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.

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.

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.

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.

Metabolic and morphometric profile of muscle fibers in chronic hemodialysis patients.

Muscle weakness and effort intolerance are common in maintenance hemodialysis (MHD) patients. This study characterized morphometric, histochemical, and biochemical properties of limb muscle in MHD patients compared with controls (CTL) with similar age, gender, and ethnicity. Vastus lateralis muscle biopsies were obtained from 60 MHD patients, 1 day after dialysis, and from 21 CTL. Muscle fiber types and capillaries were identified immunohistochemically. Individual muscle fiber cross-sectional areas (CSA) were quantified. Individual fiber oxidative capacities were determined (microdensitometric assay) to measure succinate dehydrogenase (SDH) activity. Mean CSAs of type I, IIA, and IIX fibers were 33, 26, and 28% larger in MHD patients compared with CTL. SDH activities for type I, IIA, and IIX fibers were reduced by 29, 40, and 47%, respectively, in MHD. Capillary to fiber ratio was increased by 11% in MHD. The number of capillaries surrounding individual fiber types were also increased (type I: 9%; IIA: 10%; IIX: 23%) in MHD patients. However, capillary density (capillaries per unit muscle fiber area) was reduced by 34% in MHD patients, compared with CTL. Ultrastuctural analysis revealed swollen mitochondria with dense matrix in MHD patients. These results highlight impaired oxidative capacity and capillarity in MHD patients. This would be expected to impair energy production as well as substrate and oxygen delivery and exchange and contribute to exercise intolerance. The enlarged CSA of muscle fibers may, in part, be accounted for by edema. We speculate that these changes contribute to reduce limb strength in MHD patients by reducing specific force.

A position paper on standardizing the nonneoplastic kidney biopsy report.

The biopsy report for nonneoplastic kidney diseases represents a complex integration of clinical data with light, immunofluorescence, and electron microscopic findings. Practice guidelines for the handling and processing of the renal biopsy have previously been created. However, specific guidelines for essential pathologic parameters that should be included in these pathology reports do not exist. The Renal Pathology Society has coordinated an effort through the formation of an ad hoc committee to enumerate the essential elements and pathologic parameters that should be reported for every biopsy specimen. This endeavor aims to establish a minimum reporting standard and to improve communication between pathologists and other physicians. This document represents the collective effort and consensus opinions of this ad hoc committee of the Renal Pathology Society.

A position paper on standardizing the nonneoplastic kidney biopsy report.

The biopsy report for nonneoplastic kidney diseases represents a complex integration of clinical data with light, immunofluorescence, and electron microscopic findings. Practice guidelines for the handling and processing of the renal biopsy have previously been created. However, specific guidelines for essential pathologic parameters that should be included in these pathology reports do not exist. The Renal Pathology Society has coordinated an effort through the formation of an ad hoc committee to enumerate the essential elements and pathologic parameters that should be reported for every biopsy specimen. This endeavor aims to establish a minimum reporting standard and to improve communication between pathologists and other physicians. This document represents the collective effort and consensus opinions of this ad hoc committee of the Renal Pathology Society.

Drug-induced kidney disease--pathology and current concepts.

The kidneys can be damaged by a large number of therapeutic agents. The aim of this article is to discuss the pathological features of drug-induced renal disease as diagnosed by kidney biopsy. The literature is reviewed and cases seen by the authors that have a known drug association are analysed. Mechanisms of injury are varied and all renal structures may be affected. The tubulointerstitial compartment is most frequently involved, but glomerular and vascular lesions are seen in a significant proportion of cases.

A milder variant of Pierson syndrome.

Congenital nephrotic syndrome (CNS) comprises a heterogeneous group of conditions having in common the disruption of normal glomerular permselectivity, and it carries a poor prognosis, with most patients progressing to end-stage renal disease. Recently, mutations in the LAMB2 gene encoding laminin beta2 were described as the cause of Pierson syndrome, which is characterized by CNS and a complex ocular maldevelopment with microcoria as the most prominent clinical features. Most affected children exhibit early onset of chronic renal failure, neurodevelopmental deficits, and blindness. We report on a patient with CNS, high-grade myopia, and minor structural eye anomalies, including remnants of pupillary membranes, but no microcoria. The patient had not developed renal failure by the age of 16 months, and he showed no neurodevelopmental deficits. He was identified to be homozygous for a novel LAMB2 missense mutation. This observation, together with two recent reports on milder variants of Pierson syndrome, corroborates the concept that the clinical expression of Pierson syndrome is more variable than initially described, and that milder phenotypes may be related to hypomorphic LAMB2 alleles.

Chloroquine-induced lipidosis mimicking Fabry disease.

Intracellular accumulation of phospholipids may be a consequence of inherited or acquired metabolic disorders. In Fabry disease, deficiency of alpha-galactosidase A results in storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium among others; the ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myeline figures). Chloroquine therapy may result in storage of biochemically and ultrastructurally similar inclusions in many of the same cells as Fabry disease and often results in similar clinical manifestations. We report a 56-year-old woman with rheumatoid arthritis treated with chloroquine, who developed muscle weakness and renal insufficiency; information regarding therapy was not emphasized at the time of renal biopsy, leading to initial erroneous interpretation of Fabry disease. Following muscle biopsy, genetic and enzyme evaluation, and additional studies on the kidney biopsy, a diagnosis of chloroquine toxicity was established. One year following cessation of chloroquine, renal and muscle dysfunction greatly improved. In chloroquine toxicity, inclusions in glomeruli are not only in visceral epithelial, endothelial and mesangial cells but are in infiltrating monocytes/macrophages, which are most commonly present in the mesangium. Curvilinear bodies, the ultrastructural features of chloroquine toxicity in striated muscle, are not present in renal cells. This report documents differences in appearance, cells affected and morphological differential diagnostic features to distinguish these two entities.

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg.

UNLABELLED: Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg. BACKGROUND: Mutations in the gene for apolipoprotein AII (apoAII) have recently been found to cause hereditary renal amyloidosis. In each case amyloid deposition has been associated with a peptide extension at the carboxyl-terminus of apoAII, the result of mutations in the normal stop codon. METHODS: A Caucasian man who has had progressive renal dysfunction since age of 34 was found to have amyloidosis on renal biopsy at age 56. Echocardiogram showed mild intraventricular septal thickness and technetium-99m (99mTc)-pyrophosphate scintigraphy demonstrated uptake by cardiac muscle consistent with amyloid deposition in the myocardium. His father died of renal failure and his paternal half brother has renal dysfunction. RESULTS: DNA sequencing of the apoAII gene in the proband showed a T to C transition at the first position of the stop codon indicating replacement of the stop codon by l-arginine (Arg) at residue 78. Western analysis of the proband's plasma under reducing conditions using anti-apoAII revealed an extra band at approximately 10 kD in addition to the normal apoAII band at 8 kD. Western analysis of solubilized amyloid fibrils isolated from rectal biopsy tissue contained only the variant apoAII. CONCLUSION: These results indicate that the proband's amyloid fibrils are derived from apoAII and the amyloidogenesis is linked to the peptide extension at the carboxyl-terminus of variant apoAII. Of particular interest is that this novel apoAII variant may cause amyloid cardiomyopathy in addition to renal amyloid.

Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS.

BACKGROUND: Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken. METHODS: Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment. RESULTS: After one year, the delta SDS (standardized height) was +0.49 +/- 0.10 in the treatment group (N = 30) compared to -0.10 +/- 0.08 in the control group (N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups. CONCLUSION: In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events.