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Eight cases of congenital mesoblastic nephroma (CMN) were examined. Three CMNs were of the classical (typical) variant, two were cellular (atypical), and three showed a mixed pattern. A panel of nephron segment-specific tubular epithelial markers (the lectins Tetragonolobus purpureas, Phaseolus vulgaris erythroagglutinin, and Arachis hypogaea and antibodies to epithelial membrane antigen, cytokeratin, and Tamm-Horsfall protein) were used to differentiate epithelial structures within the tumor. Antibodies against vimentin, desmin, and muscle-specific actin were used as mesenchymal markers. A monoclonal antibody to the long (embryonic) form of polysialic acid (PSA) on the neural cell adhesion molecule was used as a putative renal oncodevelopmental marker. An antibody to proliferating cell nuclear antigen also was applied, which revealed increased proliferative rate in cellular CMNs. In addition to clearly entrapped native renal tubules, CMNs contain tubular structures with immature, dysplastic epithelium and occasional epithelial cell clusters embedded deep within the tumor. These immature tubules and clusters express distal nephron, including collecting duct markers and, occasionally, vimentin and PSA. We propose that these primitive tubules and epithelial structures may originate from the ureteric bud. An epithelial differentiation of the tumor cells also is possible. In one pure cellular CMN and two mixed CMNs the cellular component showed diffuse staining for PSA. The PSA (neural cell adhesion molecule) expression of the cellular component suggests that CMN may originate from the uninduced nephrogenic mesenchyme.

The post insult administration of vascular decongestants has resulted in attenuation of experimental acute renal failure (ARF) following the introduction of various nephrotoxins including drugs, heavy metals, and endotoxin. In the present study, the dose-dependent effects of a novel methylxanthine, HWA-138, were studied in the glycerol-induced murine model of ARF. Renal function, assessed by serial inulin clearances at 24 and 48 h after glycerol injection, urinary electrolyte excretion rates, and renal morphology, was compared between controls and those given glycerol and single i.v. doses of 0.1, 0.5, 1.0, 5.0, and 10.0 mg/kg of HWA-138, or physiologic saline. Whereas significant renal dysfunction was found in all animal groups given glycerol, the mean inulin clearance values of animals given HWA-138 1 mg/kg closely approximated values found in control rats. There were no changes in renal electrolyte excretion rates in animals given HWA-138 compared with relative natriuresis found in untreated glycerol ARF rat. Although a modest decrease in medullary congestion was associated with rats given 1 mg/kg of HWA-138, there was no obvious structural improvement found with HWA-138. The present data provide further evidence of the potential of methylxanthines in the glycerol-ARF murine model.

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml/min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol-occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.

The cytoplasmic localized Janus tyrosine kinase 3 (Jak3) is activated by multiple cytokines, including IL-2, IL-4, and IL-7, through engagement of the IL-2R common γ-chain. Genetic inactivation of Jak3 is manifested as SCID in humans and mice. These findings have suggested that Jak3 represents a pharmacological target to control certain lymphoid-derived diseases. Using the rat T cell line Nb2-11c, we document that tyrphostin AG-490 blocked in vitro IL-2-induced cell proliferation (IC50 ∼20 μM), Jak3 autophosphorylation, and activation of its key substrates, Stat5a and Stat5b, as measured by tyrosine/serine phosphorylation analysis and DNA-binding experiments. To test the notion that inhibition of Jak3 provides immunosuppressive potential, a 7-day course of i.v. therapy with 5–20 mg/kg AG-490 was used to inhibit rejection of heterotopically transplanted Lewis (RT1l) heart allografts in ACI (RT1a) recipients. In this study, we report that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin. Finally, AG-490 treatment reduced graft infiltration of mononuclear cells and Stat5a/b DNA binding of ex vivo IL-2-stimulated graft infiltrating of mononuclear cells, but failed to affect IL2Rα expression, as judged by RNase protection assays. Thus, inhibition of Jak3 prolongs allograft survival and also potentiates the immunosuppressive effects of cyclosporin A, but not rapamycin.

The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxifylline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p.01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/cytotoxic T-cells (0X8+), in kidneys of rats given either treatment compared with PAN con-trol rats. In summary, both pentoxifylline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role of pentoxifylline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.

In a review of the autopsies and medical records of 22 obese patients, focal segmental glomerulosclerosis (FSGS) was present in seven. The FSGS was mild in all but one patient. The FSGS of obese patients has similar features to idiopathic FSGS; however, our findings suggest that it lacks the hyperplasia of glomerular epithelial cells, shows no predilection for the corticomedullary junction, and is probably more often seen in the hilar region of the glomeruli. FSGS or glomerulomegaly was not associated with the degree of obesity. We demonstrated lipid deposition in the kidney of obese patients. Obese patients with FSGS, compared to those without FSGS, had higher blood cholesterol (P < 0.10) and higher triglyceride levels (P < 0.01). The mean heart weight of obese patients with FSGS was greater than that of patients without FSGS (P < 0.01). Also, obese patients with FSGS had larger glomeruli (246 +/- 33 microns) than obese patients without FSGS (218 +/- 16 microns) (P < 0.05). These findings suggest that cardiomegaly with hemodynamic changes and glomerular hyperfiltration may play a significant role in the glomerulomegaly and FSGS of obese patients. The secondary or contributory role of lipids in the development of the FSGS of obese patients remains to be determined.

A patient with acquired immune deficiency syndrome (AIDS) who presented with right testicular swelling is described. Sonography demonstrated diffuse enlargement and inhomogeneity of the testicle with central hypoechoic areas. Testicular abscesses were seen at surgery and Mycobacterium tuberculosis was cultured from the surgical specimen. Tuberculosis should be considered in the differential diagnosis of testicular enlargement or abscess formation in AIDS.

Of 704 renal transplant recipients receiving long-term cyclosporine immunosuppression, 71 patients experienced proteinuria greater than 1 g/24 hr beyond the first month posttransplant. Eight patients displayed transient proteinuria, defined as lasting less than 3 months. In most cases this condition was attributed to biopsy-proved acute rejection. The transient proteinuria cohort experienced good graft outcome--namely, 87.5% one-year and 52.5% five-year actuarial graft survivals, which was similar to that observed in patients without proteinuria. In contrast, 52.4% of the 63 patients with nontransient proteinuria experienced graft loss within a median time of 6.1 months. The one- and five-year actuarial graft survivals in patients with nontransient proteinuria were 75.3% and 37.5%, respectively. Among the 63 patients with nontransient proteinuria, histopathologic diagnosis included chronic rejection in 19, transplant glomerulopathy in 14, acute rejection in 9, glomerulonephritis (GN) in 7 including 2 cases of membranous GN, and nonspecific interstitial fibrosis in 10 cases. Despite the overall poor prognosis for graft survival among the entire cohort of patients with nontransient proteinuria, the seven with allograft GN maintained prolonged graft function. They showed an 83.3% five-year actuarial graft survival versus 31.2% in patients with other causes of proteinuria (P = 0.043). These results suggest that posttransplant proteinuria in CsA-treated renal transplant recipients arises primarily as a consequence of allograft rejection and portends a poor graft outcome.

Cyclosporine (CsA), a powerful immunosuppressive agent that increases graft survival in renal transplant recipients, is often nephrotoxic. The clinical distinction between acute rejection and CsA nephrotoxicity (NT) is a common challenge in the management of these patients. To seek a histologic distinction between acute rejection and CsA-NT, we reviewed the renal biopsies performed prior to initiation of therapy for rejection or nephrotoxicity in two groups of patients. Group 1 (ten patients) had criteria consistent with acute rejection and responded to steroid pulse therapy. Group 2 (15 patients) was treated for CsA-NT and responded to a decrease in the dose of CsA. We conclude that CsA-NT has no specific histologic features. A prominent interstitial mononuclear cell infiltrate as well as tubulitis are features of acute cellular rejection. These findings do not exclude the possibility that rejection and CsA-NT can co-exist in the same patient.

Effect of exogenous ANP on initial renal function following 24-hour cold preservation. The impact of synthetic atrial natriuretic peptide (sANP) on renal function following cold ischemic injury was studied in a canine autotransplant model. Following a prenephrectomy inulin clearance determination (CIn), the left kidney was excised, flushed with Eurocollins solution, and cold-stored for 24 hours. Immediately following reperfusion and a 10 minute equilibration period, baseline CIn was measured over a 20-minute time interval (Collection Period I). Experimental animals (N = 11) then received 1 mcg/kg s ANP by intravenous bolus followed by a continuous infusion at 0.3 mcg/kg/min for 30 minutes. CIn was measured throughout the infusion (Collection Period II). Normal saline was substituted for sANP in control animals (N = 11). CIn was also measured 24 hours following reimplantation in seven control and seven sANP-treated animals. Autograft inulin clearance increased from 0.32 ± 0.11ml/min during Period I to 2.5 ± 0.6ml/min during sANP infusion (P < 0.01). This increase in CIn associated with ANP infusion was accompanied by increases in urine flow rate (V) (0.15 ± 0.05ml/min to 0.98 ± 0.21ml/min, P < 0.01) and renal blood flow (RBF) measured by electromagnetic flow probe (85 ± 17ml/min to 171 ± 13ml/min, P < 0.05). No significant changes in CIn, V, or RBF occurred in control animals between periods I and II. Although systemic blood pressure declined during sANP infusion, it did not decrease to an extent that compromised peripheral perfusion. CIn determined 24 hours after autograft reimplantation in the ANP-treated animals approximated or exceeded values determined during ANP infusion (Period II). In summary, systemic administration of sANP 30 minutes following reperfusion of canine renal autografts significantly improved immediate renal autograft function following 24 hours of cold preservation. The beneficial impact of sANP on immediate autograft function was sustained 24 hours following administration. These observations suggest that the protective effect of sANP derives from prevention or amelioration of pathophysiologic events initiated at the time of reperfusion.

Three family members, at initial evaluation, had generalized comedonal lesions with histologic changes of acantholysis and dyskeratosis. A total of nine cases of this entity, termed familial dyskeratotic comedones, have been documented in the literature. It appears to have autosomal dominant inheritance and onset in childhood or adolescence. Lesions are asymptomatic except for occasional pruritus or inflammation, and general health is undisturbed. A history of acne vulgaris is seen in four of nine patients and is the only associated skin disease. Treatment with oral isotretinoin produced no improvement in two patients. Electron microscopy revealed changes similar to those seen in Darier's disease.

A patient with membranous glomerulonephritis (MGN) presented with recurrent disease after renal transplantation. The disease on the original and the transplanted kidney was characterized by diffuse su

We describe the early lesion of focal segmental glomerulosclerosis (FSGS) as it appeared in 2 cases of recurrent FSGS with early transplant nephrectomies (approximately 2 months) due to uncontrollable nephrotic syndrome. A quantitative evaluation showed that these lesions were present more often in the glomeruli of the juxtamedullary cortex. Epithelial cell proliferation and detachment and foam cells were seen frequently and were considered the hallmarks of the early lesion of FSGS. Hyaline deposits are secondary late phenomena. We suggest that the glomerular foam cells in FSGS are mesangial in origin.

The renal pelvis of the rat is characterized by extensions called specialized fornices that penetrate into the outer zone of the outer medulla (a type II as classified by Pfeiffer, 1968, 1970). The renal pelvic epithelium, therefore, covers areas of the kidney from the inner medulla, the inner and outer stripe of the outer medulla, and the cortex. The renal pelves of seven rats were studied by transmission and scanning electron microscopy. The transitional epithelium on the nonparenchymal surface of the pelvis was three to four cell layers thick (zone 0–1). This epithelium became thinner where it covered the renal cortex (zone 1–2) or the outer medulla. Although the apical cells of the epithelium retained the asymmetric luminal unit-membrane plaques, the number of cytoplasmic fusiform vesicles decreased as one studied the epithelium progressing over the zones from cortex toward papilla. Scanning electron microscopy demonstrated a small number of surface cells of a different morphology that were characterized by apical microvilli. The number of these microvillous lining cells increased as the epithelium covering the outer (zone 2–3) and inner (zone 3–4) stripe regions of the outer medulla was viewed, until the inner medulla was entirely covered by this cell type. In a reciprocal manner, the cells with the asymmetric apical plaques decreased in numbers and in their morphologic specialization in each successive region. The epithelium surrounding the inner medulla (zone 6–7) was completely devoid of this transitional cell type. Judging from the morphologic characteristics of the epithelia, one could surmise that little exchange of urea, water, and salts would occur with the extrarenal connective tissue or the cortical parenchyma. Recycling of urea might become more important physiologically with the outer stripe parenchyma, and even more so with the increased surfaces of the inner stripe parenchyma that lined the secondary pyramid, as well as with the epithelium lining the inner medulla.

We present a case of granulomatous interstitial nephritis and renal failure after a jejunoileal bypass for obesity. Improvement of the renal function occurred after reversal of the intestinal bypass. The renal biopsy showed an interstitial nephritis, oxalate crystal deposition and several aggregates of multinucleated giant cells related to the crystal material (granulomatous reaction). By ultrastructural and histochemical studies we demonstrated mitochondrial alterations in the tubular epithelial cells, and we suggested the proximal tubule origin of the giant cells. The association of the oxalate crystals with damaged tubules and giant cells suggests that the oxalate crystals are responsible for these alterations. The possibility of an associated immunological process as the cause of the interstitial nephritis cannot be excluded.

Carotid arterial catheters, inserted for repetitive sampling of arterial blood, were associated with frequent renal infarcts in rats. Renal infarcts were not seen with jugular venous catheters alone.

A malignant fibrous histiocytoma (MFH) arising in the lungs of a 51-year-old man was studied by light and electron microscopy. Features observed were identical to those of MFHs which occur in the skin and subcutaneous tissue and less commonly in other deep locations. By light microscopy, a storiform pattern with admixture of fibroblasts and histiocytes, as well as xanthomatous and giant cells, was noted. Undifferentiated tumor cells along with fibroblasts and histiocytes in different degrees of differentiation were identified ultrastructurally. These findings lend support to the concept that MFH is a sarcoma of primitive mesenchymal cell origin. The addition of the lung as another primary site for the development of this tumor is consistent with the view that MFHs may potentially arise in any part of the body.

We present a case of acquired renal cystic disease in a patient with end-stage renal disease (ESRD) secondary to systemic lupus erythematosus who was dialysis dependent for 5 years. Renal hemorrhage and neoplastic transformation of the cyst epithelium are the two major complications of acquired renal cystic disease, and were present in this patient. The full clinical significance of the acquired renal cystic lesion is still unclear, although the possibility of renal tumors and massive renal and retroperitoneal hemorrhage should be considered in the long-term dialysis population.

Storage of glutamyl ribose-5-phosphate was identified at autopsy in the brain and kidney of an 8-year-old male who had presented clinically with progressive renal failure and neurological deterioration. In a renal biopsy during life, glomeruli were focally sclerotic and contained foam cells. By electron microscopy, lysosomal accumulation was present in renal tubular and glomerular epithelial cells, hepatic Kupffer cells, and conjunctival connective tissue cells. Ganglion cells in the brain stem had swollen, PAS-positive cytoplasm with central chromatolysis. The cerebral cortex was atrophic and there was loss of Purkinje cells in the cerebellum. The identification of storage was based on biochemical isolation of the compound from the tissues at autopsy. The enzyme deficiency responsible for the storage has not yet been identified.

Acute oliguric renal failure associated with bacterial pyelonephritis is a rarely recognized clinical entity. We report a woman with an ectopic pregnancy who developed acute renal failure requiring dialytic support. The renal biopsy revealed focal microabscess formation and leukocyte interstitial infiltration compatible with suppurative pyelonephritis. Although her renal function improved gradually with antimicrobial treatment, the process was incomplete and renal dysfunction persisted at a 10-week follow-up, suggesting permanent renal damage.

Hypertension and proteinuria were observed in a 2-year-old child with type IA (von Gierke's) glycogen storage disease (GSD). She had evidence of hyperfiltration and had elevated selective renal vein renins. On renal biopsy, increased mesangial cell matrix and cellularity were observed with focal thickening and irregularity of the basement membrane. This case may be representative of the early renal findings in type IA GSD.

A case of paravertebral extramedullary hematopoiesis in a patient with sickle-cell anemia-beta-thalassemia is reported. Interesting aspects in this case, including the high level of Hb F and large number of nucleated erythrocytes in the peripheral blood, are discussed. Fifty-five cases of intrathoracic extramedullary hematopoiesis have been reported. Most of these cases occurred in patients with thalassemia or hereditary spherocytosis. Extramedullary hematopoiesis should be considered in the differential diagnosis of a posterior mediastinal mass in a patient who has chronic anemia or other syndromes associated with extramedullary hematopoiesis.

Histochemical techniques utilizing Tetragonolobus lotus (proximal tubules), Arachis hypogaea (distal nephron, i.e., distal convoluted tubules and collecting ducts), and antibodies against Tamm-Horsfall protein (thick ascending limbs of Henle) were used to determine the site of origin of renal cysts in five children with autosomal recessive polycystic kidney disease (ARPKD) and three patients with glomerulocystic disease (GCD) presenting in the 1st year of life. The findings support a distal nephron origin for the cysts in the children who had ARPKD, whereas the majority of cysts in the children with GCD were confirmed as having a glomerular origin. Tamm-Horsfall protein was identified in the cysts of both ARPKD and GCD; this finding suggests free communication between some of the cysts with the thick ascending limb of Henle. An unexpected finding was the frequent presence of cysts surrounded by muscle fibers. We suggest that these cysts are of collecting duct origin.

A six-year-old boy presented with a history of seizures, progressive neurologic deterioration, and proteinuria. Physical examination revealed mildly coarse facies, failure to thrive, generalized hypotonia with muscle wasting, and optic atrophy; there was no organomegaly. The family history suggested an X-linked recessive inheritance. The electroencephalogram, electroretinogram, evoked potentials, and computed axial tomography of the brain were abnormal. Urine oligosaccharide chromatography, urine amino acids and organic acids, and results of leukocyte and fibroblast lysosomal-enzyme assays for the known storage diseases were normal; however, conjunctival and renal biopsy specimens contained enlarged lysosomes on electron microscopy. The patient had progressive neurologic deterioration and died of renal failure at eight years of age. A compound identified as glutamyl ribose-5-phosphate was purified from the brain (0.96 mumol per gram, wet weight) and kidney (0.60 mumol per gram, wet weight). This compound is the linkage group in ADP-ribosylation of proteins, an important regulatory process in gene expression and DNA repair. We believe this new disorder represents a glycoproteinosis that results in the cytoplasmic storage of glutamyl ribose-5-phosphate.

The patholophysiologic significance of vascular congestion in the mechanism of ischemic acute renal failure following postocclusive reflow was studied with a novel hemorheologic probe, pentoxifylline. Using the autoperfused rat kidney model, inulin clearances (CIN), urine flow rates (UFR), renal electrolyte excretions, and renal hemodynamic parameters (RVR, RBP, RBF) were compared in saline- and pentoxifylline-treated anesthetized rats prior to and following a 45-min occlusive period. Renal functional and hemodynamic parameters were significantly altered in saline controls. In contrast, postischemia treatment with pentoxifylline was associated with significant recovery in CIN and UFR, and stable RVR, RBF, and RBP. Kidneys treated with saline infusion had pronounced vascular congestion, in contrast to those administered pentoxifylline. Coupled with the absence in medullary hyperemia, the present experiments support the role of vascular congestion in ischemic acute renal failure. Pentoxifylline, administered in pharmacologic doses after the insult, provided benefit during the initiation phase of postischemic acute renal failure. These data strengthen the opinion that ischemic insult results in vascular congestion, and that restoration of blood flow will prevent further deterioration in renal function.

• Renal failure due to mitomycin chemotherapy is a poorly appreciated entity often associated with microangiopathic hemolytic anemia. We describe a 45-year-old man in whom renal failure and anemia developed, without evidence of hemolysis, five months after beginning chemotherapy with mitomycin, fluorouracil, and doxorubicin hydrochloride. A biopsy specimen taken from the patient's kidney showed fibrin thrombi in two of 18 glomeruli and in several small arteries. The patient's condition required institution of maintenance dialysis. Similar reports from the literature are reviewed. (Arch Intern Med1983;143:803-807)