Metformin has been available since 1957. Over 50 years later, one can legitimately question whether a clear definition of its "therapeutic concentrations" is available.
The objective of this ...systematic review was to establish whether or not there is a literature consensus on the "therapeutic concentrations" of metformin.
We systematically searched the scientific literature with the keywords "metformin", "therapeutic concentration", "therapeutic level", and "therapeutic range". When the suggested values were defined by citing a literature reference, the types of studies in cited references and the concordance of data between the citations and theirs sources were studied.
We identified 120 documents that reported or cited 65 different "therapeutic" plasma metformin concentrations or ranges. The values ranged from 0.129 to 90 mg/L, and the lowest and highest boundaries were 0 and 1800 mg/L. Only four original research studies determined a "therapeutic concentration". Fifty-four publications cited previous studies as defining the therapeutic concentrations, whereas 62 publications mentioned "therapeutic concentrations" but did not even cite a supporting reference. The supporting references were mostly reviews, pharmacokinetic studies and in vitro studies. In the 54 publications that cited references, concordance between the wording of the citation and the true nature of the source data was observed in only 23 cases (42.6%).
Given the nature of a systematic literature search, the only possible limitation would be incomplete identification and retrieval of publications on therapeutic concentrations. An extensive study of the literature has, however, been performed by examining nearly 1000 potentially relevant publications.
The only valid way of defining the therapeutic concentration window for metformin would be to relate dose efficacy (in terms of blood glucose control) to the corresponding plasma concentration in long-term treated patients.
Although metformin has been available for over 50 years and it is the key medication in first-line treatment of type 2 diabetes mellitus, major methodological and/or conceptual errors have confounded the literature on its therapeutic concentrations.
Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy (BEN) are chronic tubulointerstitial renal diseases associated with urothelial carcinoma. The clinical expression and pathological ...lesions observed at different stages of CHN and BEN are strikingly similar. Both have been linked to exposure to aristolochic acid (AA), a powerful nephrotoxin and human carcinogen. Jelaković et al. present molecular epidemiological evidence relating urothelial carcinoma in patients with BEN to dietary exposure to AA. It is time to abandon the terms ‘CHN’ and ‘BEN’ and introduce ‘aristolochic acid nephropathy’ to cover both clinical conditions.
This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in ...patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug’s pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.
This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of ...restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies.
Three complementary studies were performed:
) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase;
) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA
concentrations monitored monthly; and
) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4.
First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning qam +1 g in the evening qpm) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA
levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups.
Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.
Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so‐called ...“metformin‐associated lactic acidosis” (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin‐treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin‐unrelated lactic acidosis or metformin‐induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin‐treated patients. Accordingly, we propose a check‐list as a guide to clinical practice.
Increase in the prevalence of chronic kidney disease (CKD) is observed in Central America, Sri Lanka and other tropical countries. It is named chronic interstitial nephritis in agricultural ...communities (CINAC). CINAC is defined as a form of CKD that affects mainly young men, occasionally women. Its aetiology is not linked to diabetes, hypertension, glomerulopathies or other known causes. CINAC patients live and work in poor agricultural communities located in CINAC endemic areas with a hot tropical climate, and are exposed to toxic agrochemicals through work, by ingestion of contaminated food and water, or by inhalation. The disease is characterized by low or absent proteinuria, small kidneys with irregular contours in CKD stages 3–4 presenting tubulo-interstitial lesions and glomerulosclerosis at renal biopsy. Although the aetiology of CINAC is unclear, it appears to be multifactorial. Two hypotheses emphasizing different primary triggers have been proposed: one related to toxic exposures in the agricultural communities, the other related to heat stress with repeated episodes of dehydration heath stress and dehydration. Existing evidence supports occupational and environmental toxins as the primary trigger. The heat stress and dehydration hypothesis, however, cannot explain: why the incidence of CINAC went up along with increasing mechanization of paddy farming in the 1990s; the non-existence of CINAC in hotter northern Sri Lanka, Cuba and Myanmar where agrochemicals are sparsely used; the mosaic geographical pattern in CINAC endemic areas; the presence of CINAC among women, children and adolescents who are not exposed to the harsh working conditions; and the observed extra renal manifestations of CINAC. This indicates that heat stress and dehydration may be a contributory or even a necessary risk factor, but which is not able to cause CINAC by itself.
The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300pg/ml or more, serum calcium ...of 8.4mg/dl or more, bone-specific alkaline phosphatase over 20.9ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. The median PTH decreased from 985pg/ml at baseline to 480pg/ml at the end of study (weeks 44–52). Bone formation rate/tissue area decreased from 728 to 336μm2/mm2/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy.
Abstract
The introduction of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines has substantially contributed to the early detection of different stages of chronic kidney disease (CKD). ...Several recent studies from different parts of the world mention a CKD prevalence of between 8 and 13%. There are several reasons the CKD prevalence found in a study of a particular population is clearly overestimated. The structure of the population pyramid (young or older age) of the study sample may result in high or low CKD prevalence. The absence of using an isotope dilution mass spectrometry creatinine assay can be the source of high bias in CKD prevalence. In addition, using an arbitrary single threshold of estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2) for classifying CKD leads to a substantial ‘overdiagnosis’ (false positives) in the elderly (>65 years of age), particularly in those without albuminuria (or proteinuria), haematuria or hypertension. It also results in a significant ‘underdiagnosis’ (false negatives) in younger individuals with an eGFR >60 mL/min/1.73 m2 and below the third percentile for their age/gender category. The use of third percentile eGFR rates as a cut-off based on age/gender-specific reference values of eGFR allows the detection of these false positives and negatives. In the present article, we focus on an important and frequently omitted criterion in epidemiological studies: chronicity. Indeed, the two most important factors introducing a high number (up to 50%) of false positives are lack of confirming proteinuria and the absence of proof of chronicity of the eGFR found at first screening. There is an urgent need for quality studies of the prevalence of CKD using representative randomized samples of the population, applying the KDIGO guidelines correctly.
The prevalence of hypertension, diabetes, obesity, and chronic kidney disease (CKD) in an adult Arabic-Berber population was investigated according to 2012 KDIGO guidelines. A stratified, randomized, ...representative sample of 10,524 participants was obtained. Weight, height, blood pressure, proteinuria (dipstick), plasma creatinine, estimated glomerular filtration rate, and fasting glycemia were measured. Abnormal results were controlled within 2 weeks; eGFR was retested at 3, 6, and 12 months. The population adjusted prevalences were 16.7% hypertension, 23.2% obesity, 13.8% glycemia, 1.6% for eGFR under 60 ml/min/1.73 m2 and confirmed proteinuria 1.9% and hematuria 3.4%. Adjusted prevalence of CKD was 5.1%; distribution over KDIGO stages: CKD1: 17.8%; CKD2: 17.2%; CKD3: 52.5% (3A: 40.2%; 3B: 12.3%); CKD4: 4.4%; CKD5: 7.2%. An eGFR distribution within the sex and age categories was constructed using the third percentile as threshold for decreased eGFR. A single threshold (under 60 ml/min/1.73 m2) eGFR classifying CKD3–5 leads to “overdiagnosis” of CKD3A in the elderly, overt “underdiagnosis” in younger individuals with eGFR over 60 ml/min/1.73 m2, below the third percentile, and no proteinuria. By using the KDIGO guidelines in a correct way, “kidney damage” (confirmed proteinuria, hematuria) and the demonstration of chronicity of decreased eGFR <60 ml/min/1.73 m2, combined with the third percentile as a cutoff for the normality of eGFR for age and sex, overcome false positives and negatives, substantially decrease CKD3A prevalence, and greatly increase the accuracy of identifying CKD.
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