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Human Genetics Mar 2021Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same... (Review)
Review
Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are known to cause Dent disease, no such mutations are found in about 25-35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Starting from the history of Dent disease, and reviewing the clinical details of patients with and without a genetic characterization, we discuss the phenotypic and genetic heterogeneity that typifies this disease. We focus particularly on all those confounding clinical signs and symptoms that can lead to a misdiagnosis. We also try to shed light on a concealed aspect of Dent disease. Although it is a proximal tubulopathy, its misdiagnosis may lead to patients undergoing kidney biopsy. In fact, some individuals with Dent disease have high-grade proteinuria, with or without hematuria, as in the clinical setting of glomerulopathy, or chronic kidney disease of uncertain origin. Although glomerular damage is frequently documented in Dent disease patients' biopsies, there is currently no reliable evidence of renal biopsy being of either diagnostic or prognostic value. We review published histopathology reports of tubular and glomerular damage in these patients, and discuss current knowledge regarding the role of CLCN5 and OCRL genes in glomerular function.
Topics: Chloride Channels; Dent Disease; Genetic Heterogeneity; Humans; Mutation; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 32860533
DOI: 10.1007/s00439-020-02219-2 -
BMC Nephrology Aug 2020The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared...
BACKGROUND
The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances.
CASE PRESENTATION
Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved.
CONCLUSION
This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.
Topics: Acute Disease; Alanine; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemotherapy-Induced Febrile Neutropenia; Deprescriptions; Drug Interactions; Fanconi Syndrome; Gentamicins; Glycosuria; HIV Infections; Hodgkin Disease; Humans; Hypokalemia; Hypophosphatemia; Male; Middle Aged; Proteinuria; Tenofovir
PubMed: 32787843
DOI: 10.1186/s12882-020-01981-9 -
Kidney Medicine 2019Light chain proximal tubulopathy is a rare M-proteinemia-related nephropathy. The inclusions, composed of light chains in light chain proximal tubulopathy, are generally...
Light chain proximal tubulopathy is a rare M-proteinemia-related nephropathy. The inclusions, composed of light chains in light chain proximal tubulopathy, are generally crystalline, and most exhibit a rhombic shape. Noncrystalline structures, such as rods or needle shapes, may also be present. In our patient, one of the noncrystalline structures, fibrillary inclusions in the cytoplasm, were observed, as previously reported in only 4 patients whose primary disease was either multiple myeloma or monoclonal gammopathy of renal significance. This is the first report involving lymphoma. Early diagnosis of light chain proximal tubulopathy is important because those who undergo chemotherapy have an improved kidney prognosis. However, in cases of kidney involvement with blood disorders, thrombocytopenia is often present. Therefore, in our case, open kidney biopsy was selected. Noncrystalline light chain proximal tubulopathy is believed to be less likely to cause Fanconi syndrome. However, Fanconi syndrome was observed in 3 of the 4 patients with fibrillary inclusions. In our case, hypouricemia was improved by chemotherapy, suggesting that the patient presented with Fanconi syndrome. Noncrystalline light chain proximal tubulopathy with fibrillary inclusions may cause Fanconi syndrome, similar to crystalline light chain proximal tubulopathy. We report a case of light chain proximal tubulopathy with fibrillary inclusions complicated by low-grade B-cell lymphoma in which early treatment was successful.
PubMed: 32734220
DOI: 10.1016/j.xkme.2019.07.013 -
Clinical Kidney Journal Jun 2020Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our...
BACKGROUND
Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients.
METHODS
A retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) ( = 28) or the Medical department ( = 14) and were screened at least once for four markers of proximal tubulopathy.
RESULTS
The mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, = 22), hyperuricosuria (43%, = 17) and normoglycaemic glycosuria (30%, = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43-0.76) versus 0.77 (0.66-1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge.
CONCLUSION
Incomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.
PubMed: 32695327
DOI: 10.1093/ckj/sfaa109 -
BMJ Case Reports Jun 2020Kidney tubular disorders due to monoclonal immunoglobulin light chains are common manifestations of B-cell neoplasm. Cast nephropathy (CN) is the most frequent type of...
Kidney tubular disorders due to monoclonal immunoglobulin light chains are common manifestations of B-cell neoplasm. Cast nephropathy (CN) is the most frequent type of these disorders and may present with acute kidney injury (AKI) due to the presence of excess light chains in the distal tubules. Light chain proximal tubulopathy (LCPT) is an uncommon form of renal disease and may present as Fanconi syndrome due to proximal tubular cell damage by intracellular deposition of light chains. The concomitant disorder of both CN and LCPT is rare given the inherent differences in the biochemical properties of the immunoglobulin light chains of each disorder. We report a 64-year-old man who presented with AKI and Fanconi syndrome who was discovered to have both CN and LCPT due to the underlying disorder of monoclonal gammopathy of renal significance and who has responded favourably with conventional chemotherapy. We also review the existing literature on this interesting subject.
Topics: Diagnosis, Differential; Humans; Immunoglobulin Light Chains; Kidney Diseases; Kidney Tubules, Proximal; Male; Middle Aged; Multiple Myeloma; Renal Insufficiency, Chronic
PubMed: 32595131
DOI: 10.1136/bcr-2020-234361 -
Kidney360 Aug 2020Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot...
BACKGROUND
Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy.
METHODS
Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for studies.
RESULTS
In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 the mTORC1/SREBP1 pathway.
CONCLUSIONS
AOPPs may contribute to renal tubulopathy perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.
Topics: Acetyltransferases; Advanced Oxidation Protein Products; Animals; Fatty Acid Elongases; Fatty Acids; Kidney; Mice
PubMed: 35372949
DOI: 10.34067/KID.0000772019 -
BMC Nephrology Apr 2020Light chain proximal tubulopathy (LCPT) is a rare paraproteinemic renal disease that has been mostly reported in Western patients. LCPT is characterized by the...
Clinicopathological characteristics of light chain proximal tubulopathy in Korean patients and the diagnostic usefulness of immunohistochemical staining for immunoglobulin light chain.
BACKGROUND
Light chain proximal tubulopathy (LCPT) is a rare paraproteinemic renal disease that has been mostly reported in Western patients. LCPT is characterized by the accumulation of immunoglobulin (Ig)-light chain (LC) in the proximal tubule. Immunohistochemical staining for Ig-LC has not been investigated in the context of LCPT. We reported the clinicopathological characteristics and Ig-LC immunoexpression of patients with LCPT for the first time in Korea.
METHODS
We reviewed the clinicopathological findings of 5 Korean patients diagnosed with LCPT between 2016 and 2018. In addition, immunohistochemical staining for κ-LC and λ-LC was conducted on paraffin-embedded tissues.
RESULTS
The median age was 63 years, and the male-to-female ratio was 3:2. The primary renal manifestations were either azotemia or tubular proteinuria. All patients were diagnosed with multiple myeloma with monoclonal κ-LC (#1-2) or λ-LC (#3-5) in the serum and urine. Kidney biopsies revealed diverse and subtle alterations of the proximal tubule, including crystallization, vacuolization, and/or swelling. Electron microscopy revealed crystals in patients #1-2 and non-crystalline particles within numerous/large/dysmorphic lysosomes in patients #3-5. Ig-LC restriction was demonstrated in the proximal tubule as κ-type in patients #1-2 and as λ-type in patients #3-5 by immunohistochemistry and immunofluorescence. Immunohistochemical staining showed diffuse positivity to κ- and λ-LC, although immunofluorescent staining for κ-LC was focal and weak. LCPT has diverse clinicopathological characteristics and subtle morphological alterations, which necessitate ancillary tests for diagnosis.
CONCLUSIONS
We introduced immunohistochemical staining for Ig-LC as a useful tool for the diagnosis of LCPT, especially in the case of κ-type crystals.
Topics: Azotemia; Female; Fluorescent Antibody Technique; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunohistochemistry; Kidney Function Tests; Kidney Tubules, Proximal; Male; Middle Aged; Multiple Myeloma; Nephritis, Interstitial; Proteinuria; Reproducibility of Results; Republic of Korea
PubMed: 32326898
DOI: 10.1186/s12882-020-01813-w -
Clinical Nephrology. Case Studies 2020Plasma cell dyscrasias frequently involve the kidney causing renal dysfunction. Multiple morphologic manifestations of κ light chain disease occurring simultaneously in...
Plasma cell dyscrasias frequently involve the kidney causing renal dysfunction. Multiple morphologic manifestations of κ light chain disease occurring simultaneously in the same kidney biopsy are uncommon and suggest local microenvironment effects in addition to structural properties of the light chain. A 61-year-old female presented with new onset renal failure and proteinuria. Serological workup revealed monoclonal gammopathy with elevated κ : λ ratio of 1,371. Renal biopsy revealed several paraprotein manifestations including κ light chain deposition disease, monoclonal fibrillary glomerulonephritis, cryocrystalglobulenemia and fibrillar/microtubular cast nephropathy. There was also incidental leukocyte chemotactic factor 2 amyloidosis (ALECT 2), negative for κ light chain and confirmed by immunohistochemistry (IHC). Bone marrow biopsy revealed 10 - 20% κ restricted plasma cells. The patient received 10 cycles of CyBorD (cyclophosphamide, bortezomib, and dexamethasone) chemotherapy. Renal function improved with decreased κ : λ ratio. Repeat bone marrow biopsy showed no evidence of abnormal plasma cells by IHC. The renal recovery demonstrates there may be response to chemotherapy irrespective of the morphologic manifestations of light chain-related injury. Additionally, if amyloid is not demonstrated to be of light chain origin, other amyloid types should be considered.
PubMed: 32318322
DOI: 10.5414/CNCS110052 -
Gene Jul 2020Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the... (Review)
Review
Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the kidney, the chloride channel Cl/H exchanger ClC-5 encoded by the CLCN5 gene is actively involved in preventing protein loss. This action becomes evident in patients suffering from the rare proximal tubulopathy Dent disease because they carry a defective ClC-5 due to CLCN5 mutations. In fact, proteinuria is the distinctive clinical sign of Dent disease, and mainly involves the loss of low-molecular-weight proteins. The identification of CLCN5 disease-causing mutations has greatly improved our understanding of ClC-5 function and of the ClC-5-related physiological processes in the kidney. This review outlines current knowledge regarding the CLCN5 gene and its protein product, providing an update on ClC-5 function in tubular and glomerular cells, and focusing on its relationship with proteinuria and Dent disease.
Topics: Animals; Chloride Channels; Dent Disease; Endocytosis; Humans; Kidney; Mutation; Phenotype
PubMed: 32289351
DOI: 10.1016/j.gene.2020.144662 -
International Journal of Molecular... Apr 2020Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke...
Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation in proximal tubular cells were blocked by DNA-aptamer that could bind to glyceraldehyde-derived pyridinium (GLAP) (GLAP-aptamer), and then investigated whether and how GLAP caused proximal tubular cell injury. GLAP-aptamer and AGE-aptamer raised against glycer-AGEs were prepared using a systemic evolution of ligands by exponential enrichment. The binding affinity of GLAP-aptamer to glycer-AGEs was measured with a bio-layer interferometry. ROS generation was evaluated using fluorescent probes. Gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). GLAP-aptamer bound to glycer-AGEs with a dissociation constant of 7.7 × 10 M. GLAP-aptamer, glycer-AGE-aptamer, or antibodies directed against receptor for glycer-AGEs (RAGE) completely prevented glycer-AGE- or GLAP-induced increase in ROS generation, MCP-1, PAI-1, or RAGE gene expression in tubular cells. Our present results suggest that GLAP is one of the structurally distinct glycer-AGEs, which may mediate oxidative stress and inflammatory reactions in glycer-AGE-exposed tubular cells. Blockade of the interaction of GLAP-RAGE by GLAP-aptamer may be a therapeutic target for proximal tubulopathy in diabetic nephropathy.
Topics: Biomarkers; Cells, Cultured; Diabetic Nephropathies; Epithelial Cells; Glycation End Products, Advanced; Glyceraldehyde; Humans; Kidney Tubules; Kidney Tubules, Proximal; Oxidative Stress; Pyridinium Compounds; Reactive Oxygen Species
PubMed: 32283652
DOI: 10.3390/ijms21072604