Progression of minimal-change glomerulopathy to focal glomerulosclerosis in a patient with fenoprofen nephropathy

We report a patient who presented with the classical features of fenoprofen-induced nephropathy. Initial response to a cessation of the drug and prednisone therapy was recovery of renal function, but proteinuria persisted. One year later, he experienced recurrence of the nephrotic syndrome with sustained renal failure. A clear progression from minimal-change lesions to focal glomerulosclerosis was shown in sequential renal biopsies. Not previously reported, this evolution is suggestive of the possibility that fenoprofen nephropathy may lead to chronic renal failure.     

Pathophysiology of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS. KR is a Pediatric Nephrology Trainee supported by grant no. NIH T32 DK007110 30. FJK is supported in part by NIH DK63549-04.     

Poorly differentiated adenocarcinoma of the rectum in a nephrotic patient with focal segmental glomerulosclerosis

We report herein a case of poorly differentiated adenocarcinoma of the rectum occurring in a nephrotic patient with focal segmental glomerulosclerosis. The neoplasm which first appeared to be a submucosal tumor occurred in a 29-year old Japanese man with a neophrotic syndrome for 2 years and 6 months. Autopsy disclosed a large tumor located between the rectum and urinary bladder. Renal specimens showed changes consistent with focal segmental glomerulosclerosis.     

Development of focal segmental glomerulosclerosis in the renal allograft of a patient with lupus

Nephritis has been a recognized complication of systemic lupus erythematosus since the early 1900s. Almost all lupus patients have some degree of renal involvement related to their condition, but a considerably smaller proportion of these patients actually progress to end-stage renal disease (ESRD). However, lupus patients are also susceptible to other primary renal insults that may significantly contribute to the deterioration in their renal function. We present a case of a patient with clinical and pathological evidence of lupus nephritis that progressed to ESRD and subsequently developed “recurrent” focal segmental glomerulosclerosis in her transplant kidney. Retrospective clinicopathologic correlation suggested the possibility of more than 1 primary renal process that eventually led to her dialysis-dependent state. This case illustrates the importance of meticulously examining both clinical and renal biopsy data in patients with lupus nephritis and considering the presence of co-existing renal pathologies to resolve an otherwise discordant picture of disease progression. These considerations may have important therapeutic and prognostic implications.     

呈局灶节段性肾小球硬化的IgA肾病临床病理特点

目的探讨呈局灶节段性肾小球硬化（FSGS）的IgA肾病（IgAN）的临床和病理特点。方法选取我院1988年1月至2002年2月经肾活检确诊为IgAN的患者587例,其中呈FSGS85例,呈弥漫性系膜增生性肾小球肾炎（MsPGN）162例,呈弥漫性系膜增生性肾小球肾炎伴局灶节段性肾小球硬化（MsPGN伴FSGS）185例,比较3种类型IgAN临床和病理资料。结果FSGS型IgAN占同期所有IgAN的14．5％,临床类型以大量蛋白尿型为主,占37．64％。肾小球球囊黏连发生率高达74．12％,小管间质纤维化发生率97．65％,病理分级以LeeⅣ～Ⅴ级为主,免疫病理以IgA—MG型为主,与MsPGN伴FSGS型和MsPGN型的IgAN相比,FSGS型IgAN病程较长,高血压、肾功能不全发生率较高（P〈0．05）,而血尿的发生率与后两者无明显区别。结论呈FSGS型IgAN大量蛋白尿、高血压、肾功能不全的发生率高,病变较重,预后较差。     

Concurrent focal segmental glomerulosclerosis and membranous nephropathy

Focal segmental glomerulosclerosis and membranous glomerulonephropathy are two entities that may result in the nephrotic syndrome. Two young women exhibited concurrent focal segmental glomerulosclerosis and focal segmental membranous nephropathy on renal biopsy. Although the lesions were severe, both patients had asymptomatic proteinuria, normal renal function, and a benign clinical course. The concurrence of these glomerulopathies may portend a more benign clinical course than expected for a patient presenting with either lesion alone.     

Adriamycin nephropathy: a model of focal segmental glomerulosclerosis

Adriamycin nephropathy (AN) is a rodent model of chronic kidney disease that has been studied extensively and has enabled a greater understanding of the processes underlying the progression of chronic proteinuric renal disease. AN is characterized by podocyte injury followed by glomerulosclerosis, tubulointerstitial inflammation and fibrosis. Genetic studies have demonstrated a number of loci that alter both risk and severity of renal injury induced by Adriamycin. Adriamycin-induced renal injury has been shown in numerous studies to be modulated by both non-immune and immune factors, and has facilitated further study of mechanisms of tubulointerstitial injury. This review will outline the pharmacological behaviour of Adriamycin, and describe in detail the model of AN, including its key structural characteristics, genetic susceptibility and pathogenesis.     

Serum interleukin-2 levels in a patient with focal segmental glomerulosclerosis

We describe a patient with steroid-resistant focal segmental glomerulosclerosis (FSGS) whose serum interleukin-2 (IL-2) levels were markedly elevated in association with disease activity. With cyclosporin A (CsA) treatment, the patient entered remission and serum IL-2 fell to undetectable levels. After cessation of CsA, the patient relapsed and the serum IL-2 levels were elevated again. Reinstitution of CsA therapy was followed by a partial remission and disappearance of detectable serum IL-2 levels.     

Pregnancy-induced nephropathy: the significance of focal segmental glomerulosclerosis

The morphologic alterations of true preeclampsia are well described and distinct. Using available criteria to define reversible pregnancy-induced nephropathy (PIN), the pathologist can offer the clinician information useful in predicting remote renal function and hypertension. True PIN is a usually completely reversible lesion in the nullipara and carries little risk of future hypertension. Nephrosclerotic vascular lesions, however, whether arteriolar, interlobular, or glomerular and resembling focal segmental glomerulosclerosis (FSGS), signify underlying hypertensive disease. This review summarizes information concerning the nature of PIN and also surveys 20 biopsies in women who mainly had severe preeclampsia, often with persistent postpartum hypertension. This material was step-sectioned and specifically reviewed in an effort to find FSGS in women with PIN.     

C1q nephropathy: a variant of focal segmental glomerulosclerosis

BACKGROUND: C1q nephropathy is a poorly understood and controversial entity with distinctive immunopathologic features. In order to better define the clinical-pathologic spectrum, we report the largest single-center series. METHODS: Nineteen biopsies with C1q nephropathy were identified from among 8909 native kidney biopsies received from 1994 to 2002 (0.21%). Defining criteria included (1). dominant or co-dominant immunofluorescence staining for C1q, (2). mesangial electron dense deposits, and (3). no clinical or serologic evidence of systemic lupus erythematosus (SLE). RESULTS: The 19 patients were predominantly African American (73.7%), female (73.7%), young adults and children (range, 3 to 42 years; mean, 24.2 years). Presentation included nephrotic range proteinuria (78.9%), nephrotic syndrome (50%), renal insufficiency (27.8%), and hematuria (22.2%). No patient had hypocomplementemia or evidence of underlying autoimmune or infectious disease. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 17 (including six collapsing and two cellular) and minimal-change disease (MCD) in two. All biopsies displayed co-deposits of immunoglobulin G (IgG), with more variable IgM (84.2%), IgA (31.6%), and C3 (52.6%). Foot process effacement varied from 20% to 100% (mean, 51%). Twelve of 16 patients with available follow-up received immunosuppressive therapy. One patient had complete remission of proteinuria and six had partial remission. Four patients with FSGS pattern had progressive renal insufficiency, including two who reached end-stage renal disease (ESRD). Median time from biopsy to ESRD was 81 months. On multivariate analysis, the best correlate of renal insufficiency at biopsy and at follow-up was the degree of tubular atrophy and interstitial fibrosis (P = 0.0495 and 0.0341, respectively). CONCLUSION: C1q nephropathy falls within the clinical-pathologic spectrum of MCD/FSGS. Although further studies are needed to determine the pathomechanism of C1q deposition, we hypothesize that it may be a non-specific marker of increased mesangial trafficking in the setting of glomerular proteinuria.     

Thrombotic microangiopathy as a complication in a patient with focal segmental glomerulosclerosis

We report on a 12-year-old female patient with steroid-dependent nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) since her 3rd year of life. She was twice treated with oral cyclophosphamide and received antihypertensive treatment with atenolol and enalapril. After 3 years without any control or therapy, she presented in a reduced general condition with hypertensive crisis and a blood pressure of 220/130 mmHg, headache, vomiting and loss of vision. Additionally, renal insufficiency (creatinine 11.4 mg/dl, urea 157 mg/dl), with oliguria, anaemia and a severe relapse of nephrotic syndrome, was present. Initial treatment with steroids, albumin–furosemide infusions and antihypertensive drugs was unsuccessful, and dialysis treatment was necessary. Renal biopsy showed an advanced stage of the known FSGS and, surprisingly, a thrombotic microangiopathy. Further diagnostic investigations revealed no signs of haemolytic-uraemic syndrome, but echocardiography showed left ventricular hypertrophy, and hypertensive retinopathy grade 3 was diagnosed, making severe hypertension the most likely reason for the thrombotic microangiopathy. While adequate antihypertensive treatment led to regress of left ventricular hypertrophy and hypertensive retinopathy, renal function did not recover, and the patient remained dialysis-dependent. In conclusion, severe hypertension in chronic kidney disease can lead to target organ damage and thrombotic microangiopathy, which may further worsen renal function.     

Familial focal segmental glomerulosclerosis

There is increasing recognition of the importance of genetic factors in the development of focal segmental glomerulosclerosis and related proteinuric disorders. Recently, four genes have been identified which, when defective, cause focal segmental glomerulosclerosis or nephrosis. All of these genes appear to be important in the maintenance of glomerular podocyte function. However, not all cases of familial nephrosis or proteinuria are explained by defects in these genes.     

Idiopathic focal segmental glomerulosclerosis

Idiopathic focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that essentially represents a form of chronic, progressive renal fibrosis for which there is no discernible cause. Often presenting with or eventually manifesting the nephrotic syndrome, this disease is increasing in incidence in both children and adults. Therapy continues to be a challenge, although some patients clearly respond to corticosteroids or cyclosporine with a decrease in, or remission of, proteinuria. A favorable response is associated with a decreased likelihood of progression to kidney failure. Given our clinical experience and recent advances in understanding the genetics of FSGS, a stochastic model of disease pathogenesis can be proposed.     

APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.