Key PointsThis study demonstrates that peritoneal dialysis is a safe and feasible option for patients with autosomal dominant polycystic kidney disease, even with high cystic organ volumes.Larger organ volumes, including height-adjusted cumulative kidney and liver volume, were not associated with increased peritoneal dialysis-related complications.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder and the fourth leading cause of kidney failure. Peritoneal dialysis (PD), preferred for its home-based convenience and cost-effectiveness, is often underutilized in ADPKD because of concerns over enlarged kidneys and heightened risk of complications.MethodsThis retrospective cohort study used data from the Mayo Clinic Polycystic Kidney Disease Database to evaluate individuals with ADPKD undergoing PD. We analyzed demographics, clinical parameters, and PD-related parameters. Complications were correlated with kidney and liver volumes derived from pre-kidney failure imaging.ResultsA total of 155 individuals with ADPKD on PD were included, of whom 45.1% were male. The mean age at PD initiation was 54.3 +/- 12.8 years, and the mean body mass index was 28.0 +/- 7.0 kg/m2. The median duration of PD was 24.3 months (interquartile range [IQR], 10.7-43.1), with 21.9% transitioning to hemodialysis. The most common complications were abdominal hernias (30.3%) and peritonitis (23.9%), with a peritonitis rate of 0.11 episodes per patient-year. Imaging analyses performed on a subset of 50 patients showed a median height-adjusted total kidney liver volume of 2731.9 ml/m (IQR, 2102.5-3131.1) and a median height-adjusted total kidney volume of 1303.5 ml/m (IQR, 733.1-1829.4). Kaplan-Meier analysis demonstrated no differences in complications rates on the basis of height-adjusted total kidney liver volume or height-adjusted total kidney volume (above versus below median values) or body mass index categories. Multivariate Cox regression analysis revealed that higher height-adjusted cumulative organ volume was associated with a lower risk of PD-related complications (hazard ratio=0.56, P = 0.026).ConclusionsPD is a safe and feasible treatment option for patients with ADPKD, with no increased risk of PD-related complications associated with larger height-adjusted cumulative organ volumes. Infectious complication rates in this cohort were within International Society of Peritoneal Dialysis guideline thresholds, further supporting the safety of PD in this population.

Chronic kidney disease (CKD) is a major contributor to global morbidity and mortality, traditionally managed through renin-angiotensin system (RAS) inhibition and supportive care. Recent therapeutic advances have transformed this landscape, offering targeted interventions that modify disease progression and improve cardiovascular and renal outcomes. This review summarizes emerging treatments across key domains of CKD management. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated robust cardiorenal benefits, particularly in patients with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are now widely used in CKD and heart failure, including among non-diabetic populations. GLP-1 receptor agonists are approved for T2DM and cardiovascular risk reduction, with recent expansion to CKD in T2DM. Nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), particularly finerenone, provide additional cardiorenal protection with a lower risk of hyperkalemia than traditional steroidal agents. In autosomal dominant polycystic kidney disease (ADPKD), tolvaptan remains the only approved disease-modifying therapy, with clinical trials and real-world data supporting its efficacy across a range of disease stages. Emerging regenerative strategies, including mesenchymal stem cell (MSC) therapy and xenotransplantation using genetically modified pig kidneys, have shown early promise in preclinical models and limited human studies. While further research is needed to optimize patient selection and long-term outcomes, these approaches represent important future directions in nephrology. Together, these developments mark a shift toward mechanism-based, precision therapies in CKD care. Internal medicine clinicians are pivotal in identifying appropriate candidates for these treatments and integrating evolving evidence into practice to improve patient outcomes.

Background & AimChronic kidney disease (CKD) affects over 800 million individuals worldwide and has no cure. However, multiple preclinical studies in CKD animal models show therapeutic potential of mesenchymal stem/stromal cells (MSC). We aimed to investigate MSC safety in a phase I clinical trial and further examined therapy response in individuals with CKD.Methods, Results & Conclusion: MethodsAllogeneic vertebral bone marrow-derived MSC (®Ossium Health) were intravenously administered via peripheral vein (arm) to CKD participants assigned to one of two dose arms: Arm 1 (n=7) 100 x 10^6 MSCs at Days 0 and 84 and Arm 2 (n=7) 200 x 10^6 MSC at Day 0 only. Study subjects underwent testing at baseline through 6 months (interim review). Kidney function was evaluated by CKD-EPI creatinine equation (estimated glomerular filtration rate; eGFR). Clinical enzyme-linked immunosorbent assay measured serum inflammatory cytokine tumor necrosis factor (TNF)-α. Unpaired t-test was used to compare the means of two independent groups.ResultsCKD subjects (n=14) were enrolled with mean age 60.4±11.6 years, 28.6% females, 71.4% white, 36% diabetes mellitus, and baseline eGFR 30.9±7.6 mL/min/1.73m2. No infusion-related or treatment-related serious adverse events were identified. Kidney function remained stable following infusions and over study follow-up, Figure (Left). At 6 months, kidney function was similar to baseline (eGFR 32.1 vs. 30.9 mL/min/1.73m2) with mean eGFR change of 1.2±4.7 mL/min/1.73m2 (all subjects). No difference in 6-month eGFR change was found between dose arm groups (eGFR 1.0±6.5 [Arm 1] vs. 1.4±2.4 [Arm 2], p=0.9). However, proinflammatory marker, TNF-α, had a sustained trend towards lower levels at 3 and 6 months in dose Arm 1 (vs. Arm 2, p=0.09), Figure (Right).ConclusionAllogeneic bone marrow-derived MSC infusions appear safe and tolerable in CKD participants over short-term follow-up. Interim 6-month studies suggest stable to improved kidney function and a repeat of split-dose MSC administration may yield lower systemic inflammation. Additional, larger-scale and placebo-controlled studies are necessary to examine safety and efficacy of this promising therapeutic.

Introduction:Molecular adsorbent recirculating system (MARS) is an extracorporeal system combining conventional veno-venous hemodiafiltration and adsorption to provide rescue support in fulminant hepatic failure. Acute kidney injury (AKI) is common in patients with hepatic failure warranting continuous kidney replacement therapy (CKRT). Our primary aim was to characterize a cohort of patients who received MARS therapy and examine kidney events given the current paucity of available data. Methods:Patients initiating MARS in a tertiary care setting from January 2014 through December 2020 were assessed for treatment indications, transplantation, CKRT, kidney recovery, and death. Data was collected using the REDCAP software. Results:A total of 49 patients (67% female; 75% White) received MARS therapy with 29 patients (59%) requiring concomitant CKRT. Hepatic encephalopathy (HE) was the most common indication for MARS initiation (55%). In-hospital mortality was 41% (12/29) among patients who received CKRT versus 10% (2/20) among those not requiring CKRT (relative risk [RR] 4.15, 95% confidence interval [CI] 1.04 to 16.52, P = 0.044); this persisted following adjustment for prespecified patient characteristics (all RR ≥ 3.76, all P ≤ 0.060). One-year mortality post-MARS initiation was high overall but highest among the CKRT group (59% [17/29] vs. 25% [5/20] unadjusted RR 2.92, 95% CI 1.08 to 7.94, P = 0.035). Liver transplant after MARS occurred in 41% of patients (20/49). After CKRT, 39% of patients (9/29) recovered kidney function prior to hospital discharge. Conclusions:Patients requiring MARS frequently have AKI warranting the use of concomitant CKRT, which is associated with a high rate of in-hospital and 1-year mortality.

A 57-year-old woman with a history of diabetes mellitus, hypertension, and chronic obstructive pulmonary disease with a >40 pack-year smoking history was admitted to the hospital for generalized weakness and muscle cramping. She had been hospitalized 4 months prior with similar presenting symptoms, which were attributed to severe hypokalemia, as she had an undetectable (<1.5 mmol/L) admission plasma potassium level. She denied diarrhea, vomiting, laxative use, diuretic use, or alcohol abuse. She continued to smoke 2 packs per day. Her home medications included potassium chloride, 40 mEq twice per day, and rare ibuprofen use. Her vital signs at admission showed she was hypotensive (89/55 mm Hg). The physical examination was significant for 4/5 muscle strength of upper and lower extremities. The admission laboratory findings are shown in Tables 1 and 2. The electrocardiogram showed sinus arrhythmia, flattened T waves, and prolonged QT interval of 667 ms.•What is the differential diagnosis for this patient’s electrolyte and acid-base disturbances?•What further evaluation should be pursued in this patient to determine the cause of these disturbances?•How should this patient be treated?Table 1Laboratory StudiesParameterResultReference RangeSodium, mmol/L134135-145Potassium, mmol/L<1.53.6-5.2Chloride, mmol/L10398-107Bicarbonate, mmol/L2022-29Calcium, mg/dL10.28.6-10.0Magnesium, mg/dL1.81.7-2.3Phosphorus, mg/dL1.02.5-4.5Creatinine, mg/dL1.150.59-1.04Glucose, mg/dL14570-140Albumin, g/dL3.93.5-5.025-Hydroxyvitamin D, ng/mL2520-50 Open table in a new tab Table 2Urine StudiesUrine ParameterResultSodium (random), mmol/L11Potassium (random), mmol/L11.1Chloride (random), mmol/L13Urine anion gap9.1Urinary potassium-creatinine ratio, mEq/g130 (>13 suggestive of renal potassium wasting)Glucose (dipstick), mg/dLNegativepH (random)7.0 (reference: 5.0-8.0)24-Hour urine potassium, mEq108 (>30 suggestive of renal potassium wasting)β2-Microglobulin, μg/L>20,000 (reference: <300)Retinol-binding protein–creatinine ratio, μg/g173,200 (reference: <172) Open table in a new tab The patient’s admission laboratory findings revealed a normal anion gap metabolic acidosis with positive urine anion gap—suggestive of renal tubular acidosis (RTA). The differential diagnosis includes proximal and distal RTA, given this patient’s hypokalemia with renal potassium wasting. Markedly elevated urinary excretion of β2-microglobulin and retinol-binding protein support a proximal tubulopathy. Proximal RTA is caused by reduced reabsorption of filtered bicarbonate in the proximal convoluted tubule, which leads to renal bicarbonate wasting. In addition to decreased bicarbonate reabsorption, proximal RTA is commonly associated with other solute reabsorption impairments including phosphate, glucose, and amino acids. This generalized proximal tubulopathy is called Fanconi syndrome.1Soleimani M. Rastegar A. Pathophysiology of renal tubular acidosis: core curriculum 2016.Am J Kidney Dis. 2016; 68: 488-498Abstract Full Text Full Text PDF Scopus (26) Google Scholar,2Rodriguez Soriano J. Renal tubular acidosis: the clinical entity.J Am Soc Nephrol. 2002; 13: 2160-2170Crossref PubMed Scopus (308) Google Scholar Most causes of proximal RTA are acquired, but inheritable causes of primary isolated proximal RTA can occur, as well as secondary proximal RTA with familial Fanconi syndrome in certain hereditary diseases (Wilson disease, cystinosis, Lowe syndrome, Fanconi-Bickel syndrome, Dent disease, etc).1Soleimani M. Rastegar A. Pathophysiology of renal tubular acidosis: core curriculum 2016.Am J Kidney Dis. 2016; 68: 488-498Abstract Full Text Full Text PDF Scopus (26) Google Scholar,2Rodriguez Soriano J. Renal tubular acidosis: the clinical entity.J Am Soc Nephrol. 2002; 13: 2160-2170Crossref PubMed Scopus (308) Google Scholar Acquired proximal RTA in adults is commonly caused by injury to the proximal tubule secondary to paraprotein disease, autoimmune disease (Sjögren syndrome), medication toxicity, or heavy metal toxicity.1Soleimani M. Rastegar A. Pathophysiology of renal tubular acidosis: core curriculum 2016.Am J Kidney Dis. 2016; 68: 488-498Abstract Full Text Full Text PDF Scopus (26) Google Scholar,3Ram R. Swarnalatha G. Dakshinamurty K.V. Renal tubular acidosis in Sjogren’s syndrome: a case series.Am J Nephrol. 2014; 40: 123-130Crossref Scopus (19) Google Scholar Severe vitamin D deficiency can also cause proximal RTA.4Ali Y. Parekh A. Baig M. Ali T. Rafiq T. Renal tubular acidosis type II associated with vitamin D deficiency presenting as chronic weakness.Ther Adv Endocrinol Metab. 2014; 5: 86-89Crossref PubMed Scopus (4) Google Scholar Box 1 summarizes the causes of proximal RTA.Box 1Causes of Proximal RTA•Hereditary causes⋄Primary isolated proximal RTA⋄Secondary proximal RTA▪Wilson disease▪Cystinosis▪Lowe syndrome▪Fanconi-Bickel syndrome▪Dent disease▪Glycogen storage disease type I▪Fructose intolerance▪Tyrosinemia•Acquired causes⋄Paraprotein disease▪Amyloidosis▪Light chain disease▪Multiple myeloma⋄Autoimmune disease▪Sjögren syndrome⋄Medication toxicity▪Carbonic anhydrase inhibitors (topiramate, acetazolamide)▪Ifosfamide▪Valproic acid▪Tenofovir▪Aminoglycosides▪Oxaliplatin/cisplatin▪Expired tetracycline⋄Vitamin D deficiency⋄Heavy metal toxicity▪Arsenic▪Cadmium▪Mercury▪Lead▪Copper▪Zinc•Idiopathic causesAbbreviation: RTA, renal tubular acidosis. •Hereditary causes⋄Primary isolated proximal RTA⋄Secondary proximal RTA▪Wilson disease▪Cystinosis▪Lowe syndrome▪Fanconi-Bickel syndrome▪Dent disease▪Glycogen storage disease type I▪Fructose intolerance▪Tyrosinemia•Acquired causes⋄Paraprotein disease▪Amyloidosis▪Light chain disease▪Multiple myeloma⋄Autoimmune disease▪Sjögren syndrome⋄Medication toxicity▪Carbonic anhydrase inhibitors (topiramate, acetazolamide)▪Ifosfamide▪Valproic acid▪Tenofovir▪Aminoglycosides▪Oxaliplatin/cisplatin▪Expired tetracycline⋄Vitamin D deficiency⋄Heavy metal toxicity▪Arsenic▪Cadmium▪Mercury▪Lead▪Copper▪Zinc•Idiopathic causes Abbreviation: RTA, renal tubular acidosis. Given the patient’s proximal tubulopathy and absence of any known family history of potential hereditary causes, the patient was evaluated for acquired causes of proximal tubulopathy. Testing for paraprotein disease with serum protein electrophoresis with immunofixation, serum free light chains, and urine protein electrophoresis with immunofixation was unremarkable. Likewise, testing for autoimmune disease with antibodies against antinuclear and extractable nuclear antigens was unremarkable. Her 25-hydroxyvitamin D level was within normal limits. The review of this patient’s current and past prescriptions and over-the-counter medications did not identify any offending agent. A heavy metals screen was ordered to evaluate for potential heavy metal toxicity, including arsenic, cadmium, mercury, lead, copper, and zinc. The patient was found to have severe cadmium toxicity, with 4.4 μg in a 24-hour urine collection (reference range, <0.7 μg), corresponding to a cadmium-creatinine ratio of 6.24 μg/g. Cadmium is a heavy metal that can cause both severe acute and chronic toxicity. The kidneys are a primary target organ for chronic cadmium toxicity.5World Health OrganizationExposure to cadmium: a major public health concern. preventing disease through healthy environments. WHO; 2010.https://www.who.int/ipcs/features/cadmium.pdfDate accessed: June 2, 2021Google Scholar, 6Waalkes M.P. Cadmium carcinogenesis.Mutat Res. 2003; 533: 107-120Crossref PubMed Scopus (737) Google Scholar, 7Roels H. Djubgang J. Buchet J.P. Bernard A. Lauwerys R. Evolution of cadmium-induced renal dysfunction in workers removed from exposure.Scand J Work Environ Health. 1982; 8: 191-200Crossref Scopus (50) Google Scholar, 8Johri N. Jacquillet G. Unwin R. Heavy metal poisoning: the effects of cadmium on the kidney.Biometals. 2010; 23: 783-792Crossref PubMed Scopus (393) Google Scholar Sources of cadmium exposure include smoking cigarettes, eating contaminated foods (rice and grains farmed with cadmium-containing fertilizer), and occupational exposure.5World Health OrganizationExposure to cadmium: a major public health concern. preventing disease through healthy environments. WHO; 2010.https://www.who.int/ipcs/features/cadmium.pdfDate accessed: June 2, 2021Google Scholar,6Waalkes M.P. Cadmium carcinogenesis.Mutat Res. 2003; 533: 107-120Crossref PubMed Scopus (737) Google Scholar,9International Programme on Chemical SafetyCadmium. Environmental Health Criteria 134. World Health Organization; 1992.http://www.inchem.org/documents/ehc/ehc/ehc134.htmGoogle Scholar,10Agency for Toxic Substances and Disease RegistryCadmium toxicity. Case Studies in Environmental Medicine (CSEM). U.S. Department of Health and Human Services; 2008.https://www.atsdr.cdc.gov/csem/cadmium/docs/cadmium.pdfGoogle Scholar The main source of cadmium exposure in smokers is inhalation of tobacco smoke, as opposed to ingestion of contaminated foods in never-smokers.10Agency for Toxic Substances and Disease RegistryCadmium toxicity. Case Studies in Environmental Medicine (CSEM). U.S. Department of Health and Human Services; 2008.https://www.atsdr.cdc.gov/csem/cadmium/docs/cadmium.pdfGoogle Scholar,11Mannino D.M. Holguin F. Greves H.M. Savage-Brown A. Stock A.L. Jones R.L. Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey.Thorax. 2004; 59: 194-198Crossref PubMed Scopus (111) Google Scholar Smoking doubles the lifetime body burden of cadmium.6Waalkes M.P. Cadmium carcinogenesis.Mutat Res. 2003; 533: 107-120Crossref PubMed Scopus (737) Google Scholar Daily intake of cadmium through contaminated food in the United States is around 30 μg, of which only 1%-10% is absorbed.10Agency for Toxic Substances and Disease RegistryCadmium toxicity. Case Studies in Environmental Medicine (CSEM). U.S. Department of Health and Human Services; 2008.https://www.atsdr.cdc.gov/csem/cadmium/docs/cadmium.pdfGoogle Scholar,12Horiguchi H. Oguma E. Sasaki S. et al.Comprehensive study of the effects of age, iron deficiency, diabetes mellitus, and cadmium burden on dietary cadmium absorption in cadmium-exposed female Japanese farmers.Toxicol Appl Pharmacol. 2004; 196: 114-123Crossref PubMed Scopus (48) Google Scholar A single cigarette has around 2 μg of cadmium, of which up to 10% is inhaled through smoking.11Mannino D.M. Holguin F. Greves H.M. Savage-Brown A. Stock A.L. Jones R.L. Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey.Thorax. 2004; 59: 194-198Crossref PubMed Scopus (111) Google Scholar Inhalation from smoking 1 pack (20 cigarettes) daily is between 1 and 3 μg.11Mannino D.M. Holguin F. Greves H.M. Savage-Brown A. Stock A.L. Jones R.L. Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey.Thorax. 2004; 59: 194-198Crossref PubMed Scopus (111) Google Scholar,13Ashraf M.W. Levels of heavy metals in popular cigarette brands and exposure to these metals via smoking.Sci World J. 2012; 2012: 729430Crossref Scopus (75) Google Scholar The critical urinary cadmium-creatinine ratio associated with onset of renal tubular injury is 2-10 μg/g—our patient had a ratio of 6.2 μg/g.14Prozialeck W.C. Edwards J.R. Mechanisms of cadmium-induced proximal tubule injury: new insights with implications for biomonitoring and therapeutic interventions.J Pharmacol Exp Ther. 2012; 343: 2-12Crossref Scopus (137) Google Scholar After systemic absorption by inhalation or ingestion, cadmium is freely filtered across the glomerulus and reabsorbed by proximal tubular cells while bound to metallothionein. Metallothionein is degraded by lysosomes within tubular cells, releasing free cadmium that generates reactive oxygen species, which result in proximal tubulopathy and RTA.6Waalkes M.P. Cadmium carcinogenesis.Mutat Res. 2003; 533: 107-120Crossref PubMed Scopus (737) Google Scholar, 7Roels H. Djubgang J. Buchet J.P. Bernard A. Lauwerys R. Evolution of cadmium-induced renal dysfunction in workers removed from exposure.Scand J Work Environ Health. 1982; 8: 191-200Crossref Scopus (50) Google Scholar, 8Johri N. Jacquillet G. Unwin R. Heavy metal poisoning: the effects of cadmium on the kidney.Biometals. 2010; 23: 783-792Crossref PubMed Scopus (393) Google Scholar Chronic cadmium toxicity can progress to Fanconi syndrome.8Johri N. Jacquillet G. Unwin R. Heavy metal poisoning: the effects of cadmium on the kidney.Biometals. 2010; 23: 783-792Crossref PubMed Scopus (393) Google Scholar Progressive loss of kidney function from cadmium toxicity does not commonly occur.7Roels H. Djubgang J. Buchet J.P. Bernard A. Lauwerys R. Evolution of cadmium-induced renal dysfunction in workers removed from exposure.Scand J Work Environ Health. 1982; 8: 191-200Crossref Scopus (50) Google Scholar Nephrologists and other providers should be aware of the potential risk of chronic cadmium nephrotoxicity and signs of proximal tubule impairment in patients with long-term history of tobacco use. Management of this patient’s proximal tubulopathy and RTA starts with avoiding the offending agent: in this case, smoking cessation is required. Our patient reported smoking 2 packs per day—exposure to approximately 2-6 μg of inhaled cadmium daily. The patient received education on the cause of her proximal tubulopathy and the link between cigarette smoking and cadmium toxicity. Unfortunately, tubular injury from chronic cadmium toxicity is typically irreversible, even after cessation of exposure.7Roels H. Djubgang J. Buchet J.P. Bernard A. Lauwerys R. Evolution of cadmium-induced renal dysfunction in workers removed from exposure.Scand J Work Environ Health. 1982; 8: 191-200Crossref Scopus (50) Google Scholar After correction of this patient’s severe hypokalemia using intravenous potassium, she was prescribed potassium citrate with split dosing throughout the day for treatment of her proximal RTA and to maintain normokalemia. Bicarbonate supplementation in patients with proximal RTA can result in increased urinary bicarbonate excretion with resultant worsening of hypokalemia.1Soleimani M. Rastegar A. Pathophysiology of renal tubular acidosis: core curriculum 2016.Am J Kidney Dis. 2016; 68: 488-498Abstract Full Text Full Text PDF Scopus (26) Google Scholar Potassium levels must be monitored closely with alkali therapy; concurrent potassium supplementation is often required. Cadmium toxicity causing proximal tubulopathy with proximal renal tubular acidosis and severe symptomatic hypokalemia. Lyle Wesley Baker, MD, and Christopher Trautman, MD. 0000-0003-4937-8357 (LWB); 0000-0002-6762-4999 (CT). None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained consent from the patient reported in this article for publication of the information about her that appears within this Quiz. Received May 4, 2021. Direct editorial input from a Deputy Editor. Accepted in revised form June 18, 2021.

Membranous nephropathy (MN) is currently classified as either primary – often associated with positive anti-phospholipase-A2 receptor (PLA2R) autoantibodies – or as secondary – associated with malignancy, infection, medications, or autoimmune disease. We present a case of biopsy-proven MN with very high serum titer of anti-PLA2R autoantibodies in a patient with a synchronous diagnosis of poorly differentiated esophageal adenocarcinoma and renal cell carcinoma who presented with nephrotic syndrome. Based on the current classification, MN in the presence of active malignancy is diagnosed as secondary and unlikely to have positive anti-PLA2R autoantibodies. This raises several questions: whether this patient has secondary MN associated with malignancy and coincidentally discovered anti-PLA2R autoantibodies, primary MN due to anti-PLA2R autoantibodies with coincidentally discovered malignancy, or whether malignancy can induce the formation of anti-PLA2R autoantibodies that result in MN. This case report highlights the importance of age-appropriate cancer screening, even in patients with presumed primary MN and positive anti-PLA2R autoantibodies.

Fibrillary glomerulonephritis (FGN) and complement 3 glomerulopathy (C3G) are rare forms of glomerulonephritis with distinct aetiologies. Both FGN and C3G can present with nephritic syndrome. FGN is associated with autoimmune disease, dysproteinaemia, malignancy and hepatitis C infection. C3G is caused by the unregulated activation of the alternative complement pathway. We present a rare case of diffuse necrotising crescentic glomerulonephritis with dominant C3 glomerular staining on immunofluorescence-consistent with C3G-but electron microscopy (EM) findings of randomly oriented fibrils with a mean diameter of 14nm and positive immunohistochemistry for DNAJB9-suggestive of FGN. To the best of our knowledge, this is the first reported case of FGN to show dominant C3 glomerular deposits. This case report reaffirms the utility of EM in the evaluation of nephritic syndrome and highlights the value of DNAJB9-a novel biomarker with a sensitivity and specificity near 100% for FGN.

Purpose: Epigenetic alterations are one of the common cellular hallmarks of aging. Several studies have identified CpG sites whose methylation levels change with age in different tissues, and DNA methylation at 353 ‘clock’ CpG sites can be used to calculate epigenetic age independently of tissue, cell type and disease status. Several human diseases are associated with accelerated epigenetic aging, including Down syndrome and obesity, and it has been hypothesised that the age-related loss of normal epigenetic control may be responsible for the late onset of common human diseases. Given that age is the strongest risk factor for OA, we decided to investigate if OA is associated with accelerated epigenetic aging in cartilage. Methods: A meta-analysis was performed on three cartilage methylation datasets, which used identical sample types and were generated using the Infinium HumanMethylation450 BeadChip. The raw IDAT data files were normalised using the preprocessFunnorm function from the Minfi package. The following CpG probes were removed from the analysis: probes with a detection P value threshold of <0.01 in at least 50% of samples; those on the sex chromosomes and; probes containing SNPs with a MAF of greater than 5%. This resulted in a total of 422,069 CpG probes for the age analysis. After QC and normalisation, 179 cartilage samples with an age range of 45 to 95 years (mean age of 71.7 years) were included in the analysis; these were composed of non-OA hip cartilage, preserved and lesioned OA hip cartilage, and preserved and lesioned OA knee cartilage. Age regression tests were performed using the Limma package with linear models that controlled for the different origins of the datasets. A Benjamini-Hochberg adjusted P value cut-off of <0.05 was used to identify age-associated CpGs (age-CpGs). Gene ontology analysis was performed using Ingenuity Pathways Analysis. Results: No correlation was observed between mean probe methylation of all probes included in the analysis and age. 716 and 345 age-CpGs were identified when all samples (n = 179) or all OA samples (n = 144) were analysed, respectively. The majority of age-CpGs were hypermethylated with age (91.3% of cartilage and 93.3% of OA-only age CpGs). Age-CpGs were enriched relative to non-age CpGs within CpG islands (2.0 fold and 2.15 fold, respectively) and depleted in the regions >2kb away from a CpG island (p<0.05, Pearson Chi2 test). Significantly fewer age-CpGs were located in genic regions than expected, but those within gene loci were enriched in the region spanning 200bp upstream of the transcription start site (1.6 fold and 1.3 fold for cartilage age-CpGs and OA age-CpGs, respectively) and depleted in gene body and 3ʹUTR. Age-CpG sites were significantly enriched for binding sites of the polycomb proteins EZH2, SUZ12 and the co-repressor protein CTBP2, and depleted for sites where the histone demethylase KDM5A transcription factor binds (p<0.001, Pearson Chi2 test). After removing age-CpG sites identified from other studies in other tissues, we identified 605 age-CpGs specific to cartilage and 126 specific to OA cartilage. The cartilage-specific age-CpGs were enriched for in genes involved in cancer, embryonic and organismal development, and neuronal migration and function. OA-specific age-CpGs were enriched for in genes involved in cancer, analgesia, synaptic transmission, and embryonic development; relevant canonical pathways included circadian rhythm signalling and neuropathic pain signalling in dorsal horn neurons. There was limited overlap in age-CpGs between the five cartilage subtypes when analysed separately, especially between hip and knee cartilage. We used the 353 ‘clock’ CpGs to calculate DNA methylation age for each sample, and observed accelerated epigenetic aging in males relative to females (p = 0.019, Kolmogorov-Smirnov 2 sample t test), and in OA hip samples relative to OA knee samples independently of gender (p = 0.012). DNA methylation age was different between preserved and lesioned cartilage from the same joint, although the direction of this difference varied between individuals. Conclusions: We have identified CpG sites whose methylation levels significantly correlate with chronological age in cartilage, over 90% of which are hypermethylated with age. The limited age-CpG overlap and accelerated epigenetic aging observed in OA hip cartilage relative to OA knee cartilage suggests that the aging processes may be different in cartilage from different joint sites, although cell communication and development pathways are common targets of age-related methylation changes for both joints.

OBJECTIVE:To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage.METHODS:Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation.RESULTS:We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (∼75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference-processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor β1 signature (P = 1 × 10(-40) ) and a tumor necrosis factor family signature (P = 3.2 × 10(-28) ), among others.CONCLUSION:Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.

ObjectiveTo perform a genome‐wide DNA methylation study to identify DNA methylation changes in osteoarthritic (OA) cartilage tissue.MethodsThe contribution of differentially methylated genes to OA pathogenesis was assessed by bioinformatic analysis, gene expression analysis, and histopathologic severity correlation. Genome‐wide DNA methylation profiling of >485,000 methylation sites was performed on eroded and intact cartilage from within the same joint of 24 patients undergoing hip arthroplasty for OA. Genes with differentially methylated CpG sites were analyzed to identify overrepresented gene ontologies, pathways, and upstream regulators. The messenger RNA expression of a subset of differentially methylated genes was analyzed by reverse transcription–polymerase chain reaction. Histopathology was graded by modified Mankin score and correlated with DNA methylation.ResultsWe identified 550 differentially methylated sites in OA. Most (69%) were hypomethylated and enriched among gene enhancers. We found differential methylation in genes with prior links to OA, including RUNX1, RUNX2, DLX5, FURIN, HTRA1, FGFR2, NFATC1, SNCAIP, and COL11A2. Among these, RUNX1, HTRA1, FGFR2, and COL11A2 were also differentially expressed. Furthermore, we found differential methylation in approximately one‐third of known OA susceptibility genes. Among differentially methylated genes, upstream regulator analysis showed enrichment of TGFB1 (P = 4.40 × 10−5) and several microRNAs including miR‐128 (P = 4.48 × 10−13), miR‐27a (P = 4.15 × 10−12), and miR‐9 (P = 9.20 × 10−10). Finally, we identified strong correlations between 20 CpG sites and the histologic Mankin score in OA.ConclusionOur data implicate epigenetic dysregulation of a host of genes and pathways in OA, including a number of OA susceptibility genes. Furthermore, we identified correlations between CpG methylation and histologic severity in OA.