Membranoproliferative Pattern Research Articles

#2991 Two cases of chronic lymphocytic leukemia associated immunotactoid glomerulopathy: variable clinical presentation, close hematological collaboration

Abstract Background and Aims Immunotactoid glomerulopathy (ITG) is a very rare disease, observable in less than 0.1% of native kidney biopsy samples. It is most often associated with hematological diseases. We confirmed ITG in two cases among our 850 kidney biopsy patients in the past 9 years. In both patients, chronic lymphocytic leukemia (CLL) was the underlying cause. Method Case 1, a 56-year-old man was admitted due to severely increased proteinuria (2 g/day) with preserved renal function, while case 2, a 57-year-old-man was referred with rapidly decreasing eGFR (20 ml/min/1.73m2) with nephrotic syndrome (serum albumin level was 24 g/l). In case 1, no previous history of hematological disease was known, in case 2, CLL - that did not require treatment - was diagnosed half a year before admission. He still had no kidney involvement even 3 months after the CLL diagnosis. We performed kidney biopsy. Light microscopy revealed mesangial proliferative-atypical membranous pattern in case 1, and membranoproliferative pattern in case 2. Immunofluorescence microscopy showed IgG1-lambda deposition, electron microscopy confirmed the organised deposits, microtubular structures with a diameter of 44 nanometers in both cases. Neither monoclonal gammopathy nor systemic immune disease was confirmed. In case 2, low titer ANA positivity, low C3 and high anti-C1q antibody titer was detected, lupus nephritis was ruled out. Previously, lymphocyte count was slightly increased in case 1, CLL was confirmed after kidney biopsy. The immunoglobulin heavy chain variable region gene somatic hypermutation status was borderline in case 1, while in the other case it was unmutated. Fluorescein in situ hybridisation revealed trisomy 12 in both cases. In case 1, chemotherapy was not used due to Rai stage 0, and with appropriate antihypertensive treatment, we could preserve kidney function, and proteinuria was persistently low (below 1 g/day). In case 2, due to Rai stage 1, and progressive renal and lymph node involvement, immunochemotherapy was started (obinutuzumab-venetoclax). Three months later eGFR stabilized at 27 ml/min/1.73 m2, proteinuria decreased below 1 g/day, the C3 level normalized. Conclusion ITG can develop in the early stages of CLL, but it can also indicate CLL progression. The light microscopy histological pattern and, in parallel, the clinical appearance can be of varying severity. Immunochemotherapy resulting reduction of CLL tumor burden and cessation of complement damage, both play a role of improving renal status. Our cases also draw attention to the need for close collaboration with hematologists.

Hydralazine use can be associated with IgM-dominated immune complex-mediated glomerulonephritis

ABSTRACT Context IgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine. Design Seven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail. Results Patients’ ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases. Conclusion The hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.

Lipoprotein glomerulopathy with membranoproliferative pattern in a patient with cholestatic liver disease-lesson for the clinical nephrologist.

Lipoprotein glomerulopathy with membranoproliferative pattern in a patient with cholestatic liver disease-lesson for the clinical nephrologist.

Clinical features and outcomes of patients with diacylglycerol kinase epsilon nephropathy: a nationwide experience.

Thrombotic microangiopathy (TMA) is usually caused due to dysregulation of the alternative complement pathway. Rarely, thrombotic microangiopathy is caused by non-complement mediated mutations in diacylglycerol kinase epsilon (DGKE); information about therapy and outcome of these patients is limited. Medical records of patients, younger than 18years, diagnosed with TMA and variants in DGKE were reviewed to include 12 patients from seven centers. Genetic studies included targeted exome sequencing and multiplex-ligation dependent probe amplification of CFH-CFHR5. Patients presented at a median age of 11 (7.5, 12.3) months; all were younger than 2years. All patients had an infectious prodrome; enteroinvasive, enteropathogenic, and enterotoxigenic Escherichia coli were detected in two patients with diarrhea. Chief features included those of microangiopathic hemolysis (n = 11), microscopic hematuria (n = 10), nephrotic range proteinuria (n = 10), hypoalbuminemia (n = 6), elevated total cholesterol (n = 6), and hypocomplementemia (n = 4). Histopathology showed thrombotic microangiopathy (n = 4), overlapping with membranoproliferative pattern of injury (n = 1). At median 3.3years of follow-up, significant hypertension and/or proteinuria (40%), relapses (66.7%), and death or progression to CKD (60%) were common. Genetic sequencing showed 13 homozygous and compound heterozygous variants(7 pathogenic, 3 likely pathogenic) located throughout DGKE; 11 variants were novel. This case series highlights the need to suspect DGKE nephropathy in young patients with TMA, especially those with severe proteinuria. Medium-term outcomes are unsatisfactory with risk of relapses, progressive kidney failure, and death. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Case | A benign reason behind a malignant finding

A 21-year-old man presented to the office for deranged kidney function. He was diagnosed to have C3 glomerulonephritis at the age of 18 years when he presented to his first physician with hypertension. Laboratory parameters showed high serum creatinine (2.7 mg/dl), low serum albumin (2.9 g/dl), low total protein (5.2 g/dl), dysmorphic red blood cells on urinalysis, high 24-hour urine protein (5.7 g/d), low complement C3 (32 mg/dl), and low 50% hemolytic complement (10 U/ml). Kidney biopsy showed a membranoproliferative pattern of injury with 3+ reactivity for complement C3 and significant chronic changes. There was moderate tubulointerstitial fibrosis and 30% of all sampled glomeruli were globally sclerosed. Clinically, there were no signs of atypical hemolytic uremic syndrome and pathologically no evidence of thrombotic microangiopathy. He was started on steroids and mycophenolate mofetil, which were discontinued after 3 months in view of intolerable side effects. Thereafter, ravulizumab, a new complement component C5 inhibitor with a longer half-life, was started and he received 4 infusions (3 doses of 3300 mg and 1 dose of 2700 mg at 8 weekly intervals) until his recent visit to the office. Laboratory parameters at that time showed persistently high serum creatinine (2.3 mg/dl), high 24-hour urine protein (6 g/d), and dysmorphic red blood cells on urinalysis; however, 50% hemolytic complement (40 U/ml) and complement C3 (117 mg/dl) normalized. A repeat kidney biopsy was done in view of no clinical response to therapy, and the direct immunofluorescence findings of pretreatment and post-treatment kidney biopsies are shown in Figure 1.

Nephrotic-range proteinuria and membranoproliferative glomerulonephritis-like pattern caused by interferon-β1b in a patient with multiple sclerosis.

Interferon-beta (IFN-β) subtypes are widely used as immunomodulatory agents for relapsing-remitting multiple sclerosis (MS). Although generally well tolerated, a growing number of reports have recently shown association of long-term IFN-β therapy with several types of glomerulonephritis. Here, we present the case of a 42-year-old woman with MS who developed nephrotic-range proteinuria after taking IFN-β1b for nine years. Initially, due to the presence of histological features consistent with immunoglobulin A (IgA) nephropathy (granular IgA deposits in mesangial lesions), a tonsillectomy plus steroid pulse therapy was performed. However, proteinuria did not significantly decrease after these treatments. Therefore, a second renal biopsy was performed after three years, revealing a membranoproliferative glomerulonephritis-like pattern without immune complex. Further immunofluorescence analysis showed attenuated IgA staining. Consequently, IFN-β1b was replaced with dimethyl fumarate, resulting in complete remission, with proteinuria decreasing to the level of 0.2g/day. Although it is a rare adverse effect, physicians should pay careful attention to the symptoms and findings of nephritis during the follow-up of patients under treatment with this agent.

POS-126 PROLIFERATIVE GLOMERULONEPHRITIS WITH MONOCLONAL IgG DEPOSITS; A NOVEL PATHOLOGIC PRESENTATION

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare form of PGN that mimics immune-complex (IC) GN by light microscopy (LM), but shows monoclonal IgG deposits by immunofluorescence (IF). PGNMID often presents with membranoproliferative (MPGN) pattern or endocapillary hypercellularity. Focal crescents are not uncommon in PGNMID, but diffuse crescentic involvement is very rare.

A case of immune-complex mediated glomerulonephritis associated with pembrolizumab

Introduction: Immune checkpoint inhibitors (ICI) are changing the way we treat cancer. However, these novel agents have various systemic adverse events that may preclude its use and cause poor patient outcomes. ICI-associated acute kidney injury is an emerging complication of this treatment. While tubulointerstitial disease is the most common pathologic finding of patients with ICI-associated AKI, there is sparse data in medical literature describing its association with glomerular disease. Case report: Here, we present a patient with metastatic lung adenocarcinoma who developed acute kidney injury and significant proteinuria after receiving pembrolizumab. The kidney biopsy revealed a membranoproliferative and diffuse segmental endocapillary proliferative pattern of glomerular injury. Management and outcome: Pembrolizumab was then held and high-dose prednisone was initiated, resulting in a rapid and dramatic improvement in kidney function and proteinuria. Discussion: We highlight a report of a patient diagnosed with immune-complex mediated glomerulonephritis associated with the use of pembrolizumab, who was successfully treated with drug withdrawal and corticosteroids.

KM55 in the Evaluation of IgA-Containing Glomerular Diseases

Introduction: Mucosal-derived galactose-deficient IgA is central to the pathogenesis of primary IgA nephropathy (IgAN). Recent reports suggest similar pathogenesis in Henoch-Schonlein purpura (HSP) and secondary IgAN. Its role in other IgA-containing glomerular diseases is still under investigation. It can be detected in glomeruli with the recently described antibody KM55. We aimed to evaluate the role of KM55 by immunostaining a wide spectrum of IgA-containing glomerular diseases. Methods: After standardization and colocalization in a case of IgAN, a spectrum of 60 cases including IgAN, HSP, chronic liver disease (CLD)-related IgAN, other secondary IgAN, IgA-dominant/codominant membranoproliferative glomerulonephritis (MPGN), and lupus nephritis were subjected to immunofluorescence with KM55. KM55 was used to resolve diagnostic dilemma in cases of IgA deposition with confounding histology. Results: The group of primary IgAN (17 cases), HSP (4 cases), and secondary IgAN (19 cases) including CLD showed 2–3+ granular staining with KM55, suggesting mucosal-derived IgA. In contrast, cases of IgA-dominant/codominant MPGN (8 cases) and lupus nephritis (12 cases) were negative for KM55, suggesting systemic derivation of IgA. In cases of IgA deposition with confounding histology such as membranoproliferative or diffuse endocapillary proliferative pattern, KM55 helped to resolve the diagnosis. Discussion/Conclusion: This cross-sectional study concludes that KM55 is useful in the evaluation of IgA-containing glomerular diseases from a pathogenetic perspective and is a practical tool in resolving differential diagnosis in cases with overlapping histopathological features.

Characteristics and outcomes of glomerulonephritis with membranoproliferative pattern in children.

BackgroundMembranoproliferative glomerulonephritis (MPGN) is a rare histopathologic pattern of glomerular injury with limited studies in pediatric patients. Characteristics and outcomes of children with MPGN have also remained to be further explored.MethodsWe retrospectively reviewed the clinicopathological features, genetic findings, treatments and outcomes in 17 pediatric patients pathologically diagnosed with MPGN from 2007 to 2020 in the Children’s National Medical Center in China.ResultsMedian age at disease onset was 9.9 years (IQR, 5.6–11.9 years). Most of the patients (12/17) had nephrotic range of proteinuria, and nephritic-nephrotic syndrome was the most common clinical presentation (35.2%). Secondary causes were identified in eight patients including hepatitis B virus (HBV) infection (n=4), methylmalonic acidemia (MMA, n=2), rheumatoid arthritis (RA, n=1) and Aymé-Gripp Syndrome (n=1). The nine patients with primary MPGN were further identified as immune-complex mediated MPGN (n=8), and unclassifiable MPGN (U-MGPN, n=1). Genetic analyses identified pathogenic variants of MMACHC gene in two cases of MMA and established the diagnosis for Aymé-Gripp syndrome in one case with a de novo variant of MAF gene. Comparing study between the complete or partial remission group (n=8) and non-response group (n=9) showed a significant difference in the timing of renal biopsy (P<0.05). Normal renal function was preserved in ten patients at the last follow-up. Two patients developed into end-stage renal disease (ESRD).ConclusionsChildren with MPGN pattern present heterogenous clinical features. Genetic detection helps to explore underlying causes of MPGN. Early identification of the primary or secondary causes of MPGN in children is vital.

Case Report. Cryoglobulin Hyaline-thrombi Associated Acute Jejunitis in A Patient with Type 2 Cryoglobulinemic Glomerulonephritis

Abstract Introduction/Objective Only one prior case report indicates that mixed positive cryoglobulin in serum can be associated with intestinal vasculitis (Annals of Internal Medicine, 1974). Methods/Case Report We report a 63-year old man with history of positive serum cryoglobulin and hepatitis-C 4 years ago and membranoproliferative pattern of glomerulonephritis with possible cryoglobulin type of deposits by electron microscopy on renal biopsy. After treatment, his hepatitis C became negative. But he was recently found to have monoclonal IgM-kappa and positive cryoglobulin in his serum, and the concurrent renal biopsy showed membranoproliferative pattern of glomerulopathy with many hyaline-thrombi (eosinophilic vascular occlusions with no lamination, inflammatory cells or nuclear debris) in the glomerular capillary loops (Figure, left panel). Both immunofluorescent and electron microscopy confirmed a mixed IgG polyclonal and IgM monoclonal type 2 cryglobulinemic glomerulonephritis. The patient also developed abdominal pain and underwent intestinal endoscopy with biopsy. His jejunal biopsy revealed neutrophil infiltration into glands and surface epithelium, with superficial sloughed epithelial cells, consistent with acute jejunitis with features of ischemic etiology. In addition, hyaline-thrombi were identified in the submucosal vessels with surrounding vasculitis (Figure, right panel); the central part of thrombi was morphologically similar to that found in glomerular capillary loops. Therefore, we conclude that cryoglobulin associated hyaline-thrombi were the most likely etiology to cause the acute ischemic jejunitis in this patient. Results (if a Case Study enter NA) NA Conclusion NA

A rare cause of membranoproliferative patterns of injury in siblings with steroid-resistant nephrotic syndrome: Questions.

A rare cause of membranoproliferative patterns of injury in siblings with steroid-resistant nephrotic syndrome: Questions.

A rare cause of membranoproliferative patterns of injury in siblings with steroid-resistant nephrotic syndrome:Answers.

A rare cause of membranoproliferative patterns of injury in siblings with steroid-resistant nephrotic syndrome:Answers.

A Case of Vocal Cord Paralysis and Severe Hypocalcemia

Background: Tetany is the hallmark of hypocalcemia. Vocal cord paralysis is a rare presenting symptom of hypocalcemia, especially without signs of overt tetany or seizures. Clinical case: 18 year old man with history of iron deficiency anemia and dyslipidemia presented with aphasia, right sided upper and lower extremity weakness and facial tingling for 3 days. Physical exam was notable for aphasia, pallor, positive Chvostek and Trousseau sign. Admission labs showed BUN 127 mg/dL (n 8–26 mg/dL), creatinine 12.74 mg/dL (n 0.8–2.00 mg/dL), calcium 5.2 mg/dL (n 8.5–10.5 mg/dL), magnesium (1.8–2.4 mg/dL), phosphorus 10.3 (2.4–4.8 mg/dL), alkaline phosphatase 126 (8–120 U/L), albumin 3.3 g/dL (n 3.0–5.0 g/dL), 25 OH VitD3 9.1 ng/mL (n 30–80 ng/mL), PTH 594 pg/mL (n 15–65 pg.mL), COVID 19 PCR negative. Aphasia resolved with 1 gram calcium gluconate infusion. Patient underwent emergent hemodialysis. He was placed on calcium carbonate 1500 mg oral three times daily, calcitriol 1 mcg oral twice daily, ergocalciferol 50,000 IU weekly, sevelamer carbonate 1600 mg tablet three times daily. Kidney biopsy showed membranoproliferative pattern glomerulonephritis with C3 deposits. He was discharged on hemodialysis and referred to a transplant center. Conclusion: Vocal cord paralysis is rare in adults and mostly seen in patients with pseudohypoparathyroidism caused by hypomagnesaemia.2,3 Identifying vocal cord paralysis as an atypical presentation of hypocalcemia secondary to acute kidney failure requires prompt recognition and treatment.

Prediction of steroid resistance and steroid dependence in nephrotic syndrome children

BackgroundSteroid resistant (SR) nephrotic syndrome (NS) affects up to 30% of children and is responsible for fast progression to end stage renal disease. Currently there is no early prognostic marker of SR and studied candidate variants and parameters differ highly between distinct ethnic cohorts.MethodsHere, we analyzed 11polymorphic variants, 6 mutations, SOCS3 promoter methylation and biochemical parameters as prognostic markers in a group of 124 Polish NS children (53 steroid resistant, 71 steroid sensitive including 31 steroid dependent) and 55 controls. We used single marker and multiple logistic regression analysis, accompanied by prediction modeling using neural network approach.ResultsWe achieved 92% (AUC = 0.778) SR prediction for binomial and 63% for multinomial calculations, with the strongest predictors ABCB1 rs1922240, rs1045642 and rs2235048, CD73 rs9444348 and rs4431401, serum creatinine and unmethylated SOCS3 promoter region. Next, we achieved 80% (AUC = 0.720) in binomial and 63% in multinomial prediction of SD, with the strongest predictors ABCB1 rs1045642 and rs2235048. Haplotype analysis revealed CD73_AG to be associated with SR while ABCB1_AGT was associated with SR, SD and membranoproliferative pattern of kidney injury regardless the steroid response.ConclusionsWe achieved prediction of steroid resistance and, as a novelty, steroid dependence, based on early markers in NS children. Such predictions, prior to drug administration, could facilitate decision on a proper treatment and avoid diverse effects of high steroid doses.

Shunt Nephritis: A Rare and Forgotten Diagnosis

Shunt nephritis is a rare complication of ventriculoatrial and ventriculoperitoneal shunt infection. The clinical manifestations are nonspecific and include asthenia, arthralgias, anorexia, weight loss, hematuria, proteinuria, and progressive renal impairment. Therefore, diagnosis can be delayed up for to several years after the first clinical manifestations, which increases the risk of progressive renal impairment and neurological dysfunction. A 57-year-old woman who had undergone ventriculoperitoneal shunt placement in 1990 was admitted to the nephrology department to perform an elective kidney biopsy due to hematuria, proteinuria, and rapidly progressive renal failure. The patient presented with asthenia and weight loss with a duration of one year. No other symptoms were reported. The kidney biopsy was suggestive of infection associated glomerulonephritis, particularly a subacute infection, as a membranoproliferative pattern was seen in light microscopy, and IgM staining was predominant in immunofluorescence imaging. During the hospital stay, the patient developed neurological symptoms. Cerebrospinal fluid examination showed pleocytosis. Shunt nephritis was suspected, and antibiotic treatment was initiated. Due to the patient’s worsening neurological status, an urgent surgical shunt removal was performed. Two months later, her renal function was normal, and the urinalysis result was unremarkable, even though her neurological status did not improve. Although rare, shunt nephritis should be considered in patients that have a history of ventriculoperitoneal shunt placement and present with a proliferative or membranoproliferative glomerulonephritis and prominent IgM deposits in immunofluorescence imaging. Early diagnosis and shunt removal are critical for improving the neurological and renal prognosis.

C3 Glomerulopathy: Diagnosis of a Rare Entity in a Resource-Limited Setting.

C3 glomerulopathy (C3G) is a rare entity that is defined by glomerular pathology characterized by predominant deposition of C3 in the glomeruli, with absent or scant immunoglobulin deposition. The aim of this study was to diagnose this rare entity, using clinical features, light microscopy (LM) and direct immunofluorescence (DIF) findings. A retrospective study was done from January 2016 to December 2018. Out of 207 kidney biopsies, eight cases of C3G were included in the study. Clinical, laboratory, and demographic data of all patients were obtained. LM and DIF findings were further evaluated. Nephrotic syndrome was the predominant clinical presentation in this study. All eight cases showed a membranoproliferative pattern on LM. DIF showed predominant mesangiocapillary staining with C3 in all eight cases. DIF plays an important role in making the correct diagnosis, which is necessary to further perform appropriate complement investigations, as these patients respond well to complement inhibitor therapy.

Glomeruloesclerosis focal segmentaria de variante colapsante asociada a VIH

La afectación del virus de la inmunodeficiencia humana (VIH) ha cambiado tras el inicio del tratamiento antirretroviral de gran actividad, ya que este ha generado una mayor supervivencia y un menor número de comorbilidades en los pacientes. Es común que en las personas con VIH el fracaso renal agudo esté asociado a sepsis, toxicidad por fármacos o afección directa por el propio virus. La nefropatía en pacientes con VIH es variada y puede estar asociada al uso de medicamentos o directamente al efecto del virus. La prevalencia de esta patología en este tipo de pacientes es &lt;10 % y se caracteriza por un colapso glomerular. Las células del parénquima renal expresan los receptores de quimiocinas CCR5 y CXCR4, que son esenciales para la entrada de cepas de VIH-1 en las células. El presente caso es particularmente interesante ya que la insuficiencia renal aguda en el marco de un síndrome nefrótico fue la primera manifestación en un paciente con VIH/sida.

Immune-complex glomerulonephritis with a membranoproliferative pattern in Frasier syndrome: a case report and review of the literature

BackgroundMutations in the Wilms tumor 1 gene cause a spectrum of podocytopathy ranging from diffuse mesangial sclerosis to focal segmental glomerulosclerosis. In a considerable fraction of patients with Wilms tumor 1 mutations, the distinctive histology of immune-complex-type glomerulonephritis has been reported. However, the clinical relevance and etiologic mechanisms remain unknown.Case presentationA 5-year-old child presented with steroid-resistant nephrotic range proteinuria. Initial renal biopsy revealed predominant diffuse mesangial proliferation with a double-contour and coexisting milder changes of focal segmental glomerulosclerosis. Immunofluorescence and electron microscopy revealed a full-house-pattern deposition of immune complexes in the subendothelial and paramesangial areas. Serial biopsies at 6 and 8 years of age revealed that more remarkable changes of focal segmental glomerulosclerosis had developed on top of the initial proliferative glomerulonephritis. Identification of a de novo Wilms tumor 1 splice donor-site mutation in intron 9 (NM_024426.6:c.1447 + 4C > T) and 46,XY-gonadal dysgenesis led to the diagnosis of Frasier syndrome.ConclusionsOur findings, together with those of others, point to the importance of heterogeneity in clinicopathological phenotypes caused by Wilms tumor 1 mutations and suggest that immune-complex-mediated membranoproliferative glomerulopathy should be considered as a histological variant.

Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants

Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.