What lies in-between: C3 glomerulopathy with non-hemolytic renal microangiopathy and an ultra-rare C3 variant.

We report a 36-year-old female with mixed nephritic-nephrotic syndrome and recurrent pancreatitis. Kidney biopsy showed a crescentic membranoproliferative glomerulonephritis with dominant C3 staining on immunofluorescence (IF) but only scant deposits on electron microscopy (EM) and instead, evidence of severe acute and chronic microangiopathy - endothelial swelling, sub-endothelial fluff, and segmental basement membrane remodeling. Her serum C3 was normal, Factor Ba, and serum Membrane attack complex (sMAC) levels were elevated, and Properdin was low. Genetic testing revealed a heterozygous ultra rare C3 variant of unknown significance (c.4838G>T, p.Gly1613Val) as well as a heterozygous deletion of CFHR3-CFHR1. She showed an initial response to terminal complement blockade with eculizumab, but her renal disease progressed in the next year. Notably, our patient never demonstrated microangiopathic hemolysis, yet pancreatitis of unclear etiology recurred periodically. Our case suggests the existence of a "C3G/aHUS overlap" clinicopathologic syndrome and highlights the challenges of treating complement-mediated kidney disease.

Effect of iodinated contrast material on post-operative eGFR when administered during renal mass ablation.

OBJECTIVE: To evaluate the effect of intravenous iodinated contrast on estimated glomerular filtration rate (eGFR) when administered immediately after thermal ablation of clinically localized T1a (cT1a) renal cell carcinoma (RCC). METHODS: This HIPAA-compliant, dual-center retrospective study was performed under a waiver of informed consent. Three hundred forty-two consecutive patients with cT1a biopsy-proven RCC were treated with percutaneous ablation between January 2010 and December 2017. Immediate post-ablation contrast-enhanced CT was the routine standard of care at one institution (contrast group), but not the other (control group). One-month pre- and 6-month post-ablation eGFR were compared using the Wilcoxon signed-rank test or the Kruskal-Wallis test. Multivariate linear regression was used to determine the effect of contrast on eGFR. A 1:1 propensity score matching was performed for all patients with a logistic model using patient, tumor, and procedural covariates. RESULTS: In total, 246 patients (158 M; median age 69 years, IQR 62-74) were included. Median tumor diameter (2.4 vs 2.5, p = 0.23) and RENAL nephrometry scores (6 vs 6, p = 0.92), surrogates for ablation zone size, were similar. Baseline kidney function was similar for the control and contrast groups, respectively (median eGFR: 70 vs 74 mL/min/1.73 m2, p = 0.29). There was an expected mild decline in eGFR after ablation (control: 70 vs 60 mL/min/1.73 m2, p < 0.001; contrast: 75 vs 71 mL/min/1.73 m2, p = 0.001). Intravenous iodinated contrast was not associated with a decline in eGFR on multivariate linear regression (1.91, 95% CI - 3.43-7.24, p = 0.46) or 1:1 propensity score-matched model (- 0.33, 95% CI - 6.81-6.15, p = 0.92). CONCLUSION: Intravenous iodinated contrast administered during ablation of cT1a RCC has no effect on eGFR. KEY POINTS: • Intravenous iodinated contrast administered during thermal ablation of clinically localized T1a renal cell carcinoma has no effect on kidney function. • Thermal ablation of clinically localized T1a renal cell carcinoma results in a mild decline in kidney function. • A decline in kidney function is similar for radiofrequency and microwave ablation of clinically localized T1a renal cell carcinoma.

Long-Term Outcomes and Prognostic Factors in Kidney Transplant Recipients with Polycystic Kidney Disease.

Background: Polycystic kidney disease (PKD) accounts for approximately 15% of kidney transplants, but long-term outcomes in patients with PKD who have received a kidney transplant are not well understood. Methods: In primary recipients of kidney transplants at our center (1994-2014), we compared outcomes of underlying PKD (N=619) with other native diseases (non-PKD, N=4312). Potential factors influencing outcomes in PKD were evaluated using Cox proportional-hazards regression and a rigorous multivariable model. Results: Patients with PKD were older and were less likely to be sensitized or to experience delayed graft function (DGF). Over a median follow-up of 5.6 years, 1256 of all recipients experienced death-censored graft failure (DCGF; 115 patients with PKD) and 1617 died (154 patients with PKD). After adjustment for demographic, dialysis, comorbid disease, surgical, and immunologic variables, patients with PKD had a lower risk of DCGF (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.57 to 0.93; P=0.01) and death (aHR, 0.62; 95% CI, 0.51 to 0.75; P<0.001). In our multiadjusted model, calcineurin-inhibitor (CNI) use was associated with lower risk of DCGF (aHR, 0.45; 95% CI, 0.26 to 0.76; P=0.003), whereas HLA mismatch of five to six antigens (aHR, 2.1; 95% CI, 1.2 to 3.64; P=0.009) was associated with higher likelihood of DCGF. Notably, both pretransplant coronary artery disease (CAD) and higher BMI were associated with increased risk of death (CAD, aHR, 2.5; 95% CI, 1.69 to 3.71; P<0.001; per 1 kg/m2 higher BMI, aHR, 1.07; 95% CI, 1.04 to 1.11; P<0.001), DCGF, and acute rejection. Nephrectomy at time of transplant and polycystic liver disease were not associated with DCGF/death. Incidence of post-transplant diabetes mellitus was similar between PKD and non-PKD cohorts. Conclusions: Recipients with PKD have better long-term graft and patient survival than those with non-PKD. Standard practices of CNI use and promoting HLA match are beneficial in PKD and should continue to be promoted. Further prospective studies investigating the potential benefits of CNI use and medical/surgical interventions to address CAD and the immunologic challenges of obesity are needed. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2021_02_25_KID0001182019.mp3.

Urinary monocyte chemoattractant protein 1 associated with calcium oxalate crystallization in patients with primary hyperoxaluria.

BACKGROUND: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. METHODS: A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. RESULTS: Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. CONCLUSION: In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.

Polycystic Liver Disease in a Patient With Metastatic Renal Cell Carcinoma: A Case Report.

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery.

Kidney transplant recipients with polycystic kidney disease have a lower risk of post-transplant BK infection than those with end-stage renal disease due to other causes.

BACKGROUND: Polyomavirus-associated nephropathy is associated with high risk of kidney allograft loss. Whether the cause of native end-stage renal disease influences the risk of BK infection is unclear. METHODS: A retrospective, single-center study of 2741 adult kidney transplant recipients between 1994 and 2014 was performed. Recipients had end-stage renal disease due to polycystic kidney disease (PKD, n = 549), diabetes mellitus (DM, n = 947), hypertension (HTN, n = 442), or glomerulonephritis (GN, n = 803). RESULTS: A total of 327 recipients (12%) developed post-transplant BK viremia over a median follow-up time of 5 years. The incidence rate of BK viremia was lowest in patients with PKD (1.46 per 100 person-years) compared to other causes of ESRD (DM = 2.06, HTN = 2.65, and GN = 2.01 per 100 person-years). A diagnosis of PKD was associated with a lower risk of post-transplant BK viremia (adjusted HR (95% CI) = 0.67 (0.48-0.95), P = 0.02). BK nephropathy was significantly less common in patients with PKD (0.21 per 100 person-years) compared to those with HTN (0.80 per 100 person-years, P ≤ 0.001). Among patients with PKD, the risk of BK viremia was lower in patients with nephrectomy, compared to those without nephrectomy (adjusted HR (95% CI) = 0.42 (0.19-0.92), P < 0.05). CONCLUSION: ESRD due to PKD is associated with a lower risk of post-transplant BK infection. The renal tubular epithelial cells in PKD are unique; they are in a proliferative but non-differentiated state. Whether this characteristic of renal tubular epithelial cells alters the BK viral reservoir or replication in PKD patients warrants further study.

Evaluating safety of tunneled small bore central venous catheters in chronic kidney disease population: A quality improvement initiative.

INTRODUCTION: Peripherally inserted central venous catheters (PICCs) may adversely impact future successful arteriovenous fistulae (AVF). As part of a quality improvement project, the performance of tunneled small bore tunneled central venous catheters (TSB-CVCs), as alternatives to PICCs, was evaluated. METHODS: A retrospective observational study, involving individuals ≥18 years of age who underwent TSB-CVC placement by Interventional Radiology at Mayo Clinic, Rochester, MN between 1/1/2010 and 8/30/2013. FINDINGS: The study cohort included 92 patients with a median age of 55 (46-67) years, who underwent 108 TSB-CVC placements. Baseline renal disease was present in 71% (77/108). Most TSB-CVCs were placed in hospitalized patients (94%; 102/108); five French in diameter (61%; 66/108) and located in an internal jugular vein (84%; 91/108). Median catheter indwelling time was 20 (11-43) days (n = 84). TSB-CVC-related bloodstream infection, deep venous thrombosis (DVT), and superficial venous thrombosis (SpVT) rates per line were 0.009 (1/108), 0.018 (2/108), and 0.009 (1/108), respectively. Venous outcomes in a subgroup of 54 patients, who had documented PICC placements (n = 161) in addition to TSB-CVC (n = 58) were compared. TSB-CVC-DVT rate was lower than the PICC-DVT rate (0.017 [1/58] vs. 0.106 per line [17/161]; P = 0.04). The TSB-CVC-SpVT rate was not different from the PICC-SpVT rate (0 [0/58] vs. 0.037 [6/161] per line; P = 0.14). DISCUSSION: TSB-CVCs demonstrated an excellent safety profile in our study. These catheters should be preferentially utilized for arm vein preservation in advanced kidney disease. Their impact on future AVF success needs further evaluation.

Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits.

OBJECTIVE: To study the hematologic characteristics of proliferative glomerulonephritides (GNs) from nonorganized glomerular monoclonal immunoglobulin (MIg) deposition (MIPG). PATIENTS AND METHODS: The pathology database at Mayo Clinic (Rochester, Minnesota) was used to find patients with MIPG who underwent a kidney biopsy between January 1, 2008, and December 31, 2013. Retrospective medical record review was conducted in the identified cohort (N=60). RESULTS: The median patient age was 56 years (interquartile range, 47-62 years) and the estimated glomerular filtration rate was 36 mL/min/1.73 m(2) (interquartile range, 22-52 mL/min/1.73 m(2)). Most patients had IgG MIg deposits (90%; 54 of 60) and a membranoproliferative pattern (48%; 29 of 60). A circulating nephropathic MIg was detected by serum immunofixation (SIFE(+)) in 20% (12 of 59) and by abnormal serum free light chain ratio (sFLCR(+)) in 21% (12 of 56). The subsets of SIFE(+) and sFLCR(+) incompletely overlapped. The nephropathic clone was found by bone marrow testing (BM(+)) in 25% (10 of 40; 6 plasma cell clones [5 IgG; 1 IgA], 3 chronic lymphocytic leukemia [all IgG], and 1 lymphoplasmacytic clone [IgM]). The clone detection rate was significantly higher in patients with SIFE(+) (P<.001) and in those with SIFE(+) and/or sFLCR(+) (P<.001). Patients with SIFE(+) and BM(+) frequently had IgG1-restricted MIg deposits on renal biopsy immunofluorescence (P=.005). Most BM(+) patients required flow cytometry and immunohistochemical analysis of the marrow specimen for accurate diagnosis. CONCLUSION: Undetectable circulating nephropathic MIg and pathologic clones characterize most MIPG. Immunoglobulin isotype may predict detectability of MIg and clone by currently available technology. Bone marrow evaluation, including flow cytometry and immunohistochemical analysis, should be performed for SIFE(+) and/or sFLCR(+). More sensitive clone-identifying techniques in the marrow and extramedullary tissue are needed when SIFE and sFLCR test negative.

Cardiovascular disease burden and risk factors before and after kidney transplant.

Cardiovascular (CV) disease is the most common cause of mortality among kidney transplant candidates on the waiting-list and after kidney transplantation. The mechanisms of cardiovascular disease burden after transplant are multifactorial and the risk is largely determined by pre-transplant factors including CV disease and dialysis duration. Current pre-transplant cardiac evaluation protocols have proven to be inconsistent in predicting adverse cardiovascular outcome post-transplant. However, multiple biomarkers have been recognized as predictors of all-cause mortality and cardiovascular events including graft function, hemoglobin, homocysteine, C - reactive protein among others. Of these, elevation in the biomarker cardiac troponin T appears to be a significant predictor of cardiovascular events and mortality among wait-listed kidney transplant candidates and after transplantation. The relationship between CV risk reduction, normalization of cardiac troponin T levels and restoration of renal function after kidney transplant is complex but opens opportunities for the use of cardiac troponin T and other cardiovascular biomarkers as important endpoints of clinical interventions in kidney transplant recipients.

IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4(+) T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4(+) T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

Lack of TNFalpha expression protects anaplastic lymphoma kinase-positive T-cell lymphoma (ALK+ TCL) cells from apoptosis.

Here we report that T-cell lymphomas characterized by the expression of anaplastic lymphoma kinase (ALK+ TCL) fail to express the TNFalpha and frequently display DNA methylation of the TNFalpha gene promoter. While only a subset of the ALK+ TCL-derived cell lines showed a high degree of the promoter methylation, all 6 showed low to nondetectable expression of the TNFalpha mRNA, and none expressed the TNFalpha protein. All 14 ALK+ TCL tissue samples examined displayed some degree of the TNFalpha promoter methylation, which was the most prominent in the distal portion of the the promoter. Treatment with a DNA methyltransferase inhibitor, 5'-aza-2'-deoxy-cytidine (5-ADC), reversed the promoter methylation and led to the expression of TNFalpha mRNA and protein. Furthermore, in vitro DNA methylation of the promoter impaired its transcriptional activity in the luciferase reporter assay. This impairment was seen even if only either distal or proximal portion were methylated, with methylation of the former exerting a more profound inhibitory effect. Notably, the ALK+ TCL cell lines uniformly expressed the type 1 TNFalpha receptor (TNF-R1) protein known to transduce the TNFalpha-induced pro-apoptotic signals. Moreover, exogenous TNFalpha inhibited growth of the ALK+ TCL cell lines in a dose-dependent manner and induced activation of the members of the cell apoptotic pathway: Caspase 8 and caspase 3. These findings provide additional rationale for the therapeutic inhibition of DNA methyltransferases in ALK+ TCL. They also suggest that treatment with TNFalpha may be highly effective in this type of lymphoma.