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Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2022Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of...
OBJECTIVES
Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of their low prevalence and relatively insufficient understanding, which affects the treatment and prognosis of patients. This study aims to explore clinical manifestations and pathological characteristics of several rare tubulointerstitial diseases, and therefore to improve their diagnosis and treatment.
METHODS
A total of 9 363 patients diagnosed by renal biopsy in the Department of Nephrology, Second Xiangya Hospital, Central South University from November 2011 to September 2021 were selected. Six cases of light chain cast nephropathy (LCCN), 2 cases of light chain proximal tubulopathy (LCPT), 1 case of LCCN with LCPT, 4 cases of genetic tubulointerstitial disease, and 6 cases of non-genetic related tubulointerstitial lesion were screened out, and their clinical manifestations and renal biopsy pathological results were collected, compared, and analyzed.
RESULTS
Patients with LCCN presented with mild to moderate anemia, microscopic hematuria, and mild to moderate proteinuria. Compared with patients with LCPT, proteinuria and anemia were more prominent in patients with LCCN. Five patients with LCCN and 2 patients with LCPT had elevated serum free kappa light chain. Five patients with LCCN presented clinically with acute kidney injury (AKI). Two patients with LCPT and 1 patient with LCCN and LCPT showed CKD combined with AKI, and 1 LCPT patient presented with typical Fanconi syndrome (FS). Five patients with LCCN, 2 patients with LCPT, and 1 patient with LCCN and LCPT were diagnosed with multiple myeloma. Five patients with LCCN had kappa light chain restriction in tubules on immunofluorescence and a "fractured" protein casts with pale periodic acid-Schiff (PAS) staining on light microscopy. Immunohistochemical staining of 2 LCPT patients showed strongly positive kappa light chain staining in the proximal tubular epithelial cells. And monoclonal light chain crystals in crystalline LCPT and abnormal lysosomes and different morphological inclusion bodies in noncrystalline LCPT were observed under the electron microscope. Six patients with LCCN were mainly treated by chemotherapy. Renal function was deteriorated in 1 patient, was stable in 4 patients, and was improved in 1 patient. Two patients with LCPT improved their renal function after chemotherapy. Four patients with genetic tubulointerstitial disease were clinically presented as CKD, mostly mild proteinuria, with or without microscopic hematuria, and also presented with hyperuricemia, urine glucose under normal blood glucose, anemia, polycystic kidneys. Only 1 case had a clear family history, and the diagnosis was mainly based on renal pathological characteristics and genetic testing. Compared with patients with non-genetic related tubulointerstitial lesion, patients with genetic tubulointerstitial disease had an earlier age of onset, higher blood uric acid, lower Hb and estiated glomemlar fitration (eGFR), and less edema and hypertension. Renal pathology of genetic tubulointerstitial disease presented tubular atrophy and interstitial fibrosis, abnormal tubular dilation, glomerular capsuledilation, and glomerular capillary loop shrinkage. Glomerular dysplasia and varying degrees of glomerular sclerosis were observed. Genetic tubulointerstitial disease patients were mainly treated with enteral dialysis, hypouricemic and hypoglycemic treatment. Two genetic tubulointerstitial disease patients had significantly deteriorated renal function, and 2 patients had stable renal function.
CONCLUSIONS
Patients with AKI or FS, who present serum immunofixation electrophoresis and/or serum free kappa light chain abnormalities, should be alert to LCCN or LCPT. Renal biopsy is a critical detection for diagnosis of LCCN and LCPT. Chemotherapy and stem cell transplantation could delay progression of renal function in patients with LCCN and LCPT. If the non-atrophic area of the renal interstitium presents glomerular capsule dilatation, glomerular capillary loop shrinkage, and abnormal tubular dilatation under the light microscopy, genetic tubulointerstitial disease might be considered, which should be traced to family history and can be diagnosed by genetic testing.
Topics: Humans; Hematuria; Immunoglobulin Light Chains; Multiple Myeloma; Proteinuria; Nephritis, Interstitial; Acute Kidney Injury; Anemia; Renal Insufficiency, Chronic
PubMed: 36411687
DOI: 10.11817/j.issn.1672-7347.2022.220127 -
Diabetologia Jan 2023Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting...
Hedgehog interacting protein activates sodium-glucose cotransporter 2 expression and promotes renal tubular epithelial cell senescence in a mouse model of type 1 diabetes.
AIMS/HYPOTHESIS
Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (Hhip-KO), hypothesising that local deficiency of HHIP in the renal tubules would attenuate tubular cell senescence, thereby preventing DKD tubulopathy.
METHODS
Low-dose streptozotocin was employed to induce diabetes in both Hhip-KO and control (Hhip) mice. Transgenic mice overexpressing Hhip in renal proximal tubular cells (RPTC) (Hhip-Tg) were used for validation, and primary RPTCs and human RPTCs (HK2) were used for in vitro studies. Kidney morphology/function, tubular senescence and the relevant molecular measurements were assessed.
RESULTS
Compared with Hhip mice with diabetes, Hhip-KO mice with diabetes displayed lower blood glucose levels, normalised GFR, ameliorated urinary albumin/creatinine ratio and less severe DKD, including tubulopathy. Sodium-glucose cotransporter 2 (SGLT2) expression was attenuated in RPTCs of Hhip-KO mice with diabetes compared with Hhip mice with diabetes. In parallel, an increased tubular senescence-associated secretory phenotype involving release of inflammatory cytokines (IL-1β, IL-6 and monocyte chemoattractant protein-1) and activation of senescence markers (p16, p21, p53) in Hhip mice with diabetes was attenuated in Hhip-KO mice with diabetes. In contrast, Hhip-Tg mice had increased tubular senescence, which was inhibited by canagliflozin in primary RPTCs. In HK2 cells, HHIP overexpression or recombinant HHIP increased SGLT2 protein expression and promoted cellular senescence by targeting both ataxia-telangiectasia mutated and ataxia-telangiectasia and Rad3-related-mediated cell arrest.
CONCLUSIONS/INTERPRETATION
Tubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Type 1; Epithelial Cells; Hedgehog Proteins; Sodium-Glucose Transporter 2; Carrier Proteins; Membrane Glycoproteins; Mice, Transgenic; Diabetes Mellitus, Experimental; Kidney Tubules; Cellular Senescence
PubMed: 36260124
DOI: 10.1007/s00125-022-05810-6 -
Journal of Nephrology Mar 2023
Topics: Humans; Nephrologists; Kidney Diseases; Paraproteinemias; Kidney Tubules, Proximal; Immunoglobulin Light Chains
PubMed: 36242736
DOI: 10.1007/s40620-022-01443-5 -
Vnitrni Lekarstvi 2022One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of...
One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of antimicrobials. Clinical manifestations range from mild forms of tubular damage to significant deterioration of renal function requiring renal replacement therapy. Several mechanisms have been described, although the most common are acute interstitial nephritis, acute tubular necrosis, crystalic nephropathy or proximal/distal tubulopathy with electrolyte abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease and concomitant use of drugs with nephrotoxic potential. Prevention and early recognition of AKI are the standard approach to mitigate AKI and avoid morbidity.
Topics: Acute Kidney Injury; Anti-Bacterial Agents; Electrolytes; Humans; Kidney; Nephritis, Interstitial; Renal Insufficiency, Chronic
PubMed: 36220420
DOI: No ID Found -
Nefrologia 2022Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout... (Review)
Review
Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).
Topics: Genome-Wide Association Study; Gout; Humans; Hyperuricemia; Kidney Diseases; Nephrologists; Renal Elimination; Uric Acid
PubMed: 36210617
DOI: 10.1016/j.nefroe.2022.05.007 -
Journal of Medical Case Reports Sep 2022Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are...
BACKGROUND
Targeted therapy with anaplastic lymphoma kinase inhibitor alectinib has become standard therapy for selected patients with non-small cell lung carcinoma. Few data are available on the renal effects of alectinib. We report on a case of acute kidney injury in a patient using alectinib for less than 2 weeks and on serum sodium and creatinine during long-term use of alectinib.
CASE PRESENTATION
A 70-year-old Asian woman was diagnosed with metastasized non-small cell lung carcinoma (cT4N3M1c, stage IV) with echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase gene rearrangement and received alectinib, in two daily doses of 600 mg. Eleven days after the initiation of therapy, she was seen at the emergency department with acute kidney injury. Renal biopsy showed lesions in the proximal tubular epithelial cells. Nine days after alectinib cessation, renal function recovered quickly and reintroduction of alectinib in a reduced dose was tolerated, while withholding metformin, enalapril, and naproxen. In seven other patients, data on estimated glomerular filtration rate showed decreased kidney function at 3 months with stabilization at 6 months. Serum sodium at 3 months increased during alectinib treatment and increased further at 6 months.
CONCLUSIONS
Our data suggest direct or indirect toxic (proximal) tubulopathy due to alectinib with a good prognosis after cessation. Adverse acute renal effects of alectinib may be prevented by avoiding other medication influencing renal hemodynamics, in particular nonsteroidal anti-inflammatory drugs. Without these co-medications, alectinib could be reintroduced in our patient.
Topics: Acute Kidney Injury; Aged; Anaplastic Lymphoma Kinase; Anti-Inflammatory Agents; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Creatinine; Enalapril; Female; Humans; Kidney; Lung Neoplasms; Metformin; Microtubule-Associated Proteins; Naproxen; Piperidines; Protein Kinase Inhibitors; Sodium
PubMed: 36176005
DOI: 10.1186/s13256-022-03532-2 -
The Journal of Clinical Endocrinology... Dec 2022Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism....
CONTEXT
Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete.
OBJECTIVE
To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot.
METHODS
Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity.
RESULTS
In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3.
CONCLUSIONS
This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 1; Nerve Tissue Proteins; Mutation; Diarrhea; Phenotype; Pituitary Hormones
PubMed: 36149814
DOI: 10.1210/clinem/dgac554 -
HIV Research & Clinical Practice Aug 2022Tenofovir disoproxil fumarate (TDF) can induce proximal renal tubulopathy (PRT) and necessitate changes in treatment regimen. This prospective study aimed to compare...
Tenofovir disoproxil fumarate (TDF) can induce proximal renal tubulopathy (PRT) and necessitate changes in treatment regimen. This prospective study aimed to compare tubular function recovery following early switching versus late switching of TDF in human immunodeficiency virus (HIV)-infected patients with TDF-induced PRT. For this prospective study, conducted during 2017-2019, we enrolled HIV-1-infected, virologically suppressed adults undergoing TDF-containing combination antiretroviral therapy. Patients were separated into a late-switching group (LSG) and an early-switching group (ESG). The LSG included patients having an estimated glomerular filtration rate (eGFR) decrease ≥25% from the pretreatment level or Fanconi syndrome. The ESG included patients having ≥2 of the following indicators of PRT: fractional excretion of phosphate (FEUP) ≥10%, low tubular maximum reabsorption of phosphate (TmP)/GFR, or uricosuria; fractional uric acid excretion ≥10%; urine protein-creatinine index (UPCI) ≥500 mg/g creatinine, normoglycemic glycosuria, or decrease in eGFR of 15%-24%. Recovery of proximal tubular function at 6 and 12 months after TDF discontinuation was assessed. Complete recovery was defined as normalization of all abnormal tubular markers. Thirty-three HIV-infected patients were enrolled (70% male). Except for tubular function markers, baseline characteristics were not significantly different between the two groups. The proportion of patients having complete recovery was significantly higher in the ESG ( = 0.007, log-rank test). FEUP improved significantly in the ESG after TDF discontinuation; improvements of eGFR and UPCI were greater in the LSG. An eGFR change of 10% from baseline was the only independent predictor of failure to achieve complete recovery after switching. After median follow-up of 2.25 years post-trial, sustained recovery of eGFR within 5% of pre-TDF eGFR was achieved only in the ESG. Early-switching of TDF in HIV patients with PRT may allow complete recovery of proximal renal tubular function.
Topics: Adult; Anti-HIV Agents; Creatinine; Female; HIV Infections; Humans; Kidney Diseases; Male; Phosphates; Prospective Studies; Tenofovir
PubMed: 36065999
DOI: No ID Found -
BMJ Case Reports Aug 2022A woman in her 50s was referred to nephrology clinic due to progressive chronic kidney disease. She exhibited features of proximal renal tubulopathy, namely Fanconi...
A woman in her 50s was referred to nephrology clinic due to progressive chronic kidney disease. She exhibited features of proximal renal tubulopathy, namely Fanconi syndrome, including normoglycaemic glycosuria, normal anion gap metabolic acidosis, and intermittent hypouricaemia and hypophosphataemia. Kidney biopsy showed tubulointerstitial inflammation and focal chronic damage. In addition, antimitochondrial antibodies were present and she had abnormal liver blood tests. A unifying diagnosis of primary biliary cholangitis with an associated renal tubulopathy and interstitial nephritis was made. She was commenced on sodium bicarbonate, ursodeoxycholic acid and oral prednisolone, leading to an improvement in liver biochemistry. Kidney function was stabilised, but a sustained improvement was not seen. This case acts as a reminder of the rare association of tubulointerstitial nephritis and Fanconi syndrome with primary biliary cholangitis, which may be an under-recognised phenotype.
Topics: Fanconi Syndrome; Female; Humans; Liver Cirrhosis, Biliary; Nephritis, Interstitial; Phenotype; Ursodeoxycholic Acid
PubMed: 35973749
DOI: 10.1136/bcr-2021-248461 -
Current Opinion in Nephrology and... Sep 2022Kir5.1 interacts with Kir4.2 in proximal tubule and with Kir4.1 in distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) to form... (Review)
Review
PURPOSE OF REVIEW
Kir5.1 interacts with Kir4.2 in proximal tubule and with Kir4.1 in distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) to form basolateral-K+-channels. Kir4.2/Kir5.1 and Kir4.1/Kir5.1 play an important role in regulating Na+/HCO3--transport of the proximal tubule and Na+/K+ -transport in the DCT/CNT/CCD. The main focus of this review is to provide an overview of the recent development in the field regarding the role of Kir5.1 regulating renal electrolyte transport in the proximal tubule and DCT.
RECENT FINDINGS
Loss-of-function-mutations of KCNJ16 cause a new form of tubulopathy, characterized by hypokalaemia, Na+-wasting, acid-base-imbalance and metabolic-acidosis. Abnormal bicarbonate transport induced by loss-of-function of KCNJ16-mutants is recapitulated in Kir4.2-knockout-(Kir4.2 KO) mice. Deletion of Kir5.1 also abolishes the effect of dietary Na+ and K+-intakes on the basolateral membrane voltage and NCC expression/activity. Long-term high-salt intake or high-K+-intake causes hyperkalaemic in Kir5.1-deficient mice.
SUMMARY
Kir4.2/Kir5.1 activity in the proximal tubule plays a key role in regulating Na+, K+ and bicarbonate-transport through regulating electrogenic-Na+-bicarbonate-cotransporter-(NBCe1) and type 3-Na+/H+-exchanger-(NHE3). Kir4.1/Kir5.1 activity of the DCT plays a critical role in mediating the effect of dietary-K+ and Na+-intakes on NCC activity/expression. As NCC determines the Na+ delivery rate to the aldosterone-sensitive distal nephron (ASDN), defective regulation of NCC during high-salt and high-K+ compromises renal K+ excretion and K+ homeostasis.
Topics: Animals; Bicarbonates; Humans; Ion Transport; Kidney Tubules; Kidney Tubules, Distal; Mice; Potassium Channels, Inwardly Rectifying; Sodium
PubMed: 35894283
DOI: 10.1097/MNH.0000000000000817