Reply from the author

：Objective To summarizethe incidence and treatment experience of the effectiveness and adverse reactions of thedifferent immunosuppressive protocols and to increase the long-term survival rate inkidney recipients. Methods Single-center retrospective analysis was performed on 3102cases of kidney transplant recipients in effectiveness and adverse reactions of differentimmunosuppressive protocols. The immunosuppressive protocols were as follows: CsA + Aza +Pred,low dose CsA + MMF + Pred, low dose Tac + MMF + Pred, low dose CsA + SRL + Pred, andlow dose Tac+ SRL+ Pred. Results The 1-, 5-, 10-year survival rate of patients/kidney inlow dose CsA + MMF + Pred protocol was higher than that in CsA + Aza + Pred protocol. Theincidence of adverse reactions, such as hypertension, hyperuricemia, kidney and livertoxicity, and leukopenia was significantly lower, but the incidence of diarrhea wassignificantly higher in CsA + MMF + Pred protocol than in CsA + Aza + Pred protocol (all P＜0.01). The incidence of hyperglycemia was significantly higher (P＜0.05), and that of hairy and gingival hyperplsia was significantly lower (P＜0.05) in low dose Tac+ MMF+ Pred than in low dose CsA+ MMF+ Pred protocol. The incidence ofhyperlipidemia in low dose CsA (or Tac)+ SRL + Pred was significantly higher than in CsA(or Tac)+ MMF+ Pred protocol (P＜0. 05). The incidence ofhirsutism in low dose Tac + SRL + Pred was significantly lower than that in CsA + SRL +Pred protocol (P ＜ 0. 05). The incidence of hyperglycemia in low dose Tac + SRL + Pred wassignificantly higher than that in low dose CsA + SRL + Pred protocol. Conclusion Thetriple drug protocol with a low dose of CsA (or Tac)+ MMF+ Pred significantly improved thesurvival of renal transplant recipients and graft, and reduced the incidence of adversereactions, especially Tae + MMF + Pred protocol. Adjustment of the immunosuppressantdosage and protocol, improvement of eating habits, exercise, reduction of blood pressure,reduction of blood lipid, and control of blood glucose were particularly important inpreventing and controlling adverse reactions during kidney transplantation. Key words: Kidney transplantation; Immunosuppressive agents; Adversereactions; Retrospective studies

To determine whether gadodiamide is a safe and useful angiographic contrast agent for help in diagnosis and percutaneous treatment of renal artery stenosis in patients with renal insufficiency. Diagnostic renal angiography and percutaneous renal interventions were performed by using gadodiamide (total dose, 0.3 mmol/kg) and CO2 as intraarterial contrast agents in 25 procedures in 24 patients with renal insufficiency. Serum creatinine levels were obtained within 24 hours before and at 24 and 48 hours after the procedure. Increases in serum creatinine of more than 44 mumol/L were considered clinically important. Gadodiamide-enhanced angiograms were compared with CO2-enhanced angiograms. In 23 (92%) of 25 procedures, there was no increase in serum creatinine level at 48 hours. One patient with acute and chronic rejection of a renal transplant and one with evidence of cholesterol embolization had a clinically important increase in serum creatinine level at 48 hours. No marked increase in creatinine level was observed in patients with relatively low baseline levels (n = 19). Gadodiamide-enhanced angiograms appeared to be better than CO2-enhanced angiograms for help in identifying renal artery occlusions, visualizing renal vessels incompletely filled with CO2, and determining the progress of intervention. Gadodiamide appears to be a safe and useful intraarterial contrast agent in patients with renal insufficiency and can be used to supplement or confirm CO2-enhanced angiographic findings.

Renal dysfunction in allogeneic hematopoietic cell transplantation

Acute kidney injury (AKI) is a common postoperative complication following cardiopulmonary bypass (CPB) surgery. New biomarkers to identify patients with early AKI (before increases in serum creatinine) are needed to facilitate appropriate treatment. This study aimed to test the role of urinary liver fatty-acid-binding protein (L-FABP) as an early biomarker for AKI in children undergoing CPB surgery. This is a case-control study of children undergoing CPB. AKI was defined as 50 % increase in serum creatinine at 48 h after surgery. For each patient, five serum and urine samples were obtained corresponding to time 0 h (presurgery) and 2, 6, 24, and 48 h after surgery. Twenty-seven patients, median age 360 days, were enrolled. AKI developed in 11 patients (41 %); three needed renal replacement therapy (peritoneal dialysis); there were two deaths. There were significant differences between patients with and without AKI in L-FABP levels at 2, 6, and 48 h after surgery, length of hospital stay, and CPB time; there were no differences in gender, patient age, and body weight. L-FABP was normalized to urinary creatinine concentration at all time points, with area under the receiver operator curve (AUC ROC) 0.867 at 2 and 6 h postoperatively. Correlation coefficient between L-FABP and length of hospital stay after surgery was statistically significant (r = 0.722, p value = 0.000). Our results suggest that urinary L-FABP can be used to diagnose AKI earlier than rise in serum creatinine in children undergoing CPB.

Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, 0-34.9 months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, 0-29.2 months). Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels.

Daily variation in serum creatinine and the effect of a protein load was studied in 18 patients with renal transplants and in 10 healthy controls. Serum creatinine was analyzed both with a standard Jaffé method and with a specific HPLC technique. Following a protein meal, a 30% increase in serum creatinine levels was noted in both groups, but the rise in absolute terms was more prominent among the transplanted patients. Urinary excretion of creatinine did not increase in the transplanted group, indicating a reduced ability to deal with the surplus creatinine in the protein meal. It is concluded that serum creatinine levels are diet-dependent and that this variation is more pronounced when renal function is reduced. Standardized blood sampling is important when following serum creatinine in renal transplant recipients from one day to the next.

Cyclosporine (CsA) has revolutionized transplant medicine and is currently one of the most important immunosuppressive agents for a wide range of organ transplantations and of autoimmune and inflammatory diseases, such as rheumatoid arthritis, uveitis, psoriasis, and atopic dermatitis. Renal impairment represents the main limitation to CsA long-term continuous therapy. However, it has been shown that nephrotoxicity is associated with longer treatment duration, larger cumulative doses and higher daily dose of CsA. With low dose regimens (<5 mg/kg/day), stable serum creatinine levels have been observed up to 15-20 years after kidney transplantation. Intermittent therapy may offer a good therapeutic strategy to limit long-term renal dysfunction, given the fact that renal structural changes are dose- and time-dependent. The best predictor of permanent renal damage is a persistent increase in serum creatinine level one month after treatment withdrawal. In patients with autoimmune diseases, the percentage increase in serum creatinine above baseline value during CsA therapy has been shown to predict CsA-induced nephropathy. Before CsA therapy initiation, patients should undergo a thorough baseline evaluation including laboratory assessments, in particular electrolytes, serum creatinine, and urea levels. Furthermore, patients should be evaluated for factors that might increase the risk of nephrotoxicity, such as obesity, older age, hypertension, concomitant use of nephrotoxic drugs, and pre-existing renal conditions. In the present paper, CsA-induced nephropathy will be reviewed in terms of pathophysiology, pathologic and clinical findings, and strategies for prevention and management.

Clinical Implications

Background and Aims Chronic Kidney Disease (CKD) patients have increased risk of cardiovascular disease and dyslipidemia is a frequent comorbidity. Many patients are medicated with anti-lipidemic agents to reduce atherosclerotic disease and coronary vascular events. Fenofibrates are lipid-lowering agents used to treat mixed dyslipidemia and hypertriglyceridemia and are widely used by primary care physicians. Many studies described reversible increase in serum creatinine (SCr) associated with fenofibrates use, but the underlying mechanism is poorly understood. Whether hypercreatinemia is secondary to alterations in creatinine metabolism, tubular handling, or reflects a true impairment in kidney function remains unknown. This phenomenon is also fairly unknown to many primary care providers and, as a result, patients with a SCr rise while on fenofibrates are often referred to nephrology consultation. In this study, we have analyzed the effect of fenofibrate withdrawal on SCr, eGFR and hemoglobin (Hb) in patients referred to nephrology consultation for CKD or decrease of eGFR. Our aim was to understand the impact of fenofibrates withdrawal on kidney function and to look for factors that might influence the risk of fenofibrate nephrotoxicity. Methods We conducted a retrospective observational study, reviewed electronic medical records and collected data of all adult patients discontinued on fenofibrates at first nephrology consultation, between January 2022 and October 2023. Ninety patients were included, of which four were excluded due to simultaneous suspension of antihypertensive drugs. Patients were subsequently evaluated for clinical reasons from 2 to 6 months after the first appointment, with new laboratory data collected, including Hb, SCr and lipid profile. eGFR was calculated using MDRD 4 formula. Continuous variables were compared by t-test and categorical variables were compared by chi-square test. A p value of &amp;lt; 0.05 was considered statistically significant. All data was analyzed using Stata software. Results A total of eighty-six patients were included in this study, 65% (n=56) were male, mean age of 71.2 ± 11.4 years old; all patients were medicated with fenofibrates due to dyslipidemia and 77% (n=66) were also on statins; 94% (n=81) had hypertension, 60% (n=52) had type 2 diabetes mellitus, and 20% (n=17) had ischemic cardiopathy. Ninety-two percent (n=79) were taking renin-angiotensin system inhibitors (RASi). Nearly half the patients (49% n = 42) had stage 4 CKD and 45% (n = 39) had stage 3 CKD; Main causes of CKD were presumed diabetic kidney disease (34% n = 29) and ischemic nephropathy (15% n = 13), 30% (n = 26) of patients had undetermined etiology. Upon fibrate discontinuation, mean SCr was 2.1 ± 0.6 mg/dL and mean eGFR was 31.3 ± 10.9 mL/min/1.73 m2. Mean Hb was 12.5 ± 2.0 g/dL. After fenofibrate discontinuation, eGFR significantly improved in mean 15.2 mL/min/1.73 m2 (31.3 vs 46.5 mL/min/1.73 m2, p &amp;lt; 0.0001) with a mean reduction of SCr of 0.6 mg/dL (2.1 vs 1.5 mg/dL, p &amp;lt; 0.0001). Mean Hb increased 0.4 g/dL (12.4 vs 12.7 g/dL, p = 0.112). Mean total cholesterol was 168.4 ± 56.4 mg/dL and mean triglycerides was 234.8 ± 285.3 mg/dL. Only one patient was restarted on fenofibrate due to severe hypertriglyceridemia. Fenofibrate discontinuation effect on eGFR improvement remained statistically significant when adjusted for diabetes, hypertension, CKD etiology and RASi use. Conclusion Our study reports a consistent increase in eGFR and SCr decrease following discontinuation of fenofibrate, as other reports before. A true effect on eGFR could be supported by the Hb rise, though it did not reach statistical significance. The exact mechanism by which fenofibrates increase SCr remains to be clarified. Cardiovascular disease is the main cause of death amongst CKD population and the potential benefits of fenofibrates should not be disregarded. Our results suggest that patients started on fenofibrates should be carefully selected, specially if CKD is present, and kidney function monitoring should be considered. A drop in eGFR should prompt physicians to weigh on the strict indications for fenofibrates use.

The study standardized the glycerol induced (intra-peritoneal and intra-muscular) acute renal failure (ARF) models in Sprague-Dawley rats and validated its potential to predict the change in pharmacokinetics of the selected probe drugs in renal impairment. We assessed the induction of ARF by measuring the serum creatinine and blood-urea-nitrogen (BUN) levels at different time points (baseline, 6 h, 12 h, 24 h, 48 h and 72 h). Glycerol administrations via both intra-peritoneal and intra-muscular routes caused a significant increase in serum creatinine and BUN levels in rats at 6 h; however, the levels decreased within 24 h with intra-peritoneal administration. In contrast, with intra-muscular administration, a sustained increase in serum creatinine and BUN levels was observed up to 72 h post glycerol treatment demonstrating a sustained ARF like condition in rats that was suitable to evaluate the pharmacokinetics of drugs. Therefore, intra-muscular glycerol administration model was used to evaluate the pharmacokinetics of selected probe drugs including metformin, digoxin, atorvastatin and linezolid. The pharmacokinetics of metformin and digoxin were significantly altered in ARF versus control rats with increase in plasma exposure, prolonged elimination half-life and decreased systemic clearance. However, the pharmacokinetics of atorvastatin and linezolid did not show significant differences between ARF and control rats. These results demonstrated the utility of the ARF model in rats in predicting pharmacokinetic changes in patients with renal impairment. Such models may prove useful in early discovery work to screen and prioritize compounds requiring dose adjustment in patients with renal impairment.

BackgroundCreatine monohydrate is a widely used dietary supplement with proven benefits in athletic performance and potential therapeutic applications in clinical populations. However, concerns regarding its impact on renal function persist, largely due to elevated serum creatinine levels associated with creatine intake.MethodsA comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar for studies published between January 2000 and March 2025. Primary outcomes were serum creatinine and glomerular filtration rate (GFR). Meta-analyses were performed using a random-effects model, with subgroup analysis by supplementation duration.ResultsTwenty-one studies were included in the systematic review, and 12 studies (177 participants in the creatine group and 263 in control) were eligible for meta-analysis of serum creatinine levels. Creatine supplementation was associated with a small but statistically significant increase in serum creatinine (MD: 0.07 µmol/L; 95% CI: 0.01 to 0.12; p = 0.03). Subgroup analysis of the creatinine outcome based on follow-up duration revealed that the intervention effect was significant in studies with a follow-up of ≤ 1 week (MD = 0.12; 95% CI: 0.03 to 0.21). However, no significant effect was observed in studies with a follow-up of 1 to 12 weeks (MD = 0.04; 95% CI: − 0.09 to 0.17). The effect became significant again in studies with a follow-up of more than 12 weeks. The meta-analysis revealed a non-statistically significant differences in GFR following creatine supplementation compared to control.ConclusionCreatine supplementation is associated with a modest, transient increase in serum creatinine levels, likely due to metabolic turnover rather than renal impairment. No significant changes were observed in GFR, suggesting preserved kidney function.Clinical trial numberNot applicable.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12882-025-04558-6.

BackgroundAKI is a complication of intravenous vancomycin (VAN) occurring in up to 43% of patients (pts) during hospitalization. Data on AKI in pts receiving VAN through outpatient parenteral antimicrobial therapy (OPAT) are limited. There is suggestion that VAN managed through precision dosing pharmacokinetic (PK) software may limit this occurrence. We evaluated the AKI rate of pts receiving VAN as OPAT through Physician Office Infusion Centers (POICs) over a 12-month period.MethodsA review was conducted of OPAT VAN pts treated in 2021 with therapeutic drug monitoring (TDM) performed (InsightRX) and ≥2 VAN serum levels. These pts were then evaluated for AKI, defined as increase in serum creatinine (SCr) ≥1.5 times baseline. Pts on dialysis were excluded. Data included comorbidities, diagnosis, VAN regimen, concomitant medications, SCr, and VAN serum levels. PK parameters were collected with trough values and estimated 24-hr area under the curve (AUC24). Outcome of therapy was assessed following identification of AKI.ResultsA total of 330 pts from 51 POICs had TDM performed. Of these, 27 (8.2%) developed AKI. Median age was 61 years, 67% were male, and baseline SCr was 0.8 mg/dL (IQR, 0.7-1.0). Most pts (89%) were on concomitant nephrotoxic medications. Median duration of OPAT was 34 days (IQR, 18-41) with onset of AKI after 16 days (IQR, 10-21). At time of AKI, the median SCr increase was 1.7 times baseline (IQR, 1.5-2.0) with a corresponding VAN trough of 21 mg/mL (IQR, 15-28) and AUC24 of 572 mg*h/L (IQR, 495-660). As a result, VAN was discontinued in 14 (52%), dose or frequency modified in 10 (37%) with completion of VAN, and no modifications performed in 3 (11%). One pt who discontinued VAN required hospitalization due to AKI with resolution.ConclusionVAN managed by pharmacists in an OPAT setting using precision dosing software resulted in a low rate of AKI. Median rise in SCr was < 2 times baseline for those with AKI. Rapid identification of early AKI by the pharmacist resulted in changes to the regimen or VAN discontinuation, preventing serious patient sequelae. This supports the need for pharmacist-led monitoring in an outpatient setting with long VAN therapy durations.DisclosuresLucinda J. Van Anglen, PharmD, Merck & Co.: Grant/Research Support|Paratek: Grant/Research Support.

Pharmacologic blockade of neurohormonal pathways in patients with acute myocardial infarction (MI) can result in acute changes in biomarkers of kidney function. We evaluated the effect of sacubitril/valsartan versus ramipril on initial changes in serum creatinine and the association of these changes with longer-term outcomes among participants in PARADISE-MI. In this randomized, double-blind, active-controlled, event-driven trial, 5661 patients with an acute MI were assigned to receive sacubitril/valsartan or ramipril, with no run-in. The frequency of an initial pre-specified increase in serum creatinine (≥26.5 or ≥44 μmol/L) from baseline to week 1 was compared between arms. Multivariable Cox regression models were fit to examine the association of acute changes in serum creatinine with the primary cardiovascular composite outcome (cardiovascular death, first heart failure hospitalization, or outpatient heart failure), all-cause mortality, and longer-term changes in estimated glomerular filtration rate (eGFR). An initial increase in serum creatinine ≥26.5 μmol/L occurred in 155 of 2604 (6.0%) patients assigned to sacubitril/valsartan and 120 of 2603 (4.6%) patients assigned to ramipril (odds ratio [OR] 1.32; 95% confidence interval [CI] 1.03-1.68). The corresponding numbers for an increase ≥44 μmol/L were 57 (2.2%) and 42 (1.6%), respectively (OR 1.37; 95% CI 0.92-2.05). A higher odds of increased serum creatinine ≥26.5 and ≥44 μmol/L for sacubitril/valsartan versus ramipril appeared to be restricted to patients who had a greater decline in systolic blood pressure over the same period (p-interaction = 0.05 and 0.001, respectively). In multivariable analyses, neither an acute increase in serum creatinine ≥26.5 or ≥44 μmol/L was associated with a higher risk of cardiovascular outcomes, all-cause mortality, or differences in longer-term eGFR slope. Findings were similar across the randomized treatment arms (p-interaction >0.6 for all). Following acute MI, patients assigned to sacubitril/valsartan had a higher frequency of initial increases in serum creatinine at 1 week, compared with ramipril. In adjusted models, initial increases in serum creatinine with either treatment were not associated with adverse cardiovascular outcomes or changes in longer-term kidney function.

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery

Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial)