Improvement in proteinuria with sodium-glucose cotransporter 2 inhibitors and esaxerenone treatment in patients with chronic allograft kidney disease: A case report.

Proteinuria is a predictor of end-stage renal disease. The effectiveness of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker for the reduction in urinary protein excretion and renoprotection in proteinuric chronic kidney disease patients is well known, and coadministration of and sodium-glucose cotransporter inhibitor and the mineralocorticoid receptor blocker eplerenone has recently demonstrated an additive albuminuria-lowering effect in chronic kidney disease patients. Proteinuria is also an independent predictor of end-stage renal disease in kidney transplant recipients. Sodium-glucose cotransporter 2 inhibitors were administered to a 60-year-old man with chronic allograft kidney disease who had increasing urinary protein excretion with valsartan treatment. Although urinary protein excretion decreased drastically, it later increased to the same levels. A nonsteroidal mineralocorticoid receptor blocker, esaxerenone, was added to these medications, again resulting in a decrease in urinary protein excretion. Although the long-term renoprotective effect is not known, these medicines are promising and safe agents to reduce urinary protein excretion in patients with chronic allograft kidney disease.

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.

Efficacy of daprodustat on anemia in hemodialysis patients with sustained inflammation: a case report.

Hypoxia-inducible factor prolyl hydroxylase inhibitors improve anemia in CKD and dialysis patients and were approved for anemia treatment with these populations in Japan. An 89 year-old man with anemia and on maintenance hemodialysis was successfully treated with a dose-up of darbepoetin alfa from 10 to 20 µg per week, and the dose was gradually tapered to 5 µg. Later, serum hemoglobin levels decreased with the newly occurring sustained inflammation and left pleural effusion of an unknown cause, and the darbepoetin alfa dose was increased again to 20 µg per week, which was not effective. Darbepoetin alfa was switched to 4 mg of daprodustat daily, which was fairly effective under sustained inflammation, with serum hemoglobin levels maintained at 11-12 g/dL. The increase in hemoglobin levels was ascribed to the increase in the number of red blood cells, not the mean corpuscular hemoglobin level. During the inflammatory state, despite the contrasting effect on anemia by the 20 µg of darbepoetin alfa weekly and 4 mg of daprodustat daily, the reticulocyte counts were equivalent. The serum erythropoietin levels during daprodustat administration were within the physiological range (8.5-18.8 mIU/mL). For anemia treatment in hemodialysis patients, daprodustat is less influenced by the inflammatory status than darbepoetin alfa, and one of the possible reasons for this includes the extended red blood cell lifespan.

Serum carnitine concentration and the acyl to free carnitine ratio in nondialysis chronic kidney disease and hemodialysis patients.

Mechanisms of impaired fatty acid metabolism may not be the same in nondialysis and hemodialysis patients. Correlations between the serum-free carnitine concentration (FC), acylcarnitine concentration (AC), acyl to free carnitine ratio (AC/FC), and estimated glomerular filtration rate (eGFR) in the nondialysis population and the duration of hemodialysis in hemodialysis patients were investigated. As the eGFR decreased, the FC and AC increased, and as the duration of hemodialysis became longer, the FC and AC decreased. The AC/FC increased consistently as the eGFR decreased and the duration of hemodialysis increased. As an exception, the AC/FC decreased in the patients with a hemodialysis duration less than 90 days, which was not explained by carnitine removal by hemodialysis. In nondialysis patients, a functional, rather than an absolute, carnitine deficiency is a main cause of impaired fatty acid metabolism. Long-term hemodialysis exacerbates absolute carnitine deficiency, whereas hemodialysis treatment may improve impaired fatty acid metabolism.

Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Efficacy for Anemia and Changes in Serum Ferritin Levels by Long-Term Oral Iron Administration in Hemodialysis Patients.

Oral iron preparations are useful for the treatment of anemia in hemodialysis patients; however, long-term changes in the iron dynamics and effects of anemia are unknown. Serum ferritin levels and erythropoietin-stimulating agent (ESA)/hemoglobin (Hb) ratios were investigated for 750 days in the following four groups: patients treated with sodium ferrous citrate (SF) (de novo 50 mg/day and 150 mg/day switched from 50 mg/day) and patients treated with 1500 mg/day of ferric citrate (FC) (de novo and switched from 50 mg/day of SF). Compared with the other groups, serum ferritin levels increased less apparently with de novo 50 mg/day SF. ESA/Hb ratios did not change in groups switched from 50 mg/day SF. Conversely, in groups with de novo iron, ESA/Hb ratios decreased and ultimately reached the same levels in all groups. Although more iron results in higher serum ferritin levels, 50 mg/day SF has an equivalent effect for anemia treatment.

Adverse Effect of Antithrombotic Medications on Bleeding Events and Comparison of Antithrombotic Agents in Hemodialysis Patients.

Antithrombotic medications (AM) are mandatory for many hemodialysis patients, but the bleeding risk associated with this therapy is elevated. The frequency of bleeding events requiring discontinuation of AM, cessation of heparin use, and/or hospitalization was compared between hemodialysis patients with and without AM. All the hemodialysis patients in our clinic were investigated. AM were prescribed in 130 of 222 patients. Except for patients with cilostazol, those with AM had significantly more frequent bleeding events than those without AM (P < 0.01). Bleeding event frequency per 10 000 days of aspirin, clopidogrel, cilostazol, and warfarin prescription was 7.37, 5.95, 2.41, and 9.81, respectively, when restricted to administration of a single AM, which was 4.96, 2.87, 0.7, and 16.06, respectively. In patients without AM, it was 0.91. The bleeding risk associated with AM is elevated in hemodialysis patients and differs markedly depending on the agent used, with the lowest risk associated with cilostazol.

Hints to the diagnosis of uromodulin kidney disease.

BACKGROUND: Uromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm-Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy. METHODS: Immunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals. RESULTS: Fifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls. CONCLUSIONS: In the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

Efficacy of coronary artery screening tests and intervention in hemodialysis patients.

Although cardiovascular disease (CVD) is an important cause of death in patients on hemodialysis, evidence of a beneficial effect of percutaneous intervention (PCI) on stable heart disease is scarce. We investigated the cardiovascular outcomes of hemodialysis patients under our policy of encouraging coronary artery screening tests to the extent possible. A total of 147 hemodialysis patients have been treated in our clinic so far. In 98 of them, coronary artery screening tests were performed, three in unstable and 95 in asymptomatic patients. Significant coronary artery stenosis was detected in 29 at the first tests and in 11 during subsequent tests (40/98, 40.8%), and PCI or coronary artery bypass grafting (CABG) was performed. Multiple PCIs were needed in 21 patients. In the other 49 patients, coronary artery screening tests were not undertaken based on the nephrologist's decision or patient refusal. At the end of the study, 73 (74.5%) patients with tests, and 14 (28.6%) without tests were still outpatients (P < 0.01). Of 40 patients transferred to other hospitals for medical reasons or who died before transfer, there was cerebrovascular accident in eight, malignancy in six, congestive heart failure without CVD in four, infection in three, sudden cardiac death in one, and others 18. No patient with tests died of CVD and the only patient who died of sudden cardiac death probably due to myocardial infarction was a patient who had declined the screening tests. Coronary artery screening tests, intervention and subsequent periodic tests for asymptomatic hemodialysis patients can reduce the occurrence of cardiovascular events in this population.

Influence of antiplatelet medications on bleeding events in hemodialysis patients.

Although antiplatelet medication is used in various situations, including for the prevention of ischemic and thrombotic complications, long-term antiplatelet therapy in hemodialysis patients who are at high risk of bleeding may result in a harmful bleeding tendency. We investigated bleeding events that required the cessation of the use of heparin for hemodialysis in all the hemodialysis patients treated in our clinic. This analysis revealed 111 patients, of whom 52 had been treated with antiplatelet agents (female/male, 15/37; age, 70.4±11.3years; number of days of hemodialysis treatment in our clinic, 1073±696 [31-2144]days; diabetes mellitus [DM]/non-DM, 29/23), and 59 had not been treated with them (female/male, 17/42; age, 66.7±14.0 years; number of days of hemodialysis treatment in our clinic, 917±605 [26-2102]days; DM/non-DM, 21/38). During treatment in our clinic, 21 of the 52 patients undergoing antiplatelet therapy experienced a bleeding event (gastrointestinal bleeding 16, brain stem hemorrhage 2, others 3), while 7 of the 59 patients not receiving them had a bleeding event (gastrointestinal bleeding 7) (P<0.001). Of note, diabetic patients on antiplatelet therapy had the highest incidence of bleeding events (13 of 29 patients; 44.8%), followed by non-diabetic patients on antiplatelet therapy (7 of 23 patients; 30.4%), diabetic patients not receiving antiplatelets (3 of 21 patients; 14.3%), and finally non-diabetic patients not on antiplatelets (4 of 38 patients; 10.5%). Among the patients on antiplatelet therapy, no correlations were apparent between bleeding events and the duration of such therapy or the number of agents. In conclusion, antiplatelet medications can induce bleeding events more frequently in hemodialysis patients, especially in those with DM, than in non-hemodialysis patients, and such agents should be given only under prudent consideration of the associated risks and benefits.

Comparison of acetate-free citrate hemodialysis and bicarbonate hemodialysis regarding the effect of intra-dialysis hypotension and post-dialysis malaise.

Compared with acetate dialysate, bicarbonate dialysate has shown beneficial effects in reducing the morbidity associated with dialysis, but a small amount of acetate in bicarbonate dialysate may evoke hypotension or malaise. Acetate-free citrate hemodialysis (AFHD) may avoid these problems. In 44 hemodialysis patients bicarbonate hemodialysis (BHD) was conducted for three months, followed by a switch to AFHD for three months, and a further switch to bicarbonate hemodialysis (ReBHD). In BHD, AFHD and ReBHD, intra-dialysis hypotension and post-dialysis malaise were determined (hypotension: intra-dialysis systolic blood pressure (SBP) was expressed as a percentage of SBP at the start of hemodialysis, malaise was assessed by a self-reported 0 to 3 scale, 0: absence of malaise, 3: unbearable malaise). Compared with BHD, AFHD patients complained of less malaise but the intra-dialysis blood pressure change did not differ significantly (malaise: BHD 0.73 ± 0.76 vs. AFHD 0.32 ± 0.47, P < 0.0001, end hemodialysis SBP: BHD 93.6 ± 8.9 vs. AFHD 93.8 ± 10.1, P = NS). After switching to ReBHD from AFHD, the malaise score increased (AFHD 0.32 ± 0.47 vs. ReBHD 0.77 ± 0.89, P < 0.0001) and the intra-dialysis blood pressure dropped markedly (end hemodialysis SBP: AFHD 93.8 ± 10.1 vs. ReBHD 87.3 ± 10.5, P < 0.0001). Malaise was very severe in five patients who could not continue ReBHD. After ten days under ReBHD, ReBHD was changed to AFHD again in all patients. Although the exact mechanisms are not known, AFHD may be preferable to BHD to prevent hemodialysis-induced hypotension and malaise.

Histopathologic evaluation of living kidney donor candidates by pre-operative kidney biopsy.

A lack of deceased kidney donors in Japan has led to dependence on living donors in as many as 80% of cases. At the same time, indications for living-donor kidney donation have been expanding in terms of donor medical status as well as HLA matching and ABO compatibility, thus emphasizing the donor shortage. To facilitate final medical decision-making for living kidney donation, we attempted kidney biopsy in six donor candidates who had problems such as mild diabetes and slight proteinuria. The biopsy specimens showed various degrees of tissue injury ranging from partial glomerular sclerosis to arteriole hyalinization. On the basis of the biopsy findings, kidney donation was subsequently performed in three of the six cases with full informed consent, and not done in the remaining three cases. Longer-term studies will be needed to clarify the outcome in both the donors and recipients in these cases.