Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the ß-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

Tubulointerstitial nephritis and Fanconi syndrome in a patient with primary Sjögren's syndrome accompanied by antimitochondrial antibodies: A case report and review of the literature.

We describe a 53-year-old woman with primary Sjögren's syndrome and tubulointerstitial nephritis showing distal renal tubular acidosis and Fanconi syndrome. The patient showed high serum IgM levels and positivity for antimitochondrial antibodies, although her liver function was in normal range. According to our literature review, 75% of patients with tubulointerstitial nephritis who were positive for antimitochondrial antibodies showed Fanconi syndrome, suggesting that these antibodies may directly be associated with the pathophysiology of Fanconi syndrome.

Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery.

BACKGROUND: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery. METHODS: Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network. RESULTS: Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress. CONCLUSION: These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function.

How I treat monoclonal gammopathy of renal significance (MGRS).

Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.

Mechanisms of light chain injury along the tubular nephron.

The tubular nephron is responsible for reabsorption and catabolism of filtered low molecular weight proteins that include Ig free light chains. In the setting of a plasma cell dyscrasia, significant amounts of free light chains, now monoclonal proteins, present to the tubular nephron for disposal. The result may be clinical renal dysfunction in the form of AKI, progressive CKD, and end-stage kidney disease. Here, I review the mechanisms involved in these processes that result in tubular injury, including proximal tubulopathy and cast nephropathy.

[Case of fanconi syndrome positive for anti-M2 antibodies revealed by severe hypokalemia and multiple bone fracture].

A 38-year-old female developed pain in the right leg in 2006. In 2007, the diagnosis of femoral head necrosis was made based on MR images, and femoral head prosthetic replacement was performed. In April 2009, she visited a local hospital for low back pain, and was referred to our department due to electrolyte abnormalities on hemanalysis. Since marked hypokalemia (K=2.5 mEq/L), hypophosphatemia, hyperchloric metabolic acidosis, proteinuria, and urinary blood sugar suggested Fanconi syndrome, she was admitted for close examination. Bone survey showed a marked decrease in the amount of bone particularly in the four limbs and fracture at the proximal 1/3 of the left ulnar bone. In the lumbar spine, scoliosis and vertebral deformity were observed. Since impaired P re-absorption and unselected aminoaciduria and osteomalacia were also present, the diagnosis of Fanconi syndrome was made. On admission, ventricular tachycardia developed due to hypokalemia, requiring immediate electrolyte correction. For differentiation from acquired Fanconi syndrome, various examinations were performed. No apparent cause was found except for the positive antimitochondrial antibody-M2 (anti-M2). In this case, no data suggested liver dysfunction, and subsequent liver biopsy also showed no significant pathological findings pointing to PBC. We encountered a patient with Fanconi syndrome positive for anti-M2. This case may attract interest, particularly in the mechanism of nephropathy due to anti-M2, and therefore, this case is reported with a literature review.

Multiple bone fracture due to Fanconi's syndrome in primary Sjögren's syndrome complicated with organizing pneumonia.

Abstract A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren's syndrome (SS). Fanconi's syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi's syndrome with OP in SS is described.

De novo membranous nephropathy associated with donor-specific alloantibody.

Recent evidence suggests that alloantibody may play an aetiological role in the pathogenesis of membranous glomerulopathy in native kidneys. There is an increased awareness of the significance of alloantibody on renal transplant outcome, particularly with the development of more sensitive assays. We describe a kidney transplant patient who developed de novo membranous glomerulopathy (DNMG) with heavy proteinuria in the context of a donor-specific alloantibody (DSA) directed against HLA DQ7. Proteinuria resolved and kidney function stabilized following treatment with mycophenolate mofetil and an angiotensin receptor blocker. The titre of the DSA fell in parallel with resolution of the proteinuria. This is the first reported case of DNMG after kidney transplantation clearly associated with a DSA. We hypothesize that de novo membranous glomerulopathy may be an atypical manifestation of acute antibody-mediated damage. Cases of DNMG should be screened for alloantibody and the presence of alloantibody may influence the choice of therapy.

Mechanisms of renal damage in plasma cell dyscrasias: an overview.

The kidney is a target organ in plasma cell dyscrasias. Usually the offending molecules are the monoclonal light chains (LCs), but the complete immunoglobulins can participate in the pathogenesis of organ damage. The primary structure of the monoclonal proteins is at the basis of the ultrastructural organization of their aggregates which translates into characteristic kidney injuries. The kidney targeting is due to the concurrence of several factors such as the local catabolism of monoclonal LCs, specific interactions of the monoclonal proteins with tissue and cellular components, and local environmental conditions. Glomerulopathic LCs interact with mesangial cells producing, through two distinct pathways, LC amyloidosis or monoclonal immunoglobulin deposition disease. Tubulopathic LCs damage the proximal tubule causing Fanconi's syndrome or precipitate in the distal tubule determining the cast nephropathy. The use of electronmicroscopy combined with immuno-labeling has allowed the identification of other rare patterns of kidney damage. In patients with known plasma cell dyscrasia, the recognition of these patterns of renal injury should lead to appropriate therapeutic intervention.

Dangerous small B-cell clones.

The detection of a monoclonal immunoglobulin in serum or urine usually raises concerns about the size of the underlying B-cell-derived clone and possible systemic effects caused by its expansion. However, a small clone can synthesize a very toxic protein, producing devastating systemic damage and protean clinical presentations. The resulting "monoclonal component-related diseases," although difficult to diagnose, may be progressive and even fatal. The monoclonal protein can aggregate and deposit systemically as occurs in light-chain amyloidosis, monoclonal immunoglobulin deposition disease, crystal-storing histiocytosis, and monoclonal cryoglobulinemia. Alternatively, some monoclonal proteins possess antibody activity toward autogenous antigens and cause chronic cold agglutinin disease, mixed cryoglobulinemia, and peripheral neuropathies. Other humoral mediators may contribute to neuropathy in variant disorders such as the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. The clone synthesizing the noxious monoclonal proteins is often small, and sensitive techniques may be required to detect these immunoglobulins. A delay in diagnosis can allow irreversible organ damage and dramatically shorten survival. Prompt recognition of suggestive signs and symptoms should trigger a thorough diagnostic approach to reach the correct diagnosis quickly, because this is the key to effective therapy. Although the treatment of these conditions is not optimal, significant advances have been made, improving the duration and quality of life.

Tubulointerstitial nephritis and Fanconi syndrome in primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic cholestatic liver disease of unknown cause that predominantly affects middle-aged women. Distal tubular acidosis is the main renal complication of primary biliary cirrhosis. Tubulointerstitial nephritis and Fanconi syndrome have been reported more rarely. We report on 2 patients with primary biliary cirrhosis who presented with tubulointerstitial nephritis and Fanconi syndrome and review similar cases published previously. Serum from 1 patient exerted an inhibitory effect on pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, 2 mitochondrial enzymes that are the main targets of antimitochondrial antibodies in primary biliary cirrhosis. Antimitochondrial antibodies may have a role in the genesis of tubulointerstitial nephritis and Fanconi syndrome, 2 typical renal features of mitochondrial cytopathies. Tubulointerstitial nephritis and Fanconi syndrome have to be added to the spectrum of renal diseases associated with primary biliary cirrhosis.

Fanconi's syndrome induced by a monoclonal Vkappa3 light chain in Waldenstrom's macroglobulinemia.

Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal kappa LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal kappa LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vkappa1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenstrom's macroglobulinemia and full-blown FS with accumulation of a monoclonal kappa LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vkappa3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS kappaI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of kappa LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.

Cationic charge-preferential IgG reabsorption in the renal proximal tubules.

BACKGROUND: The brush border of the renal proximal tubules has a polyanionic charge. Since immunoglobulin G (IgG) molecules have a wide range of charge diversity, reabsorption of urinary IgG molecules are supposed to be influenced by the electrostatic interaction. METHODS: Charge diversity of serum and urinary IgG molecules in patients with various renal diseases (N= 12) and premature neonates (N= 3) were analyzed by isoelectric focusing and Immunoblotting. RESULTS: In patients with glomerular diseases, urinary IgG was solely composed of neutral and anionic IgG, whereas that of the cationic part (isoelectric point >8) was not observed. By contrast, in patients with proximal tubular diseases (Dent's disease and idiopathic Fanconi syndrome), the proportion of the cationic IgG was similar to that of serum IgG. In addition, the cationic part of IgG in the urine was found in the neonates with a gestational age of 28 and 31 weeks, but not found in those of 35 weeks. CONCLUSION: The results suggest that renal proximal tubules reabsorb the urinary IgG in a cationic preferential way, and this mechanism requires renal maturation.

A monoclonal V kappa l light chain responsible for incomplete proximal tubulopathy.

Calcium and phosphate metabolism abnormalities are frequent in myeloma patients and the role of renal lesions in such ionic perturbations may have been overlooked. The authors herein report the complete primary structure of a Bence Jones Vkappal light chain responsible for myeloma-associated proximal tubulopathy with increased phosphaturia. Plasma and serum biochemical evaluations indicated a proximal tubular dysfunction mainly manifested as tubular acidosis and phosphate loss. The study of a kidney biopsy showed interstitial and tubular lesions with numerous myeloma casts and peculiar features of the proximal tubular cells, which carried numerous phagolysosomal inclusions with occasional crystalline periodic striation. The nephrotoxic light chain primary structure was deduced from the bone marrow monoclonal plasma cells RNA. The kappal sequence was highly homologous to kappa chains previously characterized in patients with Fanconi syndrome. It was related to the Vkappal subgroup and was composed of a variable segment encoded by the O8/O18 germline gene rearranged to Jkappa4. The primary sequence presented unusual features restricted to the variable region, including substitutions of residues 28 and 31 in the complementary determining region 1 (CDR1) by amino acids of different charge. An unusual conformation of the kappal domain, likely resulting from somatic hypermutation, could alter the catabolism of the protein after its internalization and result in the tubular cell dysfunction. Comparison with Fanconi syndrome studies suggests that Vkappal Bence Jones proteins may damage proximal tubular cells to an extent varying according to light chain (LC) sequence and structure, either leading to crystal formation and Fanconi syndrome or inducing partial inhibition of proximal tubule function.

Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

Kappa light chain-associated Fanconi's syndrome: molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals.

Plasma cell dyscrasias may be responsible for Fanconi's syndrome, due to the toxicity of a free monoclonal kappa light chain toward kidney proximal tubules. Eight cases of Fanconi's syndrome were analyzed. We compared the structures of VkappaI variability subgroup V domains from five cases of Fanconi's syndrome and one myeloma without renal involvement. Among Fanconi cases, four putative structures were obtained after molecular modeling by homology, and the other had previously been refined by X-ray crystallography. The complete sequences of one VkappaI, one VkappaIII and N-terminal sequences of two VkappaI light chains, from patients with different forms of Fanconi's syndrome, were compared with four previously studied sequences. All three kappa chains responsible for a 'classical' form with intralysosomal crystals and a low mass myeloma, were encoded by the LCO2/O12 germline gene and had an unusual non-polar residue exposed to the solvent in the CDR-L1 loop. Of both VkappaI light chains from patients with Fanconi's syndrome without intracellular crystals, one derived from LCO2/O12 and the other from LCO8/O18 gene. Another feature that could be related to non-crystallization was the absence of accessible side chains in the CDR-L3 loop which is known to be implicated in dimer formation.

Lambda light chain induced nephropathy: a rare cause of the Fanconi syndrome and severe osteomalacia.

The Fanconi syndrome is a generalized disorder of proximal renal tubular transport characterized by wasting of phosphate, amino acids, glucose, bicarbonate, and uric acid. The association of the acquired Fanconi syndrome with lambda light-chain proteinuria is rare. We report the third case in the English language literature. A 65-year-old man presented with severe pelvic pain. Investigations showed an elevated serum creatinine level, and a 24-hour urine collection contained 2.56 g protein. The Fanconi syndrome was diagnosed, with findings of phosphaturia, glycosuria, and aminoaciduria. Bence Jones protein (lambda sub-type) was present in the urine at a concentration of 0.58 g/L. Monocytic cells in the bone marrow and proximal tubular cells in the kidney contained cytoplasmic crystalline inclusions. Undecalcified bone sections confirmed the clinical diagnosis of osteomalacia. The patient was treated with phosphate, calcium, and ergocalciferol and experienced significant symptomatic improvement. The Fanconi syndrome caused by light-chain deposition in proximal tubular cells is well described in the literature. However, it is rare for the light chains to be of the lambda subtype. This may reflect differences in the physicochemical properties of kappa and lambda light chains.