Rajanee Sensirivatana

Tubular function and tubulointerstitial disease

Tubular transport determined by the fractional excretion (FE) of filtered solutes was studied in 129 nephrotic patients; 72 patients with mesangial proliferation (MesP-NS) and intact tubulointerstitium (group 1), 13 patients with MesP-NS and superimposed tubulointerstitial fibrosis (TIF; group 2), 27 patients with mild focal segmental glomerulosclerosis (FSGS; group 3), and 17 patients with severe FSGS (group 4). In the 72 nephrotic patients with MesP-NS and normal tubulointerstitium (no TIF), tubular transport was intact (FE of sodium [FENa], 0.5 +/- 0.5; FE of calcium [FECa], 0.3 +/- 0.3; FE of phosphate [FEPO4], 14 +/- 13; FE of uric acid [FEUA], 9.8 +/- 5; FE of magnesium [FEMg], 1.3 +/- 0.5). In the 13 nephrotic patients with MesP-NS and superimposed TIF (4.9% +/- 2%), there was no difference in FE solutes from those in group 1 except for FEMg (3.3 +/- 0.9; P < 0.001). In the 27 nephrotic patients with mild FSGS (TIF, 28% +/- 9%), four of five variables of FE solutes (FENa, 1.2 +/- 0.7; P < 0.001; FECa, 0.9 +/- 0.8; P < 0.001; FEPO4, 17 +/- 12; P, not significant; FEUA, 16.5 +/- 8; P < 0.001; FEMg, 4. 1 +/-1; P < 0.001) were significantly different from those of patients with MesP-NS without TIF, and two of five variables (FECa, FEMg) were statistically different from those of patients with MesP-NS with TIF. In the severe category of FSGS (TIF, 69% +/-19%), all FE solutes were statistically different from the other groups (FENa, 4.8 +/- 3; FECa, 2 +/- 1; FEPO4, 47 +/- 24; FEUA, 37 +/- 18; FEMg, 12 +/- 6). Thus, the results imply that (1) normal tubular transport reflects an underlying intact tubulointerstitial structure, whereas tubular dysfunction indicates an underlying tubulointerstitial disease, and (2) FEMg is the most sensitive index to detect an early abnormality of tubular structure and function.

PERITUBULAR CAPILLARY FLOW DETERMINES TUBULOINTERSTITIAL DISEASE IN IDIOPATHIC NEPHROTIC SYNDROME

The spatial relationship between renal perfusion and nephronal structure was determined in 51 nephrotic patients consisting of 11 patients with steroid sensitive, minimal change (MC) nephrosis, 12 patients with steroid resistant, mesangial proliferative (MesP) nephrosis and without tubulointerstitial fibrosis (TIF), 11 patients with steroid resistant, MesP nephrosis and with low grade TIF and 17 patients with focal segmental glomerulosclerosis (FSGS). The intrarenal hemodynamic study revealed a unique correlation between renal perfusion and nephronal structure. A normal or slight reduction in peritubular capillary flow observed in MC or mild MesP nephrosis correlates with an intact tubulointerstitial structure. A moderate reduction in peritubular capillary flow observed in steroid resistant, MesP nephrosis induces a low incidence of TIF. A severe reduction in peritubular capillary flow denotes a higher incidence of TIF as that observed in nephrosis with FSGS. Thus, it is of notion that the reduction in renal perfusion precedes the development of tubulointerstitial fibrosis and thereby supports the concept of renal perfusion as a crucial determinant of nephronal structure.

Glomerular Endothelial Dysfunction Determines Disease Progression: A Hypothesis

A glomerular endothelial function with its hemodynamic impact is proposed to determine disease progression. In the clinical settings associated with an intact endothelial function, such as minimal-change steroid-sensitive nephrosis, the early phase of diabetes mellitus and the early stage of an experimental model of renal ablation in animals, it was observed that adequate renal perfusion correlates with the intact structure and function of the nephron with no evidence of disease progression. In contrast, the clinical settings associated with endothelial dysfunction, such as chronic glomerulonephropathy, the late stage of diabetes mellitus and a renal ablation model in animals, are usually associated with a reduction in renal perfusion. The magnitude of renal hypoperfusion observed in all forms of chronic glomerulonephropathies is proportional to the degree of clinical severity. A progressive pattern of renal hypoperfusion is uniquely observed when disease severity progresses. In this context, a new therapeutic maneuver aiming to improve renal perfusion is proposed for treating glomerulonephropathy with disease progression and preventing it from developing to end-stage renal disease.

Renal Dysfunctions in Glomerulonephropathy with Rapidly Declined Renal Failure

Eight patients aged between 5 and 26 years developed rapid deterioration of renal function and became oliguric/anuric with duration ranging from 1 to 21 days. The initial functional assessment revealed severe degree of glomerular, tubular, and vascular dysfunctions. The magnitude of renal dysfunction was quantified and expressed in terms of a clinical score. The degree of glomerular and tubular dysfunctions were inversely proportional to the renal plasma flow and peritubular capillary blood flow (PTCB), respectively. Similar findings have been observed in a variety of severe glomerulonephropathies. In this aspect, it is likely that the reduction of peritubular capillary blood flow and tubulointerstitial disease are interrelated. Further evidence to support the primary role of reduction of PTCB in inducing tubulointerstitial disease is provided by the following: (a) Reduction of PTCB is documented in mesangial proliferative nephrosis with steroid resistance prior to the detection of tubulointerstitial disease. (b) Ischemic insult can induce tubulointerstitial disease in experimental setting of renal artery occlusion in animal, (c) Improved tubular function can be achieved following the increase in PTCB with the enhanced renal perfusion therapy.

Renal Tubular Defect in Nephrotic Syndrome Associated with Focal Segmental Glomerulosclerosis

Prasit Futrakul, Chulalongkorn Medical School Hospital, Rama IV Road, Bangkok 10330 (Thailand) Dear Sir, Table 1. Renal function studies Tubular insult with various degrees of histopathologic expression has consistently been encountered in nephrotic syndrome associated with focal segmental glomerulosclerosis. However, relating evidence supporting tubular functional abnormality was sporadically documented of which its significance is generally underestimated by the clinician [1–3]. In this respect, we have, therefore, observed tubular functional defect attested during 10–12 h fasting in 18 children with clinically steroid-resistant nephrosis and histopathologically proven FSGS. As depicted in table 1, there was a trend of increased urinary excretions of all the solutes above those of the normal control values during active proteinuria. Nevertheless, the differences were statistically significant only in the fractional excretion of phosphate and uric acid. In addition, simultaneous assessments of effective renal plasma flow using 131I-labeled para-aminohippurate and glomerular filtration rate using 99mTc-labeled DTPA during active proteinuria revealed a preponderantly low effective renal plasma flow compared to glomerular filtration rate yielding a high filtration fraction. Therapeutic combination of prednisolone (1–2 mg/ kg/day), dipyridamole (10–15 mg/kg/day), calcium channel blocker (Nifedipine, 1–3 mg/kg/day) and ACE inhibitor (0.5–2 mg/kg/day) had been medicated to all 18 nephrotics with the duration of treatment varying from 6 to 24 months. Interestingly, reassessments of renal functions following the therapeutic trial revealed a regression of enhanced tubular excretion of solute in conjunction with the improvement of renal hemodynamics. Normal FSGS Remission active

Intrarenal hemodynamics in vesicoureteric reflux.

Accessible online at: www.karger.com/journals/nef Dear Sir, A vesicoureteric reflux (VUR), occurring either as primary or secondary, can induce renal parenchymal damage (reflux nephropathy) which may become progressive, eventually leading to end-stage renal disease. The pathogenetic mechanism of such a progressive renal destruction still remains enigmatic, although several pathogenetic triggers, namely the severity of the VUR, the associated urinary tract infections, and the associated kidney-ureter-bladder anomalies, have been previously acclaimed [1–3]. Inasmuch as the renal function deterioration correlates with the severity of the structural kidney damage, the determination of either the renal function (creatinine clearance) or the kidney structure by means of renal biopsy appears to be the mainstay for clinical diagnostic and prognostic guidances. Recently, it has been suggested that there is a correlation between the renal perfusion and the kidney structure in a variety of chronic glomerulonephropathies [4].The renal perfusion deficit correlates with the progression of the renal damage. Therefore, the determination of renal perfusion in VUR would provide an informative issue as to which would be the suitable pathogenetic marker of renal disease progression in reflux nephropathy. In this regard, we performed an intrarenal hemodynamic study in 18 patients diagnosed as having VUR and made interesting observations: The intrarenal hemodynamic assessment performed by a method previously described [5] revealed a preponderant efferent arteriolar constriction which disproportionately increased the glomerular filtration rate. Often the glomerular filtration rate may be well maintained despite the presence of a reduction in renal plasma flow. Such a finding implies that the determination of renal plasma flow would reveal a better functional status than the glomerular filtration rate. The reduction in renal perfusion correlated with the VUR grading and the renal functional deterioration. Multifactorial mechanisms are responsible for such a reduction in renal perfusion. Increased pelvis pressure associated with the reflux itself is likely to induce intraglomerular hypertension which is substantiated by the demonstration of preferential efferent arteriolar constriction and elevated intraglomerular hydrostatic pressure by the intrarenal hemodynamic study. Intrarenal invasion by microorganisms, a so-called ascending type of infection, is generally associated with elevated renal arteriolar resistance [Sutheesophon, unpubl. data]. Therefore, both these mechanisms would be incriminated in the reduction of renal perfusion. Persistent and progressive reduction in renal perfusion would induce chronic ischemic injury to the renal structure. Extension of renal scars and new scar formation are well described in association with renal functional deterioration and progressive renal hypoperfusion. The presence of renal hypoperfusion observed in VUR may be of therapeutic relevance. Inasmuch as there is a correlation between renal hypoperfusion and renal disease progression observed in a variety of chronic glomerulonephropathies, such a correlation is also likely to be applicable to the VUR as well. Therefore, therapy with vasodilator(s) aiming at improving the renal perfusion, which has been implicated in treating chronic glomerulonephropathies, may well be justified in preventing renal disease progression in reflux nephropathy. In this regard, such clinical trials by us as well as others [6] are in progress.

Consultants for the American Journal of Nephrology 1997

Consultants for the American Journal of Nephrology 1997 Abrass, Christine Adler, Sharon Agodoa, Lawrence Akmal, Mohammad Anderson, Sharon Andreucci, Vittorio Avram, Morel Bakris, George Balow, James Bennette, William Boswell, William Breyer, Julia Langman, Craig Levin, Nathan Limb, Victoria Maroni, Bradley Martinez-Maldonado, Manuel Matthew, Weir R. Mitch, William Mushnick, Robert Nissenson, Allan Nolph, Karl Nosrati, Saeid