ACE gene sequence and nucleotide variants in IgA nephropathy.

INTRODUCTION: Association studies with single nucleotide polymorphisms (SNPs) have been contradictory. Haplotypes may be more helpful. With gene sequencing, all SNPs can be found for construction of haplotypes. METHODS: The ACE gene was sequenced in four healthy Chinese subjects and 20 patients with IgA nephropathy (IgAN) to observe if differences exist among SNPs and haplotypes. 20 patients on angiotensin 1-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) therapy were then compared with another 20 patients not treated with ACEI /ATRA to determine their renal outcome in response to ACEI/ATRA therapy and whether their genetic profile of ACE gene could play a role in determining their outcome to ACEI /ATRA therapy and progression to end-stage renal failure (ESRF). RESULTS: IgAN patients had 53 variants, of which 17 were unique, whereas normal subjects had 38 variants, of which two were unique (p less than 0.005). No unique variant was a significant risk factor for IgAN. Significant genotype and allele frequency differences in five variants were observed between IgAN patients with renal impairment and those with ESRF (p less than 0.02). CONCLUSION: Our data suggests that at least in the ACE gene, haplotyping SNPs within a single gene seems to have no added advantage over genotyping the individual component SNPs. The D allele and haplotype 3 confer an adverse prognosis, while the I allele and haplotype 5 appear to be renoprotective. The data suggests that genotypes of the ACE gene are linked to certain haplotypes, which could influence IgAN patients' response to ACEI/ATRA therapy.

Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary protein in acute kidney injury.

Recent experimental and clinical studies have shown the importance of urinary proteomics in acute kidney injury (AKI). We analyzed the protein in urine of patients with clinical AKI using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) for its diagnostic value, and followed them up for 40 months to evaluate prognosis. Urine from 31 consecutive cases of AKI was analyzed with SDS-PAGE to determine the low, middle and high molecular weight proteins. Fractional excretion of sodium (FENa) was estimated from serum and urine creatinine and sodium (Na). The cases were followed-up for 40 months from the end of the recruitment of study cases. Glomerular protein was higher in the hematuria group when compared with the non-hematuria group (P <0.04) and in the AKI group than in the acute on chronic renal failure (AKI-on-CRF) group (P <0.002). Tubular protein was higher in the AKI-on-CRF group (P <0.003) than in the AKI group. Tubular protein correlated with FENa in groups with diabetes mellitus (DM), AKI-on-CRF, and without hematuria (P <0.03, P <0.02 and P <0.004, respectively). Pattern of protein did not differ between groups with and without DM and clinical acute tubular necrosis (ATN). At the end of 40 months follow-up, category with predominantly glomerular protein progressed to chronic renal failure (CRF) or end-stage renal failure in higher proportion (P <0.05). In clinical AKI, we observed that glomerular protein dominated in cases with glomerular insult, as indicated by hematuria. Tubular protein was common in the study cases with CRF, DM and cases without hematuria. This indicates tubulo-interstitial injury for AKI in these cases. Patients with predominantly glomerular protein had an adverse outcome.

Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study.

BACKGROUND: Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long-term impact of transplant proteinuria patterns on allograft function and survival. METHODS: We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. RESULTS: Group with predominantly glomerular (middle- and high-molecular-weight with or without low-molecular-weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low-molecular-weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7-7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9-12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5-4.5). CONCLUSION: Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.

The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades.

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.

Beneficial effects of high-dose losartan in IgA nephritis.

AIM: Several short-term studies have reported the efficacy of high-dose ARB in reducing proteinuria in patients with diabetic nephropathy. The benefits of long-term high-dose ARB losartan in IgA nephritis have not been explored. METHOD: This was a 6-year randomized trial in 207 patients with IgA nephritis comparing high-dose ARB (losartan 200 mg/day) with normal dose ARB (losartan 100 mg/day), normal dose ACEI (20 mg/day) and low-dose ACEI (10 mg/day). Multivariate ANOVA was used to test the effect of drug treatment on both eGFR and total urinary protein (TUP). RESULTS: Comparing patients on high-dose ARB (n = 63) with those on normal dose ARB (n = 43), normal dose ACEI (n = 61) and low-dose ACEI (n = 40), patients on high Dose ARB had significantly higher eGFR (p < 0.0005) and lower proteinuria (p < 0.005) at the end of the study. The loss in eGFR was 0.7 ml/min/year for high-dose ARB compared to 3.2 - 3.5 ml/ min/year for the other 3 groups (p = 0.0005). There were more patients on high-dose ARB with improvement in eGFR compared to other 3 groups (p < 0.001). CONCLUSION: Data from this study suggest that high-dose ARB therapy is more efficacious in reducing proteinuria and preserving renal function when compared with normal dose ARB and ACEI. In Year 5, patients on high-dose ARB had a gain in eGFR suggesting that there is possibility of recovery of renal function in these patients on long-term high-dose therapy.

Physician leadership.

Doctors, because of the nature of their training and their profession, have to be leaders. Subsequently, when they specialise, leadership qualities are even more important if they are to be effective in leading the specialty team. It is common knowledge that doctors have become leaders in various sectors of society. One of the fundamental advantages a doctor has over others in leadership positions is his basic training in studying and understanding human nature. With years of practice and experience, the doctor, a student of human nature, has a good grasp of human behaviour which enables him to become a better leader. The six universal and timeless characteristics of great leaders are: ability to share a vision, surrounding oneself with great people, ability to coach other team members, ability to focus on perfection, developing emotional intelligence and ability to train effective leaders. I would like to see three essential qualities in a strong leader: ability to secure an "envisioned future", ability to sacrifice in order to cultivate loyalty, and courage to do the right thing and protect his people. An effective leader positions himself in a situation to ensure survival. Having secured the leadership position, one must take certain steps to strengthen one's leadership so that it will survive. Six strategies from the Art of War by Sun Tzu which are of great practical value are: walk the ground, have trusted lieutenants, information gathering, confuse the enemy, win most while doing nothing, and that which is too good will not last forever. Sometimes we have to change in order to survive. We need to get rid of outmoded practices and shed old burdens to take advantage of the present. The task of exiting from leadership is facilitated if one has groomed a successor. The longer one is in a leadership position, the more difficult it is for one to step down. Some organisations retain old leaders as advisors or mentors. They should be just seen and not heard and go about their work quietly, contributing to the department. A retired leader should be able to command respect from his peers and preserve his dignity.

Long term outcome of renal allografts in patients with immunoglobulin A nephropathy.

Recurrent glomerular disease is an important cause of late allograft loss in renal transplant recipients. Immunoglobulin A nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD) worldwide and its recurrence has been reported in allografts. The present study examined outcomes following renal transplantation (RTX) in 101 patients with ESRD due to biopsy-proven IgAN, in comparison to non-IgA patients, and evaluated the incidence of recurrence. The study population (mean age 34.8 +/- 7.7 years; males 62.2%; Chinese 88.3%) underwent RTX under CsA immunosuppression between November 1984 and December 2004; as two patients underwent retransplantation during the study period, 103 allografts (56.3% cadaveric) were included for retrospective analysis. At time of analysis on 1 January 2005, 78 (75.7%) renal allografts (IgAN RTX) were functioning, of which 51 (49.5%) had normal serum creatinine, 27 (26.2%) had chronic allograft dysfunction, while 25 had graft losses, either due to patient death with functioning grafts (5.8%) or withdrawal to dialysis (18.5%). Persistent microscopic haematuria, not attributable to other causes or proteinuria > 1 g/day occurred in 42.7% and 13.6% of allografts respectively. Of 29 allografts biopsied for evaluation of proteinuria and/or renal dysfunction post-RTX, 8 (27.6%) had IgAN (overall histological recurrence, 7.8%). Of these, three had graft loss due to recurrent IgAN, three had elevated serum creatinine, while two had normal serum creatinine. Overall five and ten year patient survivals for IgAN RTX were 95.3% and 82.2%, and five and ten year actuarial graft survivals were 82.3% and 67.8% respectively. Five and ten year patient and graft survivals for IgAN RTX were not significantly different from that for non-IgAN RTX. In summary, RTX patients with IgAN have a low incidence of documented histological recurrence and recurrence contributing to graft loss occurs in only 2.9%. These results suggest that RTX is an excellent modality of renal replacement therapy in this population.

ATRA therapy restores normal renal function and renal reserve and prevents renal failure.

This article presents clinical data which suggest that the current dosage of losartan 50 to 100 mg/day may not be the optimum in many cases, especially if used as monotherapy in the treatment of proteinuria and we may have to increase to 200 mg/day. However, about 30% of patients cannot take angiotensin-converting enzyme inhibitor (ACEI) because of the side effect of cough. To potentiate the anti-proteinuric effect of losartan, especially for patients who do not adhere to a low salt diet, a 12.5-mg dose of hydro-chlorothiazide may further decrease proteinuria. The main message of this article is that we would have to, in many instances, increase the dose of losartan to a minimum of 100 mg/day or 100 mg twice a day for some patients for optimal therapy. The second message is to monitor the creatinine clearance test (CCT) and to start therapy when CCT is reduced and not wait for serum creatinine to rise to abnormal levels (renal impairment) before starting therapy. The first group involves half a dozen patients with hypertension but no proteinuria. Therapy with losartan is shown to improve the renal function. This data suggest that losartan, apart from its use in reduction of proteinuria, can be used in patients with mild renal impairment without proteinuria to reverse the mild renal impairment and preserve renal function. The second group deals with 3 patients with low creatinine clearance. After a followup period of an average of 3 years, they all developed renal impairment. In another 6 patients, the data suggest that we should perhaps treat patients with low CCT as soon as possible and with dose ranging from 100 to 200 mg/day if necessary, to derive maximum beneficial effect. The third group highlights 5 patients with high CCT due to glomerular hyperfiltration. With time, the high CCT decreases and renal impairment sets in. The data suggest that patients with high CCT should be treated early to prevent renal impairment. The fourth group illustrates 6 patients where their proteinuria was markedly reduced with the increase of losartan from 100 mg/day to 200 mg/day, suggesting that losartan 200 mg/day is probably the optimum dose. In conclusion, apart from its traditional usage in reduction of proteinuria to retard progression to renal failure, the data suggest that losartan is also indicated in patients with renal impairment in the absence of proteinuria; patients with low CCT, patients with high CCT and patients who do not respond to a dosage of 100 mg/day should have the dosage increased to 100 mg twice daily to increase efficacy of losartan. It is hoped that with these new and earlier indications as well as increased dosage of losartan starting with 100 mg, whenever possible, and increasing to 200 mg/day, if there is no response, we can prevent more patients from developing renal failure. Based on these observations, further randomised controlled trials should be designed to address these issues.

MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report.

BACKGROUND/METHODS: Molecular Adsorbent Recirculating System (MARS) was used in three consecutive critically ill patients at the Singapore General Hospital with advanced malignancy and acute liver failure (ALF). Case 1 was a male patient with hepatocellular carcinoma (HCC) for which initial right hepatectomy was followed by left hepatectomy 5 months later for recurrent HCC. The postoperative course following second surgery was complicated by severe methicillin-resistant Staphylococcus aureus (MRSA) sepsis, mild azotaemia and subacute cholestatic liver failure. MARS was used thrice in this patient. Case 2 was a female patient with advanced acute lymphoblastic leukaemia (ALL) with post bone marrow transplantation (BMT) acute haemolytic-uraemic syndrome (HUS) secondary to cyclosporin A (Cy A), cytomegalovirus (CMV) infection, severe nosocomial pneumonia, acute renal failure (ARF) treated with continuous haemofiltration and acute veno-occlusive disease resulting in Budd-Chiari syndrome. The latter precipitated ALF. MARS was instituted twice. Case 3 was a male patient with advanced, refractory Hodgkin's disease previously treated with multiple courses of chemotherapy. ALF developed secondary to acute viral hepatitis B flare. He was given a trial of MARS once in the ICU. All the three patients eventually died. RESULTS: Mean MARS intradialytic systemic pressures were as follows: systolic pressure range was 95 +/- 17 to 128 +/- 17 mmHg and diastolic pressure range was 51 +/- 5 to 67 +/- 7 mmHg. Pressure at albumin dialysate exit point from dialyser 1 (Ae) ranged from 253 +/- 11 to 339 +/- 15 mmHg and that at albumin dialysate entry point into dialyser 1 (Aa) ranged from 142 +/- 11 to 210 +/- 6 mmHg. Ultrafiltration (UF) was 633 +/- 622 mL over mean treatment duration of 6.3 +/- 0.9 h with a total heparin dose of 1583 +/- 817 IU. Coagulation status pre- and 6-h post-MARS was similar: aPTT (P=0.116) and platelet count (P=0.753). There were no bleeding complications or circuit thromboses. MARS had a significant de-uraemization effect (pre- and post-MARS serum creatinine and urea: P=0.046 and 0.028, respectively) but did not significantly attenuate blood lactate, ammonia or total bilirubin levels. Albumin dialysate (Ae - Aa) urea and creatinine concentrations appeared to be sharply attenuated after 6 h of MARS. In contrast, the removal of total bilirubin by albumin dialysate from the blood compartment appeared to plateau after 4 h of continuous MARS operation. CONCLUSIONS: MARS was well-tolerated in critically ill patients with advanced and complicated cancer. Low-dose heparin was safe and did not compromise MARS circuit integrity. Although MARS had a significant de-uraemization effect, this appeared to be limited by the duration of MARS operation. Our data suggested that such a limit was reached earlier for total bilirubin. More data are needed to confirm the present findings and further delineate the saturation limit of MARS for different toxins that accumulate in ALF. This would affect the optimal duration of MARS therapy.

ACE gene polymorphism and disease progression of IgA nephropathy in Asians in Singapore.

The deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been considered as a risk factor for IgA nephropathy and for its progression to end-stage renal failure. However, results from various studies are conflicting. We had genotyped the ACE gene in 100 patients with IgA nephropathy, 32 of whom were in end-stage renal failure and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second PCR, performed with the insert-specific forward primer. Similar genotype frequencies were obtained for the 90 normal control subjects (II: 47%, ID: 44%, DD: 9%); for the 68 patients not in end-stage renal failure (ESRF) (II: 47%, ID: 46%, DD: 7%) and for the 32 patients with ESRF (II: 53%, ID: 38%, DD: 9%). The genotype frequencies in all 3 series are in Hardy-Weinberg equilibrium. These results suggest that ACE gene polymorphism is not a risk factor for IgA nephropathy and is not a predictor for its progression. Definitive proof of association between ACE gene polymorphism and progression in IgA nephropathy will require a prospective study, controlled for important risk factors, with adequate patient numbers and facility for confirming DD genotypes.

SDS-PAGE is underutilized as a tool for investigating renal patients.

SDS-PAGE is an excellent single test for investigating proteinuria. It can provide much useful information on the underlying renal problem. Yet the literature hardly report a SDS-PAGE result in the management of renal patients. To examine how closely SDS-PAGE results may reflect biopsy findings, we investigated 11 patients scheduled for renal biopsy. Urine samples were taken at the same time for SDS-PAGE analysis using the PhastSystem (Pharmacia, Sweden). Comparing biopsy findings and SDS-PAGE results, the data show consistency in the revelation of tubular dysfunction and/or glomerular damage in all 11 patients. We concluded that the SDS-PAGE test is underutilized and suggest that its role for the management of renal patients be fully explored particularly in its potential for reducing the need for renal biopsy in certain patient groups.

Case reports of low dose cyclosporine. A therapy in adult minimal change nephrotic syndrome.

INTRODUCTION: Many centres still use steroids to induce remission in patients with minimal change nephrotic syndrome (MCNS) and failing that to give a course of cyclophosphamide, though some centres are already using cyclosporine A (CsA) as an alternative. We report the benefits of CsA therapy in 3 adults with difficult to treat MCNS in whom low dose CsA therapy proved to be efficacious. CLINICAL PICTURE AND OUTCOME: The first patient had her 1st relapse after 8 years and thereafter had 2 more relapses, within 3 months of each other, in spite of therapy with cyclophosphamide. With CsA therapy, at a dose of 3.5 mg/kg body weight (BW)/day, she achieved lasting remission of 22 months as of September 1999 and is still in remission. The second patient had his relapses of nephrotic syndrome over a period of 10 years when treated with prednisolone and cyclophosphamide. On the 13th relapse, he achieved a remission lasting 21 months after a 3 month course of CsA at a dose of 4 mg/kg BW/day. With the 14th relapse, he took half the dose of CsA prescribed [only the morning dose of neoral CsA (2 mg/kg BW/day)] and still achieved a remission and has been in remission since. The third patient was a young woman, married for 2 years without children. She could not tolerate prednisolone because of erosive gastritis and she responded to a pulse dose of intravenous cyclophosphamide for her 1st episode of nephrotic syndrome with complete remission. However, when she relapsed 5 months later she did not respond to a similar dose of i.v. cyclophosphamide and was therefore treated with CsA (4 mg/kg BW/day) which induced a prompt remission 1 month after commencement of therapy and she is still in remission. The trough CsA levels for the 3 patients (range 41 to 107 ng/mL) and the calculated average CsA levels were lower than that used for post renal transplant immunosuppression. The trough CsA levels were, however, similar to that used in patients with MCNS from other series, though achieved at lower CsA doses. CONCLUSION: Our study shows that low dose CsA is a useful agent for induction of remission of MCNS and maintenance of lasting remission. A low dose CsA regimen will make CsA more affordable.

Action of dipyridamole and warfarin on growth of human endothelial cells cultured in serum-free media.

OBJECTIVE: To study the anti-proliferative effect of Dipyridamole (anti-platelet), Dipyridamole with Warfarin, and Warfarin (anticoagulant) alone, in human endothelial cells in vitro. DESIGN AND METHODS: Human endothelial cells were harvested from umbilical cords. Primary cultures were usually successful. However, subculture yields were usually contaminated with smooth muscle cells. We have developed an improved method for the isolation of endothelial cells by using Collagenase II, coating the culture flask with fibronectin and using serum-free media. The endothelial cells were characterised by anti-PECAM-1/PE (CD31) using Flow Cytometry with viability of 95% after trypsinization with 0.05% Trypsin and 1 mM EDTA. Growth and proliferation studies were performed in vitro in the presence of 5 microM Dipyridamole, 5 microM Dipyridamole with 5 microM Warfarin, 5 microM Warfarin alone by cell counts, (3)H-thymidine and (3)H-leucine incorporation. RESULTS: The incorporation of (3)H-Leucine at day 6 in each test condition revealed no significant change. Control 12678 +/- 2968 CPM, Dipyridamole 8698 +/- 189 CPM, Dipyridamole and Warfarin 7541 +/- 413 CPM, and Warfarin alone 10711 +/- 732 CPM. With the incorporation of (3)H-Thymidine, Dipyridamole alone as well as Dipyridamole with Warfarin reduced the basal proliferation rates significantly when compared to controls. Control 14355 +/- 4441 CPM, Dipyridamole 1100 +/- 152 CPM (p<0.05), Dipyridamole with Warfarin 1092 +/- 272 CPM (p<0.05). Warfarin alone did not reduce proliferation significantly 12870 +/- 2677 CPM (NS). CONCLUSIONS: We have developed a method to isolate pure endothelial cells from human umbilical cords using Serum-Free Media (SFM). EC with high purity was characterised by anti-PECAM-1/PE (CD31) using Flow Cytometry. Dipyridamole at a concentration of 5 microM inhibited the proliferation of endothelial cells at day 6 by 93%. These techniques can be used for routine analysis and proliferation studies.

Proteinuria: clinical signficance and basis for therapy.

Proteinuria is the hallmark of renal disease and proteinuria exceeding 1 gm a day in patients with renal disease augers a poorer prognosis. Proteinuria has been shown to be tubulotoxic and directly contributes to renal deterioration. Patients with non-selective proteinuria are more likely to have progressive renal disease. Diabetic patients with persistent microhaematuria have about 20 times the risk of developing diabetic nephropathy. In essential hypertension, the onset of de novo proteinuria after years of adequate BP control is a marker of subsequent decline in renal function. In glomerulonephritis, more severe proteinuria is associated with faster rate of progression. Even though the initial phase of proteinuria in patients with glomerulonephritis is usually of immunological origin, in the vast majority of patients with established disease, the latter progressive phase of proteinuric glomerulopathy is the result of glomerular hyperfiltration which shifts glomerular non-selective pores to larger dimensions resulting in excessive leakage of protein in the urine. Endothelial injury resulting from glomerular hyperfiltration causes increase in local generation of Angiotensin II in the kidney as part of the hemodynamic response. ACE inhibitors and angiotensin II receptor antagonists (ATRA) can improve glomerular pore-selectivity by remodelling the glomerular basement membrane. In addition, these agents also have beneficial effects by decreasing TGF-beta production therapy decreasing mesangial cell proliferation, hence ameliorating disease progression in patients with diabetic nephropathy and IgA nephropathy. A number of recent clinical trials have shown that ACEI and ATRA therapy can retard the progression of renal deterioration in patients with NIDDM and those with IgA nephropathy and even restore normal renal function in those with mild renal impairment. Treatment and control of proteinuria in patients with renal disease should be regarded as important as treatment of hypertension as it can prevent renal failure.

ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis.

BACKGROUND: It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane. We therefore studied the relationship between the response of patients with IgA nephritis (IgAN) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index (SI) in these patients. METHODS: Forty-one patients with biopsy-proven IgAN entered a control trial, with 21 in the treatment group and 20 in the control group. The entry criteria included proteinuria of 1 g or more and/or renal impairment. Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage. In the control group, hypertension was treated with atenolol, hydrallazine, or methyldopa. The following tests were performed at three monthly intervals: serum creatinine, total urinary protein, SI, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and low molecular weight (LMW) proteinuria. RESULTS: After a mean duration of therapy of 13 +/- 5 months, in the treatment group, there was no significant change in serum creatinine, proteinuria, or SI, but in the control group, serum creatinine deteriorated from 1.8 +/- 0.8 to 2.3 +/- 1.1 mg/dL (P < 0.05). Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders), and the other 11 did not respond (nonresponders). Among the responders, SI improved from a mean of 0.26 +/- 0.07 to 0.18 +/- 0. 07 (P < 0.001), indicating a tendency toward selective proteinuria. This was associated with an improvement in serum creatinine from mean 1.7 +/- 0.6 to 1.5 +/- 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 +/- 1.1 to 0.7 +/- 0.5 g/day (P < 0. 001). After treatment, proteinuria in the treatment group (1.8 +/- 1. 6 g/day) was significantly less than in the control group (2.9 +/- 1. 8 g/day, P < 0.05). The post-treatment SI in the responder group (0. 18 +/- 0.07) was better than that of the nonresponder group (0.33 +/- 0.11, P < 0.002). Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group (chi2 = 4.4, P < 0. 05). Of the eight patients in the treatment group who improved their renal function, three normalized their renal function compared with one from the control group. CONCLUSION: Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria, as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria, and improvement in renal function. ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine.