Penalized likelihood and multiple testing.

The classical multiple testing model remains an important practical area of statistics with new approaches still being developed. In this paper we develop a new multiple testing procedure inspired by a method sometimes used in a problem with a different focus. Namely, the inference after model selection problem. We note that solutions to that problem are often accomplished by making use of a penalized likelihood function. A classic example is the Bayesian information criterion (BIC) method. In this paper we construct a generalized BIC method and evaluate its properties as a multiple testing procedure. The procedure is applicable to a wide variety of statistical models including regression, contrasts, treatment versus control, change point, and others. Numerical work indicates that, in particular, for sparse models the new generalized BIC would be preferred over existing multiple testing procedures.

Type III collagen regulates osteoblastogenesis and the quantity of trabecular bone.

Type III collagen (Col3), a fibril-forming collagen, is a major extracellular matrix component in a variety of internal organs and skin. It is also expressed at high levels during embryonic skeletal development and is expressed by osteoblasts in mature bone. Loss of function mutations in the gene encoding Col3 (Col3a1) are associated with vascular Ehlers-Danlos syndrome (EDS). Although the most significant clinical consequences of this syndrome are associated with catastrophic failure and impaired healing of soft tissues, several studies have documented skeletal abnormalities in vascular EDS patients. However, there are no reports of the role of Col3 deficiency on the murine skeleton. We compared craniofacial and skeletal phenotypes in young (6-8 weeks) and middle-aged (>1 year) control (Col3(+/+)) and haploinsufficient (Col3(+/-)) mice, as well as young null (Col3(-/-)) mice by microcomputed tomography (µCT). Although Col3(+/-) mice did not have significant craniofacial abnormalities based upon cranial morphometrics, µCT analysis of distal femur trabecular bone demonstrated significant reductions in bone volume (BV), bone volume fraction (BV/TV), connectivity density, structure model index and trabecular thickness in young adult female Col3(+/-) mice relative to wild-type littermates. The reduction in BV/TV persisted in female mice at 1 year of age. Next, we evaluated the role of Col3 in vitro. Osteogenesis assays revealed that cultures of mesenchymal progenitors collected from Col3(-/-) embryos display decreased alkaline phosphatase activity and reduced capacity to undergo mineralization. Consistent with this data, a reduction in expression of osteogenic markers (type I collagen, osteocalcin and bone sialoprotein) correlates with reduced bone Col3 expression in Col3(+/-) mice and with age in vivo. A small but significant reduction in osteoclast numbers was found in Col3(+/-) compared to Col3(+/+) bones. Taken together, these findings indicate that Col3 plays a role in development of trabecular bone through its effects on osteoblast differentiation.

Individualized two-stage multiple testing procedures with corresponding interval estimates.

Multiple testing models have become an important part of statistical applications. Typically they can be presented as having M hypotheses each of which concerns an individual parameter. In addition to testing each of these hypotheses, there is often a desire to obtain interval estimates for the parameters. The use of stepwise procedures arises because single-step procedures are extremely conservative. Unfortunately research into the construction of useful, computationally feasible interval estimates corresponding to stepwise procedures has been slow. We present an alternative method of constructing multiple testing procedures (MTPs) that easily admits corresponding interval estimates. The new method places greater focus on each hypothesis separately while still using all the data. This method is particularly effective in the dependent case. Not only do these new MTPs perform as well as commonly used stepwise procedures but they also have a practical interval property not usually shared by stepwise procedures. That is, acceptance regions have desirable convexity properties. Furthermore, interval estimates associated with these tests are easily obtained. In addition, these intervals (i) are typically shorter than those based on the Bonferroni, Scheffé, Tukey or Dunnett method when they are applicable, (ii) are less likely to contain the null point falsely than other methods do, (iii) are informative, i.e. they are all finite in the two-sided case, unlike some constructed by other methods which often are infinite, (iv) have a form of the interval property.

Pathologic classification of diabetic nephropathy.

Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

Oncocytoma of the kidney with prominent intracytoplasmic lumina.

Oncocytoma is a histologically distinctive neoplasm of the kidney, with a well-recognized cytoarchitectural appearance. On occasion, however, renal oncocytomas are known to exhibit unusual morphologic features that may pose diagnostic difficulties. We present the clinical and pathologic details of an oncocytoma of the kidney with an unusual histologic appearance imparted by the presence of large numbers of prominent intracytoplasmic lumens. Morphologically, the neoplasm was composed of uniform polygonal cells with copious amounts of granular, eosinophilic cytoplasm, round nuclei, and prominent nucleoli, exhibiting an organoid pattern of growth. Intracytoplasmic lumina of varying size were present throughout the tumor. There were no mitotic figures or areas of necrosis present. The diagnosis of oncocytoma was supported by immunohistochemical and ultrastructural studies. By electron microscopy, the intracytoplasmic lumens appeared as membrane bound spaces with associated microvilli. The presence of intracytoplasmic lumina in a significant proportion of cells is an uncommon feature of renal oncocytoma which can generate problems in diagnosis. Awareness of this phenomenon should allow for improved recognition of oncocytomas exhibiting this type of unusual morphology.

Thyroid hormone treatment of cultured chondrocytes mimics in vivo stimulation of collagen X mRNA by increasing BMP 4 expression.

During endochondral bone formation, chondrocytes undergo terminal differentiation, during which the rate of proliferation decreases, cells become hypertrophic, and the extracellular matrix is altered by production of collagen X, as well as proteins required for matrix mineralization. This maturation process is responsible for most longitudinal bone growth, both during embryonic development and in postnatal long bone growth plates. Among the major signaling molecules implicated in regulation of this process are the positive regulators thyroid hormone (T3) and bone morphogenetic proteins (BMPs). Both T3 and BMPs are essential for endochondral bone formation and cannot compensate for each other, suggesting interaction of the two signaling pathways. We have analyzed the temporal and spatial expression patterns of numerous genes believed to play a role in chondrocyte maturation. Our results show that T3 stimulates collagen X gene expression in cultured chondrocytres with kinetics and magnitude similar to those observed in vivo. Stimulation of collagen X gene expression by T3 occurs only after a significant delay, implying that this hormone may act indirectly. We show further that T3 rapidly stimulates production of BMP 4, concomitant with a decrease in the BMP inhibitor Noggin, potentially resulting in a net increase in BMP signaling. Finally, inhibition of BMP signaling with exogenous Noggin prevents T3 stimulation of collagen X expression, indicating that BMP signaling is essential for this process. These data position thyroid hormone at the top of a T3/BMP cascade, potentially explaining why both pathways are essential for chondrocyte maturation. J. Cell. Physiol. 219: 595-605, 2009. (c) 2009 Wiley-Liss, Inc.

Integration of signaling pathways regulating chondrocyte differentiation during endochondral bone formation.

During endochondral bone formation, chondrocytes undergo a process of terminal differentiation or maturation, during which the rate of proliferation decreases, cells become hypertrophic, and the extracellular matrix is altered by production of a unique protein, collagen X, as well as proteins that promote mineralization. The matrix surrounding the hypertrophic chondrocytes eventually becomes mineralized, and the mineralized matrix serves as a template for bone deposition. This process is responsible for most longitudinal bone growth, both during embryonic development and in the postnatal long bone growth plates. Chondrocyte maturation must be precisely controlled, balancing proliferation with terminal differentiation; changes in the rate of either proliferation or differentiation result in shortened bones. Numerous signaling molecules have been implicated in regulation of this process. These include the negative regulators Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP; Pthlh, PTH-like hormone), as well as a number of positive regulators. This review will focus on several positive regulators which exert profound effects on chondrocyte maturation: the thyroid hormones T3 and T4, retinoic acid (the major active metabolite of vitamin A) and bone morphogenetic proteins (BMPs), as well as the transcription factor Runx2. Each of these molecules is essential for endochondral bone formation and cannot compensate for the others; abrogation of any one of them prevents differentiation. The important features of each of these signaling pathways will be discussed as they relate to chondrocyte maturation, and a model will be proposed suggesting how these pathways may converge to regulate this process.

Acute lymphoblastic leukemia presenting as acute renal failure.

BACKGROUND: A 42-year-old previously healthy man presented with acute-onset headache and facial paralysis. He was treated for Bell's palsy with corticosteroids and valaciclovir. One week later, he developed acute renal failure requiring hospitalization. INVESTIGATION: Physical examination, laboratory tests, urinalysis, renal ultrasound, renal biopsy, bone marrow biopsy, lumbar puncture, CT of the chest, abdomen and pelvis, MRI of the brain, and whole-body PET scan. DIAGNOSIS: Acute lymphoblastic leukemia, bilateral renal enlargement secondary to leukemic infiltration, acute renal failure, tumor lysis syndrome, and leukemic involvement of the facial nerve. MANAGEMENT: The patient was treated with a modified induction chemotherapy regimen. He was given allopurinol for hyperuricemia and hydrated with alkalized intravenous fluids to prevent uric acid precipitation in the renal tubules. The profound tumor lysis that occurred after the cytotoxic chemotherapy required hemodialysis.

Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients.

OBJECTIVES: Muscle mass and muscle mRNA levels for certain growth factors are reduced in maintenance hemodialysis (MHD) patients. This study tested the hypothesis that in MHD patients endurance exercise training (EET) increases mRNA levels for insulin-like growth factors and reduces myostatin mRNA. DESIGN: Biopsies of the right vastus lateralis muscle were performed before and at the end of 8.9 +/- 0.9 (SEM) weeks of EET in MHD patients. Muscle tissue was analyzed histologically by electron microscopy and for fiber cross-sectional area, and, in 8 pairs of biopsies, muscle was examined for mRNA levels for the following proteins: myostatin, insulin-like growth factor-I (IGF-I), IGF-I receptor (IGF-IR), IGF binding proteins (IGFBPs)-1, -2, -3, -4, and -5, and IGF-binding protein-related protein-1 (IGFBP-rP1). SETTING: Outpatient MHD centers. PATIENTS: This was a pilot study conducted in sedentary clinically stable MHD patients undergoing EET with no control group. INTERVENTION: EET that was carefully supervised by exercise trainers. MAIN OUTCOME MEASURE: Skeletal muscle mRNA levels, especially myostatin mRNA. RESULTS: With EET, skeletal muscle myostatin mRNA decreased by 51%, mRNA levels increased significantly for IGF-IR (by 41%), IGFBP-2, -4, and -5, and IGFBP-rP1. IGF-I mRNA increased by 35%; this change was not significant. IGFBP-3 mRNA did not change, and IGFBP-1 mRNA was undetectable. There were mild to moderate alterations in skeletal muscle ultrastructure that did not change significantly with EET. Muscle fiber size, measured in 5 patients, did not change. CONCLUSION: In MHD patients who undergo approximately 9 weeks of EET, skeletal muscle mRNA for myostatin decreases and mRNA for IGF-IR, IGFBPs -2, -4, and -5 and IGFBP-rP1 increases. These changes may indicate mechanisms by which EET improves muscle exercise capacity in MHD patients.

Hypertension-attributed nephropathy: what's in a name?

Unrelated disease processes commonly occur in non-diabetic individuals with mild-to-moderate hypertension and low level or absent proteinuria who present with chronic kidney disease: primary glomerulosclerosis in those with recent African ancestry, and arteriolar nephrosclerosis with resultant glomerular ischaemia potentially related to hypertension and vascular disease risk factors in other cases. Unfortunately, nephrologists often indiscriminately apply a diagnosis of 'hypertensive nephrosclerosis' to patients in either scenario, which implies that the hypertension is causative of their renal disease. Although nephropathies that are associated with variants in the apolipoprotein L1 gene (APOL1) often cause secondarily elevated blood pressure, they belong to the spectrum of focal segmental glomerulosclerosis and are not initiated by systemic hypertension. Because genetic testing for APOL1 variants and other glomerulosclerosis-associated gene variants is available and can provide a precise definition of disease pathogenesis, we believe that the term 'hypertensive nephrosclerosis' should now be abandoned and replaced with either gene-based (for example, APOL1-associated) glomerulosclerosis or arteriolar nephrosclerosis. Precision medicine will be key to improving diagnostic accuracy in this field. Discrimination of these disparate disorders has the potential to eradicate primary forms of glomerulosclerosis that are associated with APOL1 renal-risk variants.

Minimal change disease onset observed after bevacizumab administration.

This is a report of a patient with minimal change disease (MCD) onset after bevacizumab administration. A 72-year-old man with inoperable Grade 3 astrocytoma was treated with a combination of temozolomide and the vascular endothelial growth factor monoclonal antibody bevacizumab. After two biweekly treatments, he developed nephrotic syndrome. Despite cessation of bevacizumab, his renal function deteriorated and a renal biopsy disclosed MCD. Thereafter, he was started on high-dose oral prednisone and renal function immediately improved. Within weeks, the nephrotic syndrome resolved. Although rare, biologic agents can cause various glomerulopathies that can have important therapeutic implications. MCD should be considered in patients who develop nephrotic syndrome while exposed to antiangiogenic agents.

A novel noncollagenous protein encoded by an alternative transcript of the chick type III collagen gene is expressed in cartilage, bone and muscle.

We have identified a noncollagenous protein, Col3alt, encoded by an alternative transcript of the chick type III collagen gene; its amino acid sequence is out of frame with the collagen coding sequence. This 178-amino-acid protein is unique and has no recognizable motifs other than a hydrophobic domain. Col3alt is found in embryonic cartilage, muscle and bone and in the proliferative and prehypertrophic zones of juvenile chicken growth plates. The protein is intracellular in immature chondrocytes and myoblasts, but is extracellular in well-differentiated cartilage, muscle and bone, despite the lack of a conventional signal peptide. These results demonstrate an unexpected economy of genome utilization in which a single gene, using alternative promoters, gives rise to two unrelated proteins, type III collagen and Col3alt.

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Gaucher disease with nephrotic syndrome: response to enzyme replacement therapy.

Nephrotic syndrome in patients with Gaucher disease is rare; most of the few reported cases have had a well-defined glomerulopathy often with Gaucher cells in the glomeruli. We report the case of a 54-year-old woman with Gaucher disease, who had splenectomy at age 25, preeclampsia with renal biopsy disclosing only endotheliosis at age 32, and improvement of proteinuria and reappearance of heavy proteinuria (7.2 g/24 h) at age 41. Renal biopsy disclosed Gaucher cells in glomeruli and interstitium. The patient did not receive therapy specifically for glomerular disease. Enzyme replacement, begun 4 years later and maintained until now, was associated with amelioration of systemic symptoms and virtual disappearance of proteinuria with a follow-up of 10 years. This case apparently is the first instance of nephrotic syndrome consequent to Gaucher disease itself and successful treatment with specific enzyme replacement.

Ultrastructural changes of corpora cavernosa in men with erectile dysfunction and chronic renal failure.

Erectile dysfunction (ED) is a common and often distressing side effect of renal failure. Uremic men of different ages report a high variety of sexual problems, including sexual hormonal pattern alterations, reduced or loss of libido, infertility, and impotence, thereby influencing their well-being. The pathogenic mechanisms include physiologic, psychologic, and organic causes. To determine the contribution of morphologic factors to impotence we studied the ultrastructure of the corpora cavernosa in 20 patients with end-stage renal disease who were treated with chronic dialysis and compared the findings with 6 individuals with no clinical history of impotence. Our results indicated that in male uremic patients with sexual disturbances there were major changes in smooth muscle cells. This was characterized by reduction of dense bodies in the cytoplasm, thick basement membranes, and increased interstitial collagen fibers with resultant reduction of cell-to-cell contact. In addition, there was thickening and lamination of basement membranes of endothelial cells and increased accumulation of collagen between nerve fibers. These alterations were more evident in patients with longer time on dialysis and were independent of type of primary renal disease. We hypothesize that ED in dialysis patients is not related to the primary disease but to the uremic state.

Successive increases in human cyclin A1 promoter activity during spermatogenesis in transgenic mice.

The human cyclin A1 gene is highly expressed in pachytene spermatocytes and is essential for spermatogenesis. To analyze mechanisms of cyclin A1 gene expression in vivo, we cloned a 1.3 kb fragment of the promoter upstream of the cDNA of enhanced green fluorescent protein (EGFP). Four lines of transgenic mice were generated that carried the transgene. Cyclin A1 promoter activity in the organs of the transgenic mice was analyzed using fluorescence microscopy and flow cytometry. Expression of EGFP was seen in male germ cells of all four murine lines. Spermatogonia at the basal membrane expressed low levels of EGFP, but bright green fluorescence was present in spermatocytes entering meiosis. Interestingly, a further sharp increase in EGFP expression was found in spermatocytes approximately at the stage of the first meiotic division. EGFP levels stayed high thereafter and EGFP was present in mature spermatozoa. A portion of c-kit expressing cells in the testis also expressed EGFP indicating cyclin A1 promoter activity in a subpopulation of spermatogonia. These data suggest that cyclin A1 is active not only in pachytene spermatocytes but also in earlier phases of spermatogenesis.

Stimulation of type-X collagen gene transcription by retinoids occurs in part through the BMP signaling pathway.

BACKGROUND: Chondrocyte maturation and hypertrophy during endochondral bone formation are stimulated by both retinoids and bone morphogenetic proteins (BMPs). The type-X collagen gene, which is expressed only in hypertrophic chondrocytes, provides an excellent marker for chondrocyte maturation. We previously identified a 651-base-pair region of the type-X collagen promoter that is essential for its activation by BMP. We examined the relationship between the retinoid and BMP signaling pathways in transcriptional stimulation of the type-X collagen gene to determine whether they act independently or interact to regulate endochondral bone formation. METHODS: Prehypertrophic chondrocytes from embryonic chick sterna cultured in the presence or absence of retinoic acid or BMP-2 were transiently transfected with plasmids containing various mutations of the type-X collagen promoter directing expression of a luciferase reporter gene. In addition, real-time polymerase chain reaction was used to examine the effects of retinoic acid on expression of genes encoding BMP-2, 4, and 6. RESULTS: The previously identified BMP-responsive region of the type-X collagen promoter also mediated stimulation by physiological concentrations of retinoic acid in prehypertrophic chondrocytes. Systematic deletion mutagenesis of the BMP/retinoid-responsive region of the type-X collagen promoter identified distinct regions that are responsible for promoter stimulation by retinoids and BMP. Retinoic acid rapidly and dramatically stimulated accumulation of BMP-2 and BMP-6 messenger RNAs. CONCLUSIONS: These results suggest that, while retinoic acid appears to stimulate type-X collagen gene transcription in part by stimulating the BMP signaling pathway, it also acts in part through mechanisms that are independent of BMP.

Multi-institutional comparison of whole slide digital imaging and optical microscopy for interpretation of hematoxylin-eosin-stained breast tissue sections.

CONTEXT: Whole slide imaging (WSI) is now used for educational purposes, for consultation, and for archiving and quantitation of immunostains. However, it is not routinely used for the primary diagnosis of hematoxylin-eosin-stained tissue sections. OBJECTIVE: To compare WSI using the Aperio digital pathology system (Aperio Technologies, Inc, Vista, California) with optical microscopy (OM) for the interpretation of hematoxylin-eosin-stained tissue sections of breast lesions. DESIGN: The study was conducted at 3 clinical sites; 3 breast pathologists interpreted 150 hematoxylin-eosin-stained slides at each site, 3 times each by WSI and 3 times each by OM. For WSI, slides were scanned using an Aperio ScanScope and interpreted on a computer monitor using Aperio ImageScope software and Aperio Spectrum data management software. Pathologic interpretations were recorded using the College of American Pathologists breast checklist. WSI diagnoses were compared with OM diagnoses for accuracy, precision (interpathologist variation), and reproducibility (intrapathologist variation). Results were considered accurate only if the interpretation matched exactly between WSI and OM. The proportion of accurate results reported by each pathologist was expressed as a percentage for the comparison of the 2 platforms. RESULTS: The accuracy of WSI for classifying lesions as not carcinoma or as noninvasive (ductal or lobular) or invasive (ductal, lobular, or other) carcinoma was 90.5%. The accuracy of OM was 92.1%. The precision and reproducibility of WSI and OM were determined on the basis of pairwise comparisons (3 comparisons for each slide, resulting in 36 possible comparisons). The overall precision of WSI was 90.5% in comparison with 92.1% for OM; reproducibility of WSI was 91.6% in comparison with 94.5% for OM, respectively. CONCLUSIONS: In this study, we demonstrated that WSI and OM have similar accuracy, precision, and reproducibility for interpreting hematoxylin-eosin-stained breast tissue sections. Further clinical studies using routine surgical pathology specimens would be useful to confirm these findings and facilitate the incorporation of WSI into diagnostic practice.

Association of histologic variants in FSGS clinical trial with presenting features and outcomes.

BACKGROUND AND OBJECTIVES: FSGS histologic variants have correlated with outcomes in retrospective studies. The FSGS Clinical Trial provided a unique opportunity to study the clinical impact of histologic variants in a well defined prospective cohort with steroid-resistant primary FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsies of 138 FSGS Clinical Trial participants aged 2-38 years enrolled from 2004 to 2008 were analyzed using the Columbia classification by core pathologists. This study assessed the distribution of histologic variants and examined their clinical and biopsy characteristics and relationships to patient outcomes. RESULTS: The distribution of histologic variants was 68% (n=94) FSGS not otherwise specified, 12% (n=16) collapsing, 10% (n=14) tip, 7% (n=10) perihilar, and 3% (n=4) cellular. Individuals with not otherwise specified FSGS were more likely to have subnephrotic proteinuria (P=0.01); 33% of teenagers and adults had tip or collapsing variants compared with 10% of children, and subjects with these variants had greater proteinuria and hypoalbuminemia than not otherwise specified patients. Tip variant had the strongest association with white race (86%) and the lowest pathologic injury scores, baseline creatinine, and rate of progression. Collapsing variant had the strongest association with black race (63%, P=0.03) and the highest pathologic injury scores (P=0.003), baseline serum creatinine (P=0.003), and rate of progression. At 3 years, 47% of collapsing, 20% of not otherwise specified, and 7% of tip variant patients reached ESRD (P=0.005). CONCLUSIONS: This is the first prospective study with protocol-defined immunomodulating therapies confirming poor renal survival in collapsing variant and showing better renal survival in tip variant among steroid-resistant patients.

Collagen Type III Glomerulopathies.

The 2 rare disorders characterized by the pathological accumulation of collagen type III in glomeruli are discussed. These are collagenofibrotic glomerulopathy, also known as collagen type III glomerulopathy, and the nail-patella syndrome. Although there are similarities in abnormal morphology, with type III collagen in mesangium and/or capillary walls, there is no genetic or pathogenic link to them. Collagenofibrotic glomerulopathy presents either in childhood, often with a family history suggesting autosomal recessive inheritance, or in adults as a sporadic occurrence. Proteinuria is the typical manifestation, with progression to ESRD in approximately 10 years. Although there is markedly elevated serum precursor collagen type III protein in the circulation, the usual manner of diagnosis is with kidney biopsy, which discloses type III collagen in subendothelial aspects of capillary walls and often in the mesangial matrix. Glomerular involvement in the nail-patella syndrome invariably presents in a patient with an established diagnosis of this multisystem disorder with orthopedic and cutaneous manifestations. It is owing to mutations in the gene LMX1B. Although the lesion may be asymptomatic, it is usually manifested by proteinuria. Structural lesions are of collagen type III within glomerular basement membranes, different in distribution to collagenofibrotic glomerulopathy. The clinical course is variable.