Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury: The Role of Prolonged Intermittent Hemodialysis.

Metformin intoxication with lactic acidosis, a potentially lethal condition, may develop in diabetic patients when the drug dose is inappropriate and/or its clearance is reduced. Diagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment. Thus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis. We report a case of metformin intoxication, severe lactic acidosis, and acute kidney injury in a diabetic patient with pre-existing chronic kidney disease stage 3, treated effectively with sustained low-efficiency dialysis. We discuss the pathophysiology, differential diagnosis, and treatment options and highlight specific pharmacokinetic issues that should be considered in selecting the appropriate modality of renal replacement therapy.

1,25 Dihydroxyvitamin D circulating levels, calcitriol administration, and incidence of acute rejection, CMV infection, and polyoma virus infection in renal transplant recipients.

Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels.

[Eculizumab as rescue therapy for lupus nephritis-related thrombotic microangiopathy].

Thrombotic microangiopathy (TMA) is a frequent and severe complication in systemic lupus erythematosus (SLE). It is reported in almost 20-25% of renal biopsies of patients with lupus nephritis (LN) and is associated with a poor renal prognosis. We report the case of a patient suffering from an aggressive form of proliferative LN in association with thrombotic microangiopathy (TMA-LN), who was resistant to standard combined immunosuppressive treatment with corticosteroids and cyclophosphamide, as well as to plasma exchange (PEX). Eculizumab was given as a rescue therapy with an optimal clinical response. We performed a systematic review of the literature and identified 11 papers, published between 2011 and 2018, with a total of 20 patients, in which eculizumab was used, always as rescue therapy, to treat TMA-LN. All reported cases showed a positive clinical response to eculizumab with a high rate of remission. Even if sparse, available clinical cases and case series support the use of eculizumab in highly selected cases as rescue treatment for LN-TMA resistant to conventional combined immunosuppressive treatment.

Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury.

BACKGROUND: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI). METHODS: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments. RESULTS: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels. CONCLUSIONS: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.

Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury.

Sepsis is a serious medical condition that can lead to multi-organ failure and shock, and it is associated with increased mortality. Acute kidney injury (AKI) is a frequent complication of sepsis in critically ill patients, and often requires renal replacement therapy. The pathophysiology of AKI in sepsis has not yet been fully defined. In the past, classic theories were mainly focused on systemic hemodynamic derangements, underscoring the key role of whole kidney hypoperfusion due to reduced renal blood flow. However, a growing body of experimental and clinical evidence now shows that, at least in the early phase of sepsis-associated AKI, renal blood flow is normal, or even increased. This could suggest a dissociation between renal blood flow and kidney function. In addition, the scant data available from kidney biopsies in human studies do not support diffuse acute tubular necrosis as the predominant lesion. Instead, increasing importance is now attributed to kidney damage resulting from a complex interaction between immunologic mechanisms, inflammatory cascade activation, and deranged coagulation pathways, leading to microvascular dysfunction, endothelial damage, leukocyte/platelet activation with the formation of micro-thrombi, epithelial tubular cell injury and dysfunction. Moreover, the same processes, through maladaptive responses leading to fibrosis acting from the very beginning, may set the stage for progression to chronic kidney disease in survivors from sepsis-associated AKI episodes. The aim of this narrative review is to summarize and discuss the latest evidence on the pathophysiological mechanisms involved in septic AKI, based on the most recent data from the literature.

Diet and enteral nutrition in patients with chronic kidney disease not on dialysis: a review focusing on fat, fiber and protein intake.

The clinical data available on dietary requirements of patients with chronic kidney disease (CKD) not on dialysis are limited and largely inconclusive in terms of the renal, cardiovascular and nutritional outcomes achievable through dietary modifications. Restriction of protein intake during the early stages of CKD may in fact slow its progression, but at the same time this approach may also lead to protein-energy wasting, if energy intake is not adequate and properly monitored. Unfortunately, compliance to dietary recommendations is traditionally low in this patient population. A switch from saturated to mono- and polyunsaturated fats is generally recognized as advantageous for cardiac health; however, the benefits in term of renal function are largely unknown. Similarly, the association between dietary fiber intake and kidney disease is largely unknown. In fact, while there is evidence on the positive health effects of dietary fibers in the general population, nutritional guidelines for CKD lack formal recommendations concerning fiber intake. This paper reviews data and evidence from clinical trials and meta-analyses on renal and cardiovascular outcomes related to modifications in protein, fat and fiber intake. Suggestions for maintaining nutritional status through patient-oriented dietary patterns and enteral supplementation in CKD patients on conservative therapy are also presented.

Reliability of bedside ultrasound for measurement of quadriceps muscle thickness in critically ill patients with acute kidney injury.

MAIN PROBLEM: In patients with Acute Kidney Injury there is a lack of nutritional variables that can assess nutritional status, more specifically lean body mass (LBM) and skeletal muscle mass, at the individual level. In this clinical setting, ultrasound (US)) of the quadriceps femoris could represent a widely available, non-invasive, affordable, and reliable tool to evaluate skeletal muscle. METHODS: We performed a cross-sectional observational study in adult critically ill patients with KDIGO stage 3 AKI on dialysis. Quadriceps rectus femoris and vastus intermedius thickness were measured by two assessors. Intra- and interobserver reliability was evaluated using the intraclass correlation coefficient (ICC). The same US measures were obtained before and after dialysis. RESULTS: We enrolled 34 patients, 22 (65%) were male and the mean APACHE II score was 22.7 (±5.6). In the intraobserver reliability study, assessor 1 performed 288 paired measurements and assessor 2 performed 430 paired measurements in 34 patients, with an ICC equal to 0.99 and 1.00, respectively. There were 238 paired measurements (34 patients) in the interobserver reliability study, with an ICC = 0.92. No difference was found in the measurements obtained before and after dialysis (11.5 (4.2) vs 11.4 (4.1) mm, P = 0.2498), independently from acute body weight changes due to fluid removal. CONCLUSION: In patients with AKI, US of quadriceps femoris could represent a simple, accurate, and non-invasive method to evaluate quantitative changes in skeletal muscle.

[Pathophysiology of Acute Kidney Injury in sepsis]. / Fisiopatologia dell'insufficienza renale acuta nella sepsi.

Sepsis is a serious medical condition often complicated by multiorgan failure, especially in the intensive care unit setting. Acute renal failure is a frequent complication of sepsis, leading to increased hospital mortality risk and worsening of patient outcome. Despite recent advances in the treatment of sepsis and acute renal failure, the pathophysiological mechanisms of acute renal failure in sepsis is still not fully ascertained. The aim of this review is to illustrate the pathophysiological mechanisms that are involved in the development of acute renal failure in sepsis, with special regard to the systemic hemodynamic alterations, renal microvascular and inflammatory/immunological mechanisms.

Conservative management of chronic kidney disease stage 5: role of angiotensin converting enzyme inhibitors.

BACKGROUND: Benefits and risks of angiotensin converting enzyme inhibitors (ACE-I) in advanced chronic kidney disease (CKD) are controversial. We tested the role of ACE-I in slowing the progression of renal damage in a real-world elderly population with CKD stage 5. METHODS: We evaluated all patients consecutively referred to our CKD stage 5 outpatient clinic from January 2002 to December 2013. Chronicity was defined as two consecutive estimated glomerular filtration rate (eGFR) measurements below 15 ml/min/1.73 m2. We retrieved parameters of interest at baseline and assessed eGFR reduction rate during follow-up. We estimated GFR by the 4-variable Modification of Diet in Renal Disease (MDRD) formula. RESULTS: Mean age of the 342 subjects analyzed was 72 years and eGFR 10 ml/min/1.73 m2. In the 188 patients on ACE-I at baseline, the subsequent annual rate of eGFR reduction was less than a third of that found in the 154 patients off ACE-I. Across phosphate quartiles, baseline eGFR significantly decreased while its annual reduction rate significantly increased. Of the original cohort, 60 patients (17 %) died, 201 (59 %) started dialysis and 81 (24 %) were still in conservative treatment at the end of the study. Multivariate analysis identified age, phosphate, proteinuria, baseline eGFR and its rate of progression as independent risk factors directly or inversely predictive of progression to dialysis. ACE-I use significantly reduced by 31 % the risk of dialysis. CONCLUSIONS: Our study shows that proteinuria independently predicts further renal damage progression even in end-stage renal disease patients not yet in dialysis. In our cohort of elderly patients with very advanced CKD, ACE-I was effective in slowing down further renal damage progression.

[Metabolic acidosis]. / Acidosi metabolica.

Metabolic acidosis is frequently observed in clinical practice, especially among critically ill patients and/or in the course of renal failure. Complex mechanisms are involved, in most cases identifiable by medical history, pathophysiology-based diagnostic reasoning and measure of some key acid-base parameters that are easily available or calculable. On this basis the bedside differential diagnosis of metabolic acidosis should be started from the identification of the two main subtypes of metabolic acidosis: the high anion gap metabolic acidosis and the normal anion gap (or hyperchloremic) metabolic acidosis. Metabolic acidosis, especially in its acute forms with elevated anion gap such as is the case of lactic acidosis, diabetic and acute intoxications, may significantly affect metabolic body homeostasis and patients hemodynamic status, setting the stage for true medical emergencies. The therapeutic approach should be first aimed at early correction of concurrent clinical problems (e.g. fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, hemodialysis for acute intoxications etc.), in parallel to the formulation of a diagnosis. In case of severe acidosis, the administration of alkalizing agents should be carefully evaluated, taking into account the risk of side effects, as well as the potential need of renal replacement therapy.