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.

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.

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.

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.

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.

Mucoepidermoid carcinoma of parotid gland and membranous nephropathy - differentiation between sclerosing mucoepidermoid carcinoma with eosinophilia and Kimura's disease.

BACKGROUND: When we encounter patients who present with both a neck mass and nephrotic syndrome, both malignancy and Kimura's disease need to be evaluated as the therapeutic strategies differ vastly between them. CASE PRESENTATION: We present the case of a 27-year-old male patient with neck mass and nephrotic syndrome. The presence of both eosinophilia and elevated immunoglobulin E levels were concerning for Kimura's disease, which is an allergic syndrome defined by eosinophilic granulomas of neck soft tissue along with peripheral eosinophilia. The eventual final diagnosis, however, was sclerosing mucoepidermoid carcinoma of parotid gland with both eosinophilia and membranous nephropathy. Following the surgical resection of the mass, the nephrotic syndrome completely resolved. CONCLUSION: Detailed histopathological assessments of both the parotid gland and renal tissue were key aspects of the diagnosis and management to exclude Kimura's disease.

[A case of oldest-old patient with chronic renal failure successfully treated with peritoneal dialysis].

He was a 92-year-old male patient with mild cognitive impairment while preserved activity of daily life. His renal dysfunction gradually increased due to the nephrosclerosis accompanied by systemic edema and water retention. We eventually decided to initiate peritoneal dialysis instead of standard hemodialysis for his end-stage renal dysfunction refractory to optimal medical therapy, given his preserved cognitive function and family support. He underwent an established therapeutic program for the peritoneal dialysis at home with an Information and Communication Technology (ICT).Given the increase in age of the patients with renal dysfunction, peritoneal dialysis has been receiving great attention as a home care strategy. The recent improvement in the device technology and ICT that enables us remote monitoring would reduce patients' effort in the management of peritoneal dialysis. Collaboration with home nursing and care workers would also be warranted for successful home care.

Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS.

BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤-50% change and -50 to -30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. CONCLUSION: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.

Renal vascular structural properties and their alterations by removal of uraemic toxins in a rat model of chronic kidney disease.

1. Renal vascular structural properties and their alterations by removal of uraemic toxins with AST-120, an oral adsorbent, were examined in subtotal nephrectomized rats. 2. Eight- or 9-week-old Sprague-Dawley rats received 3/4 nephrectomy (n = 18) and thereafter were fed 24.5% protein diet with (AST; n = 9) or without (AST-; n = 9) AST-120 (0.4 g/100 g bodyweight). Sham-operated rats (Sham; n = 9) received the diet without AST-120. At 21-22 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. 3. The gradient of F-P (minimal renal vascular resistance reflecting the overall luminal dimensions of pre- and post-glomerular vasculature) was lower in AST- than Sham rats. In contrast, the x-intercept (preglomerular : post-glomerular vascular resistance ratio) and gradient (glomerular filtration capacity) of P-GFR did not differ between the two groups. The vascular wall and lumen at the interlobular arteries were greater in AST- than Sham rats. 4. Although the vascular wall and lumen at the interlobular arteries were less in AST than in AST- rats, the gradient of F-P and the x-intercept of P-GFR did not differ between the two groups. In contrast, the glomerular filtration capacity was greater in AST than AST- rats. 5. In conclusion, the lumen of both pre- and post-glomerular resistance vessels increased and glomerular filtration capacity failed to increase in subtotal nephrectomized rats. Uraemic toxins could play an important role in the development of structural alterations in glomeruli rather than renal resistance vessels in chronic kidney disease.

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.

Arterioureteral fistula and refractory fatal pseudo-aneurysm in a patient receiving kidney transplantation.

Arterioureteral fistula represents a rare yet consequential urological complication characterized by persistent and refractory urinary tract bleeding. Its emergence typically involves aneurysm formation, presenting significant life-threatening implications. Nonetheless, its infrequency contributes to sparse documentation of incidences in post-kidney transplant recipients, thereby fostering numerous uncertainties concerning associated risks. A 67-year-old male patient, afflicted with end-stage renal failure and a history of urinary tract infection, underwent a living donor kidney transplant four months prior. Complications involving intraoperative bleeding necessitated the prolonged placement of a ureteral stent post-surgery. Subsequently, he experienced an abrupt onset of ureteral bleeding accompanied by shock, later diagnosed via contrast-enhanced computed tomography as pseudo-aneurysm formation in the right external iliac artery proximal to the allograft renal artery anastomosis, in conjunction with a fistula formation involving the donor ureter. Despite repeated attempts at intervention with covered stenting, the aneurysm persisted and proved refractory to resolution. Tragically, seven months later, the aneurysm ruptured, culminating in the demise of the patient. Our report details a case involving perioperative complications following kidney transplantation, persistent bacteriuria, and prolonged ureteral stenting, ultimately leading to the development of an arterioureteral fistula. Despite undergoing stent graft insertion as an intervention, the patient succumbed to aneurysm rupture associated with the arterioureteral fistula. This condition, though rare, can prove fatal following kidney transplantation. Consequently, future endeavors in this domain necessitate an emphasis on optimizing risk management, refining diagnostic approaches, and devising more effective therapeutic strategies to mitigate such complications.

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.

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.

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.

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.

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.

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.

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.

Clinical Implications of Steroid Therapy for Crescentic Glomerulonephritis and Gemella morbillorum-associated Infective Endocarditis.

A 54-year-old man was admitted to our institute with a diagnosis of infective endocarditis (IE) with vegetation on the mitral valve and severe regurgitation due to Gemella morbillorum infection together with renal dysfunction, which was eventually diagnosed as infection-related pauci-immune necrotizing crescentic glomerulonephritis. Given the refractoriness to antibiotics, the persistent activity of nephritis, and repeated cerebral hemorrhaging, we prioritized steroid therapy over early surgical mitral valve replacement. Following steroid therapy, the glomerulonephritis completely improved. Although the administration of steroid therapy in the active phase of IE remains controversial, it might be indicated if comorbid glomerulonephritis is critical.