Methods Subjects Twenty-three Japanese inpatients with IgA nephropa-

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1 Original article 13 Relationship of renal histological damage to glomerular hypertension in patients with immunoglobulin A nephropathy Yoshio Konishi a, Masahito Imanishi a, Mikio Okamura b, Katsunobu Yoshioka a, Michiaki Okumura a, Noriyuki Okada a, Shiro Tanaka a, Satoru Fujii a and Genjiro Kimura c Objective Studies of experimental animals show glomerular hypertension to be important in the progression of glomerular disease. We evaluated this connection clinically by examining the relationship between glomerular hemodynamics and histological changes in patients with immunoglobulin (Ig)A nephropathy. Methods The subjects were 23 patients with IgA nephropathy. All patients underwent renal biopsies. Glomerular hemodynamics, in terms of glomerular capillary hydraulic pressure (PGC) and the whole-kidney ultra ltration coef cient, were calculated from the renal clearance, plasma total protein concentration, and pressure±natriuresis relationship. The severity of glomerulosclerosis, tubulointerstitial damage and mesangial matrix expansion was evaluated semiquantitatively. Results PGC ranged from 33±69 mm Hg, and the mean arterial pressure (MAP) from 79±112 mm Hg. Their correlation was not signi cant (r =.29, P =.18). PGC was signi cantly correlated with the glomerulosclerosis score, and also with the score for tubulointerstitial damage (r =.65, P <.1 and r s =.59, P =.7, respectively), but not with the score for mesangial matrix expansion (r =.8, P =.72). MAP was signi cantly correlated only with the score for tubulointerstitial damage (r s =.63, P =.4). In multiple linear regression analysis of the histological changes and hemodynamics, the glomerulosclerosis score and the score for tubulointerstitial damage were correlated with PGC, but not with MAP. Conclusion These clinical results support the speculation that glomerular hypertension is involved in the glomerulosclerosis and tubulointerstitial damage that occurs in IgA nephropathy. J Hypertens 2, 18:13±19 & Lippincott Williams & Wilkins. Journal of Hypertension 2, 18:13±19 Keywords: glomerular hypertension, glomerulosclerosis, immunoglobulin A nephropathy a Department of Internal Medicine, Osaka City General Hospital, Osaka, b First Department of Internal Medicine, Osaka City University, Medical School, Osaka, Japan and c Department of Internal Medicine, Nagoya City University, Medical School, Nagoya, Japan. Correspondence and request for reprints to Dr Masahito Imanishi, Department of Internal Medicine, Osaka City General Hospital, 2±13±22 Miyakojima-Hondori, Miyakojima-ku, Osaka 534±21, Japan. Tel: ; fax: Received 21 June 1999 Revised 23 August 1999 Accepted 5 October 1999 Introduction Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis. The clinical course varies, but usually progresses slowly [1±5]. The main histological changes are glomerulosclerosis, mesangial matrix expansion, mesangial hypercellularity and tubulointerstitial damage; these changes are indicators of the prognosis [2±5]. The mechanism of the initial changes in the glomeruli may be immunological, but how the histological and functional damage progresses is not known. Brenner et al. [6±1] found that abnormalities in glomerular hemodynamics, especially increases in glomerular capillary hydraulic pressure (PGC), are important in the progress of chronic renal disease in rats. In their studies, the micropuncture method was used, but it would be dif cult to investigate glomerular hemodynamics directly by this method in humans. There are no reports of glomerular hemodynamics with assessment of histological changes in glomerulonephritis in human subjects. Recently, however, a method for the clinical assessment of glomerular hemodynamics in terms of the pressure±natriuresis relationship was published [11±13]. In the present study, we used the same method to investigate the relationship between glomerular hemodynamics and histological changes in patients with IgA nephropathy. We wanted to evaluate the importance of glomerular hypertension in the progression of renal histological damage. Methods Subjects Twenty-three Japanese inpatients with IgA nephropa & 2 Lippincott Williams & Wilkins

2 14 Journal of Hypertension 2, Vol 18 No 1 thy were studied at our hospital; the four men and 19 women were aged 2±59 years. Histological diagnosis by renal biopsies was performed for all patients before the study began. Patients with a history of other renal disease or heart disease were excluded. All patients were fully informed before obtaining their written consent, and the study was approved by an institutional ethical committee. Patients' characteristics are shown in Table 1. Protocol Percutaneous renal biopsy was performed for all patients after their hospitalization. After the patients' condition was stabilized after following the biopsy, the study began. The patients were put on a diet with a low salt level (approximately 5 g/day) or an ordinary salt level (approximately 15 g/day) for 1 week at each level, at random order, with no time intervening. The diet contained the same amount of protein (1.2 g/kg of body weight per day) and calories (35 kcal/kg of body weight per day) throughout the study. Compliance to each diet was con rmed by 24-h urine excretion of urea nitrogen. Patients were asked to maintain their usual level of physical activity and to refrain from taking any drugs 1 week before and during the 2 weeks of the study. On each of the last 3 days of the diets, 24-h urine collection was done and the urine was assayed for sodium and total protein. On the last day of each diet, a 24-h record of blood pressure was taken with an automatic monitor by oscillometry (Ambulatory Blood Pressure Monitoring System, A&D Co.; Tokyo, Japan) with measurement each hour. The mean arterial pressure each hour was calculated by addition of one-third of the pulse pressure to the diastolic pressure, and is expressed as the mean. On the last day of each diet, the hematocrit and plasma total protein concentration were measured, and the effective renal plasma ow and glomerular ltration rate (GFR) as creatinine clearance were calculated by the standard clearance technique with para-aminohippurate and endogenous creatinine, respectively, as markers. First, 8 ml of 1% para-aminohippurate was injected as a bolus followed by continuous infusion of this compound at the rate of 1 ml/h. After a 1-min equilibration period, two 3-min urine collections were done. Venous blood for plasma para-aminohippurate Table 1 Characteristics of patients at the start of the study on a diet with approximately 1 g of salt daily Sex (male/female) 4/19 Age (years) Body surface area (m 2 ) Blood urea nitrogen (mg/dl) Serum creatinine (mg/dl).7.1 Plasma total protein (g/dl) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) 74 8 Mean blood pressure (mmhg) 9 8 Values are expressed as means SD. and creatinine assays was sampled at the middle of each 3-min period. The renal clearance, obtained by averaging the two clearance data points, was standardized for a body surface area of 1.73 m 2. Calculation of pressure±natriuresis curves and glomerular hemodynamics The method we used for clinical investigation of glomerular hemodynamics has been described elsewhere [11±13]. Pressure±natriuresis curves [12,14] were plotted for each patient with the urinary sodium excretion rate (UNaV) on the ordinate as a function of mean arterial pressure (MAP) on the abscissa. We calculated one mean UNaV for the last 3 days of each diet. With the assumption of a linear relationship between MAP and UNaV, a pressure±natriuresis curve can be drawn by linkage of two data points obtained when the patient's sodium balance is in a steady state at the end of each of the two diet periods. The linearity of the pressure±natriuresis curves within the range of salt intake from 1±18 g daily has been con rmed [15,16]. The intercept, A, extrapolated to the x-axis of the pressure±natriuresis curve and the slope, B, were calculated. With A and B, UNaV can be expressed as a function of MAP: UNaV ˆ B 3 (MAP A) (1) Assuming that A indicates the critical level of blood pressure below which glomerular ltration ceases, as predicted from Equation 1, and therefore corresponds to the sum of the pressure drop from the heart to glomeruli plus the pressures opposing ltration at the glomeruli, the effective ltration pressure (PF, across the glomerular capillary walls can be estimated as the difference between MAP and A. ÄPF ˆ MAP A (2) ÄPF is the difference between PGC and the sum of pressures against ltration, so in general, PGC can be represented as: PGC ˆ ÄPF PT ÐG (3) where PT is the hydrostatic pressure in Bowman's space, assumed to be 1 mmhg, and ÐG is the mean oncotic pressure within glomerular capillaries, estimated from the mass balance law for plasma protein during glomerular ultra ltration [12,17]. GFR/ÄPF was used as an estimation of the whole-kidney ultra ltration coef cient, K f [12]. The glomerular hemodynamics is described here in terms of PGC and K f. We excluded the two subjects with MAP unchanged or increased on the diet with the low salt level, because in such cases, PGC would be underestimated, and K f

3 Glomerular hypertension in IgA nephropathy Konishi et al. 15 could not be estimated by our method. The subjects excluded here were two patients, both in their twenties. They had very mild histological damage (the least of all of the subjects) and high renin activity in plasma (more than 7. ng/ml per h on the diet with the low salt level). In nine of the 23 patients, we assessed the GFR in another way, by estimation from the fractional renal accumulation of 99 mtc-diethylenetriamine-pentaacetic acid (DTPA), calculated from computed renograms with a gamma camera (GCA 72 A/DI, Toshiba, Nasu, Japan). The assessment was performed at the same time as the renal clearance test for creatinine. Values for PGC and K f with the renal clearance of creatinine taken to be the GFR were signi cantly correlated with those with the calculated clearance of 99 mtc-dtpa taken to be the GFR (r ˆ.99 and r ˆ.98, respectively; both, P,.1). We have con rmed that the renal clearance of creatinine can be used as the GFR in an assessment of renal hemodynamics by our method detailed elsewhere [18]. Histological study Tissue specimens obtained by renal biopsy were xed in phosphate-buffered 4% formaldehyde and embedded in paraf n. Sections, 2±3 ìm thick, were stained with hematoxylin-eosin, periodic acid±schiff (PAS), and PAS-methenamine silver. Tissue specimens of all subjects had 1 or more glomeruli. All specimens were evaluated independently by two investigators who were unaware of the results about glomerular hemodynamics. The severity of glomerulosclerosis, tubulointerstitial damage, and mesangial matrix expansion was evaluated semiquantitatively. The scoring for glomerulosclerosis and mesangial matrix expansion was as described by Raij et al. [19]. This scoring recently has been applied to human disease [2]. Individual glomeruli in biopsy specimens were examined and the severity of the abnormality was graded as the percentage of the glomerulus affected:, no damage; 1, up to 25%; 2, up to 5%; 3, up to 75%; and 4, up to 1%. Injury scores were then calculated by multiplication of this grade of ±4 for individual glomeruli by the percentage of glomeruli with the same degree of injury. The severity of the injury for each tissue specimen was then obtained by the addition of these injury scores. The severity of tubulointerstitial damage for each specimen was scored as the percentage of tubulointerstitial brosis, tubular atrophy, and interstitial in ltrates in the cortex. Statistical analysis Values are expressed as mean SD, except for the urinary excretion of total protein and the whole-kidney ultra ltration coef cient, which are expressed as means (range), because the values were not in a normal distribution. The signi cance of the differences between values during each diet of urinary excretion of sodium, systemic blood pressure and renal function was evaluated by Student's t-test for paired samples. The signi cance of the differences during different diets in urinary excretion of protein was examined with the Wilcoxon test. The correlation coef cients between PGC, MAP, log-transformed K f, the glomerulosclerosis score, and the score for mesangial matrix expansion were obtained by Pearson's correlation. The correlation coef cients between PGC, MAP, log-transformed K f, and scores for the three kinds of histological damage were evaluated for signi cance by the least-squares method. The correlation coef cients between PGC, MAP, and the score for tubulointerstitial damage were obtained by Spearman's rank correlation. Multivariate analysis of the scores for histological damage, PGC, and MAP was done by multiple linear regression analysis. Statistical analysis was done with StatView J. version 4.5 (Abacus Concepts, Inc., Berkeley, California, USA). P,.5 was considered statistically signi cant. Results Urinary excretion of total protein, urinary excretion of sodium, systemic blood pressure, renal function, and glomerular hemodynamics during the two diets are shown in Table 2. Table 2 Urinary excretion of total protein, urinary excretion of sodium, systemic blood pressure, renal function, and glomerular hemodynamics in patients on the diet with an ordinary or low salt level Ordinary salt level Low salt level P-value Urinary excretion of total protein (mg/day) 713 (97, 235) 55 (38, 162),.1 Urinary excretion of sodium (meq/day) ,.1 Systolic blood pressure (mmhg) ,.1 Diastolic blood pressure (mmhg) ,.1 Mean arterial pressure (mmhg) ,.1 Creatinine clearance (ml/min per 1.73 m 2 ) Effective renal plasma ow (ml/min per 1.73 m 2 ) Glomerular capillary hydraulic pressure (mmhg) 45 1 Whole-kidney ultra ltration coef cient (ml/mmhg).43 (.48, 1.476) Values are expressed as mean SD, except for urinary excretion of total protein and the whole-kidney ultra ltration coef cient, given as means followed in parentheses by the range.

4 16 Journal of Hypertension 2, Vol 18 No 1 Figures 1 and 2 show photomicrographs of sections of the biopsy specimens from two patients, one with a high PGC and one with a low PGC; for comparison. PGC was not correlated with MAP (Fig. 3, upper part; r ˆ.29, P ˆ.18, n ˆ 23). K f was not correlated with MAP (Fig. 3, lower part; r ˆ.37, P ˆ.85, n ˆ 23). Figure 4 shows the relationship between hemodynamics and the histological changes. PGC was corre- Fig r.29 P.18 n 23 Fig. 1 4 Photomicrograph of section of biopsy specimen from a patient with high glomerular capillary hydraulic pressure (PGC). PGC was 56 mmhg, Mean arterial pressure was 91 mmhg, glomerulosclerosis score was 28, score for tubulointerstitial damage was 4, and score for mesangial matrix expansion was 4. Periodic acid±schiff stain (3 2). Whole - kidney ultrafiltration coefficient (ml/s per mmhg) r.37 P.85 n Fig. 2 Relationship between glomerular capillary hydraulic pressure (PGC), or the whole-kidney ultra ltration coef cient (K f ) and mean arterial pressure (MAP) in 23 patients with IgA nephropathy. Upper part, correlation between PGC and MAP; lower part, correlation between K f and MAP. Photomicrograph of section of biopsy specimen from a patient whose glomerular capillary hydraulic pressure (PGC) was not high. PGC was 39 mmhg, Mean arterial pressure was 86 mmhg, glomerulosclerosis score was, score for tubulointerstitial damage was 5, and the score for mesangial matrix expansion was 52. Periodic acid±schiff stain (3 2). lated signi cantly with the glomerulosclerosis score, and with the score for tubulointerstitial damage (Fig. 4±1a; r ˆ.65, P,.1 and Fig. 4±1b; r s ˆ.59, P ˆ.7; both n ˆ 23), but not with the score for mesangial matrix expansion (Fig. 4±1c; r ˆ.8, P ˆ.72, n ˆ 23). MAP was correlated signi cantly with the score for tubulointerstitial damage (Fig. 4±2b; r s ˆ.63, P ˆ.4, n ˆ 23), but not with the glomerulosclerosis score or the score for mesangial matrix expansion (Fig. 4±2a; r ˆ.15, P ˆ.5 and Fig. 4±2c; r ˆ.2, P ˆ.36; both n ˆ 23). K f was correlated signi cantly with the glomerulosclerosis score and the score for tubulointerstitial damage (r ˆ.62, P ˆ.15 and r s ˆ ±.62, P ˆ.2; both n ˆ 23), but not with the score for mesangial matrix expansion (r ˆ.53, P ˆ.81, n ˆ 23).

5 Glomerular hypertension in IgA nephropathy Konishi et al. 17 Fig. 4 1(a) r.65, P.1, n 23 1(b) r s.59, P.7, n 23 1(c) r.8, P.72 n Glomerulosclerosis score Score for tubulointerstitial damage Score for mesangial matrix expansion 2(a) r.15, P.5, n 23 2(b) r s.63, P.4 n 23 2(c) r.2, P.36, n Glomerulosclerosis score Score for tubulointerstitial damage Score for mesangial matrix expansion Relationship between glomerular capillary hydraulic pressure (PGC), mean arterial pressure (MAP), and scores for histological damage in 23 patients with IgA nephropathy: 1(a), correlation between PGC and glomerulosclerosis score; 1(b), correlation between PGC and score for tubulointerstitial damage; 1(a), correlation between PGC and score for mesangial matrix expansion; 2(a), correlation between MAP and glomerulosclerosis score; 2(b), correlation between MAP and score for tubulointerstitial damage; 2(c), correlation between MAP and score for mesangial matrix expansion. Multiple linear regression analysis of the histological changes and the hemodynamics is shown in Table 3. The glomerulosclerosis score and the score for tubulointerstitial damage was correlated with PGC, but not with MAP. Discussion Our results showed that in IgA nephropathy, PGC was higher in patients with more severe glomerulosclerosis and tubulointerstitial damage than in patients with Table 3 Multiple linear regression analysis of the scores for histological change, glomerular capillary pressure (PGC), and mean arterial pressure (MAP) Standardized regression coef cient PGC (P ) MAP (P ) Glomerulosclerosis score.67 (.1).43 (.81) Score for tubulointerstitial damage.51 (.45).39 (.24) Score for mesangial matrix expansion.15 (.51).24 (.29) Values are presented as score (P). milder changes. MAP was not correlated with PGC or two of three indices of histological change. The method we used for clinical investigation of glomerular hemodynamics was reported earlier and later re-examined carefully [11±13]. This approach to the calculation of glomerular hemodynamics has been validated by results with GoÂmez's formulae in patients with essential hypertension [12] and by those obtained by the direct micropuncture method in ve-sixths nephrectomized rats [13]. With intact normal kidneys, however, PGC may be underestimated. The estimation is based on the pressure±natriuresis relationship, and the systemic pressure does not increase much (it sometimes decreases) in subjects with healthy kidneys and normotension when sodium intake is increased. However, we studied patients who had some kidney damage. With kidneys that are not normal, systemic pressure increases with an increase in sodium intake, and the increase in pressure is proportional to the renal damage. In patients with renal disease, the PGC is

6 18 Journal of Hypertension 2, Vol 18 No 1 unlikely to be underestimated. However, in a few of the patients with little histological damage and high renin activity in plasma but with normotension (less than 12/75 mmhg, MAP 9 mmhg), MAP decreased by only 1±2 mmhg on the high-salt diet. The decrease may be caused by suppression of renin release when salt intake increased suddenly. In such patients, PGC will be underestimated by our method, as mentioned above, because the slope of the pressure±natriuresis curve is negative. Thus, we excluded two such patients from the study. In this method, K f need not be assumed to be constant, as must be the case in Go mez's formulae. This difference makes possible the estimation and comparison of K f in patients with different degrees of renal injury. By the same method, glomerular hemodynamics have been investigated in patients with essential or secondary hypertension, or with diabetic nephropathy [21±24]. In this study, renal clearance of creatinine was taken as the GFR. The values for renal clearance of inulin, iothalamate, and 99 mtc-dtpa re ect GFR more accurately than the value for creatinine. However, in Japan, it is dif cult to use inulin or iothalamate clinically, and 99 mtc-dtpa is expensive. When a measurement can be performed only once or twice, there is some doubt about any measurement error, although GFR is re- ected accurately. In contrast, the measurement of creatinine clearance is easy and repeatable. We checked the reproducibility of the results obtained on the last day of each diet by the measurement of 24-h clearance of creatinine on the last 3 days of each diet (data not shown). In addition, we found that the creatinine clearance could be used to express the GFR in the assessment of glomerular hemodynamics [18]. In actual clinical use, the creatinine clearance can be taken as the GFR in the assessment of renal hemodynamics estimated from the pressure±natriuresis relationship. In models of glomerular disease in experimental animals, the increase in PGC is one cause of the progression of renal structural injury and dysfunction [6± 1,25±28]. On the other hand, according to studies in humans, the degree of glomerulosclerosis and of tubulointerstitial brosis is a predictor for the prognosis of IgA nephropathy, but the degree of mesangial matrix expansion may not be [2±5]. There are no clinical investigations with respect to changes in the glomerular hemodynamics with histological change in patients with glomerulonephritis since it would be dif cult to assess glomerular hemodynamics directly. The importance of PGC in the progression of glomerulonephritis has been supported by studies showing that inhibitors of angiotensin converting enzyme attenuate the deterioration of renal function [29,3]. Results from our study indicate that, in patients with IgA nephropathy, glomerular hypertension may participate in the progression of the nephropathy (glomerulosclerosis and tubulointerstitial damage). Of course, in IgA nephropathy, the mechanism of initial glomerular damage may involve immunological abnormalities: immune complexes are deposited on the mesangial matrix and cause renal structural injury [31,32]. The severity of mesangial matrix expansion is proportional to the immune response. When renal structural injury has increased and the number of healthy nephrons has decreased after the initial glomerular damage, PGC seems to increase enough to maintain glomerular ultra ltration. The increase in PGC (glomerular hypertension) may contribute to the progression of glomerulosclerosis and tubulointerstitial damage. MAP was not correlated with PGC, or with two of three indices of histological change. In multiple linear regression analysis, the scores for histological damage were not correlated with MAP. K f was not correlated with MAP. One explanation for a lack of signi cant correlation may be that there were only a few subjects with systemic hypertension (14/9 mmhg or more on the diet with an ordinary salt level) in our study. Our results showed that PGC, more than the systemic blood pressure, is important in the progression of nephropathy. There were several patients with systemic blood pressure of 13/85 mmhg or less although their PGC was high. This pattern of ndings seems to be compatible with the ndings of glomerular hypertension without systemic hypertension in experimental animal models with nephritis or after uninephrectomy [24± 26,33]. Clinical examination of glomerular hemodynamics should be done to assess chronic renal disease even when the systemic blood pressure is not high. In conclusion, we found clinically that glomerular hypertension is correlated with the progression of glomerulosclerosis and tubulointerstitial damage in IgA nephropathy, and that PGC, more than the systemic blood pressure, seems to be important in the progression of the disease. Acknowledgements This study was presented in part at the 31st Annual Meeting of the American Society of Nephrology, Philadelphia, Pennsylvania, We thank Ms Caroline Latta for reading the manuscript. References 1 D'Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 1987; 64:77± Nicholls KM, Fairley KF, Dowling JP, Kincaid-Smith P. The clinical course of mesangial IgA associated nephropathy in adults. Q J Med 1984; 53:227± D'Amico G, Minetti L, Ponticelli C, Fellin G, Ferrario F, Barbiano di

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