Recurrent Fanconi Syndrome Induced by Lenalidomide: A Case Report.

Fanconi syndrome (FS) is a complex disorder characterized by a reabsorption defect in the proximal renal tubule (PT), leading to urinary loss of molecules such as glucose, phosphate, calcium, amino acids, bicarbonate, potassium, and low-molecular-weight proteins. Its etiology can be genetic or acquired, with drug toxicity being a significant cause of the acquired forms. The heterogeneous manifestations of FS, whether in its partial or complete form, can pose challenges in the emergency department; nevertheless, it should be considered in certain patients, as understanding its cause is crucial for initiating effective treatment. We present the case of a 59-year-old female patient with FS who was treated with lenalidomide in the context of stage III IgG kappa multiple myeloma according to the Salmon Durie classification. We highlight the recurrent nature of this syndrome in this patient.

When Two Syndromes Collide: Managing Fanconi and Refeeding Syndrome in a Single Patient.

Refeeding syndrome is the potentially fatal shift in fluids and electrolytes that may occur in malnourished patients after receiving artificial refeeding. Its hallmark feature is hypophosphatemia, although other electrolytes might also be affected. Fanconi syndrome is a generalized dysfunction of the proximal tubule characterized by proximal renal tubular acidosis (RTA), phosphaturia, glycosuria, aminoaciduria, and proteinuria. The etiology of Fanconi syndrome can be either acquired or inherited, and drugs, among them tenofovir, are a common acquired cause of this disease. We present the case of a patient with AIDS and polysubstance abuse who was admitted due to pneumonia, completed treatment, was then started on antiretroviral medication (ART) that included tenofovir alafenamide (TAF) and began presenting severe episodes of hypophosphatemia along with other electrolyte imbalances, leading the workup denoted in the case, severe complications and finally to the patient's demise. Most cases of tenofovir-related Fanconi syndrome are related to tenofovir disoproxil fumarate, but very few cases have been reported with TAF. Our case highlights this rare complication of therapy with TAF and how artificial feeding can contribute to severe electrolyte abnormalities and worsen outcomes.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes.

SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

Renal Proximal Tubular Epithelial Cells: From Harvesting to Use in Studies.

The kidneys are the body's main excretion organ with several additional functions, and the nephron represents their central structural unit. It is comprised of endothelial, mesangial, glomerular, and tubular epithelial cells, as well as podocytes. Treatment of acute kidney injury or chronic kidney disease (CKD) is complex due to broad etiopathogenic mechanisms and limited regeneration potential as kidney cells finish their differentiation after 34 weeks of gestation. Despite the ever-increasing prevalence of CKD, very limited treatment modalities are available. The medical community should therefore strive to improve existing treatments and develop new ones. Furthermore, polypharmacy is present in most CKD patients, while current pharmacologic study designs lack effectiveness in predicting potential drug-drug interactions and the resulting clinically relevant complications. An opportunity for addressing these issues lies in developing in vitro cell models based on patient-derived renal cells. Currently, several protocols have been described for isolating desired kidney cells, of which the most isolated are the proximal tubular epithelial cells. These play a significant role in water homeostasis, acid-base control, reabsorption of compounds, and secretion of xenobiotics and endogenous metabolites. When developing a protocol for the isolation and culture of such cells, one must focus on several steps. These include harvesting cells from biopsy specimens or after nephrectomies, using different digestion enzymes and culture mediums to facilitate the selective growth of only the desired cells. The literature reports several existing models, from simple 2D in vitro cultures to more complex ones created with bioengineering methods, such as kidney-on-a-chip models. While their creation and use depend on the target research, one should consider factors such as equipment, cost, and, even more importantly, source tissue quality and availability.

Association of metabolic syndrome traits with urinary biomarkers in Japanese adults.

BACKGROUND: Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers. METHODS: Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, ß2-microglobulin, and N-acetyl-ß-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR) < 300 mg/g in a health checkup. Metabolic syndrome traits were adopted from the National Cholesterol Education Program (third revision) of the Adult Treatment Panel criteria modified for Asians. RESULTS: Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03-1.64; albumin: 1.42 per quartile, 95% CI 1.12-1.79). CONCLUSIONS: Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.

Tenofovir alafenamide (TAF) clinical pharmacology.

Tenofovir today exists in two pharmaceutical forms, such as Tenofovir disoproxil fumarate (TDF) and the newer Tenofovir alafenamide (TAF). The two different salts are required in order to promote intestinal absorption of the active molecule (TFV). Once absorbed the distribution of TFV into compartments is driven by the salt to which the drug is conjugated; in case of TDF, following absorption most of TFV is cleared from its link with the salt and the drug is widely distributed into different tissues, while in case of TAF the reverse is true as TFV remains mostly associated to its alafenamide salt and its distribution is restricted to cells with high carboxyesterase and catepsin A activity, such as hepatocytes and lymphocytes. This generates higher plasma levels of TFV in case of TDF while in the case of TFV much higher intracellular concentrations in target cells are achieved. The main reason for TAF development was to reduce the impact of the drug on proximal renal function and this was actually obtained by the much lower plasma concentration of TFV. Numerous clinical trials consistently demonstrated the significant lesser impact of TAF vs TDF on both renal function and structural bone integrity.

Renal proximal tubular epithelial cells: review of isolation, characterization, and culturing techniques.

The kidney is a complex organ, comprised primarily of glomerular, tubular, mesangial, and endothelial cells, and podocytes. The fact that renal cells are terminally differentiated at 34 weeks of gestation is the main obstacle in regeneration and treatment of acute kidney injury or chronic kidney disease. Furthermore, the number of chronic kidney disease patients is ever increasing and with it the medical community should aim to improve existing and develop new methods of renal replacement therapy. On the other hand, as polypharmacy is on the rise, thought should be given into developing new ways of testing drug safety. A possible way to tackle these issues is with isolation and culture of renal cells. Several protocols are currently described to isolate the desired cells, of which the most isolated are the proximal tubular epithelial cells. They play a major role in water homeostasis, acid-base control, reabsorption of compounds, and secretion of xenobiotics and endogenous metabolites. When exposed to ischemic, toxic, septic, or obstructive conditions their death results in what we clinically perceive as acute kidney injury. Additionally, due to renal cells' limited regenerative potential, the profibrotic environment inevitably leads to chronic kidney disease. In this review we will focus on human proximal tubular epithelial cells. We will cover human kidney culture models, cell sources, isolation, culture, immortalization, and characterization subdivided into morphological, phenotypical, and functional characterization.

Tenofovir-induced delayed nephro-osteo toxicity.

Tenofovir disoproxil fumarate (TDF) is the foundation nucleotide reverse-transcriptase inhibitor in the recommended first-line regimen for all naive human immunodeficciency virus-1 (HIV-1) patients whose age is more than 10 years and body weight is more than 30 kg. Although it has a good safety profile overall, nephrotoxicity is a concern and its overall incidence is 1-6% with a long period of clinical latency. Nephrotoxicity may manifest as either proximal renal tubule dysfunction in the form of a partial or complete Fanconi syndrome or as decreased renal function leading to acute or chronic kidney injury. Osteomalacia can also develop secondary to complicating hypophosphataemia and low calcitriol levels. Here we report a 50-year-old HIV-positive male on tenofovir who presented with proximal renal tubular acidosis and fracture of left neck of femur four years after initiation of the drug.

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney.

Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)-induced diabetes mellitus mouse model. The results revealed that histological alterations in renal tubules, shown by a vacuolar nucleic structure, accumulations of PAS-positive substance, and accelerated restoration stress, occur initially without the presence of glomerular lesions in the early-stage diabetic kidney, and that these tubular defects are localized mainly in proximal renal tubules. Moreover, enhanced expression of RAGE, suggesting an aberrant activation of AGEs-RAGE signaling pathway, and accumulation of oxidative modified mitochondria through the impaired autophagy/lysosome system, were also seen in the damaged diabetic proximal renal tubules. Our findings indicate that proximal tubular defects are the initial pathological events increasingly linked to the progression of diabetic nephropathy, and that controlling renal tubular damage could be an effective therapeutic strategy for the clinical treatment of diabetic nephropathy.

Sodium glucose co-transporter inhibitors - A new class of old drugs.

Sodium glucose co-transporter (SGLT) inhibitors are a new class of drugs which are used in the pharmacotherapy of Type-II diabetes, which happens to be a major risk factor for developing both micro as well as macro-vascular complications. These drugs inhibit the glucose reabsorption by inhibiting SGLT, which exhibits a novel and promising mechanism of action by promoting the urinary glucose excretion hence providing a basis of therapeutic intervention. Results of SGLT-II inhibitors are very encouraging as there is a significant elevation of GLP-1 level, which forms the basis of relevance in treatment of diabetes. It targets the HbA1C and keeps a check on its levels. It also exerts other positive benefits such as weight loss, reduction in blood glucose levels, reduction in blood pressure and improvement in insulin resistance and ß-cell dysfunction: All contributing to effective glycemic control. SGLT inhibition will develop as effective modality as it has the capability of inhibiting reabsorption of greater percentage of filtered glucose load.

The vitamin D receptor in the proximal renal tubule is a key regulator of serum 1α,25-dihydroxyvitamin D3.

It is well established that the mitochondria of proximal convoluted tubule cells of the kidney are the site of production of circulating 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The production of 1,25(OH)2D3 at this site is tightly regulated. Parathyroid hormone markedly stimulates 1,25(OH)2D3 production, whereas 1,25(OH)2D3 itself suppresses production. The mechanism of suppression by 1,25(OH)2D3 has not yet been elucidated. We have now found that in the absence of vitamin D (vitamin D deficiency), the vitamin D receptor (VDR) is found in the interior of the apical brush border of the proximal tubule cells. This is unique for the proximal tubule cells, since this has not been observed in the distal tubule cells or in other epithelial cells, such as intestinal mucosa. Administration of 1,25(OH)2D3 to vitamin D-deficient rats results in the movement of VDR from the brush border to the cytoplasm and nucleus presumably bound to reabsorbed 1,25(OH)2D3. The VDR bound to 1,25(OH)2D3 suppresses expression of 25-hydroxyvitamin D3 1α-hydroxylase and stimulates the 25-hydroxyvitamin D3 24-hydroxylase. Thus, VDR in the apical brush border of the proximal convoluted tubule cells serves to "sense" the level of circulating 1,25(OH)2D3 and modulates the activity of the 1α-hydroxylase and the 24-hydroxylase accordingly.