A case of acute kidney injury due to ethylene glycol intoxication.

In this article we describe a case of acute kidney injury caused by ethylene glycol intoxication which partially reversed after temporary hemodialysis treatment. The diagnosis was obtained after the patient's clinical history and the finding of ethylene glycol in the blood, numerous intratubular crystals at renal biopsy, and the presence of large amounts of atypical - spindle-like and needle-like - calcium oxalate crystals in the urinary sediment.

Sexual dysfunction in dialytic patients. A prospective cross-sectional observational study in two hemodialysis centers.

OBJECTIVES: Incidence and prevalence of patients in dialytic therapy increased considerably in recent years. The onset of new issues, once overshadowed, linked to a lower quality of life like sexual dysfunction became increasingly common. The first study in this area, dating back to the 1970s, shows the high prevalence of sexual dysfunction among patients in dialytic therapy of both sexes. Later studies proved an association of sexual dysfunction with psyche disorders, anxiety, depression and lack of self-confidence. The aim of this study is to describe the incidence of male and female sexual main dysfunctions, the latter not least in literature, in patients in hemodialytic therapy. With this aim two dialytic centers have been compared, one located in northern Italy and one in southern Italy, and the different prevalence has been compared to the general population. METHODS: We conducted a prospective cross-sectional observational study in patients undergoing dialytic therapy in two hemodialysis centers, one located in Palermo and one in Lecco. Male sexual dysfunction was investigated by the International Index of Erectile Function-15 (IIEF15) questionnaire and the Premature Ejaculation Diagnotic Tool (PEDT) questionnaire, and the female dysfunction by Female Sexual Function Index (FSFI) questionnaire. Criteria for inclusion in our study were: age < 75 years and dialytic age > 3 months; exclusion criteria were: advanced cancer diseases, life expectancy < 6 months, previous urological manipulation, anti-androgenic therapy, sexual dysfunction unrelated to kidney disease, psychiatric disorders. Data were compared with mean-standard deviation (SD) and with the variance analysis (ANOVA). A value of p < 0.05 is considered significant. Discrete data were analyzed with contingency analysis. A chi2 < 0.05 was considered significant. RESULTS: Data of 78 patients have been collected. Mean age and dialytic time were 54 ± 12 years and 42 ± 35 month; 33 patients were from Palermo and 24 from Lecco; 21 patients were excluded. Age and dialytic age of the two subgroups did not demonstrate statistically significant differences. Between the two centers there was a statistically significant difference (p < 0.005) in the distribution of basic nephropathy: an higher incidence of diabetic and obstructive nephropathy has been observed in the southern center compared to northern center, while glomerulonephritis and polycystic kidney disease had an higher incidence in the northern center compared to southern one. The main sexual dysfunctions in both sexes, erectile dysfunction (ED) and premature ejaculation (PE) in men and orgasm disorder and pelvic pain in women, have been investigated. ED was present in 70%  of hemodialyzed patients, which is an higher incidence compared to the general population. The severity of ED between patients of the two groups was significantly different (chi2 < 0.001) with higher incidence of moderate/severe forms in northern Italy. The score, in addition to discrete data (severe, moderate, mild, absence), of ED was significantly different (p < 0.001) between patients of the two centers (22 ± 7 Palermo vs. 9 ± 8, Lecco). The PE was absent in 20 patients (54%), present in 12 patients (32%) and probable in 5 patients (14%) (scores of 7.6 ± 4.0 and 8.9 ± 6.8, respectively in Palermo and Lecco patients). For women, orgasmic dysfunction was severe in 10 patients (50%), mild in 4 patients (20%), very mild in 5 patients (25%), while it was normal in 1 patient (5%), with a statistically significant difference (p< 0.05) between Palermo and Lecco patients (3.0 ± 1.4 vs 1.2 ± 2.0). Sexual pain in women was severe in 11 patients (55%), moderate in 4 patients (20%) and mild in 5 patients (25%). Sexual pain was present in all patients (p < 0.05). CONCLUSIONS: Regardless of sex, sexual dysfunction is one of the most common side effect in patients with end stage renal disease in dialytic therapy. Our study confirms literature data. The growing number of the dialytic population with sexual disorders needs specialist support to improve quality of life of these patients.

ISPD recommendations for the evaluation of peritoneal membrane dysfunction in adults: Classification, measurement, interpretation and rationale for intervention.

GUIDELINE 1: A pathophysiological taxonomy: A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing individualized dialysis or when planning modality transfer (e.g. to automated peritoneal dialysis (PD) or haemodialysis) in the context of shared and informed decision-making with the person on PD, taking individual circumstances and treatment goals into account. (practice point). GUIDELINE 2A: Identification of fast peritoneal solute transfer rate (PSTR): It is recommended that the PSTR is determined from a 4-h peritoneal equilibration test (PET), using either 2.5%/2.27% or 4.25%/3.86% dextrose/glucose concentration and creatinine as the index solute. (practice point) This should be done early in the course dialysis treatment (between 6 weeks and 12 weeks) (GRADE 1A) and subsequently when clinically indicated. (practice point). GUIDELINE 2B: Clinical implications and mitigation of fast solute transfer: A faster PSTR is associated with lower survival on PD. (GRADE 1A) This risk is in part due to the lower ultrafiltration (UF) and increased net fluid reabsorption that occurs when the PSTR is above the average value. The resulting lower net UF can be avoided by shortening glucose-based exchanges, using a polyglucose solution (icodextrin), and/or prescribing higher glucose concentrations. (GRADE 1A) Compared to glucose, use of icodextrin can translate into improved fluid status and fewer episodes of fluid overload. (GRADE 1A) Use of automated PD and icodextrin may mitigate the mortality risk associated with fast PSTR. (practice point). GUIDELINE 3: Recognizing low UF capacity: This is easy to measure and a valuable screening test. Insufficient UF should be suspected when either (a) the net UF from a 4-h PET is <400 ml (3.86% glucose/4.25% dextrose) or <100 ml (2.27% glucose /2.5% dextrose), (GRADE 1B) and/or (b) the daily UF is insufficient to maintain adequate fluid status. (practice point) Besides membrane dysfunction, low UF capacity can also result from mechanical problems, leaks or increased fluid absorption across the peritoneal membrane not explained by fast PSTR. GUIDELINE 4A: Diagnosing intrinsic membrane dysfunction (manifesting as low osmotic conductance to glucose) as a cause of UF insufficiency: When insufficient UF is suspected, the 4-h PET should be supplemented by measurement of the sodium dip at 1 h using a 3.86% glucose/4.25% dextrose exchange for diagnostic purposes. A sodium dip ≤5 mmol/L and/or a sodium sieving ratio ≤0.03 at 1 h indicates UF insufficiency. (GRADE 2B). GUIDELINE 4B: Clinical implications of intrinsic membrane dysfunction (de novo or acquired): in the absence of residual kidney function, this is likely to necessitate the use of hypertonic glucose exchanges and possible transfer to haemodialysis. Acquired membrane injury, especially in the context of prolonged time on treatment, should prompt discussions about the risk of encapsulating peritoneal sclerosis. (practice point). GUIDELINE 5: Additional membrane function tests: measures of peritoneal protein loss, intraperitoneal pressure and more complex tests that estimate osmotic conductance and 'lymphatic' reabsorption are not recommended for routine clinical practice but remain valuable research methods. (practice point). GUIDELINE 6: Socioeconomic considerations: When resource constraints prevent the use of routine tests, consideration of membrane function should still be part of the clinical management and may be inferred from the daily UF in response to the prescription. (practice point).

Green nephrology and eco-dialysis: a position statement by the Italian Society of Nephrology.

High-technology medicine saves lives and produces waste; this is the case of dialysis. The increasing amounts of waste products can be biologically dangerous in different ways: some represent a direct infectious or toxic danger for other living creatures (potentially contaminated or hazardous waste), while others are harmful for the planet (plastic and non-recycled waste). With the aim of increasing awareness, proposing joint actions and coordinating industrial and social interactions, the Italian Society of Nephrology is presenting this position statement on ways in which the environmental impact of caring for patients with kidney diseases can be reduced. Due to the particular relevance in waste management of dialysis, which produces up to 2 kg of potentially contaminated waste per session and about the same weight of potentially recyclable materials, together with technological waste (dialysis machines), and involves high water and electricity consumption, the position statement mainly focuses on dialysis management, identifying ten first affordable actions: (1) reducing the burden of dialysis (whenever possible adopting an intent to delay strategy, with wide use of incremental schedules); (2) limiting drugs and favouring "natural" medicine focussing on lifestyle and diet; (3) encouraging the reuse of "household" hospital material; (4) recycling paper and glass; (5) recycling non-contaminated plastic; (6) reducing water consumption; (7) reducing energy consumption; (8) introducing environmental-impact criteria in checklists for evaluating dialysis machines and supplies; (9) encouraging well-planned triage of contaminated and non-contaminated materials; (10) demanding planet-friendly approaches in the building of new facilities.

Sodium toxicity in peritoneal dialysis: mechanisms and "solutions".

The major trials in peritoneal dialysis (PD) have demonstrated that increasing peritoneal clearance of small solutes is not associated with any advantage on survival, whereas sodium and fluid overload heralds higher risk of death and technique failure. On the other hand, higher sodium and fluid overload due to loss of residual kidney function (RKF) and higher transport membrane is associated with poor patient and technique survival. Recent experimental studies also show that, independently from fluid overload, sodium accumulation in the peritoneal interstitium exerts direct inflammatory and angiogenetic stimuli, with consequent structural and functional changes of peritoneum, while in patients with Chronic Kidney Disease sodium stored in interstitial skin acts as independent determinant of left ventricular hypertrophy. Noteworthy, this tissue pool of sodium is modifiable being removed by dialysis. Therefore, novel PD strategies to optimize sodium removal, including the use of bimodal and/or low-sodium solutions, are actively tested. Nonetheless, a holistic approach aimed at preserving peritoneal function and the kidney may represent the key of therapy success in the hard task of preserving adequate sodium balance in PD patients. In this review, we describe the available evidence on sodium toxicity in PD, either related or unrelated to fluid overload, and we also discuss about possible "solutions" to preserve or restore sodium balance in PD patients.

Sodium removal and plasma tonicity balance are not different in hemodialysis and hemodiafiltration using high-flux membranes.

BACKGROUND: The clinical benefits of on-line hemodiafiltration (HDF) versus high-flux membranes hemodialysis (hf-HD) are still debated. In fact, although a superiority of one treatment over the other, especially in terms of mortality, did not emerge from the analysis of clinical trials, improved intradialytic vascular stability and cardiovascular mortality have been observed in patients undergoing HDF rather than hf-HD; the lower removal of sodium (Na+) during HDF seems to play a major role. The plasma concentration of Na+ is the major determinant of plasma tonicity, which, by determining the flow of water between the intracellular and the extracellular compartment, contributes to the vascular refilling process and the maintenance of blood pressure during the hemodialysis treatment. Plasma tonicity also depends on plasma glucose concentration, especially in patients with diabetes mellitus with hyperglycaemia at the start of hemodialysis treatment. MATERIALS AND METHODS: We evaluated the removal of Na+ and plasma tonicity balance during a 2-week period by performing 2-3 consecutive sessions of hf-HD followed by 2-3 consecutive sessions of HDF, or vice versa, in 47 patients (40% diabetics) on chronic hemodialysis. Identical parameters were used in all dialytic sessions. RESULTS: Na+ removal per session was - 224 ± 144 mmol and - 219 ± 152 mmol, respectively, in hf-HD and in HDF (p = 0.79). The plasma tonicity balance per session was - 575 ± 310 mOsm and - 563 ± 328 mOsm, respectively, in hf-HD and in HDF (p = 0.75). CONCLUSIONS: The removal of Na+ and plasma tonicity balance did not differ between hf-HD and HDF. This observation suggests that factors other than those assessed in our study might explain the improved cardiovascular stability reported in HDF.

Incremental dialysis in ESRD: systematic review and meta-analysis.

BACKGROUND: Incremental dialysis may preserve residual renal function and improve survival in comparison with full-dose dialysis; however, available evidence is limited. We therefore compared all-cause mortality and residual kidney function (RKF) loss in incremental and full-dose dialysis and time to full-dose dialysis in incremental hemodialysis (IHD) and incremental peritoneal dialysis (IPD). METHODS: We performed a systematic review and meta-analysis of cohort studies of adults with ESRD starting IHD and IPD. We identified in PubMed and Web of Science database all cohort studies evaluating incremental dialysis evaluating three outcomes: all-cause mortality, RKF loss, time to full dialysis. IPD was defined as < 3 daily dwells in Continuous Ambulatory Peritoneal Dialysis and < 5 sessions per week in Automated Peritoneal Dialysis, while IHD was defined as < 3 HD sessions per week. RESULTS: 22 studies (75,292 participants), 15 in HD and 7 in PD, were analyzed. Mean age at dialysis start was 62 and 57 years in IHD and IPD subjects, respectively. When compared to full dose, incremental dialysis (IHD or IPD) had an overall mortality risk of 1.14 [95% CI 0.85-1.52] with high heterogeneity among studies (I2 86%, P < 0.001), and lower mean RKF loss (- 0.58 ml/min/months, 95% CI 0.16-1.01, P = 0.007). Overall, time to full-dose dialysis was 12.1 months (95% CI 9.8-14.3) with no difference between IHD and IPD (P = 0.217). CONCLUSIONS: Incremental dialysis allows longer preservation of RKF thus deferring full-dose dialysis, by about 1 year in HD and PD, with no increase in mortality risk. Large and adequate studies are needed to confirm these findings.

Sodium removal by peritoneal dialysis: a systematic review and meta-analysis.

Achievement of sodium and fluid balance is considered a major determinant of dialysis adequacy in peritoneal dialysis (PD). However, the contribution of different PD modalities to dialytic sodium removal (DSR) remains ill-defined. We performed a systematic review and meta-analysis to compare DSR by manual (continuous ambulatory PD, CAPD) versus automated PD (APD). Alternative PD strategies to remove sodium were also analyzed. Seven cohort studies, including 683 patients, 406 in CAPD and 277 in APD, were meta-analyzed out of the 30 studies selected based on DSR data availability. Overall, the unstandardized mean difference between CAPD and APD was significant [- 56 mmol/day (95% CI - 106, - 6), p = 0.027]. Heterogeneity was high (I2 87.2%; p < 0.001). Meta-regression showed a strict correlation of DSR difference with creatinine dialysate/plasma ratio (D/P) (p = 0.04). DSR was significantly lower in APD than CAPD [86.2 (57.3-115.1) vs. 141.3 (107.6-174.9) mmol/day, p = 0.015]. Conversely, ultrafiltration (UF) did not differ [1122.6 (891.2-1354.0) in CAPD and 893.6 (823.0-964.2) ml/day in APD, p = 0.064]. A very strong correlation between DSR and achieved UF was found in CAPD (R = 0.94; p < 0001) while no relationship was detected in APD (R = - 0.07; p = 0.85). CAPD allows a higher DSR than APD, even though UF is not different. APD removes more water than sodium; therefore, DSR should be measured rather than estimated from the achieved UF. The difference in DSR between the two modalities decreases in high transporters. Novel strategies proposed to increase DSR, e.g. lower sodium dialysate or adapted-APD, are promising, but ad hoc studies are necessary.

[Practical approach to patient therapy affected by Autosomal Dominant Autosomic Polycystic Kidney Disease].

The Autosomal Dominant Polycystic Kidney Disease(ADPKD) is the most frequent renal genetic condition and involves 7 to 10% of subjects undergoing renal replacement therapy. It is estimated that between 24,000 and 34,000 subjects in Italy are affected by this condition. For an illness that has long been neglected due to a lack of treatment options, an attractive treatment possibility is now available: tolvaptan has shown clinical efficacy regarding disease progression in two clinical trials (ADPKD patients with mild renal failure and ADPKD patients with advanced renal failure). The possible liver toxicity expressed in about 4% of the subjects exposed to the drug and an important aquaretic effect suggest prudence and attention in the use of this new molecule. Based on these critical points, some clinicians with direct experience in the use of the drug have briefly collected in the pages to follow the main clinical recommendations for the treatment of ADPKD patints. The recommendations concern the general approach to the patient affected by ADPKD but with particular attention to the aspects related to the new treatment. The delicate task of introducing the opportunities and limitations of the offered therapy to the patient will be deepened. Finally, the document wants to suggest how best to organize a clinic dedicated to this condition.

Haemodialysis or haemodiafiltration: that is the question.

Despite the technological and pharmacological advancements in the last 30 years, morbidity and mortality of dialysis patients are still astonishingly high. Today, convective treatments, such as high-flux haemodialysis (hf-HD) and haemodiafiltration (HDF), are established techniques; the online production of fresh pure dialysate has provided clinical and economic advantages. Nevertheless, the actual benefits of HDF, even with high-convective-volume treatments, are still debatable. Three recent, randomized controlled trials compared survival outcomes in prevalent patients receiving conventional HD or post-dilution HDF and reported conflicting results. The meta-analyses of the published trials were ultimately incapable of providing a clear and definitive answer on the possible beneficial effects of choosing one treatment over the other. All-cause mortality, anaemia, phosphate control and clearance of small molecules seemed to be unaffected by the treatment modality. On the other hand, cardiovascular mortality, intradialytic vascular stability and the clearance of protein-bound molecules fared better in patients treated with HDF. These results were not consistent between the studies. Thus, there is still no conclusive answer to the question that nephrologists would like to have answered: 'Which is the best treatment for my patient?' In the age of evidence-based medicine, we need strong data to support the superiority of a treatment in comparison with another, although theoretically plausible. There is the need for a well-designed clinical trial comparing outcomes for patients randomly assigned to high- or moderate-convection-volume HDF versus hf-HD to clearly prove the clinical superiority of HDF, including the effect of different infusion volumes.

The peritoneal sieving of sodium: a simple and powerful test to rule out the onset of encapsulating peritoneal sclerosis in patients undergoing peritoneal dialysis.

BACKGROUND AND AIMS: Encapsulating peritoneal sclerosis (EPS) is an uncommon but severe complication of peritoneal dialysis (PD). A reliable screening tool to identify patients at risk of developing or not EPS is currently not available. We aimed to evaluate whether the reduction in dialysate sodium concentration (sodium sieving) at 60 min (ΔDNa60), during a peritoneal equilibration test with 3.86% glucose concentration (3.86%-PET) was able to early rule out patients who will not develop EPS. METHODS: Prospective controlled longitudinal (20-year) cohort study. All eligible incident PD patients attending the hospital underwent a 3.86%-PET during the first 3 months following start of PD and then once a year. The dip in ΔDNa60 and other factors were correlated with eventual EPS onset. RESULTS: Of 161 incident PD patients, with a median PD duration of 37.8 (24.7-58.3) months and 64.1 (34.5-108.3) months of follow-up, 13 patients (8%) developed EPS at a median PD duration of 72.7 (56.6-109.4) months and 105.0 (76.4-143.2) months of follow-up. ΔDNa60 demonstrated the best sensitivity and specificity values, estimated by conventional receiver operating characteristic (ROC) curve analysis with an area under the curve (AUC) of 0.90, 0.83 and 0.85 at 1, 2 and 3 years before the onset of EPS, respectively. Multifactorial analysis showed that the most useful factors for predicting EPS were age at start of PD, duration of PD, small solutes transport (D/PCreat) and ΔDNa60; the AUC at 1, 2 and 3 years before the onset of EPS was, respectively, 0.97, 0.96 and 0.94, the positive predictive value being 0.48, 0.57 and 0.42, and the negative predictive value 1.0, 1.0 and 1.0. CONCLUSIONS: It is possible to predict the occurrence and, better, the non-occurrence of EPS using simple parameters such as age at PD start, duration of PD, and parameters obtained by 3.86%-PET such as D/PCreat and ΔDNa60.

Assessment of intradialysis calcium mass balance by a single pool variable-volume calcium kinetic model.

INTRODUCTION: A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single-pool variable-volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients. METHODS: Thirty-four patients on thrice-weekly HD were studied during 240 dialysis sessions. All patients were dialyzed with a nominal total calcium concentration of 1.50 mmol/L. The main assumption of the model is that the calcium distribution volume is equal to the extracellular volume during dialysis. This hypothesis is assumed valid if measured and predicted end dialysis plasma water ionized calcium concentrations are equal. A difference between predicted and measured end-dialysis ionized plasma water calcium concentration is a deviation on our main hypothesis, meaning that a substantial amount of calcium is exchanged between the extracellular volume and a nonmodeled compartment. FINDINGS: The difference between predicted and measured values was 0.02 mmol/L (range -0.08:0.16 mmol/L). With a mean ionized dialysate calcium concentration of 1.25 mmol/L, calcium mass balance was on average negative (mean ± SD -0.84 ± 1.33 mmol, range -5.42:2.75). Predialysis ionized plasma water concentration and total ultrafiltrate were the most important predictors of calcium mass balance. A significant mobilization of calcium from the extracellular pool to a nonmodeled pool was calculated in a group of patients. DISCUSSION: The proposed single pool variable-volume Calcium kinetic model is adequate for prediction and quantification of intradialysis calcium mass balance, it can evaluate the eventual calcium transfer outside the extracellular pool in clinical practice.

Peritoneal Equilibration Test Reference Values Using a 3.86% Glucose Solution During the First Year of Peritoneal Dialysis: Results of a Multicenter Study of a Large Patient Population.

BACKGROUND: The original peritoneal equilibration test (PET) was used to classify peritoneal dialysis (PD) patients using a 2.27% glucose solution. It has since been suggested that a 3.86% glucose solution be used because this provides better information about ultrafiltration (UF) capacity and the sodium (Na) sieving of the peritoneal membrane. OBJECTIVE: The aim of this study was to determine reference values for a PET using a 3.86% glucose solution (PET-3.86%). METHODS: We evaluated the PET-3.86% in a large population of incident PD patients attending 27 Italian dialysis centers. RESULTS: We evaluated the results of 758 PET-3.86% in 758 incident PD patients (1 test per patient). The mean duration of PD was 5 ± 3 months. The ratio of the concentrations of creatinine in dialysate/plasma (D/PCreat) was 0.73 ± 0.1 (median 0.74). The ratio between the concentrations of glucose at the end/beginning of the test (D/D0) was 0.25 ± 0.08 (median 0.24). Ultrafiltration uncorrected and corrected for bag overfill was respectively 776 ± 295 mL (median 781 mL) and 675 ± 308 mL (median 689 mL). Sodium sieving was 8.4 ± 3.8 mmol/L (median 8.0 mmol/L). CONCLUSION: The results of the study provide PET-3.86% reference values for the beginning of PD that can be used to classify PD patients into transport classes and monitor them over time.

Haemodiafiltration at Higher Volumes and Patient Survival.

Patient morbidity and mortality rates are still very high in standard low-flux haemodialysis (lf-HD). On-line haemodiafiltration (OL-HDF) is considered the most efficient dialysis technique, as clearances of small solutes, like urea, may be even higher than in lf-HD and clearances of middle solutes, like ß2-microglobulin, are much higher than in lf-HD. OL-HDF has been suggested to reduce mortality compared to HD, possibly due to more effective removal of larger uraemic retention solutes and/or better fluid removal. Only 1 out of the 3 largest randomized trials was able to demonstrate a positive effect of OL-HDF on patient survival in comparison to those randomized to HD. Post hoc analyses of these studies consistently showed that the patients randomized to OL-HDF who received the highest convection volumes had a lower risk of mortality and cardiovascular events than those randomized to HD. Four meta-analyses showed inconsistent results concerning the effect of convective treatments in improving general and cardiovascular survival, while they showed a significant reduction of the intradialytic symptomatic hypotension. An individual pooled participant analysis of the 4 largest trials confirmed these findings, suggesting a better survival when a convection volume of at least 23 litres/session was delivered, while other studies did not confirm these conclusions. Even after extensive statistical adjustments, residual confounding always remain; therefore, randomized control trials targeting different convection volumes are required to definitively confirm a dose-response effect of OL-HDF convection volume on patient survival.

[The use of drugs in chronic renal insufficiency: primum non nocere! (First do not harm!). The paradigmatic cases of azathioprine, metformin and denosumab]. / Uso dei farmaci nell'insufficienza renale: primum non nocere! I casi esemplificativi di azatioprina, metformina e denosumab.

Renal function reduction rises difficulties in dealing with many drugs. These problems are mainly due to the need of decreasing progressively the doses of the drugs that are cleared by the kidneys, in parallel with the progressive reduction in renal function. The degree of renal impairment should be better measured as the estimated glomerular filtration rate, avoiding to simply rely on plasma creatinine. Physicians should also be aware of the important potential side effects of some very effective and safe drugs, when they are used in patients with relevant reduction in renal function, independently of their possible plasma accumulation. As paradigmatic, we will discuss here the case of azathioprine, metformin and denosumab use, when renal function is heavily decreased.