiolysis. Severe aortic regurgitation may have altered renal hemodynamics and caused glomerular lesions, resulting in nephrotic syndrome. We should be aware of the rare but critical comorbidity of nephrotic syndrome in patients with Takayasu arteritis and concomitant aortic regurgitation.

Urinary levels of cortisol but not catecholamines are associated with those of 8-hydroxy-2'-deoxyguanosine in uncomplicated primary hypertension.

OBJECTIVES: The relationships between stress hormones and oxidative DNA damage have not yet been explored in human hypertension. We investigated the associations of urinary levels of cortisol or catecholamines with those of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage in primary hypertension. METHODS: Untreated 156 primary hypertensives without apparent cardiovascular diseases were entered into the study. Following blood sampling after an overnight fast, 24-h blood pressure monitoring and 24-h urinary sampling were performed simultaneously to determine 24-h averaged values for blood pressure and urinary levels of cortisol, catecholamines and 8-hydroxy-2'-deoxyguanosine. RESULTS: Urinary cortisol significantly correlated positively with urinary 8-hydroxy-2'-deoxyguanosine in all studied participants (r = 0.334, P < 0.001). Contrary, either urinary adrenaline or urinary noradrenaline did not significantly correlate with urinary 8-hydroxy-2'-deoxyguanosine (r = 0.050, P = 0.553 or r = 0.063, P = 0.435). Additionally, the positive association of urinary cortisol with urinary 8-hydroxy-2'-deoxyguanosine remained highly significant after the adjustments for multiple confounders of oxidative stress such as age, gender, body mass index, smoking status, 24-h blood pressure, C-reactive protein and estimated glomerular filtration rate (partial r = 0.323, P < 0.001), although only approximately 10% of the variance in urinary cortisol was attributable to differences in urinary 8-OHdG (partial r2 = 0.104). Thus, our data indicate that cortisol but not catecholamines could at least partially contribute to the occurrence of oxidative DNA damage in primary hypertensives. CONCLUSION: The present study suggested the possibility that the overactivation of hypothalamic-pituitary-adrenal axis rather than sympathoadrenal system could enhance oxidative stress and attendant DNA oxidation in uncomplicated primary hypertension.

Implication of serum growth differentiation factor-15 level in patients with renal diseases.

BACKGROUND: The synthesis of growth differentiation factor-15 (GDF-15) is induced by inflammation, hypoxia, and oxidative stress and is receiving great interest as a predictive biomarker for cardiovascular disease. However, its detailed impact on patients with renal disease remains uncertain. METHODS: Patients who underwent renal biopsy for evaluation of renal disease between 2012 and 2017 in our institute were prospectively included. Serum GDF-15 levels were measured and its association with baseline characteristics and its impact on the 3-year composites of renal prognosis (composites of > 1.5 folds of serum creatinine and renal replacement therapy) were investigated. RESULTS: A total of 110 patients (64 [42, 73] years old, 61 men) were included. The median serum GDF-15 level at baseline was 1885 (998, 3496) pg/mL. A higher serum GDF-15 level was associated with comorbidities including diabetes mellitus, anemia, renal impairment, and pathologic features including crescent formation, hyaline degeneration, and interstitial fibrosis (p < 0.05 for all). Serum GDF-15 level was a significant predictor of 3-year composite renal outcomes with an odds ratio per 100 pg/mL of 1.072 (95% confidence interval 1.001-1.103, p = 0.036) after adjustment for potential confounders. CONCLUSIONS: Serum GDF-15 levels were associated with several renal pathological features and renal prognosis in patients with renal diseases.

Prognostic impact of renal sinus fat accumulation in patients with chronic kidney disease.

BACKGROUND: Obesity is associated with the development and progression of chronic kidney disease (CKD). In the general population, the amount of renal sinus fat was associated with hypertension and renal impairment. However, its impact upon those with CKD remains uncertain. METHODS: We prospectively included CKD patients who underwent renal biopsy and simultaneously measured their renal sinus fat volume. The association between the percentage of renal sinus fat volume, which was adjusted by kidney volume, and renal outcomes was investigated. RESULTS: A total of 56 patients (median 55 years old, 35 men) were included. Among baseline characteristics, age and visceral fat volume were positively correlated with the percentage of renal sinus fat volume (p < 0.05). The percentage of renal sinus fat volume was associated with hypertension (p < 0.01) and tended to be associated with max glomerular diameter (p = 0.078) and urine angiotensinogen creatinine ratio (p = 0.064) after adjustment with several clinical factors. The percentage of renal sinus fat volume was significantly associated with a future > 50% decline in estimated glomerular filtration rate (p < 0.05). CONCLUSIONS: Among those with CKD who required renal biopsy, the amount of renal sinus fat was associated with poor renal outcomes accompanied by systemic hypertension.

Malignant Hypertension and Bilateral Primary Aldosteronism.

Malignant hypertension triggers incremental renin activity, whereas primary aldosteronism suppresses such activity. We encountered a patient with malignant hypertension refractory to multiple anti-hypertensive agents. Repeated neurohormonal assessments, instead of a single one, eventually uncovered trends in an incremental aldosterone concentration, ranging from 221 up to 468 pg/mL, with a decline in the renin activity from 2.3 to <0.2 ng/mL/h. Adrenal venous sampling confirmed bilateral aldosterone secretion. Following the diagnosis of bilateral primary aldosteronism, we initiated a mineralocorticoid receptor antagonist, which improved his blood pressure. Repeated neurohormonal assessments are encouraged to correctly diagnose underlying primary aldosteronism with malignant hypertension.

Impact of urine cyclic AMP relative to plasma arginine vasopressin on response to tolvaptan in patients with chronic kidney disease and heart failure.

BACKGROUND: The clinical utility of tolvaptan in chronic kidney disease (CKD) patients with heart failure remains uncertain. The level of urine cyclic adenosine monophosphate (AMP) relative to plasma arginine vasopressin (AVP) indicates the residual function of the collecting ducts in response to AVP stimulation and might be a key to predicting response of tolvaptan. METHODS: CKD patients who were hospitalized to treat their congestive heart failure refractory to conventional loop diuretics were considered to receive tolvaptan and included in this prospective study. The impact of urine cyclic AMP/plasma AVP ratio for prediction of response to tolvaptan, which was defined as any increase in urine volume at day 7 from day 0, was investigated. RESULTS: A total of 30 patients (median 75 years old, 24 men, and median estimated glomerular filtration rate 14.4 mL/min/1.73 m2) were included. As compared to baseline, urine volume increased at day 7 in 17 responders, whereas urine volume decreased at day 7 in 13 non-responders. Baseline urine cyclic AMP/plasma AVP ratio distributed between 0.25 and 4.01 with median 1.90. The urine cyclic AMP/plasma AVP ratio was a significant predictor of response to tolvaptan, which was adjusted for 6 potential confounders with a cutoff of 1.24. CONCLUSIONS: Baseline urine cyclic AMP/plasma AVP ratio is an independent predictor of response to tolvaptan in advanced CKD patients with heart failure. CLINICAL TRIAL REGISTRATION: UMIN000022422.

Implication of changes in xanthine oxidase activity following hemodialysis.

BACKGROUND: Xanthine oxidase activity has a key role in the development of oxidative stress and progression of cardiovascular diseases. However, the change of xanthine oxidase activity following hemodialysis and its prognostic impact remain uncertain. METHODS: We prospectively included hemodialysis patients who did not take any anti-hyperuricemic agents and measured their xanthine oxidase activity before and after the index hemodialysis. The impact of change in xanthine oxidase activity during hemodialysis on cardiovascular death were investigated. RESULTS: A total of 46 patients (median 72 years old, 29 men) were included. During hemodialysis, a common logarithm of xanthine oxidase activity decreased significantly from 1.16 (0.94, 1.27) to 1.03 (0.80, 1.20) (p < 0.01). Of them, xanthine oxidase activity remained unchanged or increased in 16 patients, who had a greater decrease in blood pressure and more hemoconcentration compared with others. Two-year survival from cardiovascular death was not significantly stratified by the changes in xanthine oxidase activity (p = 0.43). CONCLUSIONS: During hemodialysis, xanthine oxidase activity decreased among the overall cohort, whereas some patients experienced its increases, which might be associated with hypotension and hemoconcentration during hemodialysis. Further larger-scale studies are required to validate our findings and find clinical implication of change in xanthine oxidase activity during hemodialysis.

Factors Associating with Non-Dipping Pattern of Nocturnal Blood Pressure in Patients with Essential Hypertension.

Background: In patients with essential hypertension, a non-dipping blood pressure pattern is a strong risk factor for cardiovascular diseases. However, background factors associating with such a blood pressure pattern remain unknown. Methods: Untreated essential hypertensive patients without chronic kidney diseases who were admitted to our outpatient clinic were included. Blood sampling and 24 h ambulatory blood pressure monitoring were mandatorily performed. Non-dipper status was defined as a maximum decrease in nocturnal systolic blood pressure within 10%. Clinical factors associating with non-dipper status were investigated. Results: A total of 154 patients (56 ± 12 years old, 86 men) were included. Among baseline characteristics, a higher serum uric acid level was independently associated with non-dipper status (odds ratio 1.03, 95% confidence interval 1.00−1.05, p < 0.05). Among those with non-dipper status, a higher high-sensitivity C-reactive protein level tended to be associated with incremental nighttime systolic blood pressure levels (p = 0.065). Conclusions: Hyperuricemia and micro-inflammation might be associated with attenuated nocturnal blood pressure dipping and incremental nighttime systolic blood pressure levels.

Acute Kidney Injury with Severe Metabolic Alkalosis Caused by Habitual Vomiting in an Alcohol Abuser with Pyloric Stenosis.

A 47-year-old man was complaining of consciousness disorder. He had acute kidney injury, hypokalemia, and severe metabolic alkalosis. Initial treatment using intravenous infusion of 0.9% saline and potassium chloride improved his consciousness. It was clarified that he was a severe alcohol abuser who habitually self-vomited. We diagnosed him with volume depletion and pseudo-Bartter's syndrome due to loss of chloride by habitual vomiting. Gastrointestinal endoscopy demonstrated pyloric stenosis, which was ameliorated by Helicobacter pylori eradication therapy. We should consider volume depletion and pseudo-Bartter's syndrome as differential diagnoses when we encounter patients with acute kidney injury and severe metabolic alkalosis.

Prognostic impact of urine cyclic AMP levels in patients with chronic kidney disease.

BACKGROUND: Urine cyclic adenosine monophosphate (cAMP) is a biomarker to assess the residual function of the collecting duct in the kidney. Prognostic implication of urine cAMP levels in patients with chronic kidney disease (CKD) remains unknown. METHODS: Patients who were followed at our specific outpatient clinic to treat their CKD between December 2015 and December 2019 were included in this prospective study. The impact of urine cAMP levels on the composite of dialysis administration, cardiovascular death, and doubling of serum creatinine concentration was investigated. RESULTS: A total of 106 patients (median 72 years old, 80 men, and median estimated glomerular filtration rate 28.4 mL/min/1.73 m2) were included. Urine cAMP levels ranged widely between 0.35 and 4.08 nmol/mg of creatinine with a median value of 1.99 nmol/mg of creatinine. A urine cAMP level was an independent predictor of the primary endpoint with a hazard ratio of 0.41 (95% confidence interval 0.18-0.91, p = 0.029) adjusted for 5 potential confounders with a cutoff of 1.55 nmol/mg of creatinine. CONCLUSIONS: A lower urine cAMP is an independent predictor of renal deterioration and cardiovascular death in patients with CKD.

Altered arginine vasopressin-cyclic AMP-aquaporin 2 pathway in patients with chronic kidney disease.

BACKGROUND: In the collecting ducts of the kidney, arginine vasopressin (AVP), cyclic adenosine monophosphate (cAMP), and aquaporin 2 (AQP2) play a pivotal role in maintaining fluid volume and serum osmolality in humans. However, their association among those with chronic kidney disease (CKD) remains uncertain. METHODS: We prospectively included the out-patients with CKD and measured osmolality-related biomarkers including plasma AVP, urine cAMP, urine AQP2, and urine osmolality levels. Association among these parameters at each CKD stage was investigated. RESULTS: A total of 121 patients were included (median age 71 years old [61-78], 89 men, estimated glomerular filtration ratio 28.6 [16.4-45.3] mL/min/1.73 m2). Serum osmolality increased as CKD progression, accompanying incremental plasma AVP levels, whereas urine cAMP, urine AQP2, and urine osmolality decreased as CKD progression. At advanced CKD stage, urine cAMP remained low irrespective of the AVP stimulation, whereas urine cAMP levels varied according to the levels of plasma AVP at less advanced CKD stage. The associations between urine cAMP and urine AQP2 and between urine AQP2 and urine osmolality remained preserved irrespective of the CKD stages. CONCLUSIONS: Vasopressin type-2 receptor seems to be particularly impaired in patients with advanced CKD, whereas the signal cascade of the downstream of vasopressin type-2 receptor is relatively preserved. Urine cAMP might be a promising marker to estimate the residual function of the collecting duct.

Plasma and Urinary Levels of Nerve Growth Factor Are Elevated in Primary Hypertension.

Nerve growth factor (NGF) is the main neurotrophic factor that can control sympathetic nerve innervation and sympathetic neural activity in cardiovascular organs. Although NGF overproduction and its influences on the sympathetic nervous system have been shown in hypertensive animals, NGF status and its association with sympathetic nerve activity have not yet been explored in human hypertension. In the present study, therefore, plasma and urinary levels of NGF and those of catecholamines (i.e., indices for NGF status and sympathoadrenal activity, respectively) were compared between 83 untreated primary hypertensives without apparent cardiovascular damages and 81 healthy normotensive subjects. Plasma and urinary levels of NGF were significantly greater in the hypertensive group (311 ± 158 pg/mL and 72.7 ± 54.0 ng/g of Cr) than in the normotensive group (168 ± 188 pg/mL and 54.5 ± 38.8 ng/g of Cr) (p < 0.05 for each measurement), even if the baseline differences of age and gender between the groups were adjusted. Similarly, plasma and urinary levels of catecholamines were significantly higher in the hypertensive group than in the normotensive group except for plasma noradrenaline. In addition, despite no significant correlations between plasma levels of NGF and catecholamines in both groups, urinary NGF significantly correlated positively with both urinary noradrenaline and urinary adrenaline in the hypertensive group (r = 0.259, p=0.018 and r = 0.232, p=0.035), but not in the normotensive group (r = 0.115, p=0.307 and r = -0.018, p=0.871). On the contrary, plasma and urinary levels of NGF as well as those of catecholamines did not associate with any systemic hemodynamic indices such as blood pressure and pulse rate in either group. Thus, primary hypertension was characterized by the enhancements of both NGF status and sympathoadrenal activity and the positive relationship between them. Our data indicate that enhanced NGF status and subsequent NGF-induced sympathoadrenal overactivity could occur in primary hypertension.

Initial Experience to Follow Lung Fluid Levels during Hemodialysis: A Possibility of Remote Dielectric Sensing-Guided Hemodialysis.

Remote dielectric sensing (ReDSTM) is a novel technology that noninvasively quantifies lung fluid levels. Trends in ReDS values following hemodialysis remain uninvestigated. In a 64-year-old man with clinically stable hemodynamics, 2.7 L of fluid was drained during hemodialysis whereas the ReDS value remained almost unchanged (from 32 to 30%). In a 60-year-old woman with unstable hemodynamics, only 1.8 L of fluid was drained during hemodialysis, whereas ReDS value decreased considerably from 37 to 27%. Given our initial experience measuring ReDS values during hemodialysis, the ratio of fluid removal by hemodialysis between systemic plasma and lung fluid might vary in each patient. ReDS value might be a promising marker to determine the degree of fluid removal in addition to the conventional multidisciplinary index, particularly for those with unstable hemodynamics. The implications of ReDS-guided hemodialysis remain a future concern.

Impact of Geriatric Nutritional Risk Index and Modified Creatinine Index Combination on Mortality in Hemodialysis Patients.

The prognostic impact of the combination of a geriatric nutritional risk index (GRNI) and modified creatinine index, both of which assess nutritious status in hemodialysis patients, has not yet been well investigated thus far. Patients receiving maintenance hemodialysis in our institutes between February 2011 and January 2017 were retrospectively included. The baseline GRNI and modified Creatinine index were calculated and the impact of their combination on 5-year all-cause mortality following the index hemodialysis was investigated. A total of 183 patients (68.3 ± 12.4 years, 98 men, hemodialysis duration 97 ± 89 months) were followed from the index hemodialysis for 5.5 years. Mean GNRI was 91.2 and mean modified Creatinine index was 22.2 in men and 19.6 in women. The 5-year survival was significantly stratified by the median values of GNRI and modified Creatinine index (p < 0.05 for both). Patients with low GNRI and a low modified Creatinine index had lower 5-year survival than those with the other three combination patterns (p < 0.05). A combination of GNRI and modified Creatinine index may be a promising tool to risk stratify mortality in dialysis patients.

Cryofibrinogen-associated glomerulonephritis accompanied by advanced gastric cancer.

We had a 72-year-old man with advanced gastric cancer, poorly differentiated adenocarcinoma, receiving chemotherapy with S-1 (tegafur, gimeracil, and oteracil potassium) plus oxaliplatin. Ascites developed despite remission of gastric cancer and metastasis. Given no malignant cells in ascites, leg edema, renal impairment, hypoalbuminemia, and massive proteinuria, we diagnosed as nephrotic syndrome with microscopic hematuria. Renal biopsy showed membranoproliferative glomerulonephritis with no deposition of immunoglobulins and complements. Of note, electronic microscopy found organized deposits with microtubular structures in the glomerular capillary lumens and subendothelial spaces. The liquid chromatography-tandem mass spectrometry method detected fibrinogen alpha chain, beta chain, gamma chain, and fibronectin, and we eventually diagnosed cryofibrinogen-associated glomerulonephritis. Cryofibrinogen was not detected in plasma. He was expired at 5 months following renal biopsy due to the progression of refractory nephrotic syndrome. In addition to the detailed assessment of specifically organized deposits, the analysis using liquid chromatography-tandem mass spectrometry method is useful to diagnose cryofibrinogen-associated glomerulonephritis. We should consider cryofibrinogen-associated glomerulonephritis as a differential diagnosis when the patients with malignancy showed abnormal urinalysis and renal impairment, though it is a rare disease.

Renal Cell Carcinoma on the Native Kidney Following Kidney Transplantation.

A 48-year-old man with histories of IgA nephropathy for 33 years, hemodialysis for 29 years, and a kidney transplant from a deceased donor 5 years ago was admitted to our institute complaining of high fever and back pain. Although repeated follow-up of computed tomography failed to detect any de novo issues, he was eventually diagnosed as a renal cell carcinoma with multiple metastases, developing from his native-acquired cystic disease kidney with multiple cysts using a positron emission tomography. We should be cautious of de novo renal cell carcinoma in kidney transplantation recipients, and careful follow-up might be helpful to detect it.

A Case of Systemic Lupus Erythematosus and Antineutrophil Cytoplasmic Antibodies-Associated Vasculitis Overlap Syndrome.

An overlap of systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibodies- (ANCA-) associated vasculitis (AAV) is extremely rare: approximately 40 cases have been reported to date. A literature review indicates that they are more common in women in their forties, and simultaneous onset has been reported in 69% of cases. In addition, both lupus nephritis and ANCA-associated glomerulonephritis were observed on renal biopsy. This report presents the case of a 35-year-old woman with an 8-month history of polyarthralgia who was admitted to our hospital. She was diagnosed with SLE due to typical clinical presentation of the disease: polyarthritis, lymphocytopenia, hypocomplementemia, presence of antinuclear and anti-dsDNA antibodies, and proteinuria. However, purpura were scattered, and the titer of antimyeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA) was high. A skin biopsy revealed leukocytoclastic vasculitis that involved poor immune complex deposition. A renal biopsy showed necrotizing glomerulonephritis with cellular and fibrocellular crescent formation that involved deposition of IgM and C3c only in the mesangial area and the peripheral capillaries. Additionally, no electron-dense deposits were observed under electron microscopy. These pathological findings were consistent with AAV rather than with SLE. Therefore, we finally diagnosed the patient with both SLE and microscopic polyangiitis. After treatment with methylprednisolone and intravenous cyclophosphamide pulse therapies, renal function improved and MPO-ANCA levels decreased. In cases of suspected overlap between SLE and AAV, appropriate diagnosis and treatment are important.

Expression of aquaporin-2 in the collecting duct and responses to tolvaptan.

Tolvaptan, a vasopressin type-2 receptor antagonist, is indicated for fluid retention. It is considered that the response to tolvaptan reduces as renal function deteriorates, whereas we sometimes experience "non-responders" to tolvaptan despite well-preserved renal function. While the expression of aquaporin-2 might be a key to response to tolvaptan, detailed mechanism of refractoriness to tolvaptan remains unknown. We experienced two patients with congestive heart failure and diabetic nephropathy, in whom the responses to tolvaptan were uniquely opposite. In one case, immunohistochemical staining showed expression of aquaporin-2 in the collecting duct despite severely reduced renal function, followed by the good response to tolvaptan with increased urine output. In another case, immunohistochemical staining showed absence of aquaporin-2 with infiltration of inflammatory cells in the kidney medulla despite relatively preserved renal function, followed by refractoriness to tolvaptan without any increase in urine output. Inactivated aquaporin-2 expression in the collecting duct, which was for example caused by pre-clinical urinary infection as our latter case, might have an association with refractoriness to tolvaptan.