Twenty-year follow-up of acquired renal cystic disease.

AIMS: Since 1979 the diseased kidneys of 96 patients on replacement therapy with chronic renal failure due to chronic glomerulonephritis have been followed to investigate the development of acquired cysts and tumors. This is a report of the 20-year follow-up. MATERIALS AND METHODS: Ninety-six patients were followed using periodic CT scan and were divided into hemodialysis, renal transplantation, bilateral nephrectomy and deceased groups during the follow-up. In the hemodialysis group, 36 patients (19 males, 17 females) were followed for 20 years. RESULTS: Kidney volumes which were 57.8 (1.51) (geometric mean (geometric SD)) ml at start of the follow-up had become 185.3 (2.03) ml 20 years later in males, and in females, 57.3 (1.64) ml had become 99.7 (2.36) ml. The increased rate was 3.2 (2.06) fold in males and 1.7 (2.57) fold in females. This enlargement of the kidneys was due to acquired cysts. Kidney volumes at the 20-year follow-up had increased more significantly than those at the 15-year follow-up in males; however, kidney volumes at the 20-year follow-up had not changed in females, if compared with data at the 15-year follow-up. Kidney volumes in males at 20-year follow-up were significantly larger than those in females (p = 0.0232). Males with more than 3.2-fold in kidney volume increase at the 20-year follow-up were under the age of 40 at entry into this study (p = 0.0055), although the correlation between the degree of kidney volume increase and age was not significant (p = 0.0910). Kidney volumes in the transplantation group remained small. There was no new renal cell carcinoma development after 15-year follow-up except for the local recurrence of a previous operated case. Although 7 of 44 patients died during the past 20 years due to malignancy, no patient died of renal cell carcinoma because of early detection and treatment. One patient died of retroperitoneal bleeding, which is a complication of acquired renal cystic disease. CONCLUSION: Male preponderance of acquired cysts was maintained at the 20-year follow-up. There was a tendency for the rate of increase in acquired renal cystic disease to be larger in young males. No one died of renal cell carcinoma, although the incidence of renal cell carcinoma was high.

Involvement of p38 mitogen-activated protein kinase followed by chemokine expression in crescentic glomerulonephritis.

p38 Mitogen-activated protein kinase (MAPK) is involved in the production and signal transduction of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and chemokines in vitro. However, the crucial role of p38 MAPK in the inflammatory processes of crescentic glomerulonephritis in vivo remains to be investigated. We showed a dramatic decrease in IL-1beta-induced phosphorylation of p38 MAPK, not extracellular signal-regulated kinases 1/2 or jun NH2-terminal kinase, in rat cultured mesangial cells by FR167653. We explored the effects of FR167653 as a specific inhibitor of p38 MAPK on renal injury and subsequent renal expression of chemokines in a progressive experimental crescentic glomerulonephritis model in Wistar-Kyoto rats. Rats developed crescentic glomerulonephritis leading to glomerulosclerosis and interstitial fibrosis by 56 days after the administration of nephrotoxic sera. The number of phosphorylated p38 MAPK-positive cells, detected mainly in crescents, correlated well with the percentage of crescents and number of ED-1-positive cells. Phosphorylated p38 MAPK-positive cells were downregulated in glomeruli in rats with the daily subcutaneous administration of FR167653 for 6 days. Concomitantly, renal expression of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1/monocyte chemotactic and activating factor was markedly reduced by day 6. The severity of glomerulosclerosis and interstitial fibrosis significantly decreased by day 56, and renal function was preserved. These results suggest that p38 MAPK phosphorylation is pivotal for crescentic glomerulonephritis, followed by the subsequent expression of renal chemokines. This study provides evidence that regulation of p38 MAPK is a novel appealing therapeutic target for crescentic glomerulonephritis.

Acute glomerulonephritis after human parvovirus B19 infection.

We evaluated clinical and histological characteristics of four adult patients who presented with acute glomerulonephritic syndrome with serological confirmation of recent HPB19 infection. All patients had generalized edema with urinary abnormalities. Body weight gain ranged from 3 to 10 kg. Three of the patients had contact with erythema infectiosum simultaneously with or within 10 days before development of flu-like symptoms. Two patients had an erythematous rash, and one patient had lower-extremity purpura. Joint pain was present in three of the patients. All patients had proteinuria and hematuria. Renal functions were normal except in one patient who had a serum creatinine of 3.2 mg/dL. Three of the patients had hypocomplementemia. All renal biopsy specimens were characterized by glomerular leukocyte infiltration and endothelial cell swelling. Mesangiolysis was seen in three of the patients. C3 was deposited in a coarse granular pattern along the capillary walls in all cases. Electron microscopic examination showed marked expansion of the subendothelial space of glomerular capillaries in all patients. Subendothelial electron-dense deposits were present in all patients. Immunohistochemical analysis using monoclonal anti-HPB19 antibody showed that one of the four patients had positive staining in the glomeruli. DNA extracted from renal biopsy specimens contained HPB19 DNA, as shown by polymerase chain reaction (PCR) analysis in all patients. PCR amplification of the renal DNA generated a 104-bp product, which hybridized to an HPB19-specific probe. No control group subjects contained HPB19 DNA as determined by PCR. This circumstantial evidence indicates that HPB19 infection may be one of the causes of acute glomerulonephritis in normal individuals.

Digital glomerular reconstruction in a patient with a sporadic adult form of glomerulocystic kidney disease.

This study describes a sporadic adult form of glomerulocystic kidney disease in a 52-year-old man. To determine whether the aperture of the proximal tubule was stenosed or obstructed to clarify the pathogenesis of glomerular cyst development, 100 serial sections of the open biopsy specimen were made. Ten glomerular cysts were reconstructed using three-dimensional imaging analysis. Bowman's capsule (glomerular cyst) volume, the volume of glomerular tufts, and the area of the proximal tubular opening were estimated using imaging analysis. The volumes of Bowman's capsule and of glomerular tufts were 0.0098 +/- 0.0039 mm3 (mean +/- SD) (normal: 0.0041 to 0.0083 mm3) and 0.0026 +/- 0.0013 mm3, respectively. The area of the proximal tubular opening was 0.0017 +/- 0.0003 mm2 (normal: 0.0012 to 0.0028 mm2). There was neither obstruction nor stenosis of the opening of the renal tubule in this sporadic adult form of glomerulocystic kidney disease. After 4 years of hemodialysis, the glomerular cysts, as well as the kidneys, enlarged. This study shows that the main cause of glomerular cyst development is not glomerulotubular neck obstruction.

Fifteen-year follow-up of acquired renal cystic disease - a gender difference.

In 1979, 96 patients who had undergone hemodialysis for a mean of 3 years and 4 months were entered into this study. This follow-up study revealed that the bilateral kidney volume significantly increased over 10 years in 33 male patients. Kidneys were found to have enlarged 2.7 times over the 10-year follow-up period. However, in 24 females kidney volume did not change over 10 years. This paper reports further results in 39 dialysis patients (21 males and 18 females) who were followed from the 10th to 15th year. In male patients, mean volume was 196 +/- 218 ml (mean +/- SD) at the 10th year and had significantly increased to 225 +/- 213 ml at the 15th year (p < 0.02). In female patients, mean kidney volume was 78 +/- 51 ml at the 10th year and had increased to 117 +/- 91 ml at the 15th year (p < 0.01). The enlargement in kidney volume during the recent 5 years was 1.26 +/- 0.39-fold in males and 1.43 +/- 0.45-fold in females. These rates did not significantly differ between males and females. During this recent 5-year period, there were no surgical cases due to renal cell carcinoma. Therefore, over the entire patient-time dialysis period, there were 6 renal cell carcinomas in 1,470 patient years. In conclusion, 10- to 15-year follow-up studies of kidney size revealed that the enlargement in the kidney due to acquired cysts persisted in male patients, but the rate of increase slowed after 13.0 years of hemodialysis, while the enlargement in the kidney in female patients became significant at 17.7 years of hemodialysis, revealing the slowly progressive nature of acquired cysts in women.

Rapidly progressive glomerulonephritis concomitant with diabetic nephropathy.

We describe a rare case of a rapidly progressive glomerulonephritis (RPGN) superimposed on diabetic nephropathy. A 68-year-old woman with non-insulin-dependent diabetes mellitus (NIDDM) complicated with diabetic triopathy demonstrated a rapid deterioration of renal function. Her urinary sediment contained many red blood cell (RBC) cells and casts, suggesting an additional renal disease accompanying diabetic nephropathy. Renal biopsy revealed crescent formation in many glomeruli characteristic of the pauci-immune type of RPGN. Steroid pulse therapy transiently halted the deterioration in renal function, but the patient died of pneumonia complicated with methicillin-resistant staphylococcus aureus (MRSA) infection. The unusual findings in diabetic nephropathy indicated the coexistence of primary glomerulonephritis and diabetic glomerulosclerosis in this case.

High incidence of common bile duct dilatation in autosomal dominant polycystic kidney disease patients.

Two autosomal dominant kidney disease (ADPKD) patients with cholecystitis or communicating extrahepatic dilatation of the common bile duct accompanied by tiny common bile duct stones prompted us to examine the incidence of gall stone disease and dilatation of the common bile duct in ADPKD patients. Computed tomography scans were examined retrospectively in 55 ADPKD patients and 55 age-, gender-, and duration of dialysis-matched non-ADPKD patients. The incidence of calcium-containing gall stones found on tomography scans was the same: eight of the 55 ADPKD patients and nine of the 55 non-ADPKD patients. However, common bile duct dilatation, defined as measuring more than 7 mm in diameter at the pancreatic head on CT scans, was found more frequently in the ADPKD patients (22 patients; 40.0%) than in the non-ADPKD patients (5 patients; 9.1%) (P = 0.0002). These results suggest that the high incidence of intrapancreatic common bile duct dilatation in ADPKD is a previously undescribed sign of extracellular matrix remodeling in ADPKD.

[Shortening of life expectancy in patients with membranous nephropathy--based on 20 years follow up study].

It is not certain whether the life expectancy of patients with membranous nephropathy is shorter than that of an age-matched healthy population. Forty-one patients (21 males, 20 females) aged between 16 and 70 years (average age: 33.3 years) were followed for 20 years. The patients were divided into two groups: group I (n = 18), consisting of patients in whom nephrotic syndrome persisted for more than two years or until death, and group II (n = 23), consisting of patients except for group I. The non-survival criteria are death or renal death. Twelve patients (29.3%) died during the study period. Eight patients belonged to group I and 4 to group II. The causes of death in group I patients were end-stage renal failure in 3 cases, ischemic heart disease in 1 case, subarachnoid hemorrhage in 1 case, malignancy in 2 cases, suicide in 1 case, and those in the group II patients were pneumonia, malignancy, cerebral softening, and diabetes mellitus, respectively. Eight patients who died in group I had a significantly longer difference between their actual life span (ALS) and life expectancy (LE) and a significantly smaller ratio of ALS to LE than the patients who died in group II (ALS-LE: -29.9 +/- 4.5 years in group I vs. -9.0 +/- 6.8 years in group II, p < 0.05, ALS x 100/LE: 22.5 +/- 8.0% in group I vs. 80.9 +/- 25.2% in group II, p < 0.05). In group I, the ratio of observed to expected death was 4.76 (95% confidence interval, 2.05 to 9.37) and significantly higher than that of the control population. In group II, however, the ratio was 1.09 (95% confidence interval, 0.30 to 2.80), and the difference from the control population was not statistically significant. These results suggest that longstanding nephrotic syndrome is associated with a shortened life expectancy in patients with membranous nephropathy.

Detection and clinical usefulness of urinary interleukin-6 in the diseases of the kidney and the urinary tract.

Interleukin-6 (IL-6) plays a key role in inflammatory and immune responses in the host. In the present study, the IL-6 activity in urine from patients with various renal diseases was examined to elucidate the pathological and clinical significance of urinary IL-6. In patients with mesangial proliferative glomerulonephritis (mes-PGN) including, IgA nephropathy, the urinary IL-6 activity tended to increase with the progression of mesangial hypercellularity. In four patients with IgA nephropathy, urinary IL-6 activity increased markedly but transiently during episodes of acute exacerbation associated with upper respiratory tract infection. In addition, it was demonstrated that urine from patients with other types of PGN such as poststreptococcal acute glomerulonephritis and membrano-proliferative glomerulonephritis contained large quantities of IL-6. However, the levels of urinary IL-6 activity were almost within the normal range in non-proliferative glomerular diseases such as membranous nephropathy, minimal change nephrotic syndrome and lupus nephritis (WHO class I and V), non-glomerular bleeding and orthostatic proteinuria. It should be noted that a marked increase in urinary IL-6 was often observed in the patients with urinary tract infection. These results indicated that IL-6 in urine might be derived from various types of cells participating in inflammatory reactions not only in the renal parenchyma but also in the urinary tract.

Neurogenic bladder due to peripheral neuropathy and a visual disturbance in an elderly man with systemic lupus erythematosus.

A 63 year old man with central nervous system lupus with a neurogenic bladder and visual disturbance is described. The diagnosis of neurogenic bladder, attributed to peripheral neuropathy, was made on the basis of cystometrography and clinical symptoms. A brain magnetic resonance imaging scan showed gliosis along the cerebral vessels and the optic nerve. This case shows that systemic lupus erythematosus can be accompanied by a peripheral neurogenic bladder and visual disturbance, and that these symptoms may not improve despite the amelioration of other lupus symptoms on treatment with steroids.

Intraglomerular expression of MHC class II and Ki-67 antigens and serum gamma-interferon levels in IgA nephropathy.

In order to clarify intraglomerular cellular activation and cytokine involvement in IgA nephropathy, the glomerular expression of MHC class II antigens (HLA-DR and DQ) and cellular proliferative nuclear antigen (Ki-67), and serum gamma-interferon (gamma-IFN) levels were evaluated in 49 patients with IgA nephropathy. HLA-DR was detected in all but 4 patients in whom glomerular sclerosis was present. HLA-DQ and Ki-67 were observed in 51 and 38% of the patients, respectively. Proteinuria, recent macroscopic hematuria, mesangial proliferation, and extracapillary and endocapillary lesions were more frequent and more severe in HLA-DQ-positive than in HLA-DQ-negative patients. In 10 patients with acute exacerbation, endocapillary lesions and HLA-DQ and Ki-67 expression were present in 70, 80 and 88%, respectively. Serum gamma-IFN levels were high in the patients (2.0 +/- 0.3 U/ml, n = 40), especially during acute exacerbation (3.4 +/- 1.1 U/ml, n = 9). Glomerular HLA-DO and Ki-67 expression correlated with serum gamma-IFN levels (r = 0.73, p less than 0.01 for HLA-DQ; r = 0.75, p less than 0.01 for Ki-67). Renal biopsy specimens taken before and after prednisolone and/or urokinase therapy were available from 4 patients. There was strong reactivity to HLA-DQ in the glomerular tufts of all 4 pretreatment samples. However, HLA-DQ reactivity disappeared after treatment in 3 samples, concomitant with normalization of serum gamma-IFN levels. We conclude that serum gamma-IFN levels are related to glomerular HLA-DQ and Ki-67 expression and acute exacerbation in patients with IgA nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of plasminogen activator inhibitor on nephrotoxic nephritis and its modulation by tumor necrosis factor.

To evaluate the suggested imbalance between coagulation and fibrinolysis in the development of glomerulonephritis, plasminogen activator inhibitor (PAI) activity was studied in the plasma of rats with nephrotoxic nephritis. PAI activity rose within 1 h of the injection of nephrotoxic globulin (NTG), peaked at 2 h and returned to the normal range within 24 h. PAI activity was dependent on the dose of NTG and increased significantly during passage through the kidney. PAI activity was also detected in the culture supernatant from isolated glomeruli with nephrotoxic nephritis. Intracapillary fibrin deposits were formed within 2 h; their numbers increased gradually over 24 h. Tumor necrosis factor (TNF) also induced a progressive increase in PAI activity in normal rats. The injection of TNF to rats with NTG synergistically accelerated both the increase in PAI activity and the prevalence of fibrin deposits. These results suggest that PAI may be released from the glomeruli affected by nephrotoxic nephritis and imply that PAI may play a role in the local coagulation in the capillaries of the nephritic kidneys, although this is probably not the only mechanism which explains the continued formation of the glomerular fibrin deposits.

Cyclosporine A (CyA)-induced decrease of serum gonadotropin levels in a case of Klinefelter's syndrome.

We report a case of Klinefelter's syndrome who developed a decrease of serum gonadotropin levels, particularly LH, after CyA treatment for complicated focal glomerulosclerosis (FGS). A 38-year-old man suffering from general malaise and pretibial edema was diagnosed FGS by renal biopsy in October 1988, and was referred to our hospital for further evaluation and treatment for FGS in December 1988. He was not married, and closer anamnesis revealed that he had had impaired seminal ejaculation from the age of 30. The physical examination showed 37% obesity, scanty body hair, pretibial edema and small bilateral testes (3.0 x 1.5cm). Laboratory findings included marked proteinuria (5.3g/day) and mild renal dysfunction (serum creatinine 1.3mg/dl, glomerular filtration rate 57.2ml/min). Endocrinologically, high basal levels of LH and FSH (133.6mIU/ml and 93.7mIU/ml, respectively) and the hyperresponses of LH and FSH to LH-RH stimulation were found, but the other pituitary hormone levels, thyroid and adrenal status, were in the normal range. In testicular biopsy, nodularly proliferated Leydig cells and no seminal tubules could be seen. The chromosome analysis showed 47,XXY karyotype, which confirmed the diagnosis of Klinefelter's syndrome in this patient. From 9 January 1989, CyA (6mg/Kg.day) was orally administered for 4 weeks in order to treat for FGS. After CyA administration, basal levels of LH and FSH remarkably decreased, particularly LH, and their decrease lasted for at least 6 weeks after cessation of CyA (final levels; LH 28.2mIU/ml, FSH 69.8mIU/ml). On the other hand, serum testosterone level was low normal or slightly under normal, and no apparent changes could be seen during CyA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary glomerular fibrosis: a new nephropathy caused by diffuse intra-glomerular increase in atypical type III collagen fibers.

A 38-year-old Japanese man suffering from nephrotic syndrome and slowly progressive impairment of renal function underwent renal biopsy. Light microscopy revealed diffuse lobular accentuation of glomerular tufts, occupied by homogeneous material which was eosinophilic, lightly stained with periodic acid silver methenamine and deeply with aniline blue. Further examinations using an electron microscope after treatment with phosphotungstic acid revealed that this material exhibited a diffuse increase in fibers having a periodicity of 65 +/- 4 nm (mean +/- SD) like type III collagen fibers and was reactive to the anti-type III collagen monoclonal antibody. In addition, the serum level of procollagen III peptides was markedly elevated to 221 ng/dl (normal range 2-13 ng/dl). However, the fibers were peculiarly curved and frayed as reported in the nail-patella syndrome, but were not observed in the lamina densa of the glomerular basement membrane (GBM) as seen in this syndrome. No family history or physical findings of bony and nail dystrophy, no laboratory data or pathological findings compatible with already described renal diseases including mesangiocapillary glomerulonephritis, light chain disease, immunotactoid nephropathy, amyloidosis, and non-amyloidotic fibrillary glomerulonephritis were observed. These data strongly suggest that the nephropathy is caused by a primary increase in atypical type III collagen fibers in glomeruli (primary glomerular fibrosis), which to our knowledge has not yet been described in the English literature.

A case of diffuse panbronchiolitis (DPB) with benign monoclonal IgA gammopathy and IgA nephropathy with monoclonal IgA deposition.

A case of diffuse panbronchiolitis (DPB), associated with benign monoclonal IgA gammopathy and IgA nephropathy is described. The IgA deposition in the glomeruli of the patient was identified as consisting mainly of the monoclonal IgA having the same idiotype as that of serum monoclonal IgA. Recurrent infections of Hemophilus influenzae and Pseudomonas aeruginosa in the respiratory tract might have enhanced IgA-mediated immunity at the mucosal surface of the bronchiole, and ultimately induced monoclonal IgA gammopathy and IgA nephropathy.

Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1.

We have investigated the effects of LPS, human rTNF (hrTNF) and human rIL-1 beta (hrIL-1 beta) pretreatment on the intensity of antibody-mediated injury in vivo by using a passive model of anti-glomerular basement membrane (GBM) antibody-mediated nephritis in rats. The experiments show that all three pretreatments exacerbate injury in this model whether judged by albuminuria or the prevalence of glomerular capillary thrombi. The effect on albuminuria was dose dependent with all three treatments. The lowest effective dose of LPS was 0.025 microgram while those for hrTNF and hrIL-1 beta were 0.4 microgram and 0.5 microgram, respectively. All three pretreatments also increased the prevalence of glomerular capillary thrombi which were rare in rats injected with anti-GBM antibodies without pretreatment. LPS pretreatment appeared to be more effective in causing glomerular capillary thrombi than hrTNF or hrIL-1 beta and this was reflected in the correlations between albuminuria and the proportion of glomeruli with capillary thrombi. This relation was linear for all three pretreatments but the slope was appreciably greater for rats pretreated with LPS (0.37) when compared with results from rats given either hrTNF (0.22) or hrIL-1 beta (0.29). Pretreatment of nephritic rats with both cytokines increased the slope to 0.42 demonstrating a synergistic effect. The synergism of hrTNF with hrIL-1 beta was also demonstrated by the effective doses needed to induce albuminuria which was evident in rats treated with 0.05 microgram of IL-1 beta and 0.4 microgram of TNF. Neither the cytokines nor LPS caused clinical, morphologic, or biochemical evidence of renal toxicity when given alone in the dose used here but they did cause a transient increase in the number of neutrophils marginated in glomerular capillaries. Pretreatment of rats with LPS or cytokines increased the glomerular neutrophil influx after anti-GBM antibodies by roughly sixfold. Our experiments show that TNF and IL-1 can increase the severity of glomerular injury in nephritis; they may be important in modulating glomerular injury clinically.

[Influence of pregnancy on IgA nephropathy].

In an attempt to clarify the influence of pregnancy on the natural course of IgA nephropathy, the courses of 79 pregnancies occurring in 47 patients with the disease were studied. These resulted in 3 artificial and 10 spontaneous abortions, and two pre-term and 64 full-term deliveries. Fifty four maternity passbooks were analyzed. In 22 pregnancies (40.7%) proteinuria was increased during the third trimester, and in 13 (76.5%) of 17 pregnancies receiving postpartum urinalysis, urinary protein was decreased to the level of the first trimester within one month after delivery. In two of the remaining four patients with a persistent increase in proteinuria, renal biopsy was carried out two months after delivery, revealing focal glomerular sclerotic lesions, in addition to mild mesangial proliferation compatible with IgA nephropathy. These findings indicated that increased urinary protein observed in the two pregnancies might be attributed to a complication of pre-eclamptic focal glomerular sclerosis rather than exacerbation of underlying IgA nephropathy. The glomerular filtration rate (GFR), examined in 27 patients both before and after pregnancy, was decreased in only two patients (7.4%), but these reductions appeared to go with the individual natural course. In 6 (15.0%) of 40 pregnancies, proteinuria was increased within one month after delivery, and one of them was diagnosed both clinically and pathologically as the acute exacerbation of IgA nephropathy. These data suggest that patients with IgA nephropathy might show transient acute exacerbation just after delivery rather than during pregnancy, and that even if such exacerbations occurred, pregnancy might have little influence on the natural course of the disease.