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Pathologica Aug 2021Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the...
Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the presence of a serum monoclonal spike (M-spike) of more than 3 g/dL or more than 10% clonal plasma cells in the bone marrow and at least one myeloma-defining event, such as hypercalcemia, anemia, bone lesions, or renal impairment. The kidney is a major target organ, and renal impairment is frequently the first manifestation of the disease. Renal damage occurs in up to 40% of patients and 10-20% will require dialysis. Monoclonal immunoglobulin light chains are the major causes of renal complications in multiple myeloma. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease, AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components, are constituted by light chain cast nephropathy, light chain proximal tubulopathy, and crystal-storing histiocytosis. We report the case of a 66-year-old woman who presented with albumin-predominant moderate proteinuria and renal failure. Serum and urine immunofixation electrophoresis showed monoclonal κ light chain in both. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving proximal tubular epithelial cells and crystal storing histiocytosis. Multiple myeloma with crystal storing histiocytosis was discovered in bone marrow biopsy. Thus, we present an unusual case of a myeloma patient presenting light chain proximal tubulopathy and crystal-storing histiocytosis both in the kidney and in the bone marrow.
Topics: Aged; Female; Histiocytosis; Humans; Kidney; Kidney Diseases; Multiple Myeloma; Paraproteinemias
PubMed: 34463673
DOI: 10.32074/1591-951X-154 -
Frontiers in Pharmacology 2021The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting...
The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting in renal tubulointerstitial disease. These pathophysiological responses are collectively described as diabetic tubulopathy (DT). Thus, therapeutic strategies targeting DT hold significant promise for early DKD treatment. Shenkang injection (SKI) has been widely used to treat renal tubulointerstitial fibrosis in patients with chronic kidney disease in China. However, it is still unknown whether SKI can alleviate DT. We designed a series of experiments to investigate the beneficial effects of SKI in DT and the mechanisms that are responsible for its effect on epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress-induced apoptosis in DT. The modified DKD rat models were induced by uni-nephrectomy, streptozotocin intraperitoneal injection, and a high-fat diet. Following the induction of renal injury, these animals received either SKI, rosiglitazone (ROS), or vehicle, for 42 days. For research, we exposed NRK-52E cells to high glucose (HG) and 4-phenylbutyric acid (4-PBA) with or without SKI or ROS. Changes in parameters related to renal tubular injury and EMT were analyzed Changes in the proportion of apoptotic renal tubular cells and ER stress, and the signaling pathways involved in these changes, were analyzed both and . SKI and ROS improved the general condition, the renal morphological appearance and the key biochemical parameters, and attenuated renal injury and EMT in the rat model of DKD. In addition, SKI and ROS alleviated apoptosis, inhibited ER stress, and suppressed PERK-eIF2α-ATF4-CHOP signaling pathway activation both and . Notably, our data showed that the regulatory effects of SKI on PERK-eIF2α-ATF4-CHOP signaling were similar to those of 4-PBA, a specific inhibitor of ER stress. This study confirmed that SKI can alleviate DT in a similar manner as ROS, and SKI achieves this effect by inhibiting EMT and ER stress-induced apoptosis. Our findings thereby provide novel information relating to the clinical value of SKI in the treatment of DT.
PubMed: 34408650
DOI: 10.3389/fphar.2021.662706 -
Journal of Medical Case Reports Aug 2021We report a case of light chain proximal tubulopathy associated with lupus nephritis in a patient known to have systemic lupus erythematosus. The kidney can be injured... (Review)
Review
BACKGROUND
We report a case of light chain proximal tubulopathy associated with lupus nephritis in a patient known to have systemic lupus erythematosus. The kidney can be injured in several ways in any of these disorders. Light chain proximal tubulopathy is a rare form of renal tubular injury that may occur in and complicate plasma cell dyscrasia, characterized by cytoplasmic inclusions of the monoclonal light chain within proximal tubular cells. Lupus nephritis is a common form of renal injury as it occurs in about 25-50% of adult patients with systemic lupus erythematosus.
CASE PRESENTATION
We present a 57-year-old African patient known to have systemic lupus erythematosus and hypertension presented with a new complaint of microscopic hematuria. A renal biopsy was performed and revealed lupus nephritis class II concurrently associated with light chain induced proximal tubulopathy. A subsequent bone marrow biopsy was performed, which revealed multiple myeloma.
CONCLUSIONS
We report a case of coincidental lupus nephritis and proximal tubulopathy featuring a combined constellation of rare histopathological features that might add to the relationship between systemic lupus and paraproteinemia.
Topics: Adult; Biopsy; Humans; Kidney Diseases; Kidney Tubules, Proximal; Lupus Nephritis; Middle Aged; Multiple Myeloma; Paraproteinemias
PubMed: 34344460
DOI: 10.1186/s13256-021-02990-4 -
European Journal of Pharmacology Oct 2021Diabetic kidney disease (DKD) is the foremost cause of renal failure. While the glomeruli are severely affected in the course of the disease, the main determinant for... (Review)
Review
Diabetic kidney disease (DKD) is the foremost cause of renal failure. While the glomeruli are severely affected in the course of the disease, the main determinant for disease progression is the tubulointerstitial compartment. DKD does not develop in the absence of hyperglycemia. Since the proximal tubule is the major player in glucose reabsorption, it has been widely studied as a therapeutic target for the development of new therapies. Currently, there are several proximal tubule cell lines available, being the human kidney-2 (HK-2) and human kidney clone-8 (HKC-8) cell lines the ones widely used for studying mechanisms of DKD. Studies in these models have pushed forward the understanding on how DKD unravels, however, these cell culture models possess limitations that hamper research, including lack of transporters and dedifferentiation. The sodium-glucose cotransporters (SGLT) are identified as key players in glucose reabsorption and pharmacological inhibitors have shown to be beneficial for the long-term clinical outcome in DKD. However, their mechanism of action has, as of yet, not been fully elucidated. To comprehend the protective effects of SGLT inhibitors, it is essential to understand the complete functional, structural, and molecular features of the disease, which until now have been difficult to recapitulate. This review addresses the molecular events of diabetic proximal tubulopathy. In addition, we evaluate the protective role of SGLT inhibitors in cardiovascular and renal outcomes, and provide an overview of various in vitro models mimicking diabetic proximal tubulopathy used so far. Finally, new insights on advanced in vitro systems to surpass past limitations are postulated.
Topics: Diabetic Nephropathies; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 34303664
DOI: 10.1016/j.ejphar.2021.174378 -
Journal of Medical Case Reports Jul 2021Leptospirosis is an underdiagnosed bacterial infection with nonspecific symptoms, hence, a diagnostic challenge. Identifying a case of leptospirosis in Switzerland is...
BACKGROUND
Leptospirosis is an underdiagnosed bacterial infection with nonspecific symptoms, hence, a diagnostic challenge. Identifying a case of leptospirosis in Switzerland is uncommon. Although kidney complications are frequent in severe forms, including tubular dysfunction, observing this complication is rare in our country. We report the case of a patient with leptospirosis and kidney dysfunction, which was notable for proximal tubulopathy. This case report describes the diagnosis and management of this patient's tubular dysfunction.
CASE PRESENTATION
A 34-year-old Caucasian male known for alcohol and drug abuse presented to our emergency department suffering from severe pain in the lower limbs, jaundice, and fever with flu-like symptoms. Physical examination was not contributory. Blood tests showed cytopenia, elevated inflammatory markers, acute kidney injury, and altered liver function tests with predominant cholestasis. Urinalysis showed proteinuria and significant glycosuria without concomitant hyperglycemia. Leptospirosis was suspected and confirmed by both positive serum polymerase chain reaction and elevated immunoglobulin M for Leptospira interrogans. The patient was treated with intravenous amoxicillin-clavulanate and doxycycline for 7 days. After antibiotic treatment, symptoms disappeared, and kidney dysfunction completely resolved.
CONCLUSION
Our case focuses on the description of leptospirosis-related acute kidney injury with proximal tubular dysfunction, which is a rare finding in Switzerland.
Topics: Acute Kidney Injury; Adult; Fanconi Syndrome; Humans; Leptospira interrogans; Leptospirosis; Male; Switzerland
PubMed: 34294111
DOI: 10.1186/s13256-021-02978-0 -
Nephrologie & Therapeutique Aug 2021COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is...
COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.
Topics: Acute Kidney Injury; Biopsy; COVID-19; COVID-19 Vaccines; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Tubular Necrosis, Acute
PubMed: 34266783
DOI: 10.1016/j.nephro.2021.06.002 -
American Journal of Kidney Diseases :... Feb 2022Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking.
RATIONALE & OBJECTIVE
Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking.
STUDY DESIGN
Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation.
SETTING & PARTICIPANTS
28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT).
FINDINGS
Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived.
LIMITATIONS
Small sample size, nonstandardized clinical management, retrospective design.
CONCLUSIONS
Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.
Topics: Humans; Kidney; Kidney Diseases; Kidney Transplantation; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Retrospective Studies
PubMed: 34175375
DOI: 10.1053/j.ajkd.2021.04.015 -
EMBO Molecular Medicine Jul 2021Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine...
Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide-cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.
Topics: Amino Acid Transport Systems, Neutral; Anilides; Animals; Cysteamine; Cystinosis; Humans; Nitriles; Phenotype; Tosyl Compounds; Zebrafish
PubMed: 34165243
DOI: 10.15252/emmm.202013067 -
American Journal of Physiology. Renal... Aug 2021Functional properties of the paracellular pathway depend critically on the set of claudins (CLDN) expressed at the tight junction. Two syndromes are causally linked to...
Functional properties of the paracellular pathway depend critically on the set of claudins (CLDN) expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins: hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX) syndrome caused by genetic variations in the gene and familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by genetic variations in the or genes. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, CLDN16, and CLDN19 in both paraffin-embedded and frozen kidney sections from the adult human, mouse, and rat using immunohistochemistry and immunofluorescence, respectively. Here, CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral domains and tight junctions in human and rodent kidneys. Weak expression was detected at the tight junction of proximal tubular cells. CLDN16 was primarily expressed in a subset of TAL cells in the cortex and outer stripe of outer medulla, restricted to basolateral domains and tight junctional structures in both human and rodent kidneys. CLDN19 predominantly colocalized with CLDN16 in tight junctions and basolateral domains of the TAL but was also found in basolateral and junctional domains in more distal sites. CLDN10 expression at tight junctions almost never overlapped with that of CLND16 and CLDN19, consistent with distinct junctional pathways with different permeation profiles in both human and rodent kidneys. This study used immunohistochemistry and immunofluorescence to investigate the distribution of claudin 10, 16, and 19 in the human, mouse, and rat kidney. The findings showed distinct junctional pathways in both human and rodent kidneys, supporting the existence of different permeation profiles in all species investigated.
Topics: Animals; Claudins; Epithelium; Humans; Immunohistochemistry; Kidney Tubules; Mice; Rats; Tight Junctions
PubMed: 34151590
DOI: 10.1152/ajprenal.00579.2020