Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

The effect of calcium channel blockers on the progression of renal failure is controversial. In contrast with earlier studies, we recently reported that moderately large doses of verapamil significantly accelerated chronic renal failure in the rat remnant kidney model [1]. Studies reporting beneficial effects of verapamil were characterised by a much lower dose of verapamil and by the start of treatment immediately after renal ablation, which potentially interfered with the initial phase of remnant kidney hypertrophy. We therefore studied the effects of a high, fully antihypertensive oral dose of verapamil (100-150 mg/kg/per day; group Vera high) and a low, haemodynamically almost ineffective dose (10—15 mg/kg per day; group Vera low), on the progression of chronic renal failure in female Wistar rats with 5/6 nephrectomy. The treatment was started no earlier than 5 weeks after renal ablation, and matched groups of 20 animals were followed for 16 weeks thereafter. High-dose verapamil reduced systolic blood pressure to median values of 130—140 mmHg throughout the experimental period, whereas blood pressure in Vera low animals remained elevated at median values of 165-172 mmHg similar to non-treated rats with 172-185 mmHg median systolic blood pressure. Despite control of hypertension, proteinuria increased more rapidly and to more elevated values in the Vera high animals (5.98 ± 0.91 mg/μmol creatinine before death/sacrifice) than in the Vera low and control groups (3.08 ± 0.91 and 3.60 ± 0.71 mg/μmol creatinine, respectively, P < 0.05 vs Vera high), and significantly more animals died during the observation period in the Vera high compared to the control group (6 of 20 vs 1 of 20, P < 0.05). Kidney remnants were larger in the Vera high group, mainly due to tubulointerstitial changes with filling of dilated tubular lumina with proteinaceous casts. Mean glomerular diameter did not differ between groups, and the percentage of glomeruli with segmental or global glomerulosclerosis was notsignificantly increased in the Vera high group. It is concluded that chronic high-dose verapamil therapy in the 5/6 nephrectomy model, albeit effective in controlling hypertension, is deleterious to renal function when remnant hypertrophy has previously been allowed to occur. A low, haemodynamically barely effective, dose of verapamil fails to alter the course of renal failure in this settin

The value of different resistance parameters in distinguishing biopsy-proved dysfunction of renal allografts

The data concerning the value of duplex sonography in diagnosing parenchymatous renal allograft dysfunction are controversial. Most early studies did not take into consideration the many factors influencing resistance parameters. We therefore performed a prospective, biopsy-controlled study with exclusion of all known sources of error regarding resistance parameters. Furthermore we investigated the value of a new resistance parameter, the systolic deceleration percentage. Forty-seven duplex sonographic studies were performed on 43 patients (30 male, 13 female, median age 47 years, range 7-70). Fourteen studies were done on normally functioning grafts (control group) an average of 33 days after transplantation. Thirty-three studies were performed on dysfunctional grafts immediately prior to biopsy. Grafts which had been transplanted more than a year previously or with vascular findings or any other clinical or sonographic pathology probably explaining function deterioration were excluded. In all patients, the resistive index (RI), pulsatility index (PI) and systolic deceleration percentage (DP) were calculated in the main renal artery and in the interlobar artery. Of the 33 grafts with dysfunction, nine had vascular rejection (VR), 11 interstitial rejection (IR), 11 cyclosporin A toxicity (CAT) and two other histologies (OR). The mean RI in normal grafts (NO) was 0.71±0.06 in the main artery and 0.68±0.06 in the interlobar artery, in VR 0.86±0.12 and 0.80±0.18, in IR 0.72±0.05 and 0.70±0.07, in CAT 0.67±0.06 and 0.65±0.07 and in OR 0.64±0.07 and 0.60±0.01. For PI, the values were 1.45±0.23 and 1.41±0.28 (NO), 3.5±2.13 and 2.92±2.16 (VR), 1.55±0.26 and 1.46±0.33 (IR), 1.32±0.25 and 1.27±0.26 (CAT) and 1.30±0.34 and 1.13±0.04 (OR). For DP we calculated 28±5% and 29±6% (NO), 43±14% and 36±6% (VR), 29±9% and 27±9% (IR), 31±8% and 32±7% (CAT ) and 32±4% and 28±3% (OR). The sensitivity/specificity for VR with a cutoff mean+2 SD was 0.44/1 for RI, 0.55/0.97 for PI and 0.33/0.89 for DP. It was concluded that:(1) despite the high selection of our patient group, diagnostic accuracy of duplex sonography for diagnosing parenchymatous function disorder in renal allograft remains insufficient; (2) in vascular rejection only, the resistance parameters differ significantly from the values of normal allografts; (3) the higher the cutoff of resistance parameters, the better the specificity and the worse the sensitivity for diagnosing vascular rejection; (4) of all investigated resistance parameters, the RI is the most practical due to a simple measurement techniqu

Reversible acute renal failure from gross haematuria due to glomerulonephritis: not only in IgA nephropathy and not associated with intratubular obstruction

Seven patients with acute renal failure due to gross haematuria caused by glomerulonephritis are described. Gross haematuria lasting 4-40 days led to acute impairment of renal function of variable severity (peak plasma creatinine 1.3-12 mg/dl) and duration. While partial recovery of renal function occurred in all patients within few days, complete remission was observed only some months later. Three patients had IgA nephropathy (2 the primary form and 1 nephritis secondary to Schönlein-Henoch purpura), two patients had acute postinfectious glomerulonephritis, andtwo others had focal necrotizing (pauci-immune) glomerulonephritis. The glomerular changes seen in renal biopsy were not enough to explain per se the renal function impairment. Tubular changes, however, were severe and consisted of tubular necrosis, erythrocyte casts, erythrocyte phagocytosis by tubular cells, accompanied by interstitial damage (oedema, red-cell extravasation, and inflammatory infiltrates). Study of the renal biopsies by immunofluorescence revealed retrodiffusion of Tamm-Horsfall protein into the glomerular Bowman's space, a sign of obstructed tubular flow in any case. It is concluded that acute renal failure due to gross haematuria in glomerulonephritic patients may not occur only in IgA nephropathy, as reported so far, and is not associated with intratubular obstructio

p53 protein expression but not mdm-2 protein expression is associated with rapid tumor cell proliferation and prognosis in renal cell carcinoma

The clinical course of renal cell carcinoma (RCC) is highly variable. Overexpression of the p53 protein has been suggested as a possible prognostic parameter in RCC. Overexpression of the mdm-2 oncogene product has been shown to interact with the p53 function. To investigate the immunohistochemical overexpression of mdm-2 protein in comparison with that of p53 protein in RCC, 50 nonpapillary pT3 RCCs were immunostained for p53 protein (DO-7) and mdm-2 (1172). Tumor growth fraction (Ki-67 labeling index; MIB-1) was determined by immunohistochemistry. p53 positivity was detected in 16% of tumors. mdm-2 overexpression was seen in 30% of RCCs. There was a significant association between p53 and mdm-2 immunostaining (P=0.0006), suggesting that mdm-2 protein may contribute to p53 protein stabilization in RCC. p53 overexpression was associated with a high Ki-67 LI (P=0.0002), suggesting that p53 overexpression is involved in growth control in RCC. Survival analysis showed that Ki-67 LI (P=0.04) and p53 overexpression were associated with poor prognosis (P=0.0021), whereas mdm-2 overexpression was not related to patient outcome (P=0.73). A Cox regression analysis revealed tumor stage (P<0.001) and p53 overexpression (P<0.05) to be independent prognostic parameters. It is concluded that p53 but not mdm-2 may be of practical relevance in predicting patient prognosis in RC

DNA aberrations in urinary bladder cancer detected by flow cytometry and FISH

Detection of molecular alterations is of potential significance for diagnosis and prognosis in bladder cancer. Fluorescence in situ hybridization (FISH) allows visualization and quantitation of genes and chromosomes on a cell by cell level and can easily be applied to urinary cells. To evaluate the sensitivity of FISH for detection of DNA aberrations in bladder cancer, formalin-fixed tissues of 293 tumors were examined by FISH and flow cytometry (FCM). Centromere probes for the chromosomes X, Y, 1, 7, 9, and 17 were used for FISH analysis. FISH was more sensitive for detection of quantitative DNA aberrations than FCM. An aberration of at least one chromosome was found in 107 of 108 tumors (99%), which were tetraploid, aneuploid, or multiploid, and in 29 of 49 tumors (59%), which were diploid, by FCM. The frequency of FISH aberrations showed greater differences between pTa (47%) and pT1 tumors (85%;P<0.0001) than between stages pT1 and pT2-4 (98%). The marked genetic difference between pTa and pT1 tumors argues against the concept of grouping pTa and pT1 tumors together as "superficial bladder cancer.” The frequency of tumors with chromosomal aberrations detected by FISH increased with the number of chromosomes examined. Aneusomy was seen in 68% of grade 1 tumors examined for ≥4 chromosomes, suggesting that the cytological diagnosis of bladder cancer recurrences could be substantially improved by FIS

Renal Disease in Essential Mixed Cryoglobulinaemia: LONG-TERM FOLLOW-UP OF 44 PATIENTS

The mode of presentation of renal disease in 44 patients with essential mixed cryoglobulinaemia (EMC) was: acute renal failure (two patients), acute nephritic syndrome (six patients), nephrotic syndrome (eight patients), proteinuria and/or haematuria (28 patients). Renal biopsy, performed in 35 patients, showed proliferative lesions in 33, while only minimal glomerular changes were seen in the remaining two. Immunofluorescence studies showed: IgG (85 per cent), IgA (36 per cent), IgM (90 per cent), C3 (90 per cent), Clq (47 per cent), and C4 (33 per cent) deposits, mainly located in subendothelial position. On electron microscopy, crystalloid structure of deposits and monocyte infiltration of capillary loops were the outstanding feature. The survival rate was 75 per cent at 10 years from the onset of clinical symptoms. Thirty-nine patients were followed for three to 146 months (mean 53·8). Twelve patients died, cardiovascular disease and infection being the commonest cause of death. Thirteen patients showed acute renal failure or acute nephritic syndrome: nine recovered completely, whereas the remaining four died during the acute renal episode. Three patients developed chronic renal failure, but only one required chronic dialysis. The ominous significance of renal impairment in EMC should therefore be revaluated. The high prevalence of hypertension (28/44 patients) which was refractory to treatment in six, may be important to the clinical outcom