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Background: The impact of different therapy modalities on the outcome of Immunoglobulin A glomerulonephritis (IgAGN) in individual patient is not clear. We present preliminary results from the sequential application of renin-angiotensin system (RAS) inhibition and corticosteroids to discriminate the individual effect of both therapies., Methods: Regardless of the degree of proteinuria, renal function and histological grading, patients with biopsy-proven IgAGN were treated with a standardized protocol. RAS inhibition was performed for 3 months. Thereafter, immunosuppressive therapy with prednisone (0.5 mg/kg body weight) on alternate days for 6 months was started. The primary endpoint was a maximal reduction of proteinuria (spot urine protein/ creatinine ratio (uPCR)), by RAS inhibition and by the combination of RAS inhibition and steroids., Results: 10 patients were treated according to the protocol. During a median follow-up of 18 months, uPCR decreased from initial 230 mg/mmol (2 g/g) (median, interquartile range (IQR) 146 - 396) to 154 mg/mmol (1.4 g/g) (IQR 88 - 190) at 3 months during the RAS inhibition period (33% reduction, p = 0.01) and further to 31 mg/mmol (0.3 g/g) (IQR 21 - 71) until end of the steroid period at 9 months (80% reduction compared to uPCR at 3 month, p < 0.001). At the last F/U, uPCR (median) remained stable at 41 mg/mmol (0.4 g/g). The estimated glomerular filtration rate was stable during the whole observation period., Conclusions: Sequential RAS inhibition and steroid treatment leads to a continuous decrease in proteinuria, beyond the decrease produced by isolated RAS inhibition. Our data suggest independent effects of both, RAS inhibition and steroids, on the reduction of proteinuria in a small, non selected group of patients with IgAGN. The hypothesis that patients with IgAGN, regardless of the degree of proteinuria, renal function and histological grading, may benefit from combination therapy with maximal RAS inhibition and low dose corticosteroids now has to be confirmed in a randomized study.

Aim: Reactivation of latent BK virus in kidney-transplanted patients results in severe graft dysfunction. The role of retroviruses infecting also latently target cells is not investigated so far in this setting. We determined the presence or induction of retroviruses in sera of immunosuppressed patients with renal allografts at the timepoint of organ rejection or ongoing polyomavirus nephropathy., Patients and Methods: Sera of patients with acute kidney rejection or polyomavirus nephropathy (n=25) and controls (n=8) were tested for reverse transcriptase activity by the ultrasensitive product enhanced reverse transcriptase (PERT) assay. In parallel, kidney biopsies were investigated for histological signs of kidney rejection or polyomavirus nephropathy confirmed by either immunofluorescence or immunohistochemistry., Results: None of the investigated sera, specifically those of patients with ongoing BK virus nephropathy, indicated reverse transcriptase activity., Conclusion: Our results do not support the idea of the induction of known or unknown retroviruses in patients with kidney transplantation, even under highly immunosuppressive therapies.

The coexistence of Fabry's disease, an X-linked hereditary disease, and other renal diseases, has rarely been described in the same patient. Combined Fabry's disease and pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) is hitherto unreported. We present the clinical and pathologic data of two patients with combined Fabry's disease and NCGN. Both patients presented with fevers of unknown origin and progressive renal insufficiency, however, lacked any other pathognomic signs of Fabry's disease such as acroparesthesias, dyshidrosis, and cutaneous angiokeratomas. The possible pathogenic mechanisms and causal relationship between the two disease processes are discussed.

Background: Nonsteroidal anti-inflammatory drugs (NSAID) e.g. aspirin, indomethacin are reported in epidemiological and experimental studies to reduce the risk for colo-rectal cancer and potentially other malignant tumors., Methods: We examined the effect of NSAIDs on tumor prevalence in abusers of mixed analgesics containing aspirin, phenacetine, caffeine or codein. 618 analgesic abusers who were autopsied between 1968-1983 were compared with a control group without evidence of analgesic abuse matched for sex, age and year autopsy was performed., Results and Conclusions: Abusers were found to have an overall risk of 0.40 fold of having developed a malignancy as compared with the controls. Excluding patients with urinary tract tumors which are increased in analgesic abusers the risk was further decreased to 0.28. No statistically significant effect was found for patients with prostate cancer. The results encourage prospective control studies in high risk patients.

Ciclosporine-A (CSA) has been in clinical use as an immunosuppressive drug in transplant recipients for over a decade. Unfortunately, CSA also has major side-effects (including nephrotoxic ones). In an attempt to find safer agents, tacrolimus (TAC) has been introduced recently. Despite major differences in the chemical structure, TAC and CSA seem to have many effects in common. This phenomenon can be explained by the inhibition of the calcineurin pathway characteristic for both drugs. The aim of our brief review was to compare personal observations regarding side-effects encountered under CSA or TAC therapy with data reported previously. We found that the profile of side-effects both under CSA and TAC was nearly identical. In particular, morphologic changes associated with toxic drug effects in the kidney were indistinguishable from one another, i.e. tubular lesions, arteriolopathy, HUS-like changes in glomeruli and vessels. The prevalence of defined nephrotoxic lesions was very similar. Some differences were found regarding the prevalence of clinical side effects. Hypertension, hypertrichosis and gingival hyperplasia were less pronounced in the TAC group and an elevated blood glucose level in the CSA group. We conclude that TAC and CSA are closely related immunosuppressive drugs with regard to adverse effects.

To evaluate the efficacy and safety of long-term ciclosporine A (CSA) treatment in idiopathic nephrotic syndrome, we prospectively followed immunosuppressive therapy in 22 nephrotic adults for a median of 32 months (range 7-91 months) and obtained repeat renal biopsies. CSA induced complete remission in 60.0% and 14.3% of patients with minimal change nephrotic syndrome (MCNS) (n = 7), respectively. In addition, partial remissions were achieved in 20.0% of patients with MCNS and in 42.9% of patients with FSGS. Resolution of proteinuria was strictly CSA-dependent and no sustained remission occurred following withdrawal, thereby requiring long-term treatment in 18 patients. In 10 patients CSA was administered for more than 43 months. During maintenance therapy the antiproteinuric effect of CSA was preserved and renal function as well as blood pressure remained stable in patients with MCNS, whereas renal function deteriorated in two patients with FSGS due to progression of the underlying renal disease. Renal biopsies revealed slight signs of CSA toxicity in four patients. However, in no case loss of renal function was attributable to these lesions. In conclusion, the present data suggest that long-term maintenance treatment of MCNS with CSA is efficacious and safe at least for a period of up to 43 months. In contrast, CSA has some effect on proteinuria in FSGS, but the results are less favorable.

The pathogenesis of ciclosporin (Cs) induced renal vasoconstriction and CS-associated arteriolopathy (CAA) has not been fully explained. CAA affects the part of the afferent arteriole where renin is most abundant, and an effect by Cs on the renin producing smooth muscle cells leading to necrosis has been suggested. Forty transplant biopsies with CAA of different degrees were compared with 10 transplant biopsies from Cs treated patients without CAA, and with 10 "zero-hour" control biopsies (taken from the donor kidney at implantation). Immunoreactivity to renin by the ABC method was recorded in the arterioles. Compared to the control group there was a slight increase in the proportion of renin positive arterioles in the Cs treated group without CAA, but with increasing CAA there was a decrease in the proportion of renin positive arterioles. In the group of arterioles with CAA, we found that with increase in the severity of CAA, there was an increase in renin negative arterioles, indicating a loss of renin containing cells in these arterioles. This suggests that a large proportion of the necrotic cells in CAA has once been renin producing smooth muscle cells. Our findings support the possibility that Cs stimulates renin production, and that the renin producing cells are more sensitive to Cs toxicity.

Our studies on the treatment of psoriasis with cyclosporine A (CSA) have demonstrated efficacy at doses < 5 mg/kg/day. However, the nephrotoxicity of CSA at these low doses is not known and is the focus of this current study. Twenty-nine patients prospectively had pretherapy assessment of renal function including serum creatinine and glomerular filtration rate (GFR). GFR was also measured while receiving CSA as well as posttherapy. These functional studies were compared with renal biopsies taken one month after discontinuing the drug. Pretherapy GFR values were normal in all of our subjects. However, by midstudy GFR values had dropped significantly in many patients. This trend continued so that at the end of the study mean GFR values had decreased by 12% with slightly over one quarter of the patients having reductions in GFR of at least 25%. Renal biopsy findings correlated well with the functional studies in particular the GFR, with those patients having the greatest reduction in GFR showing the most renal scarring. Thus, CSA at doses < 5 mg/kg/day induces variable chronic renal injury which correlates most closely with changes in the GFR.

Podocytes in focal segmental glomerulosclerosis (FSGS) show injury and focal detachment from the glomerular basement membrane (GBM). We studied by immunofluorescence and light microscopy the distribution of components involved in the integrin mediated adhesion of podocytes to the GBM in one case of recurrent idiopathic FSGS which developed in a renal transplant. Two major integrin and actin distribution patterns were observed in podocytes depending on the stage of the disease. Alpha 5 integrin subunit showed a gradual loss in early FSGS and became undetectable in advanced FSGS. Alpha 3 integrin subunit and the beta 3 subunit of the vitronectin receptor lost their polarized expression and could be detected intracellularly in early FSGS, while in advanced stage both integrin subunits were mostly basally polarized. In addition staining for alpha 3 was markedly decreased but enhanced for beta 3. Most of the podocytes in early FSGS showed significant loss of filamentous actin together with a nonpolarized distribution and a transient expression of the HAR/GP90 receptor. An altered matrix composition was also seen corresponding to the newly formed GBM. Based on these results we propose that podocytes loose their adhesive phenotype in early FSGS, which may contribute to the detachment of podocytes from the GBM.

This was an analysis of the renal investigations performed in 248 cyclosporin A (CyA)-treated patients who had recent-onset type I insulin-dependent diabetes mellitus (IDDM) to assess the clinicopathological relationships, risk factors and predictive indices of CyA nephrotoxicity, and renal function observed with different CyA treatment regimens. There were four different protocols, using initial CyA dosages ranging from 7.5 to 10 mg/kg/day, with dose modification according to serum creatinine concentration, which was measured regularly in some patients for up to 9 years after starting treatment. Kidney biopsies were obtained from 125 patients (74 adults and 51 children) who had received only CyA for an average duration of 13 months before biopsy and had no other sources of renal injury at this stage of IDDM. Of these patients, 58% showed normal or minimal changes on biopsy, 26% showed slight abnormalities, and 16% showed medium-grade (grade III nephropathy) abnormalities. Lesion severity was related to the degree of interstitial fibrosis and tubular atrophy which, in turn, was related to the use of high maximum CyA dosages. Patients' age, and excessive CyA dose and blood trough levels were the main risk factors, and serum creatinine increase was the best predictive factor of CyA-induced nephropathy. However, CyA-induced renal dysfunction was essentially reversible on dosage reduction, and morphological changes were not followed by progressive renal insufficiency when CyA doses were low and adjusted according to serum creatinine levels. We conclude that, at present, it is recommended that low-dose CyA in combination with other non-nephrotoxic immunosuppressive strategies be used in patients with IDDM.

An advisory board of nephropathologists with personal experience in the evaluation of biopsies from patients treated with cyclosporin A (CyA) was set up to address the following problems: 1. Definition of CyA nephropathy as seen in patients with autoimmune diseases; 2. Evaluation of the reliability and reproducibility of the diagnostic criteria for the different morphological lesions seen in CyA nephropathy; 3. Classification of the morphological lesions according to their clinical relevance; 4. Estimation of the possible progression of CyA nephropathy with continuous CyA therapy. The most frequent lesions attributable to CyA therapy in patients with autoimmune diseases are tubular atrophy, interstitial fibrosis, and arteriolar hyalinosis. All other lesions are rare. The reproducibility and diagnostic reliability is high for tubular atrophy and interstitial fibrosis, but low for arteriolar lesions even among experienced nephropathologists. The biopsies may be classified according to the severity of tubular atrophy, interstitial fibrosis and arteriolar hyalinosis with regard to their clinical relevance: In group I (within normal limits), CyA therapy can be continued; in group III (moderate-to-severe CyA-related lesions), CyA should be stopped if possible. Among group II biopsies (slight CyA-related abnormalities), no recommendation can be made in the absence of a second biopsy after a further year of CyA therapy. No clear-cut answer can be given concerning the progression of CyA-induced lesions. However, no significant progression has been found in the cases studied to date.

Cyclosporine (CSA)-associated arteriolopathy (CAA) is the second most frequent morphological diagnosis in renal allografts and its final outcome remains unclear. The present study was performed to clarify the morphological outcome of CAA by follow-up histological analysis after stopping CSA. Furthermore, the clinical management of patients showing CAA is discussed. Most of the patients came from our early experience with CSA between 1981-1983 when CSA doses and trough levels were high. Twenty recipients were divided into two groups according to the presence of CAA after stopping CSA: group A (n = 9) showed persistent CAA and group B (n = 11) showed no CAA. The majority of the patients, including five incomplete remission in group A, showed obvious improvement of CAA even if the arterioles were severely affected. Improvement of CAA was noted a few months after stopping CSA or after lower dose CSA therapy. There were no significant differences in CSA blood levels or duration of CSA therapy between the groups. The severity of preexistent CAA was significantly greater in group A. Only two patients who died from malignant tumor showed exacerbation of CAA. Eight patients died and eight grafts were lost, seven due to vascular rejection and one to hemolytic uremic syndrome-like CAA. Poor renal function was also noted in four cases with functioning graft owing to vascular rejection even though the improvement of CAA was evident. The complete regression of CAA and the remodelling of arterioles showing well preserved vascular patency were frequently found after stopping or reducing the dose of CSA.(ABSTRACT TRUNCATED AT 250 WORDS)

The extreme lack of renal grafts for transplantation stimulated us to analyze how strict the selection criteria of kidney donors must be. We investigated therefore if preexisting lesions in renal grafts influence initial and late renal function. 147 zero-hour biopsies of 101 donors (mean age 33, from 6-64 years) were examined. By ligh microscopy 38% of biopsies showed no, 44% showed nonspecific and 18% specific lesions. Nonspecific lesions comprised intimal fibrosis of small arteries in 44%, interstitial fibrosis in 8% and an arteriolar hyalinosis in 29%. Out of 102 immunohistologically examined biopsies 74.5% showed nonspecific IgM/C3 deposits in glomeruli and/or arterioles. An age dependent decrease of normal renal biopsies was found which was most evident in donors older than 40 years. Specific findings consisted of glomerulosclerosis (n = 4), glomerulonephritis (n = 11), intravascular coagulation (n = 10) and eclamptic kidney (n = 1). In case of nonspecific immunohistologic findings and in glomerulonephritis rebiopsies showed that antigen deposits usually disappeared within 4 months. Independent of morphologic findings 82% of transplant recipients had a good initial and late renal function. Since donor age, glomerulosclerosis, glomerulonephritis, intravascular coagulation or eclamptic changes seem not to compromise renal function after transplantation a more liberal choice of donors should be considered.

In 17 consecutive cadaver kidney transplant recipients treated with cyclosporine (CsA) and steroids, the median of antigenic and functional levels of von Willebrand factor (vWF) and factor VIII (FVIII) before transplantation were elevated (vWF:Ag: 206%, vWF:RCof: 202%; FVIII:Ag: 248%, FVIII:C: 224%; normal values 50-150%). Sequential measurements after transplantation and during CsA treatment revealed a transient significant increase of median values with highest amounts of vWF:Ag of 362% (2 p less than 0.0001), FVIII:Ag of 398% (2 p less than 0.001) and FVIII:C of 360% (2 p less than 0.0001) (Friedman test). vWF:RCof did not show statistically significant changes. After 4 months, levels of vWF and FVIII comparable to those obtained before transplantation were observed. In univariate statistical analysis no correlation was found between vWF of FVIII on the one hand and plasma creatinine levels, CsA dose or CsA whole blood through levels on the other hand. However, multivariate statistics revealed to some extent a positive influence of CsA blood levels on vWF:Ag levels. Patients with vascular rejection or chronic CsA nephrotoxicity showed significantly lower levels of vWF:Ag as compared with patients without endothelial cell damage in the kidney (2 p less than 0.05). However, the difference in vWF:Ag levels already existed before transplantation. In contrast to recent reports, plasma vWF levels were not indicative of vascular injury in kidney graft recipients nor was the marked elevation of vWF and FVIII associated with thromboembolic complications ascribed to CsA treatment.

The aim of the present investigation was to localize cyclosporine (CSA) in the rat kidney. The experimental approaches included autoradiography after i.v. injection of 3H-CSA, immunofluorescence after i.v. injection of fluorochrome labeled CSA and immunohistochemistry using the rabbit-alpha-CSA antibody. It was not possible to localize CSA in specific structures of the rat kidney. Finally, immunohistochemistry of human renal tissue gave only an unspecific staining of proximal tubular cells, which was lost when the antibody was absorbed on renal tissue homogenate. In vitro binding of 3H-CSA on renal homogenate indicated only unspecific absorption of the highly lipophilic compound; no specific binding was detected on cytosolic renal fractions. The failure to demonstrate CSA in tubular or arteriolar lesions might have been due to the fact that the affinity of binding is too low for detection, or that CSA does not accumulate within these structures.

Cyclosporine (CSA) caused functional and morphologic renal changes in spontaneously hypertensive rats. The development of hypertensive arterial lesions were accelerated by CSA. Blood pressure was significantly increased especially in young rats. The influence of age of the animals, dose and duration of CSA administration on the development of vascular lesions and blood pressure was investigated.

Morphology, frequency and significance of capillary sclerosis (CS) in the ureter and electron microscopic findings in early papillary necrosis are described. CS of the urinary tract is characterized by a thickening of the basement membrane of capillaries lying just underneath the urothelium. The basement membrane changes can be demonstrated by PAS, Sudan stain and autofluorescence with equal reliability. By electron microscopy the thickened basement membranes exhibit a tree ring like pattern permeated by lipid vacuoles. CS is most often present in the renal pelvis and the ureter and only in particularly severe cases also in the urinary bladder. The most severe CS is found in the proximal and middle third of the ureter. In a prospective autopsy study CS was found in 3.5% of autopsies of adults and in 83% of clinically recognized phenacetin abusers. Since there is no association with other renal or metabolic diseases, CS can be considered as specific for phenacetin abuse. This finding is further substantiated by a significant correlation between the degree of severity of capillary sclerosis and the daily dose of phenacetin in grams. In about half of the patients with known analgesic abuse but without CS, possible causes for the lack of CS can be identified, of which the most important is regression of CS after stopping the abuse. Electron microscopic studies of early papillary necrosis show the same BM changes as in the ureter in peritubular capillaries, loops of Henle and similar BM alterations in the collecting ducts. The morphologic findings in the ureter and in the renal papilla suggest that CS in papillary necrosis are the consequence of a toxic damage of endothelial and in the kidney of endothelial and epithelial cells.

Experiments were conducted on a renovascular model of hypertension to investigate the effect of high blood pressure and CyA nephrotoxicity combined on arteriolar and tubular morphology and renal function. A two kidney, one clip model of Goldblatt hypertension was selected in which were given 20 or 40 mg/kg/d CyA by gastric gavage for 3-4 weeks while receiving isotonic saline as drinking fluid. CyA was found to suppress feeding and drinking and, as a result, lead to volume depletion and weight loss, with a corresponding lowering of blood pressure and renal function and an increase in plasma renin. When CyA and control animals were pair-fed these effects disappeared, except for a modest depression of renal function, unaccompanied by a reduction in urinary concentrating power. Histological damage to the tubules was equally prevalent in both kidneys despite different levels of renal perfusion, suggesting that plasma concentration, rather than toxin delivery, determines tubular damage. The occurrence of arteriolopathy and glomerulosclerosis was infrequent, and if present, it was only found in the unclipped kidney and was not potentiated by CyA. Glomerular prostaglandin synthesis after substrate incubation was suppressed by CyA to an equal extent in both kidneys, clipped and unclipped.

Ninety CSA-treated kidney transplants recipients entered the study. The patients were allocated to three groups based on serum creatinine at 12 months and kidney biopsy findings: control group (serum creatinine less than 177 mumol/l), rejection group (verified by biopsy, serum creatinine greater than 177 mumol/l), nephrotoxicity group (verified by biopsy, serum creatinine greater than 177 mumol/l). Thirty variables were systematically evaluated. The following parameters had a predictive value for the development of chronic CSA-nephrotoxicity: number of CSA-induced episodes of acute deterioration of renal function, CSA trough level (day 0-30, day 31-90), number of unexplained episodes of acute deterioration of renal function, number of nephrotoxic drugs, number of rejection treatments, number of rejection episodes and primary poor renal function. The results indicate that all factors leading to acute renal failure, favor the development of CSA-nephrotoxicity.

Cyclosporine (CSA) nephrotoxicity was investigated in the rat. Morphologically, CSA nephrotoxicity is characterized by the following features: (a) Tubular inclusion bodies (TIB) corresponding to autolysosomes and giant mitochondria; (b) tubular vacuolization (TV) due to dilatation of the endoplasmatic reticulum; (c) tubular microcalcification (TM); and (d) tubular regeneration (TR). The morphologic features are limited to (a and b) or predominate (c and d) in the proximal tubule. CSA tubulopathy as defined above is dose dependent, independent of the route of a drug administration, develops quickly (within a week), is reversible after CSA withdrawal, is more pronounced in male than in female rats and shows no clear cut differences in various rat strains. Body weight shows a dose dependent reduction. The functional changes are usually slight. No significant correlation exists between functional changes and morphologic lesions. The type of CSA nephrotoxicity in the rat is very similar to CSA-tubulopathy in man but associated with less severe functional changes.

We examined whether ultrastructural changes in renal mitochondria associated with Cyclosporine A treatment might reflect underlying alterations in mitochondrial molecular structure. A nonrejected renal transplant removed from a patient treated with Cyclosporine A showed a decreased level of beta subunit antigen of mitochondrial F1-ATPase compared to controls. This decrease was more marked in the medulla than in the cortex (56% vs. 70% of pooled controls). Spontaneously hypertensive rats treated with a high dose of Cyclosporine A showed a similar decrease of beta-subunit antigen in the renal medulla and decreased levels of two subunit antigens of cytochrome c oxidase, but had increased medullary levels of the alpha subunit antigen of the F1-ATPase. Such changes were not detected in a normotensive strain of rats. Our data indicate that Cyclosporine A administration is associated with structural alterations in renal mitochondria at the molecular level, predominantly in the medulla, and that additional renal damage due to ischemia or hypertension may predispose to this cyclosporine effect.

20 biopsies were studied in order to determine whether or not the pathologist is able to predict on morphological grounds the etiology and prognosis of acute renal hypoxic change in renal transplants. We concluded that: 1) Intertubular blood stasis seems to be pathognomonic of peripheral vascular rejection and/or renal artery thrombosis. 2) A focal distribution of acute tubular luminal dilatation suggests peripheral vascular rejection. 3) The finding of lymphatic casts suggests the presence of ureteric obstruction. 4) Linear fluorescent staining of the peripheral glomerular basement membrane appears to be due to leakage of plasma proteins in the presence of endothelial damage. 5) The histological distinction between camouflaged rejection and genuine shock kidney is impossible in a biopsy. 6) The precise cause of acute renal hypoxic change and the prognosis of kidney transplants with this alteration often cannot be determined.

A 6 year old girl is reported who suffered from dermatitis herpetiformis, nephrotic syndrome and celiac disease. HLA typing in our patient disclosed the HLA antigens B8 and DW3, which are known to be frequently associated with nephrotic syndrome, celiac disease and dermatitis herpetiformis. In the literature six cases have been reported of the association of glomerulonephritis and dermatitis herpetiformis. An explanation for the development of different immunological diseases in one patient is offered by the HLA type.

Acute cyclosporine nephrotoxicity is characterized by the dose-dependent reduction of glomerular filtration rate both in patients and experimental animals. Administration of a vasodilator agent such as PGE2 might prevent glomerular vasoconstriction and hence reduce cyclosporine nephrotoxicity. The results of the present investigation in spontaneously hypertensive rats indicate that a synthetic PGE2 prevents cyclosporine nephrotoxicity. Pharmacokinetic studies revealed that CSA plasma peak levels and area under the plasma concentration-time curve were significantly decreased in PGE2 treated rats, indicating reduced bioavailability of oral CSA. Furthermore, the immunosuppressive effect of CSA was completely abolished by concomitant PGE2 administration. In summary, the preventive effect of a synthetic PGE2 analogue on CSA nephrotoxicity in rats is most likely due to a reduced enteral absorption of CSA, resulting in insufficient immunosuppression.

A possible drug interaction between cyclosporine (CyA) and mannitol was tested for in female Wistar rats infused continuously with CyA 10 mg (40-50 mg/kg BW) in 24 ml mannitol 20% daily for 3 to 4 days (group CIM). For comparison, two other groups of rats were infused either with the same amount of CyA in 24 ml NaCl 0.9% (group CINa) or with the same amount of mannitol without CyA (group M). No animal of groups CINa or M, but 6 out of 10 group CIM rats developed severe oligo-anuric acute renal failure (ARF). Histologically massive vacuolisation of proximal tubular epithelia was found in the kidneys of CIM rats with ARF, while CIM rats without ARF showed minor to moderate degrees of vacuolisation. No vacuolisation was seen in groups CINa and M. Moderate amounts of tubular inclusion bodies and microcalcifications were detected in the kidneys of CIM rats without ARF and in those of CINa rats. To elucidate the mechanism of ARF, renal blood flow, creatinine clearance and proximal tubular pressures were measured in the kidneys of another series of CIM rats infused for 48-96 hours with CyA and mannitol. Renal blood flow and proximal tubular pressures in the kidneys of animals that had not or not yet developed ARF did not differ from those in rats infused with mannitol alone despite histological alterations with minor to moderate degrees of vacuolisation.(ABSTRACT TRUNCATED AT 250 WORDS)

The longterm effect of cyclosporine (CyA) on chronic renal failure was studied in female Wistar rats subjected to 4/5 to 5/6 nephrectomy by partial infarction of the left kidney followed by contralateral nephrectomy. CyA was added to a standard rat diet containing 25% protein. Each rat received 14 g of food daily containing 0 (control), 1.2 (group A), 2.4 (group B), or 4.8 (group C) mg CyA. The number of rats that did not survive the whole experimental period of 20 weeks on the CyA containing diets was similar to the control. In the surviving rats no difference between groups could be detected regarding body weight, serum creatinine and creatinine clearance. Proteinuria rose progressively up to 15 weeks in the control group and similarly in groups A and B. Mean proteinuria in group C was about half the control mean at 5-20 weeks. Systolic blood pressure differed little between groups A, B and control, but was significantly lower than control in group C at 10-20 weeks. Histologically groups B and C showed significantly less glomeruli with segmental sclerosis and less hypertensive vasculopathy than groups A and control. Histological signs of tubular CyA toxicity correlated with the doses applied: inclusion bodies were more frequent in all groups while the score of vacuolisation was increased significantly in group C only. In conclusion, CyA appears not to adversely affect or - at moderately toxic dosage - even to slow down progressive glomerular sclerosis in rats with reduced renal mass.

The morphology of kidneys from heart (n = 55) and bone marrow (n = 112) transplant recipients treated either with cyclosporine (CSA) or conventional immunosuppression was investigated at autopsy. The major findings were: In the bone marrow transplant recipients glomerular collapse, tubular atrophy, interstitial fibrosis, striped form, CSA-associated arteriolopathy and thrombi in glomeruli and/or arterioles were more often found in the CSA group as compared to conventional immunosuppression. In the heart transplant recipients glomerular collapse and obsolescence, tubular atrophy and intimal fibrosis in arteries were more frequent in the CSA group. Vascular interstitial toxicity known to be associated with CSA treatment from renal transplant patients was found in 54% (25% severe) of the bone marrow and 19.5% (9.7% severe) of the the heart transplant recipients. The prevalence of vascular interstitial toxicity in bone marrow versus heart transplant recipients is possibly due to higher CSA dosage and pretreatment with cytostatic drugs and irradiation. Analyses of the lesions from early stages to the full picture of vascular interstitial toxicity suggests that CSA causes a form of thrombotic microangiopathy with focal glomerular and/or arteriolar thrombosis followed by typical CSA-associated arteriolopathy which results in interstitial fibrosis with tubular atrophy.

Sixteen adult patients with Schönlein-Henoch nephritis, selected by strict inclusion criteria, were studied retrospectively. At the time of discovery of the nephropathy, 11 patients had normal plasma creatinine and 5 other patients had renal insufficiency. All patients had renal biopsies, which were studied by both light and immunofluorescence microscopy. After a mean follow-up of 90.5 +/- 59.1 months (range 16-261), 3 patients were in chronic dialysis (18.7%), 8 other patients had renal function deterioration (50%), with creatinine clearance ranging from 31 to 60 ml/min. Four other patients had mild urinary abnormalities with normal plasma creatinine (25%) and only 1 patient was in complete clinical remission (6%). No clinical features at onset were predictive for the clinical outcome of the disease, while in the biopsies the percentage of crescents was higher in patients who developed renal insufficiency. High IgA serum levels were correlated (p = 0.0242) with a favorable course. It is concluded that Schönlein-Henoch nephritis of the adult carries a high long-term risk of renal dysfunction.

A nine-year-old girl had several ex novo episodes of acute glomerulonephritis with clinical evidence of rapid progression in two of them. Guillain-Barré syndrome was diagnosed 10 days after the second episode of acute glomerulonephritis. Two renal biopsies (performed at about a four-year interval) gave morphological evidence of new episodes of acute glomerulonephritis. To our knowledge this is the first report of an association between ex novo episodes of acute glomerulonephritis and Guillain-Barré syndrome.

In 3 patients, two 26 and one 29 years of age, a nephropathy was accidentally discovered which progressed to end stage renal failure within 4 to 6 years. Renal biopsy revealed an unusually marked karyomegaly particularly of the tubular epithelium. These cytopathological changes were associated with chronic interstitial nephritis. Biopsies of other organs, i.e. liver, colon, bronchus and lungs indicated in 2 patients a systemic distribution of the karyomegaly, particularly in mesenchymal cells. Neither the chronic interstitial nephritis nor the karyomegaly could be ascribed to a recognized etiology. This suggests, therefore, that there is a relationship between these changes. The karyomegaly could be the result of the action of some antimitotic agent such as chemical toxins or virus infections.

This study was conceived to identify specific morphological characteristics associated with cytomegalovirus (CMV) infection of the kidney. 33 patients with manifest CMV infection at autopsy and 32 biopsies of kidney transplants with active or inactive CMV infection were studied. In 8 patients of the autopsy group a CMV infection of the kidney was detected (CMV cells in 3 cases, positive viral tissue culture in 4 cases, positive in-situ hybridization in one case), which was associated with severe dissemination into different organs. In situ hybridization was not superior to ordinary light microscopy in the detection of CMV cells. The biopsies were screened for the presence of glomerulopathy. No association of glomerulopathy with CMV could be found by light microscopy, whereas a significant correlation of glomerulopathy with vascular rejection was demonstrated. No differences as to the incidence of glomerulopathy were found, when non-transplant patients with manifest CMV infection at autopsy were compared with matched controls. With active infection electron microscopy revealed no osmiophilic deposits, but in immunofluorescence tiny IgG deposits were identified within the glomeruli (p less than 0.01). IgM or C3 deposition in the glomeruli was not specifically associated with either CMV infection or vascular rejection. Thus morphological identification of CMV infection of the kidney is difficult, necessitating the detection of CMV cells, positive viral tissue culture or positive in-situ hybridization. Glomerulopathy in light microscopy is associated with vascular rejection and is therefore termed transplant glomerulitis. Tiny IgG deposits may be indicative of CMV infection, although these are not always present.

The influence of cyclosporine A on renal function was investigated in unilaterally nephrectomized rats subjected to 30 or 45 min of ischemia. Acute i.v. administration of high dose CyA equivalent to 1000 mg/kg/d, did not produce a decrease in glomerular filtration or renal blood flow within 2 hours and its influence on proximal tubular pressure could be attributed to the cremophor vehicle. Chronic oral administration of 20 mg/kg/d CyA after ischemia produced no alteration in renal function after 2 or 9 days, but 40 mg/kg/d CyA lowered renal function demonstrably by 9 days. When pair-fed to eliminate CyA-induced weight loss as a cause of depressed renal function, the loss of renal function after 9 days was smaller but still evident. At this time renal cortical prostaglandin E2 and thromboxane B2 production were also reduced, but plasma renin remained unaltered because of the exclusion of volume depletion through weight loss. These kidneys showed no signs of delayed regeneration from ischemic renal injury but did show signs of tubulotoxicity, which seemed to be more apparent after longer periods of ischemia.

A 32 year old female patient demonstrates the rare combination of a typical IgA nephritis and familial immunothrombocytopenia. Although this association may be purely fortuitous, our observation adds a new facet to a spectrum of reports on (familial) "thromborenal syndromes". The pathogenesis of the IgA nephritis has not yet been clarified. However, since IgA deposits are found relatively frequently in the mesangium in a number of diverse underlying diseases, there might be common etiological factors. In view of this possibility more attention should be directed to the investigation of IgA associated diseases.

The role of cyclosporine (CSA) alone or in combination with various chemotherapeutics in the development of renal toxicity was evaluated in rats. Administration of 20 mg/kg/day CSA for 4 weeks caused renal functional and structural changes similar to those reported in man. The combined administration of CSA and various chemotherapeutic drugs with a nephrotoxic potential, such as gentamicin (at therapeutic doses), amphothericin B and ketoconazole, which are frequently used in immunosuppressed patients, did not aggravate the CSA induced toxicity in the rat model. Gentamicin at toxic doses, however, increased CSA nephrotoxicity. Thus, the nephrotoxicity induced by CSA has a different pathogenetic mechanism.

The influence of Cyclosporine A (CyA) on the development of renal injury in in situ immune complex glomerulonephritis (ICGN) in rats was examined. Left kidneys of male Wistar rats were perfused with cationized human IgG followed by an intravenous injection of rabbit anti-human IgG. CyA was given orally in a dosage of either 2.5, 15 or 25 mg/kg body weight per day in two daily injections. The amount of immune complexes deposited in the left kidney was not affected by CyA application as shown by isotopic studies. There were no differences between the control and CyA groups in respect to immunofluorescence, light and electron microscopy. Proteinuria was significantly inhibited with all treatment schedules, even when rats were first treated five days after inducing nephritis. These results show that CyA inhibits proteinuria without affecting glomerular cell accumulation/proliferation in in situ ICGN, and indicates that cellular activation at glomerular level might be prevented by CyA.