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Journal of the American Society of... Mar 2018Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular... (Review)
Review
Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Antigens, Neoplasm; Bartter Syndrome; Child; Child, Preschool; Fanconi Syndrome; Gitelman Syndrome; Humans; Infant; Infant, Newborn; Kidney Tubules; Renal Reabsorption; Sodium Chloride; Solute Carrier Proteins
PubMed: 29237739
DOI: 10.1681/ASN.2017060600 -
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 -
Clinical Journal of the American... Dec 2016Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated... (Review)
Review
Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.
Topics: Amyloidosis; Glomerulonephritis; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Distal; Kidney Tubules, Proximal; Paraproteinemias; Paraproteins
PubMed: 27526707
DOI: 10.2215/CJN.02560316 -
Renal Failure 2023Tubular injury is the main cause of acute kidney injury (AKI) in critically ill COVID-19 patients. Proximal tubular dysfunction (PTD) and changes in urinary biomarkers,...
Tubular injury is the main cause of acute kidney injury (AKI) in critically ill COVID-19 patients. Proximal tubular dysfunction (PTD) and changes in urinary biomarkers, such as NGAL, TIMP-2, and IGFBP7 product ([TIMP-2]•[IGFBP7]), could precede AKI. We conducted a prospective cohort study from 2020/03/09 to 2020/05/03, which consecutively included all COVID-19 patients who had at least one urinalysis, to assess the incidence of PTD and AKI, and the effectiveness of PTD, NGAL, and [TIMP-2]•[IGFBP7] in AKI and persistent AKI prediction using the area under the receiver operating characteristic curves (AUCs), Kaplan-Meier methodology (log-rank tests), and Cox models. Among the 60 patients admitted to the ICU with proven COVID-19 (median age: 63-year-old (interquartile range: IQR, 55-74), 45 males (75%), median simplified acute physiology score (SAPS) II: 34 (IQR, 22-47) and median BMI: 25.7 kg/m (IQR, 23.3-30.8)) analyzed, PTD was diagnosed in 29 patients (48%), AKI in 33 (55%) and persistent AKI in 20 (33%). Urinary NGAL had the highest AUC for AKI prediction: 0.635 (95%CI: 0.491-0.779) and persistent AKI prediction: 0.681 (95%CI: 0.535-0.826), as compared to PTD and [TIMP-2]•[IGFBP7] (AUCs <0.6). AKI was independently associated with higher SAPSII (HR = 1.04, 95%CI: 1.01-1.06, = 0.005) and BMI (HR = 1.07, 95%CI: 1.00-1.14, = 0.04) and persistent AKI with higher SAPSII (HR = 1.03, 95%CI: 1.00-1.06, = 0.048) and nephrotoxic drug use (HR = 3.88, 95%CI: 1.20-12.5, = 0.02). In conclusion, in critically ill COVID-19 patients, the incidence of PTD and AKI was relatively high. NGAL was the best urinary biomarker for predicting AKI, but only clinical severity was independently associated with its occurrence.
Topics: Male; Humans; Middle Aged; Tissue Inhibitor of Metalloproteinase-2; Prospective Studies; Critical Illness; Lipocalin-2; COVID-19; Kidney; Acute Kidney Injury; Biomarkers
PubMed: 38078385
DOI: 10.1080/0886022X.2023.2292152 -
Renal Failure Dec 2023Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma... (Review)
Review
Combined crystal-storing histiocytosis, light chain proximal tubulopathy, and light chain crystalline podocytopathy in a patient with multiple myeloma: a case report and literature review.
BACKGROUND
Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging.
CASE PRESENTATION
In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period.
CONCLUSIONS
In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.
Topics: Humans; Female; Aged; Multiple Myeloma; Fanconi Syndrome; Pronase; Kidney Diseases; Immunoglobulin kappa-Chains; Antibodies, Monoclonal; Histiocytosis
PubMed: 36632756
DOI: 10.1080/0886022X.2022.2145970 -
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 -
Journal of the American Society of... May 2016Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus...
Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients.
Topics: Adult; Aged; Aged, 80 and over; Biopsy; Crystallization; Fanconi Syndrome; Female; Humans; Kidney; Male; Middle Aged; Retrospective Studies
PubMed: 26374607
DOI: 10.1681/ASN.2015020185 -
Frontiers in Genetics 2024Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and... (Review)
Review
Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.
PubMed: 38606357
DOI: 10.3389/fgene.2024.1381174 -
Children (Basel, Switzerland) Dec 2021Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature... (Review)
Review
Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature review was conducted on the United States National Library of Medicine, Excerpta Medica, and Web of Science databases. Twenty-three reports describing 57 individual cases could be included. The majority ( = 35) of the 57 patients were ≤18 years of age and affected by thalassemia ( = 46). Abnormal urinary findings were noted in 54, electrolyte or acid-base abnormalities in 46, and acute kidney injury in 9 patients. Latent tubular damage was diagnosed in 11 (19%), overt kidney tubular damage in 37 (65%), and an acute kidney injury in the remaining nine (16%) patients. Out of the 117 acid-base and electrolyte disorders reported in 48 patients, normal-gap metabolic acidosis and hypophosphatemia were the most frequent. Further abnormalities were, in decreasing order of frequency, hypokalemia, hypouricemia, hypocalcemia, and hyponatremia. Out of the 81 abnormal urinary findings, renal glucosuria was the most frequent, followed by tubular proteinuria, total proteinuria, and aminoaciduria. In conclusion, a proximal tubulopathy pattern may be observed on treatment with deferasirox. Since deferasirox-associated kidney damage is dose-dependent, physicians should prescribe the lowest efficacious dose.
PubMed: 34943300
DOI: 10.3390/children8121104 -
Nephron 2019Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been... (Review)
Review
Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood. Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN. Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs. These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN.
Topics: Animals; Diabetic Nephropathies; Endocannabinoids; Glucose; Glucose Transporter Type 2; Humans; Kidney Tubules, Proximal; Receptor, Cannabinoid, CB1; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 30636250
DOI: 10.1159/000494512