Pembrolizumab-induced Acute Tubulointerstitial Nephritis Accompanying Fanconi Syndrome and Type 1 Renal Tubular Acidosis.

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Renal histology of Fanconi syndrome associated with adefovir dipivoxil: A case report.

A sporadic occurrence of Fanconi syndrome associated with adefovir dipivoxil (ADV) has been reported, particularly when confirmed by renal biopsy. This study presents the case of a 53-year-old man who had been taking ADV 10 mg daily for 10 years to treat chronic hepatitis B (CHB) and subsequently developed Fanconi syndrome. The clinical manifestations included hypophosphatemic osteomalacia, glucosuria, renal tubular acidosis, low-molecular-weight proteinuria, and renal insufficiency. Renal biopsy revealed significant injury to proximal tubular epithelial cells, including vacuolar degeneration and regeneration of tubular epithelial cells. The ultrastructural pathology indicated severe morphological abnormalities of mitochondria, such as densely packed and enlarged mitochondria, with loss, blunting, and disordered arrangement of cristae. Following discontinuation of ADV and supplementation with oral phosphate, hypophosphatemia, glucosuria, and proteinuria were resolved. These findings support the previous hypothesis that ADV-induced nephrotoxicity may involve mitochondrial injury.

An Infant Case of Transient Distal Renal Tubular Acidosis and Fanconi Syndrome Caused by Rotavirus Gastroenteritis.

We report an infant case of transient distal renal tubular acidosis and Fanconi syndrome caused by rotavirus gastroenteritis. A 10-month-old boy was admitted to the hospital because of frequent vomiting, lack of vitality, and dehydration. He was diagnosed with rotavirus gastroenteritis on account of his positive stool rotavirus antigen test. Although he presented with acidemia and severe mixed metabolic acidosis, he also had a urine pH of 6.0, indicating impaired urinary acidification. Therefore, he was diagnosed with distal renal tubular acidosis. On the third day of hospitalization, a relatively low %tubular reabsorption of phosphate level with hypophosphatemia, increased fractional excretion of uric acid with hypouricemia, and high urinary ß2-microglobulin levels were observed. Moreover, he was diagnosed with Fanconi syndrome on account of multiple proximal tubular dysfunctions. After remission of rotavirus gastroenteritis, the signs of renal tubular dysfunction improved. This was a case of rotavirus gastroenteritis-caused transient distal renal tubular acidosis and Fanconi syndrome. Severe metabolic acidosis resulted from anion-gap metabolic acidosis due to acute kidney injury by rotavirus gastroenteritis and normal anion-gap acidosis due to renal tubular acidosis. When renal tubular acidosis is associated with a disease that causes anion-gap metabolic acidosis, mixed metabolic acidosis occurs and becomes exacerbated. Furthermore, it is important to consider the complications of renal tubular acidosis in the case of severe metabolic acidosis.

Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies.

OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. METHODS: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. RESULTS: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years). CONCLUSION: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

A report of three cases of patients with tubulointerstitial nephritis with IgM-positive plasma cells, treatment, and serum-IgM as a sensitive marker for relapse.

BACKGROUND: Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined. CASE PRESENTATION: Case 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement. Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement. Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient's serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day). CONCLUSION: We report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary ß2-microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated.

Fanconi syndrome, diabetes insipidus, and acute kidney injury due to tenofovir disoproxil fumarate: A case report.

BACKGROUND: Tenofovir disoproxil fumarate is widely used in Botswana as part of the first-line antiretroviral regimen in the 'Treat All' strategy implemented in 2016 by the Ministry of Health. Its use has been associated with several uncommon adverse renal effects, though rarely all in conjunction or without the combined use of protease inhibitors. CASE PRESENTATION: A 49-year-old woman living with HIV whose viral load is suppressed on tenofovir disoproxil fumarate, lamivudine, and dolutegravir presented with 1 day of generalized weakness and myalgia causing an inability to ambulate. This was associated with nausea and vomiting and profound fatigue. She was found to have an acute kidney injury, non-anion-gap metabolic acidosis, hypernatremia, hypokalemia, and hypophosphatemia. Urinalysis revealed pyuria with white blood cell casts, glucosuria, and proteinuria. The diagnosis was made of tenofovir-induced nephrotoxicity. The tenofovir was discontinued, and the patient was initiated on intravenous fluids and electrolyte and bicarbonate supplementation with improvement in her symptoms and laboratory values. CONCLUSIONS: This report suggests the possibility of severe tenofovir-induced nephrotoxicity with combined acute kidney injury, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors such as use with protease inhibitors or advanced HIV disease, chronic kidney disease, and age. With its wide use in Botswana and other countries, health-care providers should have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on tenofovir with deranged renal function tests and electrolytes.

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.

A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease.

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.

Non-crystalline light chain proximal tubulopathy associated with monoclonal gammopathy of renal significance: A case report and review of the literature.

BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare M-proteinemia-related nephropathy. Non-crystalline LCPT is even rarer. We herein report an unusual case of renal dysfunction and proteinuria due to κ-restricted and non-crystalline LCPT in a context of monoclonal gammopathy of renal significance (MGRS) without Fanconi syndrome (FS). CASE PRESENTATION: A 67-year-old man was admitted for a 2-year history of proteinuria and renal dysfunction. Fanconi syndrome (FS) was not observed. He was noted to have IgG-κ M protein, and the previous bone marrow biopsy revealed that atypical plasma cells accounted for 1.5% of the cells, which did not meet the diagnostic criteria for multiple myeloma. A renal biopsy revealed proximal tubular injury, including increased lysosomes with irregular contours and a mottled appearance without crystalline structure and the accumulation of κ light chains. He was diagnosed with non-crystalline LCPT with MGRS. Concurrently, we reviewed the non-crystalline LCPT cases previously published in the literature. Our patient finally received chemotherapy with a bortezomib and dexamethasone regimen. The patient did not seem to achieve evident nephrological and hematological remission after chemotherapy, but he was in a stable condition. CONCLUSION: Very few similar cases are reported in the literature. It is considered crucial to enhance our knowledge about these cases to establish the definition of the non-crystalline LCPT entity and allow for early diagnosis. Chemotherapy may not be necessary for all patients to maintain good renal function. Future prospective clinical research studies are necessary.

Fanconi Syndrome Associated with Long-term Treatment with Zoledronate.

Intravenous bisphosphonate therapy is used to prevent fractures in the management of bone metastasis. However, it may induce renal damage. We herein report an 81-year-old woman with Fanconi syndrome and osteomalacia who had been diagnosed with metastatic breast cancer and received treatment with zolendronate for over 5 years. Her bone markers normalized after switching zolendronate to denosmab and starting vitamin D and mineral supplementation. This case shows that chronic renal damage induced by zolendronate can cause osteomalacia. In patients with intravenous zolendronate therapy, close monitoring of renal and bone markers is needed, even under long-term therapy.

Primary biliary cholangitis presenting with Fanconi syndrome: an important phenotype.

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.

Lambda light chain-induced monoclonal gammopathy of renal significance, manifesting with Fanconi Syndrome and osteomalacia.

BACKGROUND: Monoclonal gammopathy of renal significance (MGRS) encompasses a heterogeneous group of kidney diseases in which a monoclonal immunoglobulin secreted by a clone of B cells or plasma cells causes kidney damage without meeting the hematological criteria for malignancy. Among the various forms of involvement, MGRS can manifest as a proximal tubule disorder, such as Fanconi syndrome (FS), characterized by urinary loss of phosphate, glucose, amino acids, uric acid and bicarbonate. Few cases of MGRS have been described in the literature, manifesting as FS and monoclonal production of lambda light chains, almost all of which are secondary to the production of kappa light chains. CASE PRESENTATION: Here we report a clinical case of a 45-year-old Brazilian male, African descent, with proximal weakness of the lower limbs, whose initial assessment showed a urine summary with the presence of proteinuria and glycosuria without hyperglycemia, associated with mild worsening of renal function, hypouricemia, hypocalcemia and phosphaturia. Evolution was characterized by a MGRS manifesting as FS and osteomalacia. CONCLUSION: The diagnosis of MGRS is not always easy, it requires knowledge of the clinical characteristics, diagnostic criteria and prognosis of each case. Therefore, all possible efforts should be made for multidisciplinary diagnosis.

Fanconi syndrome-associated interstitial lung disease.

A middle-aged man was referred to our respiratory department with dyspnoea progressively deteriorating and non-productive cough over the past 8 months. High-resolution CT revealed multiple bilateral consolidations, traction bronchiectasis, reticular pattern and honeycombing with basal and peripheral predominance. Serology tests were negative. Pulmonary function tests showed moderate restrictive functional impairment and severe reduction in diffusing capacity for carbon monoxide. Meticulous evaluation of patient's medical history revealed recent administration of oral corticosteroid due to pulmonary fibrosis potentially in the context of Fanconi syndrome diagnosed at childhood. The working diagnosis of interstitial lung disease (ILD) as a rare complication of Fanconi syndrome was proposed following multidisciplinary discussion. Despite combination treatment with low doses of corticosteroids and antifibrotic compound, the patient exhibited clinical, radiological and functional deterioration, was admitted to intensive care unit due to respiratory failure following infection-driven progression of fibrotic ILD and finally died.

Beneficial effects of starting oral cysteamine treatment in the first 2 months of life on glomerular and tubular kidney function in infantile nephropathic cystinosis.

Nephropathic cystinosis is a rare lysosomal storage disease whose basic defect, impaired transport of cystine out of lysosomes, results in intracellular cystine storage. Affected individuals exhibit renal Fanconi Syndrome in infancy, end-stage kidney disease at approximately 10 years of age, and many other systemic complications. Oral cysteamine therapy mitigates the detrimental effects on glomerular function and prevents most of the late complications of the disease but has not shown benefit with respect to the early tubular damage of cystinosis. This is because cystinosis is generally diagnosed in the second year of life, after the damage to kidney tubular function has already occurred. We longitudinally evaluated 6 infants diagnosed and treated with cysteamine from before 2 months of age. The 4 infants with good compliance with cysteamine and consistently low leucocyte cystine levels maintained normal eGFR values, exhibited only minor degrees of renal Fanconi Syndrome, and maintained normal serum levels of potassium, bicarbonate, phosphate, and calcium without electrolyte or mineral supplementation through 2, 4, 10 and 16 years of age. Thus, renal Fanconi syndrome can be attenuated by early administration of cysteamine and renew the call for molecular-based newborn screening for cystinosis.

Newborn Screening: Review of its Impact for Cystinosis.

Newborn screening (NBS) programmes are considered to be one of the most successful secondary prevention measures in childhood to prevent or reduce morbidity and/or mortality via early disease identification and subsequent initiation of therapy. However, while many rare diseases can now be detected at an early stage using appropriate diagnostics, the introduction of a new target disease requires a detailed analysis of the entire screening process, including a robust scientific background, analytics, information technology, and logistics. In addition, ethics, financing, and the required medical measures need to be considered to allow the benefits of screening to be evaluated at a higher level than its potential harm. Infantile nephropathic cystinosis (INC) is a very rare lysosomal metabolic disorder. With the introduction of cysteamine therapy in the early 1980s and the possibility of renal replacement therapy in infancy, patients with cystinosis can now reach adulthood. Early diagnosis of cystinosis remains important as this enables initiation of cysteamine at the earliest opportunity to support renal and patient survival. Using molecular technologies, the feasibility of screening for cystinosis has been demonstrated in a pilot project. This review aims to provide insight into NBS and discuss its importance for nephropathic cystinosis using molecular technologies.