Focal Global Glomerulosclerosis Research Articles

Emerging Perspectives on the Rare Tubulopathy Dent Disease: Is Glomerular Damage a Direct Consequence of ClC-5 Dysfunction?

Dent disease (DD1) is a rare tubulopathy caused by mutations in the CLCN5 gene. Glomerulosclerosis was recently reported in DD1 patients and ClC-5 protein was shown to be expressed in human podocytes. Nephrin and actin cytoskeleton play a key role for podocyte functions and podocyte endocytosis seems to be crucial for slit diaphragm regulation. The aim of this study was to analyze whether ClC-5 loss in podocytes might be a direct consequence of the glomerular damage in DD1 patients. Three DD1 kidney biopsies presenting focal global glomerulosclerosis and four control biopsies were analyzed by immunofluorescence (IF) for nephrin and podocalyxin, and by immunohistochemistry (IHC) for ClC-5. ClC-5 resulted as down-regulated in DD1 vs. control (CTRL) biopsies in both tubular and glomerular compartments (p < 0.01). A significant down-regulation of nephrin (p < 0.01) in DD1 vs. CTRL was demonstrated. CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/Caspase9) gene editing of CLCN5 in conditionally immortalized human podocytes was used to obtain clones with the stop codon mutation p.(R34Efs*14). We showed that ClC-5 and nephrin expression, analyzed by quantitative Reverse Transcription/Polymerase Chain Reaction (qRT/PCR) and In-Cell Western (ICW), was significantly downregulated in mutant clones compared to the wild type ones. In addition, F-actin staining with fluorescent phalloidin revealed actin derangements. Our results indicate that ClC-5 loss might alter podocyte function either through cytoskeleton disorganization or through impairment of nephrin recycling.

PD-1 inhibition in aged podocytes and glomerular disease

Kidney function is influenced by the complex process of aging, and the global increase in prevalence of chronic kidney disease is partially driven by increases in life expectancy and associated comorbidities. Histologically, kidney aging is characterized by a pattern of nephrosclerosis, with focal segmental and focal global glomerulosclerosis (FSGS and FGGS), tubulointerstitial fibrosis, and arteriolosclerosis. The precise mechanisms underlying glomerular filtration rate (GFR) decline and nephron loss that occur during the process of aging remain poorly understood, but alterations in podocyte homeostasis play a key role.

MO347: When Aki is Not Due to Rhabdomyolysis: A Rare Case of Nsaid-Related Rhabdomyolysis

Abstract BACKGROUND AND AIMS Non-steroidal anti-inflammatory drugs (NSAIDS) have well-understood side effects. Rhabdomyolysis, though, is a rare adverse effect of NSAIDs and only a few cases have been reported. Here, we report a case of NSAID-related acute kidney injury (AKI) in an old diabetic woman who was found to have high muscle enzymes. METHOD A 75-year-old diabetic woman was referred to a nephrology clinic due to nausea, vomiting and high serum creatinine. She was a known case of type 2 diabetes that was well controlled by oral hypoglycemic agents (metformin, gliclazide and linagliptin). The patient was not known to have documented hypertension. She had never visited a nephrologist but her baseline creatinine was 1.2 mg/dL. Her family also admitted that she has frequently used different NSAIDs (celecoxib, diclofenac and ibuprofen) due to knee pain in the past few weeks. The patient had developed lower extremity weakness 3 days before referral followed by nausea and vomiting, 2 days later. Physical examination showed mild pitting edema of both feet. Her new data were as followings: Blood urea nitrogen: 85 mg/dL, creatinine: 7.5 mg/dL, uric acid: 4.5 mg/dL, sodium: 135 meq/L, potassium: 4.7 meq/L, hemoglobin 11.3 g/dL, white blood cells 5400 U/micL, platelets 186 000 U/micL, creatinine phosphokinase (CPK): 12730 U/L, lactate dehydrogenase (LDH) 1344 U/L, alanine transaminase (ALT) 78 U/L and aspartate transaminase (AST) 203 U/L. Urinalysis showed specific gravity 1.020, protein 4+, sugar 1+, blood trace, red blood cells (RBC) 2–4/hpf, white blood cells (WBC) 4–6 per hpf, and also, 2–4 granular casts per hpf were reported. Urine culture result was negative. 24-h urine specimen showed proteinuria of 7300 mg. Renal ultrasound showed normal-sized kidneys with increased corticomedullary differentiation and bilateral simple cortical cysts. Renal cortical thickness was &amp;gt;1 cm bilaterally, and there was no hydronephrosis or other pathologies. Hemodialysis was started for the patient and she underwent a kidney biopsy to define the cause of acute kidney injury (AKI). RESULTS Renal biopsy showed: membranous glomerulonephritis stage 2/4, severe acute tubulointerstitial nephritis, focal global glomerulosclerosis and vascular thickening. Interstitial fibrosis and tubular atrophy (IFTA) were reported to be about 20%. There was no sign of acute tubular necrosis. (pictures). Immunofluorescent (IF) study showed a 1+ granular pattern deposition of IgG along the glomerular basement membrane. CONCLUSION NSAID-related rhabdomyolysis is a rare side effect of this class of analgesics. Although any agent from this class can be causative, most reports involve the most widely used ones: diclofenac and Ibuprofen. AKI in the presented patient could have different etiologies regarding data and medical history. The value of renal biopsy is well depicted in this case. Although rhabdomyolysis seemed to be the principal etiology, at the first sight, NSAID-related interstitial nephritis played the main role in AKI. The patient was put on hemodialysis for 2 weeks. Any forms of NSAIDs were withheld. Acceptable renal recovery was achieved in 3 weeks; the patient was free from dialysis. Two months later, she has creatinine of 1.2 mg/dL and normal CPK and LDH levels. Angiotensin receptor blocker (ARB) was started as the beginning treatment of membranous nephropathy. Renal biopsy is of great value to differentiate causes of non-typical cases of AKI especially in rare cases where laboratory data may be confusing or misleading.

P053 Interstitial Nephritis from IBD: Complicated Conclusions.

BACKGROUND: Kidney injury in IBD is challenging. Tubulointerstitial nephritis (TIN) is linked to aminosalicylates, but also described in drug-naïve patients, suggesting that TIN may be a direct manifestation of IBD. We describe three cases of TIN in IBD to illustrate the challenges in determining the etiology of the injury. Case #1: 58-year-old male with a horseshoe kidney deformity, uncontrolled hypertension, GERD and small bowel stricturing Crohn's disease (CD), previously on mercaptopurine and allopurinol, subsequently transitioned to adalimumab, maintaining clinical and radiologic remission. Two years later, he developed acute kidney injury in setting of high fevers and sweats, with negative infectious evaluation. Medications included adalimumab, PPI, valacyclovir and torsemide. Renal biopsy revealed TIN with dense, zonal and focal granulomatous features suggestive of drug-induced hypersensitivity, chronic infection, sarcoidosis or an extra-intestinal manifestation of CD. Case #2: 45-year-old female with SLE, nephrolithiasis, GERD, hypertension and ulcerative colitis (UC), initially on mesalamine, then vedolizumab, with clinical and endoscopic remission. Her SCr increased at the time of her UC diagnosis, and worsened over 6 months while on mesalamine, vedolizumab, PPI and losartan. Renal biopsy demonstrated acute and chronic TIN with eosinophils raising concern for an allergic/drug-induced injury. Nephrology concluded that her TIN was secondary to either UC or one of her medications. Case #3: 33-year-old male with UC transitioned to vedolizumab, having failed budesonide and mesalamine. He had latent TB and received 9 months of isoniazid. While on mesalamine, vedolizumab and PPI, he developed fever, chills and night sweats, with an acute rise in SCr, prompting discontinuation of meds. Three months later, still in remission and with improved SCr, he restarted vedolizumab. A year later he developed low-grade fever with elevated SCr, prompting discontinuation. Renal biopsy revealed acute and chronic TIN with severe interstitial fibrosis, tubular atrophy and focal global glomerulosclerosis. He started prednisone and remained off other IBD therapy for 6 months, but repeat colonoscopy revealed mild colitis. He restarted mesalamine, but again developed elevated SCr 2 months later. Repeat renal biopsy revealed TIN with less interstitial fibrosis and focal global glomerulosclerosis, and nephrology suggested his interstitial nephritis was likely secondary to UC over his medications. He started azathioprine with significant improvement in SCr and clinical remission of UC. In all three cases, neither nephrology consultation nor renal biopsy helped distinguish the etiology of renal injury, defaulting to either the IBD meds or an extra-intestinal manifestation of IBD, and not accounting for the acute inflammatory symptoms in two of the cases. While literature review reveals several cases that allege kidney injury as an extra-intestinal target of IBD serious doubts remain. TIN secondary to aminosalicylates is well-documented, but there are few reports of adalimumab-induced granulomatous TIN and only one report of vedolizumab-induced TIN. Each of our patients had well-controlled IBD and multiple confounding variables that could impact kidney function or cause TIN, including hypertension and multiple potential culprit medications, illustrating the dilemma of determining the etiology of renal injury in IBD patients.

Clinical features and genetic variants of Dent disease in 10 children

Objective: To summarize the clinical features and genetic analysis results of 10 children with Dent disease. Methods: The clinical data and gene test results of 10 boys aged from 8 months to 12 years with Dent disease diagnosed in Children's Hospital of Nanjing Medical University from January 2014 to July 2017 were analyzed retrospectively. Results: All patients had insidious onset, 5 cases were found to have proteinuria on routine urine examination after hospitalization duo to other diseases, 4 cases were admitted to hospital because increased foams in the urine, and 1 case was found to have proteinuria on health checkup. All cases presented with low molecular weight proteinuria, urine protein electrophoresis showed that the proportion of low molecular weight protein was greater than 50%, 7 cases had nephrotic-range proteinuria, but none had hypoproteinemia. Six cases had hypercalciuria, 3 cases had nephrocalcinosis, 1 case had nephrolithiasis, 2 cases had glomerular microscopic hematuria, in 1 case urine glucose wa weakly positive but blood glucose was normal. All patients had normal renal function, normal serum calcium, no hypophosphoremia and none had rickets. Genetic analysis results showed that 7 patients with variants in the CLCN5 gene, including 2 nonsense variants (p.R637X, p.Y143X), 3 missense variants (p.A540D, p.G135E, p.G703V), 1 deletion variant (exons 9, 10, 11, 12, 13, 1 missing), and 1 frameshift variant (p.T260Tfs*10). Three cases had missense variants of OCRL gene (p.I274T, p.I371T, p.F399S). Except for p.R637X and p.I274T, the other 8 cases had newly discovered variants. Five patients underwent a renal biopsy, the biopsy revealed focal global glomerulosclerosis in 3 patients, mild mesangial proliferative glomerulonephritis in 1 patient and renal minimal change in 1 patient. Mild focal tubular atrophy and interstitial fibrosis were noted in three cases. Mild segmental foot process effacement was noted under electron microscope in all five cases. Conclusions: All the children with Dent disease had insidious onset, low molecular weight proteinuria is the main clinical manifestation, most cases presented with nephrotic-range proteinuria, but there was no hypoalbuminemia, some cases were not associated with hypercalciuria. The pathogenic genes in most cases were CLCN5 and a few were OCRL. The types of genetic variation include missense variant, nonsense variant, deletion variant and frameshift variant. Although Dent disease is a renal tubular disease, renal biopsy suggests that most cases are associated with glomerular lesions.

Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach.

FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.

145 RENAL BIOPSY OUTCOMES IN PATIENTS WITH UNEXPLAINED RISE IN SERUM CREATININE

Introduction: Renal biopsy is an invasive but necessary procedure to determine the exact diagnosis of patients, especially in patients with an unexplained renal impairment. The histopathological examination is vital not only for diagnosis, but also to prognosticate patients’ condition. Objective: This study was aimed at evaluating the results of renal bi- opsy in patients with unexplained rise in serum creatinine, and its association with the patients’ clinical characteristics. Methodology: This was a retrospective study done with data collected from biopsy results in Hospital Tg Ampuan Afzan, Kuantan between 2016 until April 2017. Baseline demographics, risk factors, rate and duration of worsening serum creatinine and the biopsy results were recorded. Results: There were 21 patients in which 14 (66.6%) were males, and 7 (33.3%) of the patients were females. The median age of the patients were 32.0 (IQR 21.0) years. A total of 15 (71.4%) patients have got no other disease comorbidities, and 5 (23.8%) were di- abetics. Three (14.2%) patients have history of taking herbal supplements. The median duration of deranged creatinine was 14.0 (IQR 13.0) days. The median urea on presentation was 10.0 (IQR 11.1) mmol/L, and the median Creatinine was 306.0 ( IQR 324.0) mmol/L. The median rise in creatinine was 137.0 (IQR 182.0) mmol/ L. Biopsy complications which were perinephric collection were noted in two patients (9.5%). The median glomeruli number attained was 20 (IQR 16). Mesangial matrix expansion and hyper- cellularity was noted in 12 (57.0%) patients. Tubular atrophy and interstitial inflammation was present in 17 (80.9%) patients. Out of the 21 biopsies, 13 (61.9%) were diagnosed to have glomerulone- phritis. Within that group, two (9.5%) of the patients were diag- nosed with Crescentic Lupus Nephritis Class IV. Other glomerulonephritis included IgA Nephropathy in 2 patients (9.5%) and Minimal change GN (9.5%). Eight (38.1%) of the results showed hypertensive changes (14.3%), Diabetic changes (4.3%), focal global glomerulosclerosis (4.3%) and Thrombotic micro- angiopathy (4.3%). The creatinine on presentation and also inter- stitial inflammation and tubular atrophy is not significantly correlated with the glomerulosclerosis group. Conclusion: Renal biopsy definitely still plays the most vital and irre- placeable role in the investigation of cases with unexplained renal impairment. Despite a vastly variable biopsy results between patients, renal biopsy has helped in determining the best treatment and prog- nosis for the patients in our study.

047 COMBINATION OF TENOFOVIR/EMTRICITABINE WITH PROTEASE INHIBITOR - BASED REGIMEN INDUCED ACUTE KIDNEY INJURY REQUIRING HAEMODIALYSIS: A CASE REPORT

Category: Other Presenter: Dr CHUI MUNN ANG Keywords: Human Immunodeficiency Virus, Tenofovir, Protease Inhibitor, Acute Kidney Injury 51 years old with Human Immunodeficiency Virus and Hepatitis C; non compliant to medication, was switched to Tenofovir/Emtricitabine (TDF/FTC) and Lopinavir/ Ritonavir (LPV/r). Renal profile (RP) was normal and urine FEME showed protein 2+ with viral load of 311 748 copies/ml and CD 4 count of 55 cell/ul prior to initiation of therapy. He presented with uraemia after 4 months; normotensive, afebrile with no evidence of fluid overload or infection. Blood parameters showed acute kidney injury with severe metabolic acidosis (ph 7.052, HCO3 9.6mmol/L, urea 48.7mmol/L, creatinine 1771umol/L); Urine showed microscopic haematuria, proteinuria and glycosuria. Ultrasound showed no evidence of obstruction. TDF/FTC and LPV/r were withheld. Regular hemodialysis was only required for 1 month. RP after 3 months showed urea 5.8mmol/L, creatinine 209 umol/L. Renal biopsy showed 33% of focal global glomerulosclerosis with moderate chronic tubulointerstitial damage and acute tubular necrosis. TDF is eliminated by a combination of glomerular filtration and proximal tubular secretion with 20 - 30% of the drug actively transported into renal proximal tubule cells by anion transporters; hence drug interaction of LPV/r with these transporters favours intracellular accumulation and increases risk of renal toxicity (AUC of TDF increased by 32%). The proximal tubular cells injury leads to failure of reabsorption of low molecular weight proteins, glucose, amino acids, phosphate and uric acid; as well as failure of H+ secretion which reflects on the proteinuria, glycosuria, acute kidney injury with renal tubular acidosis requiring renal replacement; supported by evidence of acute tubular necrosis with interstitium occasionally infiltrated by eosinophils from renal biopsy which suggest a case of drug induced nephropathy likely TDF. The combination of TDF/FTC with LPV/r is associated with greater declines in renal function hence patient should be closely monitored to look for any early signs of renal impairment.

Glomerular Pathology in Dent Disease and Its Association with Kidney Function.

Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was recently reported in several patients. Thus, Dent disease renal histopathologic features were characterized and assessed, and their association with kidney function was assessed. Clinical renal pathology reports and slides (where available) were collected from 30 boys and men in eight countries who had undergone clinical renal biopsy between 1995 and 2014. Median (25th, 75th percentiles) age at biopsy was 7.5 (5, 19) years with an eGFR of 69 (44, 94) ml/min per 1.73 m2 and a 24-hour urine protein of 2000 (1325, 2936) mg. A repeat biopsy for steroid-resistant proteinuria was performed in 13% (four of 30) of the patients. Prominent histologic findings included focal global glomerulosclerosis in 83% (25 of 30; affecting 16%±19% glomeruli), mild segmental foot process effacement in 57% (13 of 23), focal interstitial fibrosis in 60% (18 of 30), interstitial lymphocytic infiltration in 53% (16 of 30), and tubular damage in 70% (21 of 30). Higher percentages of globally sclerotic glomeruli, foot process effacement, and interstitial inflammation were associated with lower eGFR at biopsy, whereas foot process effacement was associated with steeper annual eGFR decline. These associations suggest a potential role for glomerular pathology, specifically involving the podocyte, in disease progression, which deserves further study. Furthermore, Dent disease should be suspected in boys and men who have unexplained proteinuria with focal global glomerulosclerosis and segmental foot process effacement on renal biopsy.

APOL1 Risk Alleles Are Associated With More Severe Arteriosclerosis in Renal Resistance Vessels With Aging and Hypertension

IntroductionThe increased risk of end-stage kidney disease among hypertensive African Americans is partly related to APOL1 allele variants. The initial glomerulosclerosis of hypertension-associated arterionephrosclerosis consists of focal global glomerulosclerosis, but in biopsy studies, focal segmental glomerulosclerosis is found with progression to end-stage kidney disease, particularly in African Americans.MethodsThis is a study of arterionephrosclerosis in successfully APOL1-genotyped autopsy kidney tissue of 159 African Americans and 135 whites aged 18 to 89 years from a general population with no clinical renal disease.ResultsGlomerulosclerosis was nearly exclusively focal global glomerulosclerosis with 3 subjects having focal segmental glomerulosclerosis–like lesions that were unrelated to APOL1 risk status. For both races, in multivariable analysis, the dependent variables of arteriosclerosis and glomerulosclerosis were significantly related to the independent variables of older age (P < 0.001) and hypertension (P < 0.001). A relationship between APOL1 genotype and arteriosclerosis was apparent only after 35 years of age, when, for any level of elevated blood pressure, more severe arteriosclerosis was found in the interlobular arteries of 14 subjects with 2 APOL1 risk alleles compared to African Americans with none (n = 37, P = 0.02) or 1 risk allele (n = 35, P = 0.02).DiscussionWith the limitation of the small number of subjects contributing to the positive results, the findings imply that APOL1 risk alleles recessively augment small-vessel arteriosclerosis in conjunction with age and hypertension. Focal segmental glomerulosclerosis was not a significant finding, indicating that in the early stages of arterionephrosclerosis, the primary pathologic influence of APOL1 genotype is vascular rather than glomerular.

Glomerular Aging and Focal Global Glomerulosclerosis: A Podometric Perspective.

Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) µm(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) µm(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages and podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, in older kidneys, proteinaceous material accumulated in the Bowman space of glomeruli with low podocyte density. In a subset of these glomeruli, mass podocyte detachment events occurred in association with podocytes becoming binucleate (mitotic podocyte catastrophe) and subsequent wrinkling of glomerular capillaries, tuft collapse, and periglomerular fibrosis. In kidneys of young patients with underlying glomerular diseases similar pathologic events were identified in association with focal global glomerulosclerosis. Podocyte density reduction with age may therefore directly lead to focal global glomerulosclerosis, and all progressive glomerular diseases can be considered superimposed accelerators of this underlying process.

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans. Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2,571 African Americans from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary or carotid artery revascularization) and CKD (eGFR under 60 ml/min/1.73m2 and/or UACR over 30 mg/g). African American SPRINT participants were 45.3% female with mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mmHg, eGFR 76.3 (77.1) ml/min/1.73m2, UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope [β] 0.33) and negatively associated with eGFR (β −3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not prevalent CVD in African American with a UACR under 1000 mg/g.

Mononuclear phagocyte accumulation in visceral tissue in HIV encephalitis: evidence for increased monocyte/macrophage trafficking and altered differentiation.

The invasion of circulating monocytes/macrophages (MΦ)s from the peripheral blood into the central nervous system (CNS) appears to play an important role in the pathogenesis of HIV dementia (HIV-D), the most severe form of HIV-associated neurocognitive disorders (HAND), often confirmed histologically as HIV encephalitis (HIVE). In order to determine if trafficking of monocytes/MΦs is exclusive to the CNS or if it also occurs in organs outside of the brain, we have focused our investigation on visceral tissues of patients with HIVE. Liver, lymph node, spleen, and kidney autopsy tissues from the same HIVE cases investigated in earlier studies were examined by immunohistochemistry for the presence of CD14, CD16, CD68, Ki-67, and HIV-1 p24 expression. Here, we report a statistically significant increase in accumulation of MΦs in kidney, spleen, and lymph node tissues in specimens from patients with HIVE. In liver, we did not observe a significant increase in parenchymal macrophage accumulation, although perivascular macrophage accumulation was consistently observed with nodular lesions in 4 of 5 HIVE cases. We also observed an absence of CD14 expression on splenic MΦs in HIVE cases, which may implicate the spleen as a potential source of increased plasma soluble CD14 in HIV infection. HIV-1 p24 expression was observed in liver, lymph node and spleen but not kidney. Interestingly, renal pathology suggestive of chronic tubulointerstitial nephritis (possibly due to chronic pyelonephritis), including tubulointerstitial scarring, chronic interstitial inflammation and focal global glomerulosclerosis, without evidence of HIV-associated nephropathy (HIVAN), was seen in four of eight HIVE cases. Focal segmental and global glomerulosclerosis with tubular dilatation and prominent interstitial inflammation, consistent with HIVAN, was observed in two of the eight cases. Abundant cells expressing monocyte/MΦ cell surface markers, CD14 and CD68, were also CD16(+) and found surrounding dilated tubules and adjacent to areas of glomerulosclerosis. The finding of co-morbid HIVE and renal pathology characterized by prominent interstitial inflammation may suggest a common mechanism involving the invasion of activated monocytes/MΦs from circulation. Monocyte/MΦ invasion of visceral tissues may play an important role in the immune dysfunction as well as comorbidity in AIDS and may, therefore, provide a high value target for the design of therapeutic strategies.

Gene-gene and gene-environment interactions in apolipoprotein L1 gene-associated nephropathy.

Molecular genetics have revolutionized the understanding of susceptibility to the broad spectrum of kidney diseases with light microscopic appearance of FSGS, particularly in populations with recent African ancestry. These disorders include idiopathic FSGS, HIV-associated nephropathy, severe lupus nephritis, sickle cell nephropathy, and the primary kidney disorder focal global glomerulosclerosis, which had historically been ascribed to systemic hypertension. FSGS was once thought to include a multitude of unrelated disorders with similar histologic appearance. However, variation in the apolipoprotein L1 gene locus is now known to account for the vast majority of such cases in African Americans as well as nearly all the excess risk for FSGS and related forms of progressive nondiabetic nephropathy in populations with recent African ancestry, relative to European ancestry. Inheriting two coding apolipoprotein L1 gene nephropathy risk variants is necessary for susceptibility to CKD; however, these variants alone are insufficient to produce disease. This work reviews the evidence supporting second hits or modifying factors that affect risk for apolipoprotein L1 gene-associated nephropathy and produce the protean manifestations of this common and complex syndrome. Targeting modifiable second factors will lead to preventive therapies for slowing progression of nondiabetic nephropathy in many patients possessing two apolipoprotein L1 gene risk variants. This model of genetic risk coupled with modifiable second hits will serve as a paradigm applicable to patients with CKD of various etiologies as well as a host of other complex disorders.

Generalizability of Genetic Findings Related to Kidney Function and Albuminuria

Nephrology has benefitted from several recent molecular genetics breakthroughs involving susceptibility to FSGS and focal global glomerulosclerosis, encompassing both rare and common gene variants ([1][1]–[6][2]). To date, the search for diabetic nephropathy genes has been somewhat less rewarding

P-022 Renal Disease Associated with Crohnʼs Disease, Mesalamine and Infliximab

15 year old female with 5 year history of Crohn's Disease (CD) ileocolitis developed increasing serum creatinine concentrations over a 6 month period. She was steroid and mesalamine (50 mg/kg/day) dependant for 1 year after diagnosis of CD prompting addition of Remicade therapy at 5 mg/kg/dose every 8 weeks. Relapsing disease continued and dose of Remiade was increased to 10 mg/kg every 8 weeks 2 years post diagnosis. Interval of administration was gradually shortened to every 4 weeks by 3 years post diagnosis. Symptoms stabilized on this regimen. However, ESR increased to 50–60 for the 6 months period (4.5–5 yrs post CD diagnosis) prior to renal disease recognition. No urinary tract symptoms noted, Creatinine 1.22 mg/dL, Creatinine Clearance 53 mL/min/1.73 m2, ANA 1:320. No other serum immune abnormalities detected. Renal Biopsy revealed active chronic tubulointerstitial nephritis, mesangioproliferative immune complex glomerulopathy with focal global glomerulosclerosis. Discontinuation of Remicade and mesalamine led to rapid decrease in ESR to 11, and gradual decrease over the next year in serum creatinine to range of 0.99–1.07 mg/dL and rise in creatinine clearance to 68 mL/min/1.73 m2 which although improved continues to be compatible with quiescent chronic renal disease stage 2. Biweekly Humira 40 mg/dose was initiated 3 months after discontinuing pentasa and Remicade. Differential diagnoses of renal disease incriminate: CD, mesalamine, infliximab or autoimmune disease and or combination of these processes. Clinical History recounted above. Clinical History recounted above. Included in abstract.

A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis

Dent disease is an X-linked proximal tubulopathy that typically presents with hypercalciuria, low-molecular-weight proteinuria and slow progression to endstage renal disease. We report the case of a 5-year-old boy who presented with asymptomatic nephrotic range proteinuria and was later diagnosed with Dent disease. Absence of specific glomerular pathology in the first kidney biopsy led to erroneous treatment for presumably unsampled primary focal segmental glomerulosclerosis. Aggressive angiotensin blockade and immunosuppression resulted in significant side effects with marginal benefit. The continued nonspecific findings after a second kidney biopsy 2 years later led to the suspicion of a congenital tubulopathy. We detected a novel CLCN5 gene mutation, c.1396G > C, that creates a G466R missense change in the ClC-5 protein. Dent disease should be considered in the differential diagnosis of asymptomatic proteinuria for male patients. Profiling proteinuria in these patients by spot urine albumin/creatinine ratio may give the first clue to a tubulopathy. Determining the extent to which the clinical work-up should proceed for females with Dent phenotype or asymptomatic proteinuria remains to be a challenging clinical dilemma.

A Patient with Nephrotic-Range Proteinuria and Focal Global Glomerulosclerosis

A young male is evaluated for nephrotic-range proteinuria, hypercalciuria, and an elevated serum creatinine. A renal biopsy is performed and shows focal global glomerulosclerosis. The absence of nephrotic syndrome suggest that glomerulosclerosis was a secondary process. Further analysis of the proteinuria showed it to be due mainly to low-molecular weight proteins. The case illustrates the crucial role of electron microscopy as well as evaluation of the identity of the proteinuria that accompanies a biopsy finding of focal and global or focal and segmental glomerulosclerosis.

Sickle cell trait is not independently associated with susceptibility to end-stage renal disease in African Americans

Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 (MYH9), and apolipoprotein L1 (APOL1) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.

Focal Segmental Glomerulosclerosis with Acute Renal Failure Associated with Eltrombopag Therapy

Eltrombopag, a small‐molecule nonpeptide agonist of the thrombopoietin receptor, is used for treatment of thrombocytopenia of various causes, including chronic idiopathic thrombocytopenic purpura (ITP) and hepatitis C‐related liver cirrhosis. During clinical trials, eltrombopag was discontinued in three patients due to ascites, neutropenia, and retinal exudates. Another recently reported major adverse event was reversible acute renal failure in a patient with antiphospholipid syndrome; nephrotoxicity caused by eltrombopag was highly suspected, but a kidney biopsy was not performed. We describe a 46‐year‐old woman with a history of mitral valve prolapse who had an incidental finding of an isolated low platelet count of 22 × 103/mm3. A tentative diagnosis of ITP was made, and oral prednisolone 25 mg twice/day was started. Despite prednisolone dosage adjustments over the next several weeks, her platelet count remained at 15–40 × 103/mm3, and oral eltrombopag 75 mg/day was begun. After seven doses, the patient came to the emergency department with persistent nausea and vomiting. Laboratory work‐up revealed renal failure, and eltrombopag was discontinued. The patient was hospitalized, and on day 2, her renal failure had progressed, and proteinuria was detected. On day 6, emergency hemodialysis was begun. A complete blood count on day 21 revealed progression of anemia and thrombocytopenia. Splenectomy was performed on day 35, which successfully reversed her thrombocytopenia. She was discharged on day 39, and hemodialysis was discontinued on day 44. At follow‐up on day 56, the patient's platelet count was within normal limits. On day 70, kidney biopsy results revealed a typical pattern of focal segmental and diffuse global glomerulosclerosis. By day 210, her ITP had resolved, and her renal function was stable. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of acute renal failure and eltrombopag therapy. To our knowledge, this is the first case report of a patient who experienced acute renal failure and proteinuria concomitant with a pathology of focal segmental glomerulosclerosis after treatment with eltrombopag. This report of a serious case of reversible renal failure after treatment with eltrombopag may serve to inform clinicians about the possible severe renal adverse effects of eltrombopag before commencing with more extensive clinical use in the future.